Novel tricyclic compounds and use as KRAS inhibitors

Abstract

The present application relates to a novel tricyclic derivative compound as a KRAS mutant protein inhibitor, and use thereof. The compound according to one embodiment of the present application inhibits the activity of a KRAS mutant protein and thus can be used in the prevention or treatment of diseases induced by KRAS mutation.

Description

[0001]

specification

[0002]

Title of invention

[0003] Novel tricyclic compounds as KRAS inhibitors and their uses

[0004]

Technical Field

[0005]

Background Technology

[0006] Kristen rat sarcoma virus (KRAS) is a protein belonging to the RAS family (NRAS, HRAS, KRAS) that transmits important signals for cell proliferation and differentiation. It receives signals from cell membrane receptors and transmits signals to downstream signaling proteins such as PI3K, Raf, MEK, and ERK.

[0007] The KRAS protein acts as a molecular switch, and through endogenous nucleotide exchange, GDP at the nucleotide binding site is exchanged for GTP, and the signal transmission to the downstream signaling protein occurs in the “activated (GTP-bound form, Turn-on) state.” Conversely, when the GTP bound to the KRAS protein is endogenously hydrolyzed to GDP, and the “inactivated (GDP-bound form, Turn-off) state,” the downstream signal transmission does not occur. At this time, in an actual cell, the exchange of GDP to GTP is promoted by the guanine exchange factor (GEF), and the hydrolysis of GTP to GDP is rapidly increased by the GTPase activating protein (GAP).

[0008] KRAS gene mutations have been shown to play an important role in cancer cell proliferation in many malignant tumors, and about 89% of KRAS gene mutant cancer patients are caused by mutations in which glycine in codon 12 of the KRAS gene (KRAS G12) is changed to another amino acid. KRAS G12 mutations appear in 86% of pancreatic adenocarcinomas (PDAC), 41% of colorectal cancers (CRC), and 32% of non-small cell lung cancers (NSCLC), and the frequency of mutations among all KRAS G12 mutations is reported to be in the order of G12D (36%), G12V (23%), and G12C (14%). KRAS G12 mutant protein maintains the activated (GTP-bound form) state by inhibiting GTP hydrolysis by GAP, thereby rapidly increasing cancer cell proliferation and survival through continuous downstream signaling. Previous KRAS inhibitors were created as competitive inhibitors of GTP binding to inhibit the activated KRAS, but many KRAS inhibitors failed because GTP exists significantly more than the concentration of inhibitors in actual cells. For this reason, the development of targeted therapies directly targeting KRAS was considered impossible, and alternatives for suppressing KRAS mutant cancers included inhibition of downstream signaling proteins such as PI3K, MEK, AKT, and mTOR other than KRAS protein, or inhibition of posttranslational modification of KRAS protein to inhibit KRAS's farnesyltransferase.

[0009] Although attempts were made to indirectly suppress the activity of KRAS mutant cancer cells, such as by inhibiting fanesyltransferase, good clinical effects were not achieved. Recently, based on the identification of the switch-II pocket, an allosteric binding pocket of the KRAS G12C mutant protein, selective KRAS G12C-targeting small molecule substances, sotorasib (LUMAKRAS®) and adagrasib (KRAZATI®), which inhibit KRAS activity through covalent binding to cysteine ​​of GDP-bound KRAS G12C, were developed and received FDA approval for non-small cell lung cancer. However, KRAS G12D mutation, which accounts for the most common KRAS mutation, occurs at a high frequency in various cancers, such as about 34% of pancreatic adenocarcinoma, 10-12% of colorectal cancer, 4% of lung adenocarcinoma, 11% of cholangiocarcinoma, and 5% of endometrial cancer. Despite this, most of the development of targeted therapies remains in the research or preclinical stage, leaving it as a very large unmet medical need. In addition, according to the clinical results of KRAS G12C inhibitors that have been recently reported, it was confirmed that patients who received KRAS G12C inhibitors acquired new KRAS mutations, including G12D / R / V / W, G13D, Q61N, R68S, H95D / Q / R, and Y96C, as resistance mechanisms. In addition, a resistance mechanism in which the expression of the KRAS G12C gene is increased has also been reported. To overcome this, pan-KRAS inhibitors that can simultaneously inhibit various KRAS mutations rather than being limited to a single KRAS mutation are also being developed, and a development trend to overcome this resistance mechanism through combination therapy among KRAS inhibitors is also being confirmed.

[0010]

Detailed Description of the Invention

[0011]

Technical Problem

[0012]

Technical Solution

[0013] [Chemical Formula 1] Coming C or N;

[0014] Ri is hydrogen, halogen, Ci-3 alkyl, or Ci-3 alkoxy;

[0015] L is a direct bond, 0, or NR6;

[0016] R2 is C1-6 alkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C2-6 alkoxyalkyl, C1-6 haloalkyl, R X , — Zl— R X , — Zl— Ry— R X , — Zl— Ry— Z2— N(R15)2, — Zl— Ry— Z2— N(R15)2, — Zl— Ry— Z2— Rx , — N(R15)2, — Z1- N(R15)2, -Z1-C(O)N(R15)2, or - Zl- 0R15 ;

[0017] Rx and Ry are independently a 3- to 10-membered cycloalkyl, a 3- to 12-membered heterocyclyl, a 6- to 20-membered aryl, or a 6- to 20-membered heteroaryl, which may be optionally substituted with one or more R7;

[0018] R7 is in each case independently H, D, halogen, hydroxy, Ci-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 hydroxyalkyl, C1-4 haloalkyl, C2-4 haloalkenyl, C2-4 haloalkynyl, C1-4 alkoxy, C1-4 alkyl - N(R16)2, =C-(R16)2, cyano, C(0)R16, C(=0)0R16, C(=O)N(R16)2, - NHC(O)- 6 to 20 membered aryl, -N(R16)2, (C1-4 alkoxy) C1-4 alkyl, oxo, -0R16, -SR16, - (C1-4 alkyl) C(O)R16, 3 to 10 membered cycloalkyl, 3 to 10-membered heterocycloalkyl, 6- to 20-membered aryl, 6- to 20-membered heteroaryl, - Z3- 3- to 10-membered cycloalkyl, - Z3- 3- to 10-membered heterocycloalkyl, - Z3- 6- to 20-membered aryl, - Z3- 6- to 20-membered heteroaryl, - Z3- 0C(0)N(Ri6)2, or - Z『 0C(0)- 3- to 10-membered heterocyclyl; wherein R7 is 1 to 3 cyano, halogen, Ci-6 haloalkyl, amino, -0Ri4, -SR14, or - N(R M )2 can be replaced by ;

[0019] R15 is independently in each case H, C1-6 alkyl, C1-6 haloalkyl, 3- to 10-membered cycloalkyl, or 3- to 10-membered heterocycloalkyl; wherein said cycloalkyl or said heterocycloalkyl may be substituted with 1 to 4 halogens or Ci-6 alkoxy;

[0020] R16 is independently H, halogen, or Ci-6 alkyl in each case;

[0021] Zi to Z3 are independently Ci-4 alkyl; optionally substituted with D, hydroxy, Ci-4 hydroxyalkyl, or 6- to 20-membered heteroaryl;

[0022] R6, R14, R17, R18, R20, R22, R23, R24 and R25 are each independently H or C1-6 alkyl;

[0023] R3 is a 3- to 10-membered cycloalkyl, a 3- to 10-membered heterocycloalkyl, a 6- to 20-membered aryl, or a 6- to 20-membered heteroaryl, which may be optionally substituted with one or more R8;

[0024] R8 and R21 are each independently H, halogen, hydroxy, -N(R18)2, 0Ri8, 0C(=0)N(Ri8)2, SH, S(CI-3 alkyl), S(Ci-3 haloalkyl), S(=0)(Ci-6 alkyl), S(=0)2(Ci-6 alkyl), C(=0)(Ci-6 alkyl), C(=O)OH, C(=O)N(R18)2, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 haloalkyl, C1-3 hydroxyalkyl, C1-3 alkoxyalkyl, C1-4 alkyl - N(R18)2, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 cyanoalkyl, cyano, oxo, 3- to 10-membered cycloalkyl, 3-membered A 6- to 20-membered heterocycloalkyl, a 6- to 20-membered aryl, or a 6- to 20-membered heteroaryl;

[0025] Y1 is H, halogen, C1-4 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl- C1-4 alkyl, 6- to 20-membered aryl, 6- to 20-membered aryl- C1-4 alkyl, 6- to 20-membered heteroaryl, 6- to 20-membered heteroaryl-Ci-4 alkyl, 3- to 6-membered heterocycle, or 3- to 6-membered heterocycle-Ci-4 alkyl, which may be optionally substituted with one or more R21;

[0026] Y2 is H, CD3, C1-4 alkyl, or Ci-4 haloalkyl; or Yi and Y2 are linked to form a 3- to 10-membered heterocycloalkyl, or a 3- to 10-membered heterocycloalkenyl, which may be optionally substituted with one or more R9; R9 is in each case independently H, hydroxy, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkenyl, -NH-R17, -N(R17)2, C1-3 alkyl - N(R17)2, oxo, -I (C1-3 alkyl), - (C1-3 alkyl)- OH, -(C1-3 alkyl)- 0-(Ci-3 alkyl), -(C1-3 alkyl)- 0-(Ci-3 haloalkyl), -C(O)OH, - C(0)0(Ci-3 alkyl), -C(0)NH2, -C(O)N(R17)2, cyano, C1-3 cyanoalkyl, 3-10 membered heterocyclyl, 6-20 membered aryl, or 6-20 membered heteroaryl; Two R9s, which are the same or different, may form a 3- to 6-membered cycloalkyl, or a 3- to 6-membered heterocycle from the same atom, which may be optionally substituted with one or more halogens, hydroxy, oxo, C1-3 alkyl, C1-3 haloalkyl, or -0- C1-3 alkyl; Two R9s, which are the same or different, may be directly bonded to adjacent atoms, or may form a condensed ring with a 3- to 6-membered cycloalkyl, a 3- to 6-membered heterocycloalkyl, a 6- to 20-membered aryl, or a 6- to 20-membered heteroaryl, which may be optionally substituted with one or more Rio;

[0027] Rio is independently H, Ci-3 alkyl, hydroxy, halogen, - N(R22)2, -CH2N(R in each case 22 )2, oxo, - o- (C1-3 alkyl), - (C1-3 alkyl)- OH, -C(O)OH, - C(0)0(Ci-3 alkyl), - C(0)N(R22)2, cyano, C1-3 cyanoalkyl, or 3- to 10-membered heterocyclyl;

[0028] Rn is H, CD3, Ci-6 alkyl, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocycloalkyl, - C(=0)Ri3, or N(RW)2; When Rii is 3- to 12-membered cycloalkyl, or 3- to 12-membered heterocycloalkyl, optionally one or more D, hydroxy, cyano, halogen, oxo (=0), Ci-3 alkyl, hydroxy C1-3 alkyl, C1-3 haloalkyl, - 0- C1-3 alkyl, C1-3 alkyl- 0- R19, - N(R19)2, C1-3 alkyl- N(R19)2, -C(O)R19, -C(O)O-R19, - C(0)NH2, -C(O)NH(R19)2, Co-2 alkyl- 3- to 6-membered cycloalkyl, Co-2 alkyl- 3- to 6-membered heterocycloalkyl, Co-2 alkyl- 6- to 20-membered aryl, or Co-2 alkyl- 6- to 20-membered may be substituted with heteroaryl; R no] In case of C1-6 alkyl, optionally one or more halogen, hydroxy, cyano, - N(R19)2, C1-3 alkyl, halo C1-3 alkyl, CD3C1-3 alkyl, hydroxy C1-3 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered heterocycloalkenyl, 5-6 membered aryl, 5-6 membered heteroaryl, - C(0)N(R19)2, - C(0)R19, - S- C1-3 alkyl, - S(0)2- C1-3 alkyl, - S(0)2- N(R19)2, - N(R19)- S(0)2- R19, - NHC(O)R19, - NHC(O)N(R19)2, , - o- C(O)N(R19)2, - o- CI-3alkyl, - o-halo Ci-3alkyl, - o- CD3, -0-(CI-3alkyl)- 0-C1-3alkyl, - o- Ci-3alkyl- OH, - o- C(0)- Ci-3alkyl, - 0- P(0)(- 0- R19)- R19, or - P(0)2- o- R19; The above 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered heterocycloalkenyl, 5- to 6-membered aryl, or 5- to 6-membered heteroaryl may be optionally substituted with one or more D, hydroxy, cyano, halogen, C1-3 alkyl, C1-3 haloalkyl, hydroxy C1-3 alkyl, - 0- C1-3 alkyl, C1-3 alkyl- 0- C1-3 alkyl, oxo (= 0), or N(R19)2;

[0029] R19 is independently H, C1-6 alkyl, or C1-6 haloalkyl in each case;

[0030] R12 is independently in each case D, halogen, hydroxy, C1-3 alkyl, C1-

[0031] 3-haloalkyl, C1-3hydroxyalkyl, C1-3alkenyl, C1-3alkynyl, C1-3alkyl-0-R20, C1-3alkyl-0-C1-

[0032] 3-haloalkyl, C1-3 alkyl - S(0)2R20, - N(R20)2, -CH2N(R20)2, oxo (=0), cyano, cyano Cl~

[0033] 3-alkyl, Co-3-alkyl-3 to 10-membered cycloalkyl, or Co-3-alkyl-3 to 10-membered heterocyclyl;

[0034] R13 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-3 alkyl-0- C1-6 alkyl, - N(R23)2, - OR23, -SR23, 3 to 10 membered cycloalkyl, 3 to

[0035] 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclyl, 6- to 20-membered aryl, 6- to 20-membered heteroaryl, or -Cl-

[0036] 6-Alkyl-3 to 10-membered cycloalkyl; 3 to 10-membered cycloalkyl, 3 to

[0037] 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclyl, 6- to 20-membered aryl, 6- to 20-membered heteroaryl, or -C1-

[0038] 6-alkyl- 3- to 10-membered cycloalkyl may be optionally substituted with one or more D, hydroxy, halogen, Ci-3 alkyl, halo Ci-3 alkyl, 3- to 6-membered cycloalkyl, - N(R24)2 or oxo (=0); n is an integer from 0 to 4; m is an integer from 0 to 4;

[0039] R5 is H, halogen, Ci-6 alkyl, Ci-3 haloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, cyano, cyano Ci-3 alkyl, hydroxy, Ci-3 hydroxyalkyl, C(0)(NR25)2, 6-20 membered aryl, - Ci-3 alkyl- 3-6 membered cycloalkyl, - Ci-3 alkyl- 3-6 membered heterocycloalkyl, - Ci-3 alkyl- 6-20 membered aryl, - Ci-3 alkyl- 0- Ci-3 alkyl- 6-20 membered aryl, or - Ci-3 alkyl- 6-20 membered heteroaryl. However, when Y2 is shown, Yi may not be cycloalkyl, cycloalkyl-alkyl-, heterocycloalkyl, and heterocycloalkyl-alkyl-. However, when Y2 is shown, Yi is H, halogen, Ci-4 alkyl, 6- to 20-membered aryl, 6- to 20-membered aryl-Ci-4 alkyl-, 6- to 20-membered heteroaryl, or 6- to 20-membered heteroaryl-C1-4 alkyl-, and may be optionally substituted with one or more R21. However, when Rn is shown, R12 is independently in each case D, halogen, Ci-

[0040] 3-haloalkyl, C1-3hydroxyalkyl, C1-3alkenyl, C1-3alkynyl, C1-3alkyl-0-R20, C1-3alkyl-0-C1-

[0041] 3-haloalkyl, C1-3 alkyl - S(0)2R20, oxo(=0), cyano C2-3 alkyl, C0-3 alkyl- 3- to 10-membered cycloalkyl, or C0-3 alkyl-tetrahydrofuran; Rx is pyridinyl, piperazinyl, diazepanyl, oxaazabicyclohexanyl, oxaazabicyclooctanyl, oxaazabicyclononanyl, azabicyclohexanyl, azabicycloheptanyl

[0042] (azabicycloheptanyl), azaspirohexanyl

[0043] (azaspiroheptanyl), oxaazaspiroheptanyl, oxaazaspirooctanyl, oxaazaspirononanyl, oxaazaspirodecanyl, oxaazaspiroundecanyl, oxaazaspirododecanyl

[0044] (oxaazaspirododecanyl), octahydropyrrolo[3,4 - c]pyrrolyl

[0045] (octahydropyrrolo[3,4 - c]pyrrolyl), hexahydro - 1H - furo[3,4 - c]pyrrolyl

[0046] (hexahydro - 1H - furo[3,4 - c]pyrrolyl), octahydro - 1H - cyclopenta[b]pyridinyl

[0047] (octahydro-L¥-cyclopentaL이pyridinyl), hexahydro-1方 2-pyrrolo[2, 1-c][1,4]oxazinyl, spiro[cyclopropane-1,2'-pyrrolizidinyl], or 1-azaspiro[bicyclo[3.2.heptane-3,1'-cyclopropanyl]; or R5 may be -Ci-3alkyl-0-Ci-3alkyl-6- to 20-membered aryl. However, when Rn is - C(=0)Ri3, R13 is a 3- to 10-membered cycloalkyl substituted with one or more selected from the group consisting of D, hydroxy, halogen, Ci-3 alkyl, halo Ci-3 alkyl, 3- to 6-membered cycloalkyl, - N(R24)2 and oxo (=0), a 3- to 10-membered cycloalkenyl, a 3- to 10-membered cycloalkynyl, a 3- to 10-membered heterocyclyl, a 6- to 20-membered aryl, or a 6- to 20-membered heteroaryl; or R13 may be Ci-4 haloalkyl, C1-6 cyanoalkyl, C1-3 alkyl- 0- C1-6 alkyl, or - C1-6 alkyl- 3- to 10-membered cycloalkyl.Specifically, the R11 is CD3, substituted C1-4 alkyl, substituted or unsubstituted C5-9 alkyl, substituted or unsubstituted C5-9 haloalkyl, substituted cyclopropyl, substituted or unsubstituted 4- to 12-membered cycloalkyl, substituted or unsubstituted 3- to 12-membered heterocycloalkyl, or -C(=0)R13, ​​wherein the R13 is C5-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C5-6 haloalkyl, C1-6 cyanoalkyl, C1-3 alkyl-0-C1-6 alkyl, -SR23, substituted 3-membered cycloalkyl, substituted or unsubstituted 4- to 10-membered cycloalkyl, substituted or unsubstituted 3- to 10-membered cycloalkenyl, substituted or unsubstituted 3- to 10-membered cycloalkynyl, substituted or It may be an unsubstituted 3- to 10-membered heterocyclyl, a substituted or unsubstituted 6- to 20-membered aryl, a substituted or unsubstituted 6- to 20-membered heteroaryl, or a substituted or unsubstituted -Ci-6alkyl- 3- to 10-membered cycloalkyl.However, when Rii is cycloalkyl or heterocycloalkyl, Rii is 4-12 membered cycloalkyl, or 3-12 membered heterocycloalkyl, and optionally one or more D, hydroxy, cyano, halogen, oxo (=0), Ci-3 alkyl, hydroxy C1-3 alkyl, C1-3 haloalkyl, - 0- C1-3 alkyl, - C1-3 alkyl- 0- R19, - N(R19)2, C1-3 alkyl- N(R19)2, -C(O)R19, -C(O)O-R19, - C(0)NH2, -C(O)NH(R19)2, Co-2 alkyl- 3-6 membered cycloalkyl, Co-2 alkyl- 3-6 membered heterocycloalkyl, Co-2 alkyl- 6-20 membered Aryl, or Co-2alkyl- 6 to 20 membered heteroaryl may be substituted; or Rii is cyclopropyl, and one or more D, hydroxy, cyano, halogen, oxo (=0), C1-3alkyl, hydroxy C1-3alkyl, C1-3haloalkyl, - 0- C1-3alkyl, - C1-3alkyl- 0- R19, - N(R19)2, C1-3alkyl - N(R19)2, -C(O)R19, -C(O)O-R19, -C(0)NH. 2I-C(0)NH(RI9)2, Co-2 alkyl- 3 to 6 membered cycloalkyl, Co-2 alkyl- 3 to 6 membered heterocycloalkyl, Co-2 alkyl- 6 to 20 membered aryl, or Co-2 alkyl- 6 to 20 membered heteroaryl may be substituted. However, when Rii is alkyl, Rii is Ci-4 alkyl, and one or more CD3C1-3 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered heterocycloalkenyl, 5-6 membered aryl, 5-6 membered heteroaryl, - C(0)N(Ri9)2, -C(O)RI9, - S- C1-3 alkyl, -S(0)2-Ci- 3 alkyl, - S(0)2- N(RW)2, - N(Ri9)- S(0)2- R19, - NHC(0)N(Ri9)2, - 0- C(0)N(Ri9)2, - 0- CD3, - 0- (C1-3 alkyl)- O-C1-3 alkyl, - o- Ci-3 alkyl- OH, - 0- C(0)- C1-3 alkyl, - o- P(0)(- o- R19)- R19, or - P(0)2- 0- R19 is substituted; Rll is C5-6 alkyl, optionally one or more halogen, hydroxy, cyano, - N(R19)2, C1-3 alkyl, halo C1-3 alkyl, CD3C1-3 alkyl, hydroxy C1-3 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered heterocycloalkenyl, 5-6 membered aryl, 5-6 membered heteroaryl, -

[0048] C(0)N(R19)2, — C(0)R19, — S— Cl-3alkyl, — S(0)2— Cl-3alkyl, — S(0)2— N(R19)2, — N(R19)— S(0)2— R19, -NHC(O)R19, -NHC(O)N(R19)2, -OC(O)N(R19)2, -0- Cl-3alkyl, -o-halo Cl-3alkyl, - o- CD3, - o- (Cl-3alkyl)- o- Cl-3alkyl, -o- Cl-3alkyl- OH, -0-C(0)- Cl-3alkyl, - o- P(0)(- o- R19)- R19, or - P(0)2- o- R19; The above 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered heterocycloalkenyl, 5- to 6-membered aryl, or 5- to 6-membered heteroaryl optionally comprises one or more D, hydroxy, cyano, halogen, Ci-3 alkyl, Ci-

[0049] 3-haloalkyl, hydroxy C1-3 alkyl, - 0- C1-3 alkyl, C1-3 alkyl- 0- C1-3 alkyl, or N(R19)2 may be substituted. However, when R11 is - C(=0)R13, ​​R13 is C5-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C5-6 haloalkyl, C1-6 cyanoalkyl, C1-3 alkyl- 0- C1-6 alkyl, - SR23, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-20 membered aryl, 6-20 membered heteroaryl, or - C1-6 alkyl- 3-10 membered cycloalkyl; 3-membered cycloalkyl is optionally substituted with one or more D, hydroxy, halogen, C1-3 alkyl, halo C1-3 alkyl, 3-6 membered cycloalkyl, - N(RW)2 or oxo; 4-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-20 membered aryl, 6-20 membered heteroaryl, or -Ci-6 alkyl- 3-10 membered cycloalkyl may be optionally substituted with one or more D, hydroxy, halogen, C1-3 alkyl, halo C1-3 alkyl, 3-6 membered cycloalkyl, - N(R24)2, or oxo (=0). Specifically, the Ri may be hydrogen, halogen, or Ci-3 alkoxy. For example, the Ri may be hydrogen or halogen. Specifically, the L may be a direct bond or 0. For example, the L may be 0. Specifically, the R2 may be Ci-6 alkyl, Rx, -Zi-Rx, -Zi-Ry-Rx, -Zi-R y-Z2-N(Ri5)2, - Zi- Ry- Z2- Rx, or - Zi- N(Ri5)2. For example, the R2 may be Ci-6 alkyl, Rx, -Z1- Rx, - Zi- Ry- Z2- N(Ri5)2, - ZI- Ry- Z2- RX, or - Zi- N(Ri5)2. Specifically, the Rx and Ry are each independently a 3- to 10-membered cycloalkyl, a 3- to 12-membered heterocyclyl, or a 6- to 20-membered heteroaryl, which may be optionally substituted with one or more R7s. More specifically, Rx is a 3- to 12-membered heterocyclyl, or a 6- to 20-membered heteroaryl, Ry is a 3- to 10-membered cycloalkyl, and Rx and Ry may be optionally substituted with one or more R7s. More specifically, Rx is a 3- to 12-membered monocyclic, bicyclic or tricyclic heterocyclyl, or a 6- to 20-membered monocyclic heteroaryl, and may be optionally substituted with one or more R7s. More specifically, the Rx and Ry are each independently a 3- to 5-membered cycloalkyl, pyridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, diazepanyl, morphol inyl, pyrrol izidinyl, methylenepyrrol izidinyl, oxaazabicyclohexanyl, oxaazabicycloheptanyl, oxaazabicyclooctanyl,Oxaazabicyclononanyl, azabicyclohexanyl, azabicycloheptanyl, azaspiroheptanyl, azaspiroctanyl, oxaazaspiroheptanyl, oxaazaspirooctanyl, oxaazaspirooctanyl, oxaazaspirononanyl, oxaazaspirodecanyl, oxaazaspiroundecanyl oxaaz asp iroundecanyl , oxaazaspirododecanyl , octahydropyrrolo[3,4-c]pyrrolyl , hexahydro- 1H-furo[3,4-c]pyrrolyl , octahydro- 1H-furo[3,4-c]pyr roly 1 ...

[0050] (octahydro-L¥-cyclopentaL pyridinyl), tetrahydro-1'H,3'H~ spiro[cyclopropane-1,2'-pyrrolizidinyl], hexahydro-1'-pyrrolo[2,1-c][1,4]oxazinyl, spiro[cyclopropane-1,2'-pyrrolizidinyl], 1-azaspiro[bicyclo[3.2.heptane- 3,1'-cyclopropanyl] (1-azasp iro [ bi eye 1 o [ 3.2.0 ] hept ane-3 , 1 ' -cyclopropanyl ] ), quinolizidinyl, indolinyl, benzimidazolyl, benztriazolyl, thioxanthinyl, carbazolyl, carbol inyl, or acridinyl, and may be optionally substituted with one or more R7. More specifically, Rx and Ry are each independently a 3- to 5-membered cycloalkyl, pyridinyl, azetidinyl, pyrrolidinyl , piperidinyl, piperazinyl, etc. 0]Azepanyl, morphol inyl, oxaazabicyclo [2.2. 1]heptanyl, oxaazabicyclo [3. 1.1]heptanyl (oxaazabicyclo [3.1. Uheptanyl), oxaazabicyclo [4.1. 0]heptanyl (oxaazabicyclo [4.1. 0]hept any 1), oxaazabicyclo [2.2. 2]octanyl (oxaazabicyclo [2.2. 2]oct any 1), oxaazabicyclo [3.2. 1]octanyl (oxaazabicyclo [3.2. 1]oct any 1), oxaazabicyclo [3.3. 0]oct any 1), oxaazabicyclo [3.3. 1]nonanyl (oxaazabicyclo[3.3. Unonanyl), azabicyclo[3.1. hexanyl), azabicyclo[3.2. heptanyl), azabicyclo[2.2.1]heptanyl, azabicyclo[4.1. hexanyl), pyrrolizidinyl, methylenepyrrolizidinyl, octahydro-L¥-cyclopenta-Lepyrridinyl (octahydro- 1-pyrrolidinyl), tetrahydro-1'-H,3'-spiro[cyclopropane- 1,2'-pyrrolizidinyl], azaspiro[2.3]hexanyl ( az asp iro [ 2.3 ] hexany 1 ), azaspiro [2.4]heptanyl ( azaspiro [2.4]heptanyl ), azaspiro [2.5]octanyl ( az asp iro [ 2.5 ] oct any 1 ), oxaazaspiro [3.3]heptanyl.

[0051] ( oxaazaspiro [ 3 .3 ] hep t any 1 ), oxaazaspiro [2.5] octanyl ( oxaazaspiro [ 2.5] oct any 1 ), oxaazaspiro [3.4] octanyl ( oxaazaspiro [3 .4]octanyl ), oxaazaspiro [2.5] octanyl ( oxaazaspiro [2.5] oct any 1 ), oxaazaspiro [4.4] nonanyl ( oxaazaspiro [4.4 J nonanyl ), oxaazaspiro [4.5] decanyl ( oxaazaspiro [4.5 J decanyl ), oxaazaspiro [5.5] undecanyl ( oxaazaspiro [5.5 Jundecanyl ), Octahydropyrrolo[3,4-c]pyrrolyl, hexahydro-lH-furo[3,4-c]pyrrolyl, hexahydro-lH-furo[3,4-c]pyrrolyl, hexahydro-l-upyrrololo[2,1-c][l,4]oxazinyl, spiro[cyclopropane-1,2'-pyrrolizidinyl], 1-azaspiro[bicyclo[3.2.heptane-3,1'-cyclopropanyl] 1-azasp iro [ bi eye 1 o [ 3.2.0 ] hept ane-3 , 1 ' -cyclopropanyl ] ), quinolizidinyl, indolinyl, benzimidazolyl, benztriazolyl, thioxanthinyl, carbazolyl, carbol inyl, or acridinyl, which may be optionally substituted with one or more R7.More specifically, the Rx is pyridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, diazepanyl, morpholinyl, 1-azabicyclo[3.2.heptanyl], 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2—oxa— 5—azabicyclo[2.2.2]octanyl ab i eye lo[2.2.2] oct any 1 ), 3 —oxa— 8— azabicyclo [3.2.1]octanyl ( 3— oxa— 8— az ab i eye lo[3.2.1] oct any 1 ), 8 -oxa-} -3- azabicyclo [3.2.1]octanyl ( 8— oxa— 3— az ab i eye lo[3.2.1] oct any 1 ), 6 -oxa- 1- azabicyclo [3.3. 0]octanyl , 6 -oxa- 2- azaspiro [3.4]octanyl , 7 -oxa- 4- Azaspiro[2.5]octanyl (7—oxa—4—azabicyclo[2.5]octanyl), 6-oxa-3-azabicyclo[3.11]heptanyl (6—oxa—3—azabi eye lo[3.1. l]heptanyl), 2-oxa-5-azabicyclo[4.1. diheptanyl (2—oxa—5—azabicyclo[4.1. O]heptanyl), 3-oxa-azabicyclo[3.3. l]nonanyl (3—oxa—7—azabicyclo[3.3. l]nonanyl), 3-azabicyclo[3.1. dihexanyl (3-azabicyclo[3.1,0]hexanyl), 1-azabicyclo[3.2.0]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl, pyrrolidinyl, octahydro-1H-cyclopenta[b]pyridinyl, tetrahydro-1’H,3’H-spiro[cyclopropane-1, 2’-pyrrolidinyl], 5-azaspiro[2.3]hexanyl, 5-azaspiro[2.4]heptanyl, 6-azaspiro[2.5]octanyl, 2-oxa-6-azaspiro[3.4]octanyl, 4-oxa-7-azaspiro[2.5]octanyl, 6-oxa-2-azaspiro[3.4]octanyl, 7-oxa-4-azaspiro[2.5]octanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 1-oxa-7-azaspiro[4.4]nonanyl, 7-oxa-1-azaspiro[4.4]nonanyl, 7-oxa-1-azaspiro[4.4]nonanyl ), l-oxa-8-azaspiro[4.5]decanyl , 2—oxa—8—azaspiro[4.5]decanyl , 2—oxa—8—azaspiro[5.5]undecanyl , hexahydropyrrolo[3,4-c]pyrrole-2(1-oxa-yl.

[0052] (hexahydr opyr ro lo [ 3 , 4- c ] pyr ro 1 - 2 ( L60 -yl ) , hexahydro- 1H-furo [ 3 , 4- c ] pyrrolyl

[0053] (hexahydro-lH-furo[3,4-c]pyrrolyl), hexahydro-1-penta[2, 1-c][1,4]oxazinyl, spiro[cyclopropane-1,2'-pyrrolizidinyl], or 1-azaspiro[bicyclo[3.2.heptane-3,1'-cyclopropanyl], and may be optionally substituted with one or more R7. More specifically, the Ry is a 3- to 5-membered It may be cycloalkyl, and may be optionally substituted with one or more R7. For example, Ry may be a 3- to 5-membered cycloalkyl, and may be optionally substituted with halogen or Ci-4 haloalkyl. Specifically, R7 is, in each case, independently H, D, halogen, hydroxy, Cl-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 hydroxyalkyl, C1-4 haloalkyl, C2-4 haloalkenyl, C2-4 haloalkynyl, C1-4 alkoxy, C1-4 alkyl - N(R16)2, =CH2, =CHF, =CF2, C(=O)N(R16)2, -N(R16)2, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, - Z3- 3- to 10-membered Cycloalkyl, or - Z3- 3- to 10-membered heterocycloalkyl; wherein R7 may be substituted with 1 to 3 cyano, halogen, haloalkyl, amino, -0R14, -SR14, or - N(R14)2.More specifically, the R7 is independently in each case H, D, halogen, hydroxy, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 hydroxyalkyl, C1-4 haloalkyl, C2-4 haloalkenyl, C2-4 haloalkynyl, C1-4 alkoxy, =CH2, =CHF, =CF2, C(=0)N(R16)2, -N(R16)2, (Cl-4 alkoxy) Cl-4 alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl (e.g., morpholine, pyrrolidine), or -Z『 3-10 membered heterocycloalkyl (e.g., azetidine), which may be substituted with 1 to 3 halogens or - N(R14)2. It may be. Specifically, the R3 is a 6- to 20-membered monocyclic or bicyclic aryl, or a 6- to 20-membered monocyclic or bicyclic heteroaryl, which may be optionally substituted with one or more R8. More specifically, the R3 is phenyl, biphenyl, naphthyl, toluyl, naphthalenyl, pyridinyl, anthracenyl, indenyl, dihydroindenyl, indanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzthiazolyl.

[0054] (benzothiazolyl), benzothiophenyl, benzofuranyl, indazolyl, or thienopyridinyl, which may be optionally substituted with one or more R8. Specifically, R8 may in each case independently be H, halogen, hydroxy, -NH2, 0C(=0)NH2, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 haloalkyl, C1-3 hydroxyalkyl, C1-3 cyanoalkyl, or cyano. Specifically, the Rn is H, CD3, Ci-6 alkyl, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocycloalkyl, - C(=0)R13, ​​or N(R19)2,

[0055] When Rn is a 3- to 12-membered cycloalkyl, or a 3- to 12-membered heterocycloalkyl, it may be optionally substituted with oxo (=0), hydroxy C1-3 alkyl, - 0- C1-3 alkyl, or - C1-3 alkyl- 0- R19,

[0056] When Rn is Ci-6 alkyl, optionally one or more halogen, hydroxy, cyano, halo C1-3 alkyl (e.g., CF3), - C(0)N(R19)2, - S- C1-3 alkyl, - S(0)2- C1-3 alkyl, - 0- C(O)N(R19)2, - o- C1-3 alkyl, - 0-halo C1-3 alkyl, - 0- CD3, - 0-(Ci-3 alkyl)- 0-C1-3 alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl (e.g., azetidine, oxetane, thietane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran (tetrahydropyran), or oxaspiro [3.4]octane

[0057] (oxaspiro[3.4]octane)), a 3- to 10-membered heterocycloalkenyl (e.g., dihydroimidazole), or a 5- to 6-membered heteroaryl (e.g., furan or imidazole), wherein the 3- to 6-membered cycloalkyl, the 3- to 6-membered heterocycloalkyl, the 3- to 10-membered heterocycloalkenyl, or the 5- to 6-membered heteroaryl may be optionally substituted with one or more halo, C1-3 alkyl, C1-3 haloalkyl, hydroxy C1-3 alkyl, - O- C1-3 alkyl, C1-3 alkyl- O- C1-3 alkyl, or oxo (= O). Specifically, the R12 is independently in each case H, D, halogen, hydroxy, C1-3 alkyl, C1-3 haloalkyl, C1-3 hydroxyalkyl, C1-3 alkenyl, C1-3 alkynyl, C1-3 alkyl- 0- R20, C1-3 alkyl- 0- C1-3 haloalkyl, C1-3 alkyl - S(0)2R20, -N(R2O)2, -CH2N(R2O)2, oxo (=0), cyano, cyano C1-3 alkyl, or tetrahydrofuran

[0058] (tetrahydrofuran). Specifically, the Y1 is C1-4 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-4 alkyl-, 3-6 membered heterocycle, or 3-6 membered heterocycle-C1-4 alkyl-, and may be optionally substituted with one or more R21. Specifically, the Y2 may be C1-4 alkyl, or C1-4 haloalkyl. Specifically, the Y1 and Y2 are connected to piperidine, pyrrolidine, piperazine, azepane, azetidine, morpholine, oxazepane, dihydropyridine.

[0059] (dihydropyridine), tetrahydroazepine, or hexahydrodiazepine, and may be optionally substituted with one or more R9. Specifically, R9 may be independently H, hydroxy, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkenyl, - NH- R17, -N(R17)2, C1-3 alkyl - N(R17)2, oxo, - 0- (C1-3 alkyl), - (C1-3 alkyl)- OH, -(C1-3 alkyl)- 0-(Ci-3 alkyl), - (C1-3 alkyl)- 0- (C1-

[0060] 3-haloalkyl), -C(O)OH, -C(O)O(C1-3alkyl), -C(O)NH2, -C(O)N(R17)2, cyano, C1-3cyanoalkyl, 3- to 10-membered heterocyclyl, 6- to 20-membered aryl, or 6- to 20-membered heteroaryl. Specifically, when the ring structure formed by the connection of Y1 and Y2 is substituted by several R9s, two identical or different R9s may form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycle on the same atom to form a spiro ring with the ring formed by the connection of Y1 and Y2, and may be optionally substituted by one or several halogens, hydroxy, oxo, C1-3alkyl, C1-3haloalkyl, or -O-C1-3alkyl. Specifically, when the ring structure formed by the connection of Y1 and Y2 is substituted by several R9s, two identical or different R9s may be connected at adjacent atoms to form a 3- to 6-membered heterocycloalkyl to form a fused ring with the ring formed by the connection of Y1 and Y2, and may be optionally substituted by one or several R10s. Specifically, each R10 may be independently H, CCI-3alkyl, halogen, or -C(O)N(R22)2 in each case. Specifically, the R5 may be H, C1-3alkyl, C1-3hydroxyalkyl, or -C1-3alkyl-O-C1-3alkyl-6- to 20-membered aryl. For example, in Formula 1 above, L-R2 may be selected from the following structures. When having the following structures, not only is the inhibitory activity against KRAS G12D excellent, but it is also suitable for various purposes of the present application mentioned above.

[0061] 人。'} TT人o주"、!厂人O'조Q人。(T접'人。즈丁개、F3人0-'2으厂人0으"、厂人。주스 \己、人 0 It should be noted that there are some characters in the original text that seem to be incorrect or unclear (such as "人。'} TT人o주" etc.), and the translation is based on the best understanding of the overall context. If possible, it is recommended to clarify the original text for a more accurate translation.gf"\3Q factory people 0 ; Oh people 0 ; 5" ratio. This section’ people., people 0 ;} warehouse people people: flat 어 c 으: '으」? 으히 people. 유이 people.; Asia '•〔magic people‘’;} rt〉자 people‘’;}에 _ people‘’; px., people.; Asia three people 0 ;} rt〉’°、 people 0 ; 조 ">、 people​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​For example, in Formula 1 above, R3 may be selected from the following structures. When having a structure as below, not only is the inhibitory activity against KRAS G12D excellent, but it is also suitable for various purposes of the present application mentioned above. For example, in Formula 1 above, R4 may be selected from the following structures. When having a structure as below, not only is the inhibitory activity against KRAS G12D excellent, but it is also suitable for various purposes of the present application mentioned above.

[0063] The present application provides the above-mentioned compounds, their optical isomers, stereoisomers, isotopic variants, hydrates, solvates, or pharmaceutically acceptable salts thereof. Examples of the compounds of Formula 1 according to the present application are the compounds prepared in Examples 1 to 506 below. Each example number corresponds to the compound number. For example, the number of the final compound prepared in Example 90 is Compound 90. As an example, representative compounds of Formula 1 according to an example of the present application include, but are not limited to, those listed below:

[0064] (1) 1—(4—(8—Ethynyl—7—fluoro—3—hydroxynaphthalen—1—yl)—7—(((2ʹ,7aS)—2—fluorotetrahydro—1H—pyrrolizin—7a(5H)yl)methoxy)—2—methyl—2H—pyrazolo[4,3—f]quinazolin—9—yl)azepane—4—carbonitrile;

[0065] (2) 1-(4-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-7-(((2'R,7aS)-2-fluorotetrahydro-1'H-pyrrolizin-7a(5'H)-yl)methoxy)-2-methyl-2'H-pyrazolo[4,3-f]quinazolin-9-yl)azepane-4-carboxamide; (3) 1-(4-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1'H-pyrrolizin-7a(5'H)-yl)methoxy)-2-methyl-2'H-pyrazolo[4,3-f]quinazolin-9-yl)azepane-4-carbonitrile; pyrrolizin-7a(5'H)-yl)methoxy)-2-methyl-9-(2,3,6,7-tetrahydro-1'H-azepirrl-yl)-2'H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0066] (5) (R)-1-(4-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-7-

[0067] (((2'R,7aS)-2-fluorotetrahydro-1'H-pyrrolizin-7a(5'H)-yl)methoxy)-2-methyl-2'H-pyrazolo[4,3-f]quinazolin-9-yl)-3-methylpiperidin-3-ol;

[0068] (6) 4—(4—(8—Ethyl—7—fluoro—3—hydroxynaphthalen—1—yl)—7—(((2ʹ,7aS)—2—fluorotetrahydro—1ʹH—pyrrolizin—7a(5ʹH)—yl)methoxy)—2—methyl—2H—pyrazolo[4,3—f]quinazol—9—yl)—6—methyl—1,4—oxazepan—6—ol;

[0069] (7) 4-(9-(2,5-Diazabicyclo[2.2.2]octan-2-yl)-5-fluoro-7-(((2ʹ,7aS)—2-fluorotetrahydro—1ʹH—pyrrolizin—7a(5ʹH)—yl)methoxy)—2—methyl—2H—pyrazolo[4,3—f]quinazol—4—yl)—5—ethynyl—6—fluoronaphthalen-2-ol;

[0070] (8) (R)—1—(4—(8—Ethynyl—7—fluoro—3—hydroxynaphthalen—1—yl)—7—(((2ʹ,7aS)—2—fluorotetrahydro—1ʹH—pyrrolizin—7a(5ʹH)—yl)methoxy)—2—methyl—2H—pyrazolo[4,3—f]quinazol—9—yl)—3—methylpiperidin—3—ol;

[0071] (9) 4—(9—(3,6-Dihydropyridin-1(2H)-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0072] (10) 5-Ethynyl-6-fluoro-4-(5-fluoro-9-(5-fluoro-3,6-dihydropyridin-1(2H)-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0073] (11) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-

[0074] 1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-(4,7-diazaspiro[2.5]octan-7-yl)-

[0075] 2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0076] (12) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0077] (13) 2-((R)-1-(4-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)piperazin-2-yl)acetonitrile; (14) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-morpholino-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0078] (15) 4-(9-(((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0079] (16) 4-(4-(8-Ethynyl-7-fluoronaphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)morpholine;

[0080] (17) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-((1R,5S)-8-((R)-2-hydroxypropyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-methyl-5a,9a-dihydro-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0081] (18) 4-(8-Ethynyl-7-fluoronaphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-((1R,5S)-8-( (2-methoxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazoline;

[0082] (19) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)-8-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0083] (20) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1 J 6 i -pyrrolizin-7a(5 J 60 _ yl)methoxy)-9-((1R,5S)-8-(2-(2-methoxyethoxy)ethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0084] (21) 4-(2-(2-(Benzyloxy)ethyl)-9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethyl-6-fluoronaphthalen-2-ol;

[0085] (22) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2′,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-((1′,5S)-8-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (23) 1-(4-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2′,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3-methylazetidin-3-ol;

[0086] (24) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2′,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1′,5S)-8-(oxetan-2-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0087] (25) 4-(9-((1ʹ,5ʹ)-3,8-Diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-7-(((2ʹ,7aS)-2-fluorotetrahydro-1ʹH-pyrrolizin-7a(5ʹH)-yl)methoxy)-2-methyl-2ʹH-pyrazolo[4,3- / ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0088] (26) 4-(9-((1ʹ,4ʹ)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-5-fluoro-7-(((2ʹ,7aS)-2-fluorotetrahydro-1ʹH-pyrrolizin-7a(5ʹH)-yl)methoxy)-2-methyl-2ʹH-pyrazolo[4,3- / ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0089] (27) 4-(9-((1ʺ,5ʺ)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(((2ʺ,7aS)-2-fluorotetrahydro-1ʺH-pyrrolizin-7a(5ʺH)-yl)methoxy)-2-(2-hydroxyethyl)-2ʺH-pyrazolo[4,3- / ]quinazolin-4-yl)-5-ethyl-6-fluoronaphthalen-2-ol;

[0090] (28) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-(piperidin-1-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0091] (29) 1-((1R,5R)-3-(4-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethan-1-one;

[0092] (30) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5R)-1-vinyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0093] (31) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1 J 6 i -pyrrolizin-7a(5 J 60 _yl)methoxy)-2-methyl-9-((lS,5S)-l-vinyl-3,8- di azabi cyclo [3.2.1] oct an-3-yl)-2^pyr azo lo [4,3- / ] quinazolin-4-yl )naphthalen- 2-ol; (32) 4- (9- ((』?)- 3- Amino- 3- methylpiper idin- 1- yl)- 5- f luoro- 7- (((2』?, 7aS)- 2-f luorotetrahydro— 1月— pyrrol izin— 7a(5方 0— yl )methoxy)— 2— methyl— 27¥—pyrazolo[4,3 — / ]quinazol in— 4— yl )— 5— ethynyl— 6— f luor onaphtha 1 en-2-o 1;

[0094] (33) 3— ((1』?, 55)— 3— (4— (8— Ethynyl— 7— f luoro— 3— hydroxynaphthalen— 1— yl )—5 — f luoro— 7— (((2』?, 7aS)— 2— f luorotetrahydro— 1月— pyrrol izin— 7a(5方 0— yl)methoxy)— 2— methyl— 2月— pyrazolo[4,3— / ]quinazolin— 9— yl)— 3,8— diazabicyclo[3.2.!]octan-8_ yDpropanenitri le;

[0095] (34) 4- (9- ((1』?, 4』?)- 2,5- Diazabicyclo[2.2.1]heptan- 2- yl)- 5- f luoro- 7- (((2』?, 7aS)— 2— f luorotetrahydro— 1月— pyrrol izin— 7a(5方 0— yl)methoxy)— 2— methyl— 2月— pyrazolo[4,3— / ]quinazol in— 4— yl)— 5— ethynyl— 6— f luoronaphthalen— 2— amine;

[0096] (35) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-(6R)-3-(methylamino)pyrrolidin-1-yl)-2H-pyrazolo[4,3-c]quinazolin-4-yl)naphthalen-2-ol;

[0097] (36) 5-Ethynyl-6-fluoro-4-(5-fluoro-9-((1R,5S)-8-(2-fluoroethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-c]quinazolin-4-yl)naphthalen-2-ol;

[0098] (37) 6-(4-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-c]quinazolin-9-yl)-6-azaspiro[3.5]nonan-2-ol;

[0099] (38) (3』?,4S)— 1—(4— (8— Ethynyl— 7— f luoro— 3— hydroxynaphthalen— 1—yl )—5 — f luoro— 7— (((2』?, 7aS)— 2— f luorotetrahydro— 1月— pyrrol izin— 7a(5方 0— yl)methoxy)— 2— methyl— 2月— pyrazolo[4,3— / ]quinazolin— 9— yl)pyrrolidine— 3,4— diol;

[0100] (39) 2— Amino— 7— f luoro— 4— (5— f luoro— 7— (((2』?, 7aS)— 2— f luorotetrahydro— pyrrolizin-7a(5750 _ yl)methoxy)-9-((17?,5S)-8-(2-methoxyethyl)-3,8- diazabicyclo[3.2. l]octan— 3— yl )— 2— methyl— 2月— pyrazolo[4,3— / ]quinazol in— 4— yl)benzoL이 thiophene— 3— carboni tri le;

[0101] (40) (品 )- 4- (9- ((1S,5 ^)-l-Ethyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-5- f luoro— 7— (((2』?, 7aS)— 2— f luorotetrahydro— 1月— pyrrol izin— 7a(5方 0— yl)methoxy)— 2— methyl— 2月— pyrazolo[4,3— / ]quinazol in— 4— yl )—5— ethynyl— 6— f luor onaphtha len-2-ol;

[0102] (41) (a)-4-(9-((1S,5S)-1-Ethyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (42) (5a)-4-(9-((1S,5S)-1-Ethyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0103] (43) (A , (a)-4-(9-((1S,5S)-1-Ethyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0104] (44) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1 J 6 i -pyrrolizin-7a(5 J 60 _yl)methoxy)-9-((17?,5S)-8-(2-methoxyethyl)-3,8- diazabicyclo[3.2. l]octan— 3— yl )— 2— methyl— 2月— pyrazolo[4,3— / ]quinazol in— 4— yl )naphthalen— 2— ol;

[0105] (45) 5— Ethynyl— 6— fluoro— 4— (5— fluoro— 7— (((2』?, 7aS)— 2— fluorotetrahydro— 1月— pyrrol izin— 7a(5方 0— yl )methoxy)— 2— methyl— 9— ((5)— 3— (methylamino)pyrrol idin— 1— yl )— 2月— pyrazolo[4,3— / ]quinazol in— 4— yl )naphthalen— 2— ol;

[0106] (46) 4— (7— (((5)— 2— (Di f luoromethylene)tetrahydro— 1月— pyrrol izin— 7a(5方 0— yl )methoxy)-5-f luoro— 9— ( (1』?, 5 S) -8 - ( 3-me t hoxypr opy 1 )-3 , 8- diazabicyclo[3.2. l]octan— 3— yl )— 2— methyl— 2月— pyrazolo[4,3— / ]quinazol in— 4— yl )—5— ethynyl-6-f luoronaphthalen— 2— ol;

[0107] (47) 4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-(2-hydroxyethyl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0108] (48) 5-Ethynyl-6-fluoro-4-(5-fluoro-9-((1R,5S)-8-(3-fluoropropyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0109] (49) 7-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-1-ethyl-2,3-dihydro-1H-inden-5-ol;

[0110] (50) 4-(7-(((5)-2-(Difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5'H,6'H)-yl)methoxy)-5-fluoro-2-methyl-9-((1R,5S)-8-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2H-pyrazolo[4,3-c]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (51) 4-(9-(3,6-Diazabicyclo[3.1.1]heptan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5'H,6'H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-c]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0111] (52) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1 J 6 i -pyrrolizin-7a(5 J 6'H _ yl)methoxy)-2-methyl-9-((1R,5S)-8-(2,2,2-trifluoroethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2H-pyrazolo[4,3-c]quinazolin-4-yl)naphthalen-2-ol;

[0112] (53) (S)-1-(4-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3-methylpiperidin-3-ol;

[0113] (54) (S)-1-(7-((1-((1,1-Difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methoxy)-4-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3-methylpiperidin-3-ol;

[0114] (55) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-(1-oxa-6-azaspiro[3.5]nonan-6-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0115] (56) 4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-c]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0116] (57) 4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-c]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0117] (58) 4-(7-(((5)-2-(Difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5'H)-yl)methoxy)-5-fluoro-9-((1R,5S)-8-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-methyl-2H-pyrazolo[4,3-c]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0118] (59) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-(1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (60) 4-(9-(Dimethylamino)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-

[0119] 1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0120] (61) (±)-4-(9-((1R,5R)-2,6-diazabicyclo[3.2.1]heptan-2-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0121] (62) (5》)- 4- (9- ((1』?, 5』?)- 2,6- Diazabicyclo[3.2J3]heptan-2-yl)-5-fluoro- 7— (((2』?, 7aS)— 2— f luorotetrahydro— 1月— pyrrolizin— 7a(5方 0— yl)methoxy)— 2— methyl— 2月— pyrazolo[4,3— / ]quinazol in— 4— yl )—5— ethynyl— 6— f luoronaphthalen— 2— ol

[0122] (63) 5— Ethynyl— 6— fluoro— 4— (5— fluoro— 7— (((2』?, 7aS)— 2— fluorotetrahydro— l J 6 i -pyrrolizin-7a(5 J 60 _ yl)methoxy)-2-methyl-9-((17?,5S)-8-methyl-3,8- di azabi cyclo [3.2.1] oct an-3-yl)-2^pyr azo lo [4,3- / ] quinazolin-4-yl )naphthalen-

[0123] 2-ol;

[0124] (64) 5— Ethynyl— 6— fluoro— 4— (5— fluoro— 7— (((2』?, 7aS)— 2— fluorotetrahydro— 1月— pyrrol izin— 7a(5方 0— yl )methoxy)— 2— methyl— 9— (6— (oxetan— 3— ylmethyl )—3,6— diazabicyclo[3.1. l]heptan— 3— yl )— 2月— pyrazolo[4,3— / ]quinazol in— 4— yl )naphthalen—

[0125] 2-ol;

[0126] (65) 3-(9-((1S,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2S,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H))-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-chloro-4-(trifluoromethyl)aniline;

[0127] (66) 4-(7-((1-((1,1-Difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methoxy)-5-fluoro-2-methyl-9-((1S,5S)-8-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0128] (67) 4-(7-(((1S,7a'S)-2,2-Difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5'H))-yl)methoxy)-5-fluoro-2-methyl-9-((1S,5S)-8-(oxetan-

[0129] 3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2H-pyrazolo[4,3-f]quinazolin-

[0130] 4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0131] (68) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (69) 4-(9-(1-((Difluoromethoxy)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; J 6 i -pyrrolizin-7a(5 J 60 _ yl)methoxy)-2-methyl-9-((1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (69) 4-(9-(1-((Difluoromethoxy)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0132] (70) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-(1-((R)-tetrahydrofuran-2-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0133] (71) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-(1-((5)-tetrahydrofuran-2-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0134] (72) 4-(9-(4,4-Difluoropiperidin-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0135] (73) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1 J 6 i -pyrrolizin-7a(5 J 60 _ yl)methoxy)-2-methyl-9-((1R,5S)-8-(methyl-δ)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; pyrrolizin-7a(5H0 _yl)methoxy)-9-((17?,5S)-8-(2-methoxyethyl)-3,8-diazabicyclo[3.2. l]octan—3—yl)—2—methyl—2月—pyrazolo[4,3— / ]quinazol in—4—yl)—4—(trifluoromethyl)aniline;

[0136] (75) 9- ((1』?, 55)- 3,8-Diazabicyclo[3.2.1]octan- 3- yl)- 4- (5- ethynyl- 6 - fluoroisoquinolin—4—y 1)—5—fluoro—7—(((2』?, 7aS)—2—fluorotetrahydro—L¥—pyrrolizin—7a(5方0—yl)methoxy)—2—methyl—2月—pyrazolo[4,3— / ]quinazoline;

[0137] (76) 4- (9- ((1』?, 55)- 3,8-Diazabicyclo[3.2.1]octan- 3- yl)- 5- fluoro- 7- (((2』?, 7aS)—2—fluorotetrahydro—1月—pyrrolizin—7a(5方0—yl)methoxy)—2—methyl—2月—pyrazolo[4,3— / ]quinazol in—4—yl)—2—amino—7—fluorobenzofuran—3—carbonitrile;

[0138] (77) 4-(9-((1^5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2』?, 7aS)—2—fluorotetrahydro—1月—pyrrolizin—7a(5方0—yl)methoxy)—2—methyl—2月—pyrazolo[4,3— / ]quinazolin—4—yl)—2—amino—5—fluorobenzofuran—3—carbonitrile; (78) 5—Ethynyl—6—fluoro—4—(5—fluoro—7—(((2』?, 7aS)—2—fluorotetrahydro—1月—pyrrolizin—7a(5方0—yl)methoxy)—2—methyl—9—(2—oxa—6—azaspiro[3.5]nonan—6—yl)—2月—pyrazolo[4,3— / ]quinazolin—4—yl)naphthalen—2—ol;

[0139] (79) 5—Ethynyl—6—fluoro—4—(5—fluoro—7—(((2』?, 7aS)—2—fluorotetrahydro—1月-pyrrolizin—7a(5方0—yl)methoxy)—9—(1—(2—methoxyethyl)—3,8—diazabicyclo[3.2. l]octan—3—yl)—2—methyl—2月—pyrazolo[4,3— / ]quinazolin—4—yl)naphthalen—2—ol;

[0140] (80) 5—Ethynyl—6—fluoro—4—(5—fluoro—7—(((2』?, 7aS)—2—fluorotetrahydro—

[0141] 1H - Pyrrolizin - 7a(5'H)-yl)methoxy)-9-(1-(1-methoxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0142] (81) 4-(9-(1-(Ethoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2'H,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5'H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0143] (82) 7-(4-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2'H,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5'H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one;

[0144] (83) 6—(4—(8—Ethynyl—7—fluoro—3—hydroxynaphthalen—1—yl)-5 -fluoro-7-(((2ʹ,7aS)—2—fluorotetrahydro—1ʹH—pyrrolizin—7a(5ʹH)-yl)methoxy)—2—methyl—2ʹH—pyrazolo[4,3—b]quinazolin—9—yl)—1,6—diazaspiro[3.5]nonan—2—one;

[0145] (84) 1—(4—(8—Ethynyl—7—fluoro—3—hydroxynaphthalen—1—yl)-5 -fluoro-7-(((2ʹ,7aS)—2—fluorotetrahydro—1ʹH—pyrrolizin—7a(5ʹH)-yl)methoxy)—2—methyl—2ʹH—pyrazolo[4,3—b]quinazolin—9—yl)-3-(fluoromethyl)piperidin—3—ol;

[0146] (85) 4-(9-((1ʹ,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5 -fluoro-7-(((6S,8aS)—hexahydro—1ʹH—pyrrolo[2,1—c][1,4]oxazin—6—yl)methoxy)—2—methyl—2ʹH—pyrazolo[4,3—b]quinazolin—4—yl)—5—ethynyl—6—fluoronaphthalen—2—ol;

[0147] (86) (ʹ)-4-(9-((1ʹ,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7—(((6ʹ,8aʹ?)-hexahydro—1ʹH—pyrrolo[2,1—c][1,4]oxazin—6—yl)methoxy)—2—methyl —

[0148] 2H-pyrazolo[4,3-c]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0149] (87) (5a)-4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((6R,8aR)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-2-methyl-

[0150] 2H-pyrazolo[4,3-c]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (88) (2R,4S)-6-(7-(((5)-2-(Difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-2-methyl-2H-pyrazolo[4,3-c]quinazolin-9-yl)-6-azaspiro[3.5]nonan-2-ol;

[0151] (89) (2S,4S)-6-(7-(((5)-2-(Difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-2-methyl-2H-pyrazolo[4,3-c]quinazolin-9-yl)-6-azaspiro[3.5]nonan-2-ol;

[0152] (90) Methyl (1ʹ,5ʹ)- 3- (4- (8- ethynyl- 7- fluoro- 3- hydroxynaphthalen- 1- yl)— 5— fluoro— 7— (((2ʹ, 7aS)— 2— fluorotetrahydro— 1ʹH— pyrrolizin— 7a(5ʹH)-yl )methoxy)— 2— methyl— 2ʹH— pyrazolo[4,3— i]quinazol in— 9— yl )—3,8— diazabicyclo[3.2.1] octane-8-carboxylate;

[0153] (91) 1— ((1ʹ, 5ʹ)— 8— (4— (8— Ethynyl— 7— fluoro— 3— hydroxynaphthalen— 1— yl )—5 — fluoro— 7— (((2ʹ, 7aS)— 2— fluorotetrahydro— 1ʹH— pyrrolizin— 7a(5ʹH)-yl)methoxy)— 2— methyl-2ʹH— pyrazolo[4,3-i]quinazol in-9-yl)-3, 8~diazabicyclo [3.2.1] octan-3-yl)- 2,2, 2~trifluoroethan-l-one;

[0154] (92) 1—(6— (8— Ethyl— 7— fluoro— 3— hydroxynaphthalen— 1—yl )-5 -fluoro-3- (((2ʹ, 7aS)— 2— fluorotetrahydro— 1ʹH— pyrrolizin— 7a(5ʹH)-yl)methoxy)— 8— methylfuro[3,2— i] quinazol in— 1—yl)— 3,3— difluoropiperidin— 4—ol;

[0155] (93) (3ʹ)-1-(6-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-3-(((2ʹ,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3-methylpiperidin-3-ol;

[0156] (94) (3ʹ)-1-(6-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-3-(((2ʹ,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3-methylpiperidin-3-ol;

[0157] (95) 6-(8-Ethynyl-7-fluoronaphthalen-1-yl)-5-fluoro-3-(((2ʹ,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-1-morpholinofuro[3,2-f]quinazoline;

[0158] (96) 4-(1-((1ʹ,S)-3,8-Diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-3-(((2ʹ,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine;

[0159] (97) 2-Amino-7-fluoro-4-(5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-pyrrolizin-7a(5H)-yl)methoxy)-1-((1R,5S)-8-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-methylfuro[3,2-f]quinazolin-6-yl)benzo[b]thiophene-3-carbonitrile;

[0160] (98) 5-Ethynyl-6-fluoro-4-(5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1 J 6 i -pyrrolizin-7a(5 J 60 _ yl)methoxy)-1-((1R,5S)-8-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-methylfuro[3,2-f]quinazolin-6-yl)naphthalen-2-ol;

[0161] (99) 5-Ethynyl-6-fluoro-4-(5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1R-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-1-((1R,5S)-8-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)furo[3,2-f]quinazolin-6-yl)naphthalen-2-ol;

[0162] (100) 4-(1-(3,6-Diazabicyclo[3.1.1]heptan-6-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0163] (101) 5-Ethynyl-6-fluoro-4-(5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-1-((1R,SS)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)furo[3,2-f]quinazolin-6-yl)naphthalen-2-ol;

[0164] (102) 5-Ethynyl-6-fluoro-4-(5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1-(3-(3-methoxypropyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)-8-methylfuro[3,2-f]quinazolin-6-yl)naphthalen-2-ol;

[0165] (103) 2-Amino-7-fluoro-4-(5-fluoro-3-(((2',7aS)-2-fluorotetrahydro-pyrrolizin-7a(5'H)-yl)methoxy)-8-methyl-1-((R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)furo[3,2-f]quinazolin-6-yl)benzo[b]thiophene-3-carbonitrile;

[0166] (104) 5-Ethynyl-6-fluoro-4-(5-fluoro-3-(((2',7aS)-2-fluorotetrahydro-1'H-pyrrolizin-7a(5'H)-yl)methoxy)-1-(3-(2-methoxyethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)-8-methylfuro[3,2-f]quinazolin-6-yl)naphthalen-2-ol;

[0167] (105) 4-(1-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile; (106) 4-(1-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0168] (107) 5-Ethynyl-6-fluoro-4-(5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-1-((1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)furo[3,2-f]quinazolin-6-yl)naphthalen-2-ol;

[0169] (108) 4-(1-((1R,5S)-3-(Cyclopropylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0170] (109) 4-(1-(3,6-Diazabicyclo[3.1.1]heptan-6-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile;

[0171] (110) 2-Amino-7-fluoro-4-(5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1-((1R,5S)-3-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-8-methylfuro[3,2-f]quinazolin-6-yl)benzo[b]thiophene-3-carbonitrile; _ yl)methoxy)-l-((1R,5S)-3-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-8-methylfuro[3,2-f]quinazolin-6-yl)benzo[b]thiophene-3-carbonitrile;

[0172] (111) 1— ((1』?, 55)— 3— (6— (8— Ethynyl— 7— f luoro— 3— hydroxynaphtha len—l—yl )—5 — f luoro— 3— (((2』?, 7aS)— 2— f luorotetrahydro— 1月— pyrrol izin— 7a(5方 0— yl)methoxy)— 8— methylfuro[3,2- / ]quinazol in-l-y 1)-3, 8~di azabi cyclo [3.2.1] oct an-8-y 1)-2, 2,2- trif luoroethan-l-one;

[0173] (112) 2— Amino— 7— f luoro— 4— (5— f luoro— 3— (((2』?, 7aS)— 2— f luorotetrahydro— pyrrol iz in— 7a(5方 0—yl)methoxy)— 1—((1』?, 55)— 8— (3— methoxypropyl)— 3, 8 — diazabicyclo[3.2.1]octan— 3— yl)— 8— methylfuro[3,2— / ]quinazolin— 6— yl)benzoL이 thiophene— 3— carbonitr i le;

[0174] (113) 4-(l-((1^5S)-3-Ethyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-5- f luoro— 3— (((2』?, 7aS)— 2— f luorotetrahydro— 1月— pyrrol izin— 7a(5方 0— yl)methoxy)— 8— methylfuro[3 ,2— / ]quinazol in— 6— yl )—5— ethynyl— 6— f luoronaphthalen— 2— ol;

[0175] (114) 5-Ethynyl-6-fluoro-4-(5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-1-((1R,5S)-3-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)furo[3,2-f]quinazolin-6-yl)naphthalen-2-ol;

[0176] (115) 5-Ethynyl-6-fluoro-4-(5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)]] _ yl)methoxy)-1-((1R,5S)-3-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-8-methyl furo[3,2-f]quinazolin-6-yl)naphthalen-2-ol;

[0177] (116) 5-Ethynyl-6-fluoro-4-(5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1]] J 6 i -pyrrolizin-7a(5]] J 60 _ yl)methoxy)-1-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-8-methyl furo[3,2-f]quinazolin-6-yl)naphthalen-2-ol;

[0178] (117) 5-Ethynyl-6-fluoro-4-(5-fluoro-1-((1R,5S)-3-(3-fluoropropyl)-

[0179] 3.8-Diazabicyclo[3.2.1]octan-8-yl)-3-(((2ʹ,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5ʹH)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)naphthalen-

[0180] 2-ol;

[0181] (118) 4-(1-((1ʹS,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-3-(((S)-3,3-difluoro-1-azabicyclo[3.2.0]heptan-5-yl)methoxy)-5-fluoro-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0182] (119) 4-(1-((1ʹS,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-3-(((S)-3,3-difluoro-1-azabicyclo[3.2.0]heptan-5-yl)methoxy)-5-fluoro-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0183] (120) 2-Amino-7-fluoro-4-(5-fluoro-3-(((2ʹ,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5ʹH)-yl)methoxy)-8-methyl-1-(3-methyl-3,6-diazabicyclo[3.1.1]heptan-6-yl)furo[3,2-f]quinazolin-6-yl)benzo[b]thiophene-

[0184] 3-carbonitrile;

[0185] (121) 5-Ethynyl-6-fluoro-4-(5-fluoro-1-((1R,5S)-8-(3-fluoropropyl)-

[0186] 3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H))-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)naphthalen-2-ol;

[0187] (122) 5-Ethynyl-6-fluoro-4-(5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1 J 6 i -pyrrolizin-7a(5 J 60 _ yl)methoxy)-1-((1R,5S)-8-(3-hydroxypropyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-methylfuro[3,2-f]quinazolin-6-yl)naphthalen-2-ol;

[0188] (123) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((S)-2,2-difluorotetrahydro-1H-pyrrolizin-7a(5H))-yl)methoxy)-5-fluoro-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0189] (124) 5-Ethynyl-6-fluoro-4-(5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)) _ yl)methoxy)-8-methyl-1-((1R,5S)-8-(3,3,3-trifluoropropyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)furo[3,2-f]quinazolin-6-yl)naphthalen-2-ol;

[0190] (125) 5-Ethynyl-6-fluoro-4-(5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1 J 6 i -pyrrolizin-7a(5 J 60 _ yl)methoxy)-1-((1R,5S)-8-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-methyl furo[3,2-f]quinazolin-6-yl)naphthalen-2-ol;

[0191] (126) 5-Ethynyl-6-fluoro-4-(5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1-(3-(3-hydroxypropyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)-8-methylfuro[3,2-f]quinazolin-6-yl)naphthalen-2-ol;

[0192] (127) 4-(1-((1R,5S)-8-(Cyclopropylmethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0193] (128) 1-((1R,5S)-3-(6-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2-difluoropropan-1-one;

[0194] (129) 1-((1R,5S)-3-(6-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)ethan-1-one;

[0195] (130) 4-(3-(((1R,7a'R)-2,2-Difluorodihydro- 3'-Spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5',6'-dihydroxy)-5-fluoro-1-((1R,5S)-8-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0196] (131) 1-((1R,5S)-3-(3-(((1R,7a'R)-2,2-difluorodihydro-1',3',7a'-spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5',6'-dihydroxy)methoxy)-6-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethanone;

[0197] (132) 4-(1-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-3-(((1R,7a'R)-2,2-difluorodihydro-1',3',7a'-spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5',6'-dihydroxy)methoxy)-5-fluoro-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0198] (133) 4 - (3 - (((1α, 7aα)-2,2 - Difluorodihydro - 1α, 3α - spiro[cyclopropane - 1,2’ - pyrrolizin]-7a'(5’H)-yl)methoxy)-5 - fluoro - 1 - ((1α, 5S)-8 - (2 - methoxyethyl)-3,8 - diazabicyclo[3.2.1]octan - 3 - yl)-8 - methylfuro[3,2 - f]quinazolin - 6 - yl)-5 - ethynyl - 6 - fluoronaphthalen - 2 - ol;

[0199] (134) 4 - (3 - (((1α, 7aα)-2,2 - Difluorodihydro - 1α, 3α - spiro[cyclopropane - 1,2’ - pyrrolizin]-7a'(5’-yl)methoxy)-5 - fluoro - 8 - methyl - 1 - ((1α, 5S)-8 - (oxetan - 3 - ylmethyl)-3,8 - diazabicyclo[3.2.1]octan - 3 - yl)furo[3,2 - f]quinazolin - 6 - yl)-5 - ethynyl - 6 - fluoronaphthalen - 2 - ol;

[0200] (135) 5 - Ethynyl - 6 - fluoro - 4 - (5 - fluoro - 3 - (((2α, 7aS)-2 - fluorotetrahydro - 1 J 6 i -pyrrolizin - 7a(5 J 60 _ yl)methoxy)-1 - ((1α, 5S)-8 - (2 - hydroxyethyl)-3,8 - diazabicyclo[3.2.1]octan - 3 - yl)-8 - methylfuro[3,2 - f]quinazolin - 6 - yl)naphthalen - 2 - ol;

[0201] (136) 5-Ethynyl-6-fluoro-4-(5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1 J 6 i -pyrrolizin-7a(5 J 60 _ yl)methoxy)-1-((1R,5S)-8-((S)-2-hydroxypropyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-methylfuro[3,2-f]quinazolin-6-yl)naphthalen-2-ol;

[0202] (137) 4-(6-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1R-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-1-methylpiperazin-2-one;

[0203] (138) 4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1R-pyrrolizin-7a(5H)-yl)methoxy)-2-methyloxazolo[5,4-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0204] (139) 5-Ethynyl-6-fluoro-4-(7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)-8-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)oxazolo[5,4-f]quinazolin-4-yl)naphthalen-2-ol;

[0205] (140) 5-Ethynyl-6-fluoro-4-(3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H) _ yl)methoxy)-1-((1R,5S)-3-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)imidazo[1',2':1,6]pyrido[3,2-b]pyrimidin-6-yl)naphthalen-2-amine;

[0206] (141) tert-Butyl (1R,5S)-8-(6-(3-amino-8-ethynyl-7-fluoronaphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-b]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate;

[0207] (142) 3 - ((1ʹ,5ʹ)-8-(6-(3 - Amino - 8 - ethynyl - 7 - fluoro - 1 - naphthalenyl)-3 - (((2ʹ,7aS)-2 - fluorotetrahydro - 1H - pyrrolizin - 7a(5H)-yl)methoxy)imidazo[1ʹ,2ʹ:1,6]pyrido[3,2 - b]pyrimidin - 1 - yl)-3,8 - diazabicyclo[3.2.1]octan - 3 - yl)propan - 1 - ol;

[0208] (143) 5 - Ethynyl - 6 - fluoro - 4 - (3 - (((2ʹ,7aS)-2 - fluorotetrahydro - 1H - pyrrolizin - 7a(5H)-yl)methoxy)-1 - ((1ʹ,5ʹ)-3 - methyl - 3,8 - diazabicyclo[3.2.1]octan - 8 - yl)imidazo[1ʹ,2ʹ:1,6]pyrido[3,2 - b]pyrimidin - 6 - yl)naphthalen - 2 - amine;

[0209] (144) 4 - (9 - ((1ʹ,5ʹ)-3,8 - Diazabicyclo[3.2.1]octan - 3 - yl)-5 - fluoro - 7 - (((2ʹ,7aS)-2 - fluorotetrahydro - 1H - pyrrolizin - 7a(5H)-yl)methoxy)-2 - methyloxazolo[5,4 - f]quinazolin - 4 - yl)-5 - ethynyl - 6 - fluoronaphthalen - 2 - ol;

[0210] (145) 5-Ethyl-6-fluoro-4-(5-fluoro-7-(((2α,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)-3-(oxetan-2-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0211] (146) 5-Ethyl-6-fluoro-4-(5-fluoro-7-(((2α,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)-3-((tetrahydrofuran-3-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0212] (147) 1-((1R,5S)-3-(7-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)-4-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethan-1-one;

[0213] (148) 4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((S,2)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethyl-6-fluoronaphthalen-2-ol;

[0214] (149) 4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-2-aminobenzofuran-3-carbonitrile; (150) 4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-2-amino-7-fluorothieno[3,2-c]pyridine-3-carbonitrile;

[0215] (151) 4-(9-((1S,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(((S)-1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0216] (152) 3-Chloro-5-(4-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2S,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H))-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-1-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide;

[0217] (153) 4-(1-((1S,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-3-((2',2'-difluoro-1-azaspiro[bicyclo[3.2.0]heptane-3,1'-cyclopropan]-5-yl)methoxy)-5-fluoro-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0218] (154) 4-(1-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0219] (155) 4-(1-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((6R,8aR)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0220] (156) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0221] (157) 4-(1-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-3-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)-5-fluoro-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0222] (158) 5-Ethynyl-6-fluoro-4-(5-fluoro-3-(((2′,7aS)-2-fluorotetrahydro-

[0223] 1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-1-((1R,5S)-3-(methyl-azetidin-1-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)furo[3,2-f]quinazolin-6-yl)naphthalen-2-ol;

[0224] (159) 5-Ethynyl-6-fluoro-4-(5-fluoro-3-(((2′,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-1-((1R,5S)-8-(methyl-azetidin-1-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)furo[3,2-f]quinazolin-6-yl)naphthalen-2-ol; (160) 1-((1R,5S)-3-(3-(((1S,7a′S)-2,2-Difluorodihydro-1′H,3′H-spiro[cyclopropane-1,2′-pyrrolizin]-7a′(5′H)-yl)methoxy)-6-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethanone; _ y1)methoxy)-6-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethanone;

[0225] (161) 4—(3—(((1S,7a′S)—2,2—Difluorodihydro—1′H,3′H—spiro[cyclopropane—1,2′-pyrrolizin]-7a′(5′H)-yl)methoxy)-5-fluoro-8-methyl-1-((1R,5S)-8-(oxetan-3-ylmethyl)—3,8-diazabicyclo[3.2.1]octan-3-yl)furo[3,2-f]quinazolin-6-yl)—5-ethynyl-6-fluoronaphthalen-2-ol;

[0226] (162) (2,2-Difluorocyclopropyl)(1R,5S)-3-(6-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)—5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone;

[0227] (163) ((1R,5S)-3-(6-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)—5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(oxiran-2-yl)methanone;

[0228] (164) 2-Amino-7-fluoro-4-(5-fluoro-3-(((2',7aS)-2-fluorotetrahydro-pyrrolizin-7a(5'H)-yl)methoxy)-8-methyl-1-((1',5'S)-8-(methyl-sulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)furo[3,2-f]quinazolin-6-yl)benzo[b]thiophene-3-carbonitrile;

[0229] (165) 9-((1'S,5'S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-4-(3-

[0230] (difluoromethyl)-8-ethynyl-7-fluoronaphthalen-1-yl)-5-fluoro-7-(((2',7aS)-2-fluorotetrahydro-1'H-pyrrolizin-7a(5'H)-yl)methoxy)-2-methyl-2'H-pyrazolo[4,3-f]quinazoline;

[0231] (166) 4-(9-((1'S,5'S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-fluoro-2-methyl-2'H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0232] (167) 4—(1—(3—(Difluoromethyl)—3—methylpiperidin—1—yl)-5 -fluoro-3-(((2',7aS)—2—fluorotetrahydro—1'H—pyrrolizin—7a(5'H)yl)methoxy)—8—methylfuro[3,2—f]quinazolin—6—yl)—5—ethynyl—6—fluoronaphthalen—2—ol;

[0233] (168) 4—(1—(2—(Difluoromethyl)—6—azaspiro[3.5]nonan—6—yl)-5 -fluoro-3-(((2',7aS)—2—fluorotetrahydro—1'H—pyrrolizin—7a(5'H)yl)methoxy)—8—methylfuro[3,2—f]quinazolin—6—yl)—5—ethynyl—6—fluoronaphthalen—2—ol; (169) 4-(3-((1-((3-Azabicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methoxy)-1-(((1'R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-

[0234] 5-fluoro—8—methylfuro[3,2—f]quinazolin—6—yl)—5—ethynyl—6—fluoronaphtha1en~2 -ol;

[0235] (170) 5-(1-((1S,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-2-fluoro-3-methyl-4-

[0236] (trifluoromethyl)aniline;

[0237] (171) 4-(1-((1S,5S)-8-((3,3-Difluorocyclobutyl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-

[0238] 6-fluoronaphthalen-2-ol;

[0239] (172) 5-(9-((1S,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-2-fluoro-3-methyl-4-(trifluoromethyl)aniline;

[0240] (173) 4-(7-(((Z)-1-((Dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-2-methyl-9-((1'S,5'S)-8-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2H-pyrazolo[4,3-i]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0241] (174) Aziridin-2-yl((1'R,5'S)-3-(6-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-3-(((2'R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-i]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone;

[0242] (175) 1-((1'R,5'S)-3-(6-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-3-(((2'R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-i]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3,3,3-trifluoropropan-1-one;

[0243] (176) 4-(1-((1S,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-8-methyl-3-(((4aR,7aS)-1-methyloctahydro-4aR-cyclopenta[b]pyridin-4a-yl)methoxy)furo[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0244] (177) 4-(1-((1S,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-8-methyl-3-(((4aR,7aS)-1-methyloctahydro-4aR-cyclopenta[b]pyridin-4a-yl)methoxy)furo[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (178) 4-((R)-1-((1S,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1R-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-2-amino-5-fluorobenzo[b]thiophene-3-carbonitrile;

[0245] (179) 5-Ethynyl-6-fluoro-4-(5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1-(1-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-methylfuro[3,2-f]quinazolin-6-yl)naphthalen-2-ol;

[0246] (180) 4-((1R,5S)-3-(6-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)butane-1,2-diol;

[0247] (181) 4-(1-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-1,6-difluoronaphthalen-2-ol;

[0248] (182) 4-(7-(((1S,7a'S)-2,2-Difluorodihydro-1'S,3'S-spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)-5-fluoro-2-methyl-9-((1R,5S)-3-methyl-

[0249] 3.8-Diazabicyclo[3.2.1]octan-8-yl)-2^pyrazolo[4,3- / ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen—2—ol;

[0250] (183) 5-Ethynyl—6-fluoro—4-(5-fluoro—3-(((2』?, 7aS)-2-fluorotetrahydro—1月—pyrrolizin—7a(5方0—yl)methoxy)—1—((1』?, 55)—8-(3-(hydroxymethyl)cyclobutyl)-

[0251] 3.8-Diazabicyclo[3.2.1]octan—3-yl)—8-methylfuro[3,2— / ]quinazolin—6-yl)naphthalen—2—ol;

[0252] (184) 5-Ethynyl—6-fluoro—4-(5-fluoro—7-(((2』?, 7aS)-2-fluorotetrahydro—1月-pyrrolizin-7a(5方0-yl)methoxy)-2-methyl-9-((L?, 5S)-8-(oxetan-3-ylmethyl)-

[0253] 3.8-Diazabicyclo[3.2.1]octan—3-yl)oxazolo[5,4— / ]quinazolin—4-yl)naphthalen—2—ol;

[0254] (185) 1— ((1』?, 55)— 3— (6— (8— Ethynyl— 7— f luoro— 3— hydroxynaphthalen— 1—yl )—5 — f luoro— 3— (((2』?, 7aS)— 2— f luorotetrahydro— 1月— pyrrol izin— 7a(5方 0— yl)methoxy)— 8— methylfuro[3,2- / ]quinazol in-l-y 1)-3, 8~di azabi cyclo [3.2.1] oct an-8-y 1)-4, 4,4- trif 1 uor obut an-l-one; (186) 4-(9-((1^5S)-3-Ethyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-5- f luoro— 7— (((2』?, 7aS)— 2— f luorotetrahydro— 1月— pyrrol izin— 7a(5方 0— yl)methoxy)— 2— methyl— 2月— pyrazolo[4,3— / ]quinazol in— 4— yl )— 5— ethynyl— 6— f luoronaphthalen— 2— ol;

[0255] (187) 5— Ethynyl— 6— fluoro— 4— (5— fluoro— 7— (((2』?, 7aS)— 2— fluorotetrahydro— l J 6 i -pyrrolizin-7a(5 J 60 _ yl)methoxy)-9-((17?,5S)-3-isopropyl-3,8- diazabicyclo[3.2. l]octan— 8— yl )— 2— methyl— 2月— pyrazolo[4,3— / ]quinazol in— 4— yl )naphthalen— 2— ol;

[0256] (188) 5— Ethynyl— 6— fluoro— 4— (5— fluoro— 7— (((2』?, 7aS)— 2— fluorotetrahydro— l J 6 i-pyrrolizin-7a(5 J 60 _ yl)methoxy)-2-methyl-9-((17?,5S)-3-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2^pyrazolo[4,3- / ]quinazolin-4-yl)naphthalen-2-ol;

[0257] (189) (2,2-Difluorocyclopropyl)(CL / ?, 55)-3-(4-(8-ethynyl-7-fluoro-3-hydroxynaphthalen—1—yl)—5—fluoro—7—(((2』?, 7aS)—2-fluorotetrahydro—1月—pyrrolizin—7a(5方0—yl)methoxy)—2—methyl—2月—pyrazolo[4,3— / ]quinazolin—9—yl)-3,8~diazabicyclo[3.2.1]octan—8—yl)methanone;

[0258] (190) ((1』?, 55)—3—(4—(8—Ethynyl—7—fluoro—3—hydroxynaphthalen—1—yl)—5—fluoro—7—(((2』?, 7aS)—2-fluorotetrahydro—1月—pyrrolizin—7a(5方0—yl)methoxy)—2—methyl—2月—pyrazolo[4,3— / ]quinazolin—9—yl)—3,8—diazabicyclo[3.2.!]octan-8_yl)(l—(trifluoromethyl)cyclopropyl)methanone;

[0259] (191) (2,2-Difluorocyclopropyl)(CL / ?, 55)- 8-(4-(8-ethynyl- 7-fluoro- 3-hydroxynaphthalen—1—yl)—5—fluoro—7—(((2』?, 7aS)—2-fluorotetrahydro—1月—pyrrolizin—7a(5方0—yl)methoxy)—2-methyl—2月—pyrazolo[4,3— / ]quinazolin—9—yl)- 3,8—diazabicyclo[3.2.1]octan—3—yl)methanone;

[0260] (192) 1—((1』?, 55)—3-(4-(8-Ethynyl—7—fluoro- 3-hydroxynaphthalen—1—yl)—5 —fluoro—7—(((2』?, 7aS)—2-fluorotetrahydro—1月—pyrrolizin—7a(5方0—yl)methoxy)—2-methyl-2^pyrazolo[4,3- / ]quinazolin-9-y 1)-3, 8~diazabicyclo[3.2.1]octan-8-yl)- 3,3, 3~trifluoropropan-l-one;

[0261] (193) Aziridin-2-y 1 ((17?, 5 S)-3-(4-(8-ethynyl- 7-fluoro- 3-hydroxynaphthalen—1—yl)—5—fluoro—7—(((2』?, 7aS)—2-fluorotetrahydro—1月—pyrrolizin—7a(5方0—yl)methoxy)—2-methyl—2月—pyrazolo[4,3— / ]quinazolin—9—yl)- 3, 8~diazabicyclo[3.2.1]octan—8—y 1 )methanone;

[0262] (194) ((』?)-Aziridin-2-yl)((L?,55)-3-(4-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2』?,7aS)-2-fluorotetrahydro-1月-pyrrolizin-7a(5方0-yl)methoxy)-2-methyl-2月-pyrazolo[4,3- / ]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone;

[0263] (195) 4-(7-((1-((4-(Difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-fluoro-2-methyl-9-((1』?,55)-3-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2月-pyrazolo[4,3- / ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0264] (196) 4-(9-((17?,5S)-8-((2,2-Difluorocyclopropyl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2』?,7aS)-2-fluorotetrahydro-1月-pyrrolizin-7a(5方0-yl)methoxy)-2-methyl-2月-pyrazolo[4,3- / ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0265] (197) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1 J 6 i -pyrrolizin-7a(5 J 60 _ yl)methoxy)-2-methyl-9-((1R,5S)-8-(4,4,4-trifluorobutyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2H-pyrazolo[4,3-c]quinazol-4-yl)naphthalen-2-ol;

[0266] (198) 3-((1R,5S)-3-(4-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-c]quinazol-9-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropanenitrile;

[0267] (199) 1-((1R,5S)-3-(4-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-c]quinazol-9-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-4,4,4-trifluorobutan-1-one;

[0268] (200) ((1S,5S)—3—(4—(8—Ethynyl—7—fluoro—3—hydroxynaphthalen—1—yl)—5—fluoro—7—(((2S,7aS)—2—fluorotetrahydro—1H—pyrrolizin—7a(5H)—yl)methoxy)—2—methyl—2H—pyrazolo[4,3—f]quinazolin—9—yl)—3,8—diazabicyclo[3.2.1]octan-8-yl)(oxetan—3—yl)methanone;

[0269] (201) 4-(1-((1S,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-8-methyl—3—(((4aS / 7aSR—1—methyloctahydro—4aH—cyclopenta[c]pyridin—4a—yl)methoxy)furo[3,2—f]quinazolin—6—yl)—5—ethynyl—6—fluoronaphthalen—2—ol;

[0270] (202) 4-(1-((1'S,5'S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-8-methyl-3-(((4a'S,7a'S)-1-methyl octahydro-4a'H-cyclopenta[b]pyridin-4a'-yl)methoxy)furo[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (203) (5)-7-(4-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2'S,7a'S)-2-fluorotetrahydro-1'H-pyrrolizin-7a(5'H)-yl)methoxy)-2-methyl-2'H-pyrazolo[4,3-f]quinazolin-9-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione;

[0271] (204) (R)-7-(4-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2'S,7a'S)-2-fluorotetrahydro-1'H-pyrrolizin-7a(5'H)-yl)methoxy)-2-methyl-2'H-pyrazolo[4,3-f]quinazolin-9-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione;

[0272] (205) 2 - (((1R,5S)-3-(6-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)propane-1,3-diol;

[0273] (206) 4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(((1S)-2,2-difluoro-1-(((5)-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0274] (207) 5-Ethynyl-6-fluoro-4-(5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1-((1R,5S)-8-((2-

[0275] (hydroxymethyl)cyclopropyl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-methylfuro[3,2-f]quinazolin-6-yl)naphthalen-2-ol;

[0276] (208) 5-Ethynyl-6-fluoro-4-(5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-1-((1R,5S)-8-((1-methylazetidin-3-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)furo[3,2-f]quinazolin-6-yl)naphthalen-2-ol;

[0277] (209) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1 J 6 i -pyrrolizin-7a(5 J 60 _ yl)methoxy)-2-methyl-9-((1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-amine;

[0278] (210) 4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-((3,3-difluoro-1-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclobutyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0279] (211) 2— ((1』?, 55)— 3— (4— (8— Ethynyl— 7— f luoro— 3— hydroxynaphthalen— 1—yl )—5 — f luoro— 7— (((2』?, 7aS)— 2— f luorotetrahydro— 1月— pyrrol izin— 7a(5方 0— yl)methoxy)— 2— methyl— 2月— pyrazolo[4,3— / ]quinazolin— 9— yl)— 3,8— diazabicyclo[3.2.!]octan-8_yl)_

[0280] / ^dimethyl acetamide; (212) 4— (9—( (1』?, 55)— 8—( (2, 2-Di f luorocyclopropyl )methyl )—3,8— di azabi cyclo [3.2.1] oct an-3-yl )-7-( ((7?)-l-( (dimethyl amino)methyl )-2,2- di f luorocyclopropyl )methoxy)— 5— f luoro— 2— methyl— 2月— pyrazolo[4,3— / ]quinazol in— 4-yl )— 5— ethynyl— 6— f luoronaphthalen— 2— ol;

[0281] (213) 5— Ethynyl— 6— fluoro— 4— (5— fluoro— 7— (((2』?, 7aS)— 2— fluorotetrahydro— l J 6 i -pyrrolizin-7a(5 J 60 _ yl)methoxy)-2-methyl-9-((17?,5S)-8-(3,3,3- trif luoropropyl)- 3,8- diazabicyclo[3.2.1]octan- 3- yl)- 2月— pyrazolo[4,3~ / ]quinazol in— 4— yl )naphthalen— 2— ol;

[0282] (214) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0283] (215) (1-(Dimethylamino)cyclopropyl)(1R,5S)-8-(4-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methanone;

[0284] (216) ((1R,5S)-3-(4-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(oxetan-2-yl)methanone;

[0285] (217) (2,2-Difluorocyclopropyl)((1^5S)-3-(7-(((^)-l-((dimethylamino)methyl)—2,2—difluorocyclopropyl)methoxy)—4—(8—ethynyl—7—fluoro—3—hydroxynaphthalene-1-yl)-5—fluoro—2—methyl—27¥—pyrazolo[4,3 — / ]quinazolin—9—yl)—3,8—diazabicyclo[3.2.1]octan—8—yl)methanone;

[0286] (218) ((1』?, 55)—3—(4—(8—Ethynyl—7—fluoro-3-hydroxynaphthalene-1-yl)—5 —fluoro—7—(((2』?, 7aS)—2—fluorotetrahydro—1月—pyrrolizin—7a(5方0—yl)methoxy)—2—methyl—2月—pyrazolo[4,3— / ]quinazolin—9—yl)—3,8—diazabicyclo[3.2.!]octan-8_yl)(2—(trifluoromethyl)cyclopropyl)methanone;

[0287] (219) ((1』?, 55)—3—(4—(8—Ethynyl—7—fluoro—3—hydroxynaphthalene—1—yl)—5 —fluoro—7—(((2』?, 7aS)—2—fluorotetrahydro—1月—pyrrolizin—7a(5方0—yl)methoxy)—2—methyl—2月—pyrazolo[4,3— / ]quinazolin—9—yl)—3,8—diazabicyclo[3.2.!]octan-8_yl)(3—methyloxetan—3—yl)methanone;

[0288] (220) ((1R,5S)-3-(4-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(1H-1,2,4-triazol-3-yl)methanone;

[0289] (221) ((1R,5S)-3-(4-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(1-hydroxycyclopropyl)methanone;

[0290] (222) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)-8-(2-

[0291] (trifluoromethoxy)ethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0292] (223) 4-(9-((1^5S)-8-((2,2-Difluorocyclobutyl)methyl)-3,8- diazabicyclo[3.2.1]octan—3—yl)—5—fluoro—7—(((2』?,7aS)—2—fluorotetrahydro—1月—pyrrolizin—7a(5方0—yl)methoxy)—2—methyl—2月—pyrazolo[4,3— / ]quinazolin—4—yl)—5—ethynyl-6-fluoronaphthalen—2—ol;

[0293] (224) 4-(9-((17?,5S)-8-(2-(2,2-Difluorocyclopropyl)ethyl)-3,8- diazabicyclo[3.2.1]octan—3—yl)—5—fluoro—7—(((2』?,7aS)—2—fluorotetrahydro—1月—pyrrolizin—7a(5方0—yl)methoxy)—2—methyl—2月—pyrazolo[4,3— / ]quinazolin—4—yl)—5—ethynyl-6-fluoronaphthalen—2—ol;

[0294] (225) 5—Ethynyl—6—fluoro—4—(5—fluoro—3—(((2』?, 7aS)—2—fluorotetrahydro—l J 6 i -pyrrolizin-7a(5 J 60 _ yl)methoxy)-l-((17?,5S)-8-(3-(methoxy-^)propyl)-3,8- di azabi cyclo [3.2.1] octan-3-yl )-8-methyl fur o [3,2- / ] quinazolin-6-yl )naphthalen- 2-ol;

[0295] (226) 4—(9—((1R,5S)—3—((2,2-Difluorocyclopropyl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0296] (227) 5—Ethynyl—6—fluoro—4—(5—fluoro—7—(((2R,7aS)—2—fluorotetrahydro—1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)-8-((1-methyl-1H-imidazol-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0297] (228) 5—Ethynyl—6—fluoro—4—(5—fluoro—7—(((2R,7aS)—2—fluorotetrahydro—1H-pyrrolizin-7a(5H) _ yl)methoxy)-2-methyl-9-((1R,5S)-3-propyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-

[0298] 2-ol;

[0299] (229) 4-(9-((1^5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(((S)-l-((dimethylamino)methyl)—2,2—difluorocyclopropyl)methoxy)—5—fluoro—2—methyl—2H—pyrazolo[4,3—f]quinazol in—4—yl)—5—ethynyl—6—fluoronaphthalen—2—ol;

[0300] (230) (』?)- 4-((1』?, 55)- 3-(4-(8-Ethynyl- 7-fluoro- 3-hydroxynaphthalen- 1-yl)—5—fluoro—7—(((2』?, 7aS)—2—fluorotetrahydro—1H—pyrrol izin—7a(5H0—yl)methoxy)—2—methyl—2H—pyrazolo[4,3—f]quinazol in—9—yl)—3,8—diazabi eye lo[3.2.1] oct ane-8-carbony 1 ) oxet an—2—one;

[0301] (231) (5)- 4-((1』?, 55)- 3-(4-(8-Ethynyl- 7-fluoro-3-hydroxynaphtha lerrl-yl)—5—fluoro—7—(((2』?, 7aS)—2—fluorotetrahydro—1H—pyrrol izin—7a(5H0—yl)methoxy)—2—methyl—2H—pyrazolo[4,3—f]quinazol in—9—yl)—3,8—diazabi eye lo[3.2.1] oct ane-8-carbony 1 ) oxet an—2—one;

[0302] (232) 4-(7-((1-((3-azabicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methoxy)-9-((17β,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0303] (233) 4-(7-((1-((3-azabicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methoxy)-5-fluoro-2-methyl-9-((1β,5S)-8-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0304] (234) (1S,5β)-8-(4-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2β,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octan-2-one;

[0305] (235) ((5)-2,2-Difluorocyclopropyl)(CL / ?,55)-3-(4-(8-ethynyl-7-fluoro-3—hydroxynaphthalen—1—yl)—5—fluoro—7—(((2』?,7aS)—2-fluorotetrahydro—1月—pyrrolizin—7a(5方0—yl)methoxy)—2—methyl—2月—pyrazolo[4,3— / ]quinazolin—9—yl)-

[0306] 3,8~diazabicyclo[3.2.1]octan—8—yl)methanone;

[0307] (236) 5—Ethynyl—6—fluoro—4—(5—fluoro—7—(((2』?,7aS)—2-fluorotetrahydro—1月-pyrrolizin—7a(5方0—yl)methoxy)-2-methy1-9-((17?,5S)-8-((5-

[0308] (trifluoromethyl)furan—2—yl)methyl)—3,8—diazabicyclo[3.2.1]octan—3—yl)—2月—pyrazolo[4,3— / ]quinazolin—4—yl)naphthalen—2—ol; (237) 5—Ethynyl—6—fluoro—4—(5—fluoro—7—(((2』?,7aS)—2-fluorotetrahydro—l J 6 i -pyrrolizin-7a(5 J 60 _ yl)methoxy)-2-methyl-9-((17?,5S)-8-(5,5,5-trifluoropentyl)-3,8—diazabicyclo[3.2.1]octan—3—yl)-2月—pyrazolo[4,3~ / ]quinazolin—4—yl)naphthalen—2—ol;

[0309] (238) 4-(9-((1R,5S)-8-((4,5-Dihydro-1H-imidazol-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0310] (239) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-

[0311] 1H-pyrrolizin-7a(5H)-yl)methoxy)-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-4-yl)naphthalen-2-ol;

[0312] (240) 4-(9-((1R,5S)-3-((2,2-Difluorocyclobutyl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0313] (241) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)-3-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0314] (242) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-

[0315] 1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)-3-(oxetan-2-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0316] (243) 5-Ethynyl-6-fluoro-4-(5-fluoro-9-((1R,5S)-3-(2-fluoroethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0317] (244) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1 J 6i -pyrrolizin-7a(5 J 60 _ yl)methoxy)-2-methyl-9-((17?,5S)-3-(3,3,3-trifluoropropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-c]quinazol-4-yl)naphthalen-2-ol;

[0318] (245) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((17R,5S)-3-(4,4,4-trifluorobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-c]quinazol-4-yl)naphthalen-2-ol; _ yl)methoxy)-2-methyl-9-((17R,5S)-3-(4,4,4-trifluorobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-c]quinazol-4-yl)naphthalen-2-ol;

[0319] (246) 2-(2,2-Difluorocyclopropyl)-1-((1R,5S)-3-(4-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-c]quinazol-9-yl)-

[0320] 3,8-diazabicyclo[3.2.1]octan-8-yl)ethan-1-one;

[0321] (247) 1— ((1R,5S)—3—(4—(8—Ethynyl—7—fluoro—3—hydroxynaphthalen—1—yl)—5—fluoro—7—(((2R,7aS)—2—fluorotetrahydro—1H—pyrrolizin—7a(5H)—yl)methoxy)—2—methyl—2H—pyrazolo[4,3—f]quinazol—9—yl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—5,5,5—trifluoropentan—1—one;

[0322] (248) Aziridin—2—yl ((1R,5S)—8—(4—(8—ethynyl—7—fluoro—3—hydroxynaphthalen—1—yl)—5—fluoro—7—(((2R,7aS)—2—fluorotetrahydro—1H—pyrrolizin—7a(5H)—yl)methoxy)—2—methyl—2H—pyrazolo[4,3—f]quinazol—9—yl)-

[0323] 3,8—diazabicyclo[3.2.1]octan—3—yl)methanone;

[0324] (249) 4—(9—((1R,5S)—3—(Cyclopropylmethyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—5—fluoro—7—(((2R,7aS)—2—fluorotetrahydro—1H—pyrrolizin—7a(5H)—yl)methoxy)—2—methyl—2H—pyrazolo[4,3—f]quinazol—4—yl)—5—ethyl—6—fluoronaphthalen—2—ol;

[0325] (250) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)-8-(4,4,4-trifluoro-2-hydroxybutyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0326] (251) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-((1R,5S)-3-((R)-2-hydroxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0327] (252) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1 J 6 i -pyrrolizin-7a(5 J 60 _ yl)methoxy)-9-((1R,5S)-3-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0328] (253) 4-(7-(((』?)-2,2-Difluoro-1-(((5)-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-5-fluoro-2-methyl-9-((1』?,55)-8-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2H-pyrazolo[4,3- / ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalene-2-ol;

[0329] (254) 4-(9-((1^5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-((l-((4-(fluoromethylene)piperidin-l-yl)methyl)cyclopropyl)methoxy)-2-methyl-2H-pyrazolo[4,3- / ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalene-2-ol;

[0330] (255) ((1乃,55)-3-(7-((U)-2,2-Difluoro-1-(((5)-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-4-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-5-fluoro-2-methyl-2H-pyrazolo[4,3- / ]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(2-(trifluoromethyl)cyclopropyl)methanone;

[0331] (256) 1 - ((1R,5S)-3-(7-((1U)-2,2-difluoro-1-(((5)-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-4-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-2-methyl-2H-pyrazolo[4,3-i]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-4,4,4-trifluorobutan-1-one;

[0332] (257) 1 - ((1R,5S)-3-(7-((1U)-1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-4-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-2-methyl-2H-pyrazolo[4,3-i]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-4,4,4-trifluorobutan-1-one;

[0333] (258) 4 - (7 - (((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)-5-fluoro-2-methyl-9-((1R,5S)-3-(oxetan-

[0334] 3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-i]quinazolin-

[0335] 4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0336] (259) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2ʹ,7aS)-2-fluorotetrahydro-1ʹH-pyrrolizin-7a(5ʹH)-yl)methoxy)-2-methyl-9-((1ʹH,5S)-3-((tetrahydrofuran-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2ʹH-pyrazolo[4,3-i]quinazolin-4-yl)naphthalen-2-ol;

[0337] (260) 4-(7-(((1ʹS,7aʹS)-2,2-Difluorodihydro- 3ʹʹH-spiro[cyclopropane-1,2ʹ-pyrrolizin]-7aʹ(5ʹʹH)- ] (261) (2,2-Difluorocyclopropyl)(α / ?,5S)-3-(4-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2ʹʹH,7aS)-2-fluorotetrahydro-1ʹʹH-pyrrolizin-7a(5ʹʹH)-

[0338] (261) (2,2-Difluorocyclopropyl)(α / ?,5S)-3-(4-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2ʹʹH,7aS)-2-fluorotetrahydro-1ʹʹH-pyrrolizin-7a(5ʹʹH)-yl)methoxy)-2-methyl-9-((1ʹʹH,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2ʹʹH-pyrazolo[4,3-i]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; J60—yl)methoxy)—2—methyloxazolo[5,4— / ]quinazolin—9—yl)—3,8— diazabicyclo[3.2.1]octan—8—yl)methanone; (262) 4-(7-((C / ?)-l-((Dimethylamino)methyl)-2,2- difluorocyclopropyl)methoxy)—5—fluoro—9—((1』?, 55)—3—(3— methoxypropyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2月— pyrazolo[4,3— / ]quinazolin—4—yl)—5—ethynyl-6-fluoronaphthalen—2—ol;

[0339] (263) ((1』?, 55)- 3-(7-(((』?)-1-((Dimethylamino)methyl)-2,2- difluorocyclopropyl)methoxy)-4-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro—2—methyl—2月—pyrazolo[4,3— / ]quinazolin—9—yl)—3,8—diazabicyclo[3.2.1]octan—8—yl)(2—(trifluoromethyl)cyclopropyl)methanone;

[0340] (264) 4-(7-(((2S,7aS)-1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-2-methyl-9-((1R,5S)-3-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-h]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0341] (265) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2S,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)-8-((2-

[0342] (trifluoromethyl)cyclopentyl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2H-pyrazolo[4,3-h]quinazolin-4-yl)naphthalen-2-ol;

[0343] (266) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2S,7aS)-2-fluorotetrahydro-

[0344] 1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)-8-(((1R,2S)-2-

[0345] (trifluoromethyl)cyclobutyl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2H-pyrazolo[4,3-h]quinazolin-4-yl)naphthalen-2-ol;

[0346] (267) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-

[0347] 1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)-3-((2-

[0348] (trifluoromethyl)cyclopentyl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-i]quinazolin-4-yl)naphthalen-2-ol;

[0349] (268) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-

[0350] 1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)- -3-(((1R,2R)-2-

[0351] (trifluoromethyl)cyclobutyl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-i]quinazolin-4-yl)naphthalen-2-ol;

[0352] (269) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-((1-((4-(fluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-methyl-9-

[0353] ((1』?, 55)- 8- (oxetan- 3- ylmethyl)- 3,8- di azabi cyclo [3.2.1] oct an- 3- y 1)-2月- pyrazolo[4,3— / ]quinazol in— 4— yl )naphthalen— 2— ol; (270) 5— Ethynyl— 6— fluoro— 4— (5— fluoro— 7— (((2』?, 7aS)— 2— fluorotetrahydro— 1月- pyrrol iz in- 7a(5方 0-yl)methoxy)- 9- ((L?,5S)- 3- (3- hydroxypropyl)- 3,8~ diazabicyclo[3.2. l]octan— 8— yl )— 2— methyl— 2月— pyrazolo[4,3— / ]quinazol in— 4— yl )naphthalen— 2— ol;

[0354] (271) 4-(9-((1^5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-((l- (((Z)-3-(f luoromethylene)pyrrol idin-l-yl )methyl )cyclopropyl )methoxy)— 2— methyl— 2月— pyrazolo[4,3— / ]quinazol in— 4— yl )— 5— ethynyl— 6— f luoronaphthalen— 2— ol;

[0355] (272) 5— Ethynyl— 6— fluoro— 4— (5— fluoro— 7— (((2』?, 7aS)— 2— fluorotetrahydro— l J 6 i -pyrrolizin-7a(5 J 60 _yl)methoxy)-9-((17?,5S)-3-(4-methoxybutyl)-3,8-diazabicyclo[3.2. l]octan—8—yl)—2—methyl—2月—pyrazolo[4,3— / ]quinazol in—4—yl)naphthalen—2—ol;

[0356] (273) 5—Ethynyl—6—fluoro—4—(5—fluoro—7—(((2』?, 7aS)—2—fluorotetrahydro—1月—pyrrol izin—7a(5方0—yl)methoxy)—2—methyl—9—((1』?, 55)—3—((tetrahydro—2月—pyran—

[0357] 3—yl)methyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2月—pyrazolo[4,3— / ]quinazolin—

[0358] 4—yl)naphthalen—2—ol;

[0359] (274) 5—Ethynyl—6—fluoro—4—(5—fluoro—7—(((2』?, 7aS)—2—fluorotetrahydro—1月—pyrrol izin—7a(5方0—yl)methoxy)-2-methyl-9-((17?,5S)-3-((tetrahydrofuran-3-yl)methyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2月-pyrazolo[4,3— / ]quinazolin—4—yl)naphthalen—2—ol;

[0360] (275) 4-(7-((C / ?)-1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-isobutyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0361] (276) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1 J 6 i -pyrrolizin-7a(5 J 60 _ yl)methoxy)-9-((1R,5S)-3-(2-hydroxy-2-methylpropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-4-yl)naphthalen-2-ol;

[0362] (277) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)-3-((2-methyloxetan-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-i]quinazolin-4-yl)naphthalen-2-ol;

[0363] (278) 4-(7-(((5)-2-(Difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0364] (279) 4-(7-((Cis)-1-((Dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-2-methyl-9-((1R,5S)-8-(((1R,2R)-2-(trifluoromethyl)cyclopropyl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2H-pyrazolo[4,3-i]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0365] (280) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)-3-(((1R,2R)-2-

[0366] (trifluoromethyl)cyclopropyl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-i]quinazolin-4-yl)naphthalen-2-ol;

[0367] (281) 1 - ((M,5S)-8-(7-((U)-1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-4-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazol-9-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-methoxypropan-1-one;

[0368] (282) 5 - Ethynyl - 6 - fluoro - 4 - (5 - fluoro - 7 - (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-((1S,5R)-2-(hydroxymethyl)-3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazol-4-yl)naphthalen-2-ol;

[0369] (283) 4-(9-((1S,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-((1-(((1R,5S,6S)-6-fluoro-3-azabicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazol-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0370] (284) 4 - (9 - ((1S,5S)-3,8 - Diazabicyclo[3.2.1]octan-3-yl)-7 - (((S)-4-

[0371] ((difluoromethylene)-1,3—dimethylpiperidin—3—yl)methoxy)—5—fluoro—2—methyl—2H—pyrazolo[4,3—f]quinazolin—4—yl)—5—ethynyl—6—fluoronaphthalen—2—ol;

[0372] (285) 4- (9- ((1S,5S)- 3,8- Diazabicyclo[3.2.1]octan- 3- yl)- 7- (((S)- 4-

[0373] ((difluoromethylene)-1,3—dimethylpiperidin—3—yl)methoxy)—5—fluoro—2—methyl—2H—pyrazolo[4,3—f]quinazolin—4—yl)—5—ethynyl—6—fluoronaphthalen—2—ol;

[0374] (286) 4-(7-((C / ?)-1-((Dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)—9—((1』?, 55)—3—ethyl—3,8—diazabicyclo[3.2.1]octarr 8-yl)-5-fluoro—2—methyl—2月—pyrazolo[4,3— / ]quinazol in—4-yl)—5—ethynyl—6—fluoronaphthalen-2-ol; (287) 5-Ethyl-6-fluoro-4-(5-fluoro-7-(((2』?, 7aS)-2-fluorotetrahydro-1月-pyrrolizin-7a(5方0-yl)methoxy)-9-((L?,5S)-3-(3-methoxypropyl)-3,8~diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2月—pyrazolo[4,3— / ]quinazol in—4-yl)naphthalen—2—ol;

[0375] (288) 4-(9-((1乃,55)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(((乃)-2,2-difluoro—1—((3—fluoroazetidin-l-yl)methyl)cyclopropyl)methoxy)—5—fluoro-2-methyl—2月—pyrazolo[4,3— / ]quinazol in—4-yl)—5—ethynyl—6—fluoronaphthalen—2—ol;

[0376] (289) 5—Ethynyl—6—fluoro—4—(5—fluoro—7—(((2』?, 7aS)—2—fluorotetrahydro—

[0377] 1H-Pyrrolizin-7a(5H)-yl)methoxy)-9-((L,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyloxazolo[5,4-f]quinazolin-4-yl)naphthalen-2-ol;

[0378] (290)5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2L,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((L,5S)-3-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)oxazolo[5,4-f]quinazolin-4-yl)naphthalen-2-ol;

[0379] (291)4-(9-((1L,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0380] (292) 4-(9-((1S,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-c]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0381] (293) 4-(9-((1S,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-2-methyl-7-(((1-(((1R,5S,6R)-6-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methoxy)-2H-pyrazolo[4,3-c]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0382] (294) 4-(9-((1S,5S)-3,8-Diazabicyclo[3.2.1]octan-8-yl)-7-(((S)-1-((4-(difluoromethylene)piperidin-1-yl)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-c]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0383] (295) 4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-8-yl)-7-(((R)-1-((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (296) 4-(9-((1R,5S)-3-((3-(Difluoromethyl)oxetan-3-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7-(((R)-1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0384] (297) 4-(7-(((R)-1-((1,1-Difluoro-6-azaspiro[2.5]octan-6-yl)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0385] (298) 4-(7-(((』?)-1-((4-(Difluoromethylene)piperidin-1-yl)methyl)-2,2-difluorocyclopropyl)methoxy)—5—fluoro—9—((1』?,55)—3—(3-methoxypropyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2月—pyrazolo[4,3— / ]quinazolin—4—yl)—5—ethynyl-6-fluoronaphthalen—2—ol;

[0386] (299) 4-(7-((C / ?)-1-((Dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)—5—fluoro—9—((1』?,55)—3—(3-methoxybutyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2月—pyrazolo[4,3— / ]quinazolin—4—yl)—5—ethynyl-6-fluoronaphthalen—2—ol;

[0387] (300) 4-(7-(((』?)-1-((Dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)—5—fluoro—9—((l』?,5S)—3—(3-methoxy—2—methylpropyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2月—pyrazolo[4,3 — / ]quinazolin—4—yl)—5—ethynyl—6—fluoronaphtha1en-2-o1;

[0388] (301) 3— ((1』?, 55)— 8— (4— (8— Ethynyl— 7— f luoro— 3— hydroxynaphthalen— 1— yl )—5 — f luoro— 7— (((2』?, 7aS)— 2— f luorotetrahydro— 1月— pyrrol izin— 7a(5方 0— yl)methoxy)— 2— methyl— 2月— pyrazolo[4,3— / ]quinazolin— 9— yl)— 3,8— diazabicyclo[3.2.!]octan-3_ yl )propyl carbamate;

[0389] (302) 4- (9- ((1乃,55)- 3,8- Diazabicyclo[3.2.1]octan- 8- yl)- 7- (((乃)-2,2- di f luor o-l-( ( (17?, 5S, 6』?)— 6—( tri f luoromethyl)— 3— azabi cyclo[3.1.0]hexan— 3— yl )methyl )cyclopropyl )methoxy)— 5— f luoro— 2— methyl— 2』¥—pyrazolo[4,3 — / ]quinazol in— 4— yl )—5— ethynyl— 6— f luor onaphtha 1 en-2-o 1;

[0390] (303) 4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-8-yl)-7-(((R)-2,2-difluoro-1-(((1R,5S,6S)-6-fluoro-3-azabicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (304) 4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-8-yl)-7-(((R)-1-((3-(difluoromethylene)pyrrolidin-1-yl)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0391] (305) 4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-8-yl)-7-(((R)-2,2-difluoro-1-((3-fluoroazetidin-1-yl)methyl)cyclopropyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0392] (306) 4-(7-(((』?)-1-((3-(Difluoromethylene)pyrrolidin-1-yl)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-9-((1』?,55)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2月-pyrazolo[4,3- / ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0393] (307) 4-(7-((C / ?)-2,2-Difluoro-1-((3-fluoroazetidin-1-yl)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1』?,55)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2月-pyrazolo[4,3- / ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0394] (308) 4-(9-((1乃,55)-3,8-Diazabicyclo[3.2.1]octan-8-yl)-7-(((乃)-1-((diethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-2-methyl-2月-pyrazolo[4,3- / ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0395] (309) 4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-8-yl)-7-(((1R)-2,2-difluoro-1-((methylamino)methyl)cyclopropyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0396] (310) 4-(7-(((1R)-2,2-Difluoro-1-((6-fluoro-3-azabicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0397] (311) 4-(7-(((1R)-2,2-Difluoro-1-(((1R,5S,6S)-6-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0398] (312) 4-(7-(((』?)-1-(((L?,55)-6,6-Difluoro-3-azabicyclo[3.1.이hexan-3-yl)methyl)—2,2-difluorocyclopropyl)methoxy)—5-fluoro—9—((1』?,55)—3—(3-methoxypropyl)—3,8-diazabicyclo[3.2.1]octan—8-yl)—2-methyl—2月—pyrazolo[4,3— / ]quinazolin—4-yl)—5-ethynyl—6-fluoronaphtha1en-2-ol; (313) 4-(7-((1-(((3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl)cyclopropyl)methoxy)—5-fluoro—9—((1』?,55)—3—(3-methoxypropyl)—3,8-diazabicyclo[3.2.1]octan-8-yl)—2-methyl—2月—pyrazolo[4,3— / ]quinazolin—4-yl)—5-ethynyl-6-fluoronaphthalen—2-ol;

[0399] (314) 4-(7-((l-(((Dimethylamino)methyl)cyclopropyl)methoxy)—5-fluoro-9-((L?,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl—2月—pyrazolo[4,3— / ]quinazolin—4-yl)—5-ethynyl—6-fluoronaphthalen—2-ol;

[0400] (315) 4-(7-((C / ?)-1-((Diethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)—5—fluoro—9—((1』?,55)—3—(3-methoxypropyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2月—pyrazolo[4,3— / ]quinazolin—4—yl)—5—ethynyl-6-fluoronaphthalen—2—ol;

[0401] (316) 4-(7-(((』?)-1-((Ethyl(2,2,2-trifluoroethyl)amino)methyl)-2,2-difluorocyclopropyl)methoxy)—5—fluoro—9—((1』?,55)—3—(3-methoxypropyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2月—pyrazolo[4,3— / ]quinazolin—4—yl)—5—ethynyl-6-fluoronaphthalen—2—ol;

[0402] (317) 4-(7-((1-((4-Oxa-7-azaspiro[2.5]octan-7-yl)methyl)cyclopropyl)methoxy)—5—fluoro—9—((1』?,55)—3—(3-methoxypropyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2月—pyrazolo[4,3— / ]quinazolin—4—yl)—5—ethynyl-6-fluoronaphthalen—2—ol;

[0403] (318) 4-(7-((1-((Diethylamino)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0404] (319) 4-(7-(((1)-2,2-Difluoro-1-((methylamino)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0405] (320) 5-Ethynyl-6-fluoro-4-(5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-7-((1-((6-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methoxy)-2H-pyrazolo[4,3-i]quinazolin-4-yl)naphthalen-2-ol;

[0406] (321) 4-(9-((1S,5S)-3,8-Diazabicyclo[3.2.1]octan-8-yl)-7-(((S)-1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (322) 4-(7-((1-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1S,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0407] (323) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2S,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H))-yl)methoxy)-2-methyl-9-((1S,5S)-2,2,3-trimethyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-

[0408] 2-ol;

[0409] (324) 4-(7-((1-((4-(Difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0410] (325) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-2-methyl-7-((1-((6-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methoxy)-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0411] (326) 4-(7-(((R)-1-((Dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-9-((1R,5S)-3-(3-ethoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0412] (327) 4-(7-((C / ?)-1-((Dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)—5—fluoro—9—((1』?,55)—3—((3—(methoxymethyl)oxetan—

[0413] 3—yl)methyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2月—pyrazolo[4,3 — / ]quinazolin—4—yl)—5—ethynyl—6—fluoronaphthalene-2-ol;

[0414] (328) 5-Ethynyl-6-fluoro-4-(5-fluoro-9-((1』?,55)-3-(3-methoxypropyl)-3,8—diazabicyclo[3.2.1]octan—8—yl)—2—methyl—7—(((』?)—4-methylmorpholin—2—yl)methoxy)—2月—pyrazolo[4,3— / ]quinazolin—4—yl)naphthalen—2—ol;

[0415] (329) 4-(7-((5)-3-(Dimethylamino)pyrrolidin-1-yl)-5-fluoro-9-((1』?,55)-3-(3 -methoxypropyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2月—pyrazolo[4,3— / ]quinazolin—4—yl)—5—ethynyl—6—fluoronaphthalene-2-ol;

[0416] (330) 4-(7-((1-((1,1-Difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methoxy)—5—fluoro—9—((1R,5S)—3—(3-methoxypropyl)—3,8 —diazabicyclo[3.2.1]octan—8—yl )—2—methyl—2H—pyrazolo[4,3—f]quinazol in—4—yl )—5—ethynyl-6-fluoronaphthalen—2—ol;

[0417] (331) 5—Ethynyl—6—fluoro—4—(5—fluoro—7—(((2R,7aS)—2—fluorotetrahydro—1 J 6 i -pyrrolizin-7a(5 J 60 _ yl)methoxy)-2-methyl-9-((1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]octan—8—yl—2,2,4,4—d4)—2H—pyrazolo[4,3—f]quinazol in-4-yl )naphthalen—2—ol;

[0418] (332) 5-Ethynyl- 6-fluoro- 4- (5-fluoro- 7-(((2R, 7aR)- 2-fluoro- 6- pyrrol iz in—7a(5H0—yl )methoxy)-9-( (1R,5S)-3-(4-methoxybutyl)- 3,8-diazabicyclo[3.2.1]octan- 8- yl)- 2-methyl- 2H-pyrazolo[4,3~f]quinazol in—4—yl )naphthalen—2—ol;

[0419] (333) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-((1-((3-methoxy-3-methylazetidin-1-yl)methyl)cyclopropyl)methoxy)-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0420] (334) 4-(7-((1-(((4,4-

[0421] Difluorocyclohexyl)(methyl)amino)methyl)cyclopropyl)methoxy)-5-fluoro-9-

[0422] ((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0423] (335) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2S,7aR)-2-fluoro-6-methylenetetrahydro-pyrrolizin-7a(5H)-yl)methoxy)-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0424] (336) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1 J 6 i -pyrrolizin-7a(5 J 60 _ yl)methoxy)-9-((1R,5S)-8-(3-methoxybutyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazol-4-yl)naphthalen-2-ol;

[0425] (337) 4-(9-((1R,5S)-8-(3-Ethoxypropyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazol-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0426] (338) (A , a)-(2,2-Difluorocyclopropyl)((1R,5S)-3-(7-(((R)-1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-4-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazol-9-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone;

[0427] (339) (5a)-(2,2-Difluorocyclopropyl)((1^5S)-3-(7-(((^)-l-((dimethylamino)methyl)—2,2—difluorocyclopropyl)methoxy)—4—(8—ethynyl—7—fluoro—3—hydroxynaphthalene-1-yl)-5—fluoro—2—methyl—2H—pyrazolo[4,3— / ]quinazolin—9—yl)—3,8—diazabicyclo[3.2.1]octan—8—yl)methanone;

[0428] (340) (7&)-((17?, 5S)-3-(7-(( (7?)-l-((Dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)—4—(8—ethynyl—7—fluoro-3-hydroxynaphthalene-1-yl)-5—fluoro—2—methyl—2H—pyrazolo[4,3— / ]quinazolin—9—yl)—3,8—diazabicyclo[3.2.1]octan—8—yl)(2—(trifluoromethyl)cyclopropyl)methanone;

[0429] (341) (5a)-((17?, 5S)-3-(7-(( (7?)-l-((Dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)—4—(8—ethynyl—7—fluoro-3-hydroxynaphthalene-1-yl)-5—fluoro—2—methyl—2H—pyrazolo[4,3— / ]quinazolin—9—yl)—3,8—diazabicyclo[3.2.1]octan—8—yl)(2—(trifluoromethyl)cyclopropyl)methanone;

[0430] (342) (Sa)—5—Ethynyl—6—fluoro—4—(5—fluoro—7—(((2^,7aS)—2—fluorotetrahydro-1月-pyrrolizin-7a(5方0-yl)methoxy)-9-((L?,5S)_3_(3_methoxypropyl)—3,8—diazabicyclo[3.2.1]octan—8—y1)—2—methyl—2月—pyrazolo[4,3— / ]quinazolin—4—yl)naphthalen—2—ol;

[0431] (343) (乃a)—5—Ethynyl—6—fluoro—4—(5—fluoro—7—(((2^,7aS)—2—fluorotetrahydro-1月-pyrrolizin-7a(5方0-yl)methoxy)-9-((L?,5S)_3_(3_methoxypropyl)—3,8—diazabicyclo[3.2.1]octan—8—y1)—2—methyl—2月—pyrazolo[4,3— / ]quinazolin—4—yl)naphthalen—2—ol;

[0432] (344) 4-(7-((l-(((S)-3-(Dimethylamino)pyrrolidin-l-yl)methyl)cyclopropyl)methoxy)—5—fluoro—9—((1』?,55)—3—(3—methoxypropyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2月—pyrazolo[4,3— / ]quinazolin—4—yl)—5—ethynyl-6-fluoronaphthalen—2—ol;

[0433] (345) 5—Ethynyl—6—fluoro—4—(5—fluoro-7-((l-((3-

[0434] ((methoxymethyl)pyrrolidin-1-yl)methyl)cyclopropyl)methoxy)—9—((1R,5S)—3—(3-methoxypropyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2H—pyrazolo[4,3—f]quinazolin—4—yl)naphthalen—2—ol;

[0435] (346) 4-(7-((Cis)-1-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2H—pyrazolo[4,3—f]quinazolin—4—yl)—5—ethynyl-6-fluoronaphthalen—2—ol;

[0436] (347) 4-(7-((1-((6,6-difluoro-3-azabicyclo[3.1.1]hexan-3-yl)methyl)cyclopropyl)methoxy)—5—fluoro—9—((1R,5S)—3—(3-methoxypropyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2H—pyrazolo[4,3—f]quinazolin—4—yl)—5—ethynyl-6-fluoronaphthalen—2—ol;

[0437] (348) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-((1-((3-(fluoromethyl)azetidin-1-yl)methyl)cyclopropyl)methoxy)-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0438] (349) 4-(7-(((1S,2R)-1-((Dimethylamino)methyl)-2-

[0439] (trifluoromethyl)cyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0440] (350) 4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-8-yl)-7-(((1S,2R)-1-((dimethylamino)methyl)-2-(trifluoromethyl)cyclopropyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0441] (351) 4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-8-yl)-7-(((1R,2S)-1-((dimethylamino)methyl)-2-(trifluoromethyl)cyclopropyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-i]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0442] (352) 4-(7-(((1R,2S)-1-((Dimethylamino)methyl)-2-

[0443] (trifluoromethyl)cyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0444] (353) 4-(7-(((3S,4S)-4-(Difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0445] (354) 4-(7-(((3′,4′)-4-(Difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-5-fluoro-9-((1′,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-c]quinazol-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (355) 5-Ethynyl-6-fluoro-4-(5-fluoro-9-((1′,5S)-3-(3-methoxypropyl)-

[0446] 3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-7-((1-(((S)-2-methylmorpholino)methyl)cyclopropyl)methoxy)-2H-pyrazolo[4,3-c]quinazol-4-yl)naphthalen-2-ol;

[0447] (356) 4-(7-((1-(((2S,6S)-2,6-

[0448] Dimethylmorpholino)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1′,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-c]quinazol-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0449] (357) 4-(7-((1-(((3S,5R)-3,5-Difluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0450] (358) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-((1-(((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)methyl)cyclopropyl)methoxy)-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0451] (359) 4-(7-((1-((2-oxa-5-azabicyclo[2.2.2]octan-5-yl)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0452] (360) 4-(7-((1-(((6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)methyl)cyclopropyl)methoxy))-5-fluoro-9-(((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl))-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0453] (361) 4-(7-((1-((((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)cyclopropyl)methoxy))-5-fluoro-9-(((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl))-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0454] (362) 5-Ethynyl-6-fluoro-4-(5-fluoro-9-(((1R,5S)-3-(3-methoxypropyl)-

[0455] 3.8—diazabicyclo[3.2.1]octan—8—yl)—7—((1—(((5)—3—methoxypyrrolidin—1—yl)methyl)cyclopropyl)methoxy)—2—methyl—2H—pyrazolo[4,3—i]quinazolin—4—yl)naphthalen—2—ol; (363) 5—Ethynyl—6—fluoro—4—(5—fluoro—9—((1R,5S)—3—(3—methoxypropyl)-

[0456] 3.8—diazabicyclo[3.2.1]octan—8—yl)—7—((1—(((R)—3—methoxypyrrolidin—1—yl)methyl)cyclopropyl)methoxy)—2—methyl—2H—pyrazolo[4,3—i]quinazolin—4—yl)naphthalen—2—ol;

[0457] (364) 5—Ethynyl—6—fluoro—4—(5—fluoro—7—((1—(((5)—3—fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)—9—((1R,5S)—3—(3—methoxypropyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2H—pyrazolo[4,3—i]quinazolin—4—yl)naphthalen—2—ol;

[0458] (365) 5—Ethynyl—6—fluoro—4—(5—fluoro—9—((1R,5S)—3—(3—methoxypropyl)-

[0459] 3.8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-7-((l-((4-

[0460] ((trifluoromethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0461] (366) 4-(7-(((1-(((3-oxa-7-azabicyclo[3.3.1]nonan-7-yl)methyl)cyclopropyl)methoxy)-5-fluoro-9-(((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0462] (367) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((1-(((3-fluoro-3-methylazetidin-1-yl)methyl)cyclopropyl)methoxy)-9-(((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0463] (368) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-((1-((3-isopropoxyazetidin-1-yl)methyl)cyclopropyl)methoxy)-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0464] (369) 5-Ethynyl-6-fluoro-4-(5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-7-((1-((3-methylazetidin-1-yl)methyl)cyclopropyl)methoxy)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0465] (370) 1—((1— (((4— (8— Ethynyl— 7— fluoro— 3— hydroxynaphthalen—l—yl )—5 — f luoro— 9— ((L?, 55)— 3— (3— methoxypropyl)— 3,8— di azabi cyclo [3.2.1] oct an-8-y 1)-2- methyl— 2月— pyrazolo[4,3— / ]quinazol in— 7— yl ) oxy ) me t hy 1 ) eye 1 op r opy 1 )methyl )-3- (trif luoromethyl )azet idin-3-ol; (371) 4-(7-((l-((8-0xa-3-azabicyclo[3.2.1]octan-3- yl)methyl)cyclopropyl)methoxy)— 5— fluoro— 9—((1』?, 55)— 3— (3— methoxypropyl)— 3, 8 — diazabicyclo[3.2. l]octan— 8— yl )— 2— methyl— 2月— pyrazolo[4,3— / ]quinazol in— 4— yl )—5— ethynyl-6-f luoronaphthalen— 2— ol;

[0466] (372) 4- (7-(((乃 )-2, 2- Di fluoro- 1-(((1乃,55,65)-6- fluoro- 3- azabi cyclo [3.1.0]hexan— 3— yl )methyl )cyclopropyl )methoxy)— 5— f luoro—2—methyl—9— ((1』?, 55)- 3- (oxetan- 3- ylmethyl)- 3,8- diazabicyclo[3.2.1]octan- 8- yl)- 2月- pyrazolo[4,3— / ]quinazol in— 4— yl )— 5— ethynyl— 6— f luoronaphthalen— 2— ol;

[0467] (373) 4-(7-(((』?)-1-((3-(Difluoromethylene)pyrrolidin-1-yl)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-2-methyl-9-((1』?,55)-3-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3- / ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0468] (374) 5-Ethynyl-6-fluoro-4-(5-fluoro-2-methyl-9-((1』?,5S)-3-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7-((1-(((1』?,55\67?)-6-

[0469] (trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methoxy)-2H-pyrazolo[4,3- / ]quinazolin-4-yl)naphthalen-2-ol;

[0470] (375) 4-(7-(((』?)-1-((4-(Difluoromethylene)piperidin-1-yl)methyl)-2,2-difluorocyclopropyl)methoxy)—5—fluoro—2—methyl—9—((1』?,55)—3—(oxetan—3—ylmethyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2H—pyrazolo[4,3— / ]quinazolin—4—yl)—5—ethynyl—6—fluoronaphthalen-2-ol;

[0471] (376) 4-(7-(((3』?,4』?)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)—5—fluoro—2—methyl—9—((L?,5S)—3—(oxetan—3—ylmethyl)—3,8—diazabicyclo[3.2.1]octan-8-yl)-2H—pyrazolo[4,3- / ]quinazolin-4-yl)-5-ethynyl- 6-fluoronaphthalen-2-ol;

[0472] (377) 4-(7-(((5)-4-(Difluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)—5—fluoro—2—methyl—9—((L?,5S)—3—(oxetan—3—ylmethyl)—3,8—diazabicyclo[3.2.1]octan-8-yl)-2H—pyrazolo[4,3- / ]quinazolin-4-yl)-5-ethynyl- 6-fluoronaphthalen-2-ol;

[0473] (378) 4-(7-(((』?)-2,2-Difluoro-1-((3-fluoroazetidin-1-yl)methyl)cyclopropyl)methoxy)—5—fluoro—2—methyl—9—((1』?,55)—3—(oxetan-3-ylmethyl)—3,8—diazabicyclo[3.2.1]octan-3-yl)—2H—pyrazolo[4,3— / ]quinazolin-4-yl)—5—ethynyl—6—fluoronaphthalen-2-ol; (379) 5—Ethynyl—6—fluoro—4—(5—fluoro—9—((1』?,55)—3—(3-methoxypropyl)-

[0474] 3,8—diazabicyclo[3.2.1]octan-8-yl)—2—methyl—7—((1—((3—(oxetan-3-ylmethyl)azetidin-1-yl)methyl)cyclopropyl)methoxy)—2H—pyrazolo[4,3 — / ]quinazolin-4-yl)naphthalen-2-ol;

[0475] (380) 4-(7—((l—((7-0xa-1-azaspiro[4.4]nonan-1-yl)methyl)cyclopropyl)methoxy)—5—fluoro—9—((1』?,55)—3—(3-methoxypropyl)—3,8 —diazabicyclo[3.2. l]octan-8-yl)—2—methyl—2H—pyrazolo[4,3— / ]quinazolin-4-yl)—5—ethynyl-6-fluoronaphthalen-2-ol;

[0476] (381) 4-(7-((1-((6-oxa-2-azaspiro[3.4]octan-2-yl)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0477] (382) 5-Ethynyl-6-fluoro-4-(5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-

[0478] 3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-7-((1-((tetrahydro-1,7-oxa[3,4-c]pyrrol-5(3H)-yl)methyl)cyclopropyl)methoxy)-2H-pyrazolo[4,3-i]quinazolin-4-yl)naphthalen-2-ol;

[0479] (383) 4-(7-((1-((2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0480] (384) 4-(7-((1-((7,7-Difluoro-3-azabicyclo[4.1.0]heptan-3-yl)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-c]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0481] (385) 4-(7-((1-((6,6-Difluoro-2-azabicyclo[2.2.1]heptan-2-yl)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-c]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0482] (386) 4-(7-(((2,4-difluorophenyl)-1-((diethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-2-methyl-9-((1'S,5'S)-3-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (387) 4-(9-((1'S,5'S)-3-(2-oxaspiro[3.3]heptan-6-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-7-(((2'R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5'H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0483] (388) 5-Ethynyl-6-fluoro-4-(5-fluoro-9-((1'S,5'S)-3-(3-methoxypropyl)-

[0484] 3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-7-((1-((2-

[0485] (trifluoromethyl)morpholino)methyl)cyclopropyl)methoxy)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0486] (389) (2,2-Difluorocyclopropyl)((1^5S)-3-(7-(((^)-l-((dimethylamino)methyl)—2,2—difluorocyclopropyl)methoxy)—4—(8—ethynyl—7—fluoro—3—hydroxynaphthalen—1—yl)-5 -fluoro-2-methyloxazolo[5,4- / ]quinazolin-9-yl)-3, 8~diazabicyclo[3.2.1]octan-8-yl)methanone;

[0487] (390) 4-(7-((l-((3-(Diethylamino)azetidin-l-yl)methyl)cyclopropyl)methoxy)—5—fluoro—9—((1』?, 55)—3—(3—methoxypropyl)—3, 8 —diazabicyclo[3.2. l]octan—8—yl)—2—methyl—2月—pyrazolo[4,3— / ]quinazolin—4—yl)—5—ethynyl-6-fluoronaphthalen—2—ol;

[0488] (391) 1—((1—(((4—(8—Ethynyl—7—fluoro—3—hydroxynaphthalen—1—yl)—5 —fluoro—9—((L?, 55)—3—(3—methoxypropyl)—3,8—diazabicyclo[3.2.1]octan-8-y 1)-2-methyl—2月—pyrazolo[4,3— / ]quinazolin—7—yl)oxy)methyl)cyclopropyl)methyl스-N,N-dimethylazetidine-3-carboxamide;

[0489] (392) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-((1-((3-(2-hydroxypropan-2-yl)azetidin-1-yl)methyl)cyclopropyl)methoxy)-9-((1R,5S)-3-(3-methoxypropyl)-

[0490] 3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazol-4-yl)naphthalen-2-ol;

[0491] (393) 4-(7-((1-((3-((dimethylamino)methyl)azetidin-1-yl)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazol-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0492] (394) 5-Ethynyl-6-fluoro-4-(5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-

[0493] 3.8— Diazabicyclo[3.2.1]octan— 8— yl)— 2— methyl— 7— ((1— ((3,3,4— trimethylpiperazin— 1-yl )methyl )cyclopropyl )methoxy)— 2H— pyrazolo[4,3— f]quinazol in— 4— yl )naphthalen— 2— ol; (395) 4- (7- (((R)- 2,2- Difluoro- 1-((3- fluor oazeti din- 1- yl )methyl )cyclopropyl )methoxy)— 5— f luoro— 2— methyl— 9— ((1R, 5S)— 3— (oxetan— 3— ylmethyl )— 3,8— di azabi cyclo [3.2.1] oct an— 8— yl )— 2H— pyrazolo[4,3— f]quinazol in— 4— yl )— 5— ethynyl— 6— f 1 uor onapht ha 1 en-2-o 1;

[0494] (396) 5- Ethyl- 6- fluoro- 4- (5- fluoro- 7- (((S,Z)- 2-

[0495] (fluoromethylene)tetrahydro— 1H— pyrrol izin— 7a(5H0— yl ) me t hoxy ) -2~me t hy 1 -9- ((1R, 5S)- 8- (oxetan- 3- ylmethyl)- 3,8- di azabi cyclo [3.2.1] oct an- 3- y 1)-2H- pyrazolo[4,3— f]quinazol in— 4— yl )naphthalen— 2— ol;

[0496] (397) 4-(7-(((5)-2-(Difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5'H,6'H)-yl)methoxy)-5-fluoro-2-methyl-9-((1R,5S)-8-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethyl-6-fluoronaphthalen-2-ol;

[0497] (398) 4-(7-((1-((1,1-Difluoro-5-azaspiro[2.4]heptan-5-yl)methyl)cyclopropyl)methoxy)-5-fluoro-2-methyl-9-((1R,5S)-3-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalene-2-ol;

[0498] (399) 1-((1-(((4-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-2-methyl-9-((1R,5S)-3-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-f]quinazolin-7-yl)oxy)methyl)cyclopropyl)methyl)-3-methylazetidin-3-ol;

[0499] (400) 4-(7-((1-((1,1-Difluoro-5-azaspiro[2.3]hexan-5-yl)methyl)cyclopropyl)methoxy)-5-fluoro-2-methyl-9-((1R,5S)-3-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0500] (401) 4-(7-((1-((7-Oxa-4-azaspiro[2.5]octan-4-yl)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0501] (402) 4-(7-((1-((4-Ethyl-1,4-diazepan-1-yl)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-c]quinazol-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (403) (5a)-4-(9-((1R,5S)-3-Ethyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-c]quinazol-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0502] (404) (A , (a)-4-(9-((1R,5S)-3-Ethyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-c]quinazol-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0503] (405) 5-Ethynyl-6-fluoro-4-(5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-

[0504] 3.8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-7-((1-((4-(2,2,2-trifluoroethyl)piperazin-1-yl)methyl)cyclopropyl)methoxy)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0505] (406) 4-(7-((1-((3,3-Dimethylmorpholino)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1S,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0506] (407) 4-(7-((1-((2,2-Dimethylmorpholino)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1S,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0507] (408) ((1R,5S)-3-(7-(((R)-1-((Dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-4-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-2-methyloxazolo[5,4-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl) (2-(trifluoromethyl)cyclopropyl)methanone;

[0508] (409) 5-Ethynyl-6-fluoro-4-(5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-

[0509] 3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-7-((1-((3-morpholinoazetidin-1-yl)methyl)cyclopropyl)methoxy)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0510] (410) 2-Amino-5-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)-3-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)benzo[b]thiophene-3-carbonitrile;

[0511] (411) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)-3-(2-(methylsulfonyl)ethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-c]quinazolin-4-yl)naphthalen-2-ol; (412) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)-3-(3-(methylsulfonyl)propyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-c]quinazolin-4-yl)naphthalen-2-ol;

[0512] (413) 2-Amino-5-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-c]quinazolin-4-yl)benzothiophene-3-carbonitrile;

[0513] (414) Ua)- 5-Ethynyl- 6-fluoro- 4-(5-fluoro- 7-(((2^,7aS)-2-fluorotetrahydro—1月—pyrrolizin—7a(5方0—yl)methoxy)—2—methyl—9—((1』?, 55)—3—

[0514] (oxetan-3-ylmethyl)—3,8-diazabicyclo[3.2.1]octan—8—yl)-2^pyrazolo[4,3- / ]quinazolin—4—yl)naphthalen—2—ol;

[0515] (415) (Sa)—5-Ethynyl—6-fluoro—4-(5-fluoro—7-(((2^,7aS)—2 -fluorotetrahydro—1月—pyrrolizin—7a(5方0—yl)methoxy)—2—methyl—9—((1』?, 55)—3—(oxetan- 3-ylmethyl)- 3,8-diazabicyclo[3.2.1]octan- 8- yl)- 2月-pyrazolo[4,3~ / ]quinazolin—4—yl)naphthalen—2—ol;

[0516] (416) 5-Ethynyl—6-fluoro—4-(5-fluoro—9—((1』?, 55)—3—(3-methoxypropyl)- 3,8—diazabicyclo[3.2.1]octan—8—yl)—2—methyl—7—((1—((3—(pyrrolidin—1—yl)azetidin-l-yl)methyl)cyclopropyl)methoxy)—2月-pyrazolo[4,3— / ]quinazolin—4—yl)naphthalen—2—ol;

[0517] (417) 4-(9-((1^5S)-3,8-Diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-7-(((2』?, 7aS)—2—fluorotetrahydro—1月—pyrrolizin—7a(5方0—yl)methoxy)—2—methyl—2月—pyrazolo[4, 3 - / ] quinazo1in-4-yl)-2-amino-5 -fluorobenzo [b]thiophene-3 - carbonitrile;

[0518] (418) 5—Ethynyl—6—fluoro—4—(5—fluoro—7—((1—((3—fluoro-3-

[0519] (methoxymethyl)pyrrolidin-l-yl)methyl)cyclopropyl) methoxy)-2~methyl-9-((1』?, 55)-3-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2月—pyrazolo[4,3— / ] quinazo1in—4—yl)naphthalen—2—ol;

[0520] (419) 4—(7—((1—((1—Oxa—7—azaspiro[4.4]nonan—7—yl)methyl)cyclopropyl)methoxy)—5—fluoro—2—methyl—9—((1ʹR,5ʹS)—3—(oxetan—3—ylmethyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2ʹH—pyrazolo[4,3—f]quinazol—in—4—yl)—5—ethynyl—6—fluoronaphthalen—2—ol; (420) 4-(9-((1ʹR,5ʹS)-3-(2-oxaspiro[3.3]heptan-6-yl)-3,8—diazabicyclo[3.2.1]octan—8—yl)—7—(((S)-1—((dimethylamino)methyl)-2,2—difluorocyclopropyl)methoxy)—5—fluoro—2—methyl—2ʹH—pyrazolo[4,3—f]quinazol—in—4-yl)—5—ethynyl—6—fluoronaphthalen—2—ol;

[0521] (421) 5—Ethynyl—6—fluoro—4—(5—fluoro—7—((((2ʹR,7aS)—2—fluorotetrahydro-1ʹH—pyrrolizin-7a(5ʹH))-yl)methoxy)-2-methyl-9-((1ʹR,5ʹS)-3-(3-(methylthio)propyl)-3,8—diazabicyclo[3.2.1]octan—8—yl)—2ʹH—pyrazolo[4,3~f]quinazol—in—4—yl)naphthalen—2—ol;

[0522] (422) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)-3-(3-(methylthio)butyl)-

[0523] 3,8-diazabicyclo[3.2.1]octan-8-yl)-2R-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0524] (423) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)-3-(thietan-3-ylmethyl)-

[0525] 3,8-diazabicyclo[3.2.1]octan-8-yl)-2R-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0526] (424) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)-3-(thietan-2-ylmethyl)-

[0527] 3,8-diazabicyclo[3.2.1]octan-8-yl)-2R-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0528] (425) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2ʹ,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-(((1ʹ,5S)-3-((tetrahydrothiophen-

[0529] 3-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-i]quinazol in-

[0530] 4-yl)naphthalen-2-ol;

[0531] (426) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2ʹ,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-(((1ʹ,5S)-3-((tetrahydro-2H-pyran-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-i]quinazol in-4-yl)naphthalen-2-ol;

[0532] (427) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2ʹ,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-(((1ʹ,5S)-3-(3-(methoxymethyl)cyclobutyl)-

[0533] 3.8—diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2H—pyrazolo[4,3—f]quinazol—4—yl)naphthalen—2—ol;

[0534] (428) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-((1R,5S)-3-(3-methoxycyclobutyl)-3,8 -diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2H—pyrazolo[4,3—f]quinazol—4—yl)naphthalen—2—ol;

[0535] (429) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-((1R,5S)-3-((3-methoxycyclobutyl)methyl)-3,8—diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2H—pyrazolo[4,3—f]quinazol—4—yl)naphthalen—2—ol;

[0536] (430) 4-(9-((1^5S)-3-(6-oxaspiro[3.4]octan-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-7-(((2』?,7aS)-2-fluorotetrahydro-1月-pyrrolizin-7a(5方0-yl)methoxy)-2-methyl-2H-pyrazolo[4,3— / ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0537] (431) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-((((2』?,7aS)-2-fluorotetrahydro-1月-pyrrolizin-7a(5方0-yl)methoxy)-9-((17?,5S)-3-(6-methoxyspiro[3.3]heptan-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2月-pyrazolo[4,3- / ]quinazolin_4-yl)naphthalen-2-ol;

[0538] (432) 5-Ethyny1-6-fluoro-4-(5-fluoro-7-((((2』?,7aS)-2-fluorotetrahydro-1月-pyrrolizin-7a(5方0-yl)methoxy)-9-((1』?,55)-3-(2-(methoxymethyl)cyclobutyl)-3,8—diazabicyclo[3.2.1]octan—8—yl)-2-methyl-2月-pyrazolo[4,3— / ]quinazo1in—4-yl)naphthalen-2-ol;

[0539] (433) 4— (7— ((1—((2— Oxa— 8— azaspiro[ 5.5] undecan— 8— yl )methyl )cyclopropyl )methoxy)— 5— fluoro— 2— methyl— 9—((1′, 5′)— 3— (oxetan— 3— ylmethyl )— 3,8— diazabicyclo [3.2.1] octan— 8— yl )— 2H— pyrazolo[4,3— f]quinazolin— 4— yl )—5— ethynyl— 6— fluoronaphthalen-2-ol;

[0540] (434) 4- (7-((1- (((5)- 3- (Dimethyl amino)pyrrolidin-1-yl )methyl )cyclopropyl )methoxy)— 5— fluoro— 2— methyl— 9—((1′, 5′)— 3— (oxetan— 3— ylmethyl )— 3,8— diazabicyclo [3.2.1] octan— 8— yl )— 2H— pyrazolo[4,3— f]quinazolin— 4— yl )—5— ethynyl— 6— fluoronaphthalen-2-ol;

[0541] (435) 5— Ethynyl— 6— fluoro— 4—(5— fluoro-7-((l-((3-

[0542] ( methoxymethyl )pyrrolidin-l-yl )methyl )cyclopropyl ) methoxy ) -2~methyl -9- ((1′, 5′)— 3— (oxetan- 3- ylmethyl)- 3,8- diazabicyclo [3.2.1] octan- 8- yl)-2H- pyrazolo[4,3— f]quinazolin— 4— yl )naphthalen— 2— ol;

[0543] (436) 4-(9-((1^5S)-3-(6-0xaspiro[3.4]octan-2-yl)-3,8- diazabicyclo[3.2.1]octan— 8— yl)— 5— f luoro— 7— (((2』?,7aS)— 2— f luorotetrahydro— 1月— pyrrol izin— 7a(5方 0— yl )methoxy)— 2— methyl— 2月— pyrazolo[4,3— / ]quinazol in— 4— yl )—5— ethynyl-6-f luoronaphthalen— 2— ol;

[0544] (437) 4-(7-((C / ?)-l-((Dimethylamino)methyl)-2,2- difluorocyclopropyl)methoxy)— 5— fluoro— 9—((1』?, 55)— 3— (3— methoxycyclobutyl)— 3, 8 — diazabicyclo[3.2. l]octan— 8— yl )— 2— methyl— 2月— pyrazolo[4,3— / ]quinazol in— 4— yl )—5— ethynyl-6-f luoronaphthalen— 2— ol;

[0545] (438) 5— Ethynyl— 6— fluoro— 4— (5— fluoro— 7— ((1— (((』?)— 3— fluoropyrrol i din— 1— yl )methyl )cyclopropyl )methoxy)— 9— ((L?,5S)— 3— (3— (methoxymethyl )cyclobutyl )-

[0546] 3.8— di azabi cyclo [3.2.1] oct an— 8— y 1)—2— methyl— 2月— pyr azo lo [4,3— / ]quinazo 1 in— 4— yl )naphthalen— 2— ol;

[0547] (439) 5- Ethyny 1- 6- f luoro- 4- (5- f luoro- 9- ( (1乃, 5S)-3-(3-

[0548] ((methoxymethyl)(cyclobutyl))-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-7-(((3R,4R)-1-methyl-4-(trifluoromethyl)pyrrolidin-3-yl)methoxy)-2H-pyrazolo[4,3-i]quinazolin-4-yl)naphthalen-2-ol;

[0549] (440) 4-(7-((((R)-1-((Dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-9-(((1R,5S)-3-(3-

[0550] ((methoxymethyl)(cyclobutyl))-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0551] (441) 5-Ethyl-6-fluoro-4-(5-fluoro-7-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- _ yl)methoxy)-9-(((1R,5S)-3-(3-(methoxymethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-4-yl)naphthalen-2-ol;

[0552] (442) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((3′,4′)-4-methoxy-1,3-dimethylpiperidin-3-yl)methoxy)-2-methyl-9-((1′,5S)-3-(oxetan-3-ylmethyl)-

[0553] 3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-j]quinazolin-4-yl)naphthalen-2-ol;

[0554] (443) 4-(7-(((5)-4,4-Difluoro-1,3-dimethylpiperidin-3-yl)methoxy)-5-fluoro-2-methyl-9-((1′,5S)-3-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-j]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0555] (444) 4-(7-(((5?)-4,4-Difluoro-1,3-dimethylpiperidin-3-yl)methoxy)-5-fluoro-2-methyl-9-((1′,5S)-3-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-j]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0556] (445) 4-(7-(((』?)-1-((Dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)—5—fluoro—2—methyl—9—((1』?, 55)—3—(oxetan—3—ylmethyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2月—pyrazolo[4,3— / ]quinazolin—4—yl)—5—ethyl—6—fluoronaphthalen—2—ol;

[0557] (446) 5-Ethyl-6-fluoro-4-(5-fluoro-7-(((2』?, 7aS)-2-fluorotetrahydro-1月-pyrrolizin-7a(5方0-yl)methoxy)-2-methyl-9-((L?, 5$)-3-(oxetan-2-ylmethyl)-3,8~diazabicyclo[3.2. l]octan—8—yl)—2月—pyrazolo[4,3— / ]quinazolin—4—yl)naphthalen—2-ol;

[0558] (447) 4-(7-((( ^)-2,2-Difluoro-l-(((3-

[0559] (methoxymethyl)cyclobutyl)(methyl)amino)methyl)cyclopropyl)methoxy)—5—fluoro-9-((1』?, 55)—3—(3-(methoxymethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8 - yl)—2—methyl—2月—pyrazolo[4,3— / ]quinazolin—4—yl)—5—ethynyl—6—f 1 uoronaphtha 1 en-2-ol;

[0560] (448) 5-Ethynyl-6-fluoro-4-(5-fluoro-9-((1R,5S)-3-(3-

[0561] (methoxymethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7-((1-(((S)-3-methoxypyrrolidin-1-yl)methyl)cyclopropyl)methoxy)—2—methyl—2H—pyrazolo[4,3—f]quinazolin-4-yl)naphthalen-2-ol;

[0562] (449) 4-(7-(((R)-2,2-Difluoro-1-(((3-

[0563] (methoxymethyl)cyclobutyl)amino)methyl)cyclopropyl)methoxy)—5—fluoro-9-((1R,5S)-3-(3-(methoxymethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2—methyl—2H—pyrazolo[4,3—f]quinazolin-4-yl)—5—ethynyl—6—fluoronaphthalen-2-ol;

[0564] (450) 4-(7-(((1R,7a'S)-2,2-Difluorodihydro- 3'H-spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5 ] (methoxy)-5-fluoro-9-((1R,5S)-3-(3-

[0565] ((甲氧基甲基)(环丁基)-3,8-二氮杂双环[3.2.1]辛-8-基)-2-甲基-2H-吡唑并[4,3-c]喹唑啉-4-基)-5-乙炔基-6-氟萘-2-醇;

[0566] (451) 4-(7-(((R)-1-((4-(二氟亚甲基)哌啶-1-基)甲基)-2,2-二氟环丙基)甲氧基)-5-氟-9-((1R,5S)-3-(3-

[0567] ((甲氧基甲基)(环丁基)-3,8-二氮杂双环[3.2.1]辛-8-基)-2-甲基-2H-吡唑并[4,3-c]喹唑啉-4-基)-5-乙炔基-6-氟萘-2-醇;

[0568] (452) 4-(7-(((3S,4S)-4-(二氟甲基)-1-乙基-3-甲基哌啶-3-基)甲氧基)-5-氟-2-甲基-9-((1R,5S)-3-(氧杂环丁烷-3-基甲基)-3,8-二氮杂双环[3.2.1]辛-8-基)-2H-吡唑并[4,3-c]喹唑啉-4-基)-5-乙炔基-6-氟萘-2-醇;

[0569] (453) 4-(7-(((3R,4R)-4-(Difluoromethyl)-1-ethyl-3-methylpiperidin-3-yl)methoxy)-5-fluoro-2-methyl-9-((1R,5S)-3-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-i]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0570] (454) 4-(7-(((3S,4S)-4-(Difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-5-fluoro-2-methyl-9-((1R,5S)-3-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-i]quinazolin-4-yl)-5-ethyl-6-fluoronaphthalen-2-ol;

[0571] (455) 4-(7-(((3S,4S)-4-(Difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-5-fluoro-2-methyl-9-((1R,5S)-3-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-i]quinazolin-4-yl)-5-ethyl-6-fluoronaphthalen-2-ol;

[0572] (456) 4-(7-((1-((1-oxa-8-azaspiro[4.5]decan-8-yl)methyl)cyclopropyl)methoxy)-5-fluoro-2-methyl-9-((1R,5S)-3-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0573] (457) 4-(7-((1-((2-oxa-8-azaspiro[4.5]decan-8-yl)methyl)cyclopropyl)methoxy)-5-fluoro-2-methyl-9-((1R,5S)-3-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0574] (458) 4-(7-(((5)-2-(difluoromethylene)tetrahydro-1R-pyrrolizin-7a(5'6'H)-yl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-(methoxymethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0575] (459) 4-(9-((1^5S)-3-(2-0xaspiro[3.3]heptan-6-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7-(((7?)-l-(((2-oxaspiro[3.3]heptan-6-yl)amino)methyl)-2,2-difluorocyclopropyl)methoxy)—5—fluoro—2—methyl—2月—pyrazolo[4,3— / ]quinazolin—4—yl)—5—ethynyl—6—fluoronaphtha1en-2-ol;

[0576] (460) 4-(9-((1^5S)-3-(2-0xaspiro[3.3]heptan-6-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7-(((C / ?)-2,2-difluoro-l-((methyl(2-oxaspiro[3.3]heptan—6—yl)amino)methyl)cyclopropyl)methoxy)—5—fluoro—2—methyl—2月—pyrazolo[4,3— / ]quinazolin—4—yl)—5—ethynyl—6—fluoronaphthalen—2—ol; (461) 4-(7-((l-((3-(Difluoromethyl)pyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1』?, 5S)-3-(3-

[0577] (methoxymethyl)eyelobuty1)—3,8-diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2月-pyrazolo[4,3— / ]quinazolin—4—yl)—5—ethynyl—6—fluoronaphtha1en-2-ol;

[0578] (462) 5-Ethynyl-6-fluoro-4-(5-fluoro-9-((1R,5S)-3-(3-(methoxymethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-7-((1-((5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)cyclopropyl)methoxy)-2H-pyrazolo[4,3-f]quinazol-4-yl)naphthalen-2-ol;

[0579] (463) 4-(7-((1-((2-Oxa-6-azaspiro[3.4]octan-6-yl)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-

[0580] (methoxymethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazol-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0581] (464) 4-(7-((((R)-1-((Dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-

[0582] ((methoxymethyl)ethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-amine:

[0583] (465) 4-(9-((1R,5S)-3-(2-oxaspiro[3.3]heptan-6-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7-(((R)-1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-i]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-amine:

[0584] (466) 4-(9-((1R,5S)-3-(2-oxaspiro[3.3]heptan-6-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7-(((R)-1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-i]quinazolin-4-yl)-2-amino-5-fluorobenzo[b]thiophene-3-carbonitrile;

[0585] (467) 2-Amino-4-(7-(((R)-1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-

[0586] ((methoxymethyl)(ethylbutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-c]quinazolin-4-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile;

[0587] (468) 4-(7-(((R)-1-((Dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-

[0588] ((methoxymethyl)(ethylbutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-c]quinazolin-4-yl)-5-ethyl-6-fluoronaphthalen-2-ol;

[0589] (469) 4-(9-((1R,5S)-3-(2-oxaspiro[3.3]heptan-6-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7-(((R)-1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-c]quinazolin-

[0590] 4-yl)-5-ethyl-6-fluoronaphthalene-2-ol;

[0591] (470) 2-(((1R,5S)-8-(4-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-

[0592] 5-fluoro—7—(((2ʹ,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)—2-methyl-2H-pyrazolo[4,3-b]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)cyclobutan-1-one;

[0593] (471) 4-(9-((1ʹ,5S)-3-(1-oxaspiro[3.3]heptan-6-yl)-3,8-diazabicyclo[3.2.1]octan—8—yl)—5-fluoro—7—(((2ʹ,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)—2-methyl—2H-pyrazolo[4,3—b]quinazolin—4—yl)—5-ethynyl-6-fluoronaphthalen-2-ol;

[0594] (472) 5-Ethynyl-6-fluoro-4-(5-fluoro-7—(((2ʹ,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)—9—((1ʹ,5S)-3-(3-(methoxymethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan—8—yl)—2-methyl—2H-pyrazolo[4,3—b]quinazolin—4—yl)naphthalen-2-yl carbamate;

[0595] (473) 4-(7-(((』?)-2,2-Difluoro-1-((methyl(2-oxaspiro[3.3]heptan-6-yl)amino)methyl)cyclopropyl)methoxy)—5—fluoro—9—(((1』?,5S)-3-(3-

[0596] (methoxymethyl)eyclobuty1)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2月-pyrazolo[4,3— / ]quinazolin—4—yl)—5—ethynyl—6—fluoronaphtha1en-2-o1;

[0597] (474) 5-Ethynyl-l,6-difluoro-4-(5-fluoro-7-((((2乃,7aS)-2-fluorotetrahydro-1月-pyrrolizin-7a(5方0-yl)methoxy)-9-(((L?,5S)_3_(3_(methoxymethyl)eyclobuty1)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2月-pyrazolo[4,3— / ]quinazolin—4—yl)naphthalen—2—ol;

[0598] (475) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-(((1R,5S)-3-((3-methoxybicyclo[1.1.1]pentan-1-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-4-yl)naphthalen-2-ol;

[0599] (476) 3-(((1R,5S)-8-(4-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)cyclobutan-1-one;

[0600] (477) 5-(4-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-9-(((1R,5S)-3-(3-(methoxymethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-7-yl)-N,N-dimethylpicolinamide;

[0601] (478) 4-(7-(2-(Dimethylamino)ethyl)-5-fluoro-9-(((1R,5S)-3-(3-

[0602] ((甲氧基甲基)环丁基)-3,8-二氮杂双环[3.2.1]辛-8-基)-2-甲基-2H-吡唑并[4,3-f]喹唑啉-4-基)-5-乙炔基-6-氟萘-2-醇;

[0603] (479) 4-(7-(((3S,4S)-4-(二氟甲基)-1-甲基吡咯烷-3-基)甲氧基)-5-氟-9-((1R,5S)-3-(3-(甲氧基甲基)环丁基)-3,8-二氮杂双环[3.2.1]辛-8-基)-2-甲基-2H-吡唑并[4,3-f]喹唑啉-4-基)-5-乙炔基-6-氟萘-2-醇;

[0604] (480) 4-(7-((((3R,4R)-4-(二氟甲基)-1-甲基吡咯烷-3-基)甲氧基)-5-氟-9-((1R,5S)-3-(3-(甲氧基甲基)环丁基)-3,8-二氮杂双环[3.2.1]辛-8-基)-2-甲基-2H-吡唑并[4,3-f]喹唑啉-4-基)-5-乙炔基-6-氟萘-2-醇;

[0605] (481) 4-(7-((1-((Dimethylamino)methyl)cyclopropyl)methoxy)—5—fluoro-9-((1R,5S)-3-(3-(methoxymethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2—methyl—2H—pyrazolo[4,3—f]quinazolin-4-yl)—5—ethynyl—6—fluoronaphthalen-2-ol;

[0606] (482) 4-(7-((1-((Diethylamino)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-(methoxymethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2—methyl—2H—pyrazolo[4,3—f]quinazolin-4-yl)—5—ethynyl—6—fluoronaphthalen-2-ol;

[0607] (483) 5—Ethynyl—6—fluoro—4—(5—fluoro—7—(((2R,7aS)—2—fluorotetrahydro-1 J 6 i -pyrrolizin-7a(5 J 60 _ yl)methoxy)-2-methyl-9-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan—3—yl)oxazolo[5,4—f]quinazolin-4-yl)naphthalen-2-ol;

[0608] (484) 4-(7-((C / ?)-1-((Dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)—5—fluoro—2—methyl—9—((1』?,5S)—8—methyl—3,8—diazabicyclo[3.2.1]octan—3—yl)oxazolo[5,4— / ]quinazol in—4—yl)—5—ethynyl—6—fluoronaphthalen-2-ol;

[0609] (485) 5—Ethynyl—6—fluoro—4—(5—fluoro—7—(((2』?,7aS)—2—fluorotetrahydro-1月-pyrrol iz in-7a(5方0-yl)methoxy)-9-((1』?,55)-3-(3-methoxy cyclobutyl)-3,8 - diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2月—pyrazolo[4,3— / ]quinazol in—4—yl)naphtha 1 err 2—amine;

[0610] (486) 4- (7-((((』?)-1-((Diethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)—5—fluoro—9—((1』?,5S)-3-(3-

[0611] ((甲氧基甲基)环丁基)-3,8-二氮杂双环[3.2.1]辛-8-基)-2-甲基-2H-吡唑并[4,3-c]喹唑啉-4-基)-5-乙炔基-6-氟萘-2-醇;(487)4-(9-((1R,5S)-3-(2-氧杂螺[3.3]庚-6-基)-3,8-二氮杂双环[3.2.1]辛-8-基)-5-氟-7-(((2S,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-2-甲基-2H-吡唑并[4,3-c]喹唑啉-4-基)-5-乙基-6-氟萘-2-醇;

[0612] (488)4-(7-(((R)-1-((二甲基氨基)甲基)-2,2-二氟环丙基)甲氧基)-5-氟-9-((1R,5S)-3-((3-甲氧基环丁基)甲基)-3,8-二氮杂双环[3.2.1]辛-8-基)-2-甲基-2H-吡唑并[4,3-c]喹唑啉-4-基)-5-乙炔基-6-氟萘-2-醇;

[0613] (489)4-(7-((1-((7-氧杂-2-氮杂螺[3.5]壬-2-基)甲基)环丙基)甲氧基)-5-氟-9-((1R,5S)-3-(3-

[0614] ((methoxymethyl)ethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0615] (490) 4-(7-(((5)-4-(Difluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-(methoxymethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0616] (491) 4-(7-(((R)-4-(Difluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-(methoxymethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0617] (492) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((3S,4S)-4-methoxy-1,3-dimethylpiperidin-3-yl)methoxy)-2-methyl-9-((1R,5S)-3-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-h]quinazolin-4-yl)naphthalen-2-ol;

[0618] (493) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)-3-(((R)-tetrahydrofuran-

[0619] 3-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-h]quinazolin-

[0620] 4-yl)naphthalen-2-ol;

[0621] (494) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)-3-((((R)-tetrahydrofuran-

[0622] 4-yl)naphthalen-2-ol;

[0623] (495) 4-(7-(((S)-1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-9-((1S,5S)-3-(3-methoxycyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-4-yl)-5-ethyl-6-fluoronaphthalen-2-ol;

[0624] (496) 5-Ethynyl-6-fluoro-4-(5-fluoro-9-((1S,5S)-3-(3-(methoxymethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,7-dimethyl-

[0625] 2H-pyrazolo[4,3-i]quinazolin-4-yl)naphthalen-2-ol;

[0626] (497) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-((((2S,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H))-yl)methoxy)-9-((1S,5S)-3-(3-(methoxymethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-4-yl)naphthalen-2-amine;

[0627] (498) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-((1R,5S)-3-((IS,2S)-2-

[0628] ((methoxymethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol;

[0629] (499) (5S)- (4-(7-(((R)-1-((Dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-

[0630] ((methoxymethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0631] (500) (R)- 4-(7-(((R)-1-((Dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-

[0632] ((methoxymethyl)ethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-c]quinazol-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0633] (501)(5a)-(4-(9-((1S,5S)-3-(2-oxaspiro[3.3]heptan-6-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7-(((R)-1-(((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-c]quinazol-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0634] (502)(A , a)-4-(9-((1S,5S)-3-(2-oxaspiro[3.3]heptan-6-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7-(((R)-1-(((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-c]quinazol-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0635] (503)4-(7-(((R)-2,2-Difluoro-1-(((3-(methoxymethyl)cyclobutyl)amino)methyl)cyclopropyl)methoxy)-5-fluoro-9-

[0636] ((1ʹ,5ʹ)-3-(3-(methoxymethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-c]quinazol-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0637] (504)2-Amino-7-fluoro-4-(5-fluoro-3-(((2ʹ,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H))-yl)methoxy)-1-((1ʹ,5ʹ)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-8-methylfuro[3,2-c]quinazolin-6-yl)benzothiophene-3-carbonitrile;

[0638] (505)4-(9-((1ʹ,5ʹ)-3-(2-oxaspiro[3.3]heptan-6-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7-((1-

[0639] ((dimethylamino)methyl)cyclopropyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-c]quinazol-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;

[0640] (506)4-(3-(((R)-1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-1-((1ʹ,5ʹ)-3-(3-

[0641] ( me t hoxyme t hy 1 ) eye 1 obu ty 1 )— 3 ,8— di azabi cyclo [3.2.1] oct an— 8— yl )— 8— methylfuro[3 ,2— / ]quinazol in— 6— yl )— 5— ethynyl— 6— f luoronaphthalen— 2— ol . According to another embodiment of the present application, a compound of the following formula 2, an optical isomer, a stereoisomer, a racemate, an isotopic variant, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof is provided:

[0642] [Chemical Formula 2] In the above Chemical Formula 2, R, R2, R3, R4, R5, and L are as described above in the above Chemical Formula 1. All technical terms used in this application, unless otherwise defined, are used in the same meaning as commonly understood by a person skilled in the art in the relevant field of this application. In addition, although exemplary methods or samples are described in this specification, similar or equivalent ones are also included in the scope of this application. In addition, the numerical values ​​described in this specification are considered to include the meaning of ''about'' even if not specified. The contents of all publications cited as references in this specification are incorporated herein by reference in their entirety. In the above Chemical Formula 1 or Chemical Formula 2, the residues listed as Ri to R24, Rx, and Ry are used in the same meaning as commonly understood by a person skilled in the art. Unless otherwise stated, the term "halogen" as used herein, alone or in combination with additional terms (e.g., haloalkyl), refers to fluorine, chlorine, bromine, or iodine, specifically but not limited to fluorine and chlorine. The term "alkoxy" as used herein, unless otherwise stated, refers to alkyloxy, for example, alkyloxy having 1 to 7 carbon atoms. The term "haloalkyl" as used herein, unless otherwise stated, refers to alkyl, as defined herein, wherein one or more hydrogens are replaced by the same or different halogens. Examples of haloalkyl groups include, but are not limited to, -CH2CI, -CH2CF3, -CH2CCI3, -CF2H, -CF3, and the like. Unless otherwise stated, the term "hydroxyalkyl" as used herein includes alkyl groups in which one or more hydrogen atoms are replaced by one or more hydroxyl (-0H), for example, divalent or trivalent hydroxy.Unless otherwise specified, as used herein, the term “aminoalkyl” includes one or more hydrogen atoms within an alkyl group being substituted with one or more amino (-NH₂), for example divalent or trivalent amino. Unless otherwise specified, as used herein, the term "oxo" means a group of the formula =O (i.e., oxygen having a double bond). Unless otherwise specified, as used herein, the term "alkyl" refers to a saturated, straight-chain or branched monovalent hydrocarbon radical if there is no other mention. For example, the alkyl may be C1-10 alkyl, C1-8 alkyl, C1-6 alkyl, C1-4 alkyl, or C1-3 alkyl. Unless otherwise specified, as used herein, the term "alkenyl" refers to a monovalent hydrocarbon radical containing at least one carbon-carbon double bond if there is no other mention, and each double bond may have an E- or Z-configuration. For example, the alkenyl may be C2-10 alkenyl, C2-8 alkenyl, C2-6 alkenyl, or C2-4 alkenyl. Unless otherwise specified, as used herein, the term "alkynyl" refers to a monovalent group derived from an unsaturated, straight-chain or branched hydrocarbon moiety having at least one carbon-carbon triple bond if there is no other mention. For example, the alkynyl may be C2-10 alkynyl, C2-8 alkynyl, C2-6 alkynyl, or C2-4 alkynyl. These “alkyl”, “alkenyl” and “alkynyl” may be straight-chain or branched-chain when used alone or in combination with other additional terms (e.g., haloalkyl). According to each definition, it means a radical of a saturated aliphatic hydrocarbon group having 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, or 1 to 3 carbon atoms within an alkyl group. Examples of common alkyls are methyl, ethyl, 〒propyl,. 〒propyl, 〒butyl, Examples thereof include, but are not limited to, hexamethyl-butyl, hexamethyl-butyl, hexamethyl-pent ... Examples of alkenyl and alkynyl include, but are not limited to, ethenyl, prop-1-enyl, prop-2-enyl, but-2-enyl, 2-methylprop-2-enyl, 3-methylbut-2-enyl, hex-3-enyl, hex-4-enyl, prop-2-ynyl, but-2-ynyl, but-3-ynyl, hex-4-ynyl, or hex-5-ynyl. Unless otherwise stated, the terms "cycloalkyl," "cycloalkenyl," or "cycloalkynyl" herein mean a cyclic alkyl which may be substituted or unsubstituted and which is a radical of a hydrocarbon group forming a single or fused cyclic ring having unsaturated or partially or fully saturated (e.g., from 3 to 24) carbon atoms. Specifically, the cycloalkyl, cycloalkenyl, or cycloalkynyl may have 3 to 10, 3 to 8, 3 to 6, 3 to 5, 4 to 10, 4 to 8, 4 to 6, or 4 to 5 carbon atoms. The cycloalkyl may include, but is not limited to, carbocyclyl, spirocarbocyclyl, fused carbocyclyl, and bridged carbocyclyl. According to one specific example of the present invention, the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclohepsenyl, cyclooctyl, cyclooctenyl, 2,5-cyclohexadienyl, spiro [3.5]nonane, spiro [3.3]heptane, bicyclo [1.1.1]pentane, bicyclo [2.2.2]octyl, adamant-1-yl, decahydronaphthyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, 2-oxobicyclo[2.2.1]hept-1-enyl, benzene, naphthalene and all possible isomers thereof may be included without limitation. Unless otherwise stated, the term "saturated or unsaturated heterocyclyl" as used herein means a substituted or unsubstituted 3 to 24 membered hydrocarbon group forming an unsaturated or partially or fully saturated single or fused cyclic ring containing one or more heteroatoms selected from the group consisting of nitrogen (N), oxygen (O), and sulfur (S), for example, 1 to 8 heteroatoms. Specifically, the heterocyclyl may be a 3 to 10-membered, 3 to 8-membered, 3 to 6-membered, 4 to 10-membered, 4 to 8-membered, or 4 to 6-membered hydrocarbon having 1 to 3 heteroatoms. The heterocycle may include, but is not limited to, heteroaryl, heterocyclyl, heterospirocarbocyclyl, fused heterocyclyl, and bridged heterocyclyl. According to one specific example of the present invention, the heterocyclyl is pyrrolidinyl, morpholinyl, pyrrol izidinyl, quinol izidinyl, azaspirooctanyl, piperidinyl, pyrrolidinyl, imidazolinyl, piperazinyl, piperazinyl-1-oxide, morpholinyl, thiamorpholinyl, tetrahydrofuranyl, diazabicyclooctanyl, diazaspirooctanyl, tetrahydropyridinyl, dihydropyridinyl, dihydropyranyl, tetrahydropyranyl, 2-oxa-6-azaspiroheptanyl, azetidinyl, oxazepanyl, 2-oxa-5-azabicyclo [2.2.1]heptanyl, pyridyl, tetrahydrofuranyl, 8-azabicyclo [3.2.1]octanyl, 2-azaspiro [3.3]heptanyl, 2-oxa- 7-azaspiro [3.4]octanyl, 2-azabicyclo[2.2.1]heptanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, pyrimidinyl, pyrazolyl, oxetane and similar groups, but are not limited thereto. For example, in the case of C2-10 heterocyclyl, the carbon number designation C2-10 means a ring size of at least 3-membered ring including at least one heteroatom. The term "aryl" in this application, unless otherwise stated, represents an aromatic group which may be substituted or unsubstituted, and may be, for example, 6 to 20 membered. For example, the aryl may include, without limitation, phenyl, biphenyl, naphthyl, toluyl, naphthalenyl, anthracenyl, indenyl, indanyl, or all possible isomers thereof. In this application, the term "heteroaryl" means a monocyclic or bicyclic or higher aromatic group containing one or more heteroatoms selected from 0, N and S, for example, 1 to 4, 1 to 3, or 1 to 2, unless otherwise stated, and may be, for example, 6 to 20 membered. For example, examples of monocyclic heteroaryl include, but are not limited to, thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, isoxazolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, indazolyl, 2-oxa-5-azabicyclo [2.2.1]heptanyl or similar groups.For example, examples of bicyclic heteroaryl include, but are not limited to, pyrrolizidinyl, indolyl, indolinyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzthiazolyl, benzthiophenyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, indazolyl, quinolinyl, isoquinolinyl, azaspirooctanyl, purinyl, furopyridinyl, or similar groups. For example, examples of tricyclic heteroaryl include, but are not limited to, thioxanthinyl, carbazolyl, carbol inyl, acridinyl, or similar groups. The numerical range indicated using the term "to" in this application refers to a range that includes the numerical values ​​described before and after the term "to" as the lower limit and the upper limit, respectively. Since the compounds of the present application may have an asymmetric carbon center and an asymmetric axis or an asymmetric plane, they may exist as all optical and stereoisomers, including substantially pure enantiomers such as the R and S enantiomers, as well as mixed racemates, and all of these isomers and mixtures are included in the scope of the present application. With respect to pure enantiomers, the optical purity of such enantiomers and pharmaceutically acceptable salts thereof represented by Formula 1 or Formula 2 is preferably at least 60 %ee, more preferably at least 95 %ee, and most preferably at least 98 %ee. The term "ee" refers to enantiomeric excess. For example, one enantiomer in a particular compound is present in a mixture of enantiomers in a larger amount than the other enantiomer.Enantiomerically enriched forms can include enantiomeric mixtures of a particular compound in which a single enantiomer has a concentration of at least 50%, more typically at least 60%, 70%, 80%, or 90% (e.g., >95%, >97%, >99%, >99.5%) relative to the other enantiomers of the compound. In this specification, for convenience, unless otherwise specified, the compound of Formula 1 or Formula 2 is used to encompass all of the compounds of Formula 1 or Formula 2, their optical isomers, stereoisomers, isotopic variants, solvates, hydrates, and pharmaceutically acceptable salts. The term “isotopic variant” as used herein refers to a compound that contains an unusual ratio of isotopes at one or more atoms constituting the compound. For example, isotopic variants of a compound may be radiolabeled, for example, hydrogen atoms may be selected from hydrogen, deuterium and tritium, and carbon-13 (. 13 C), nitrogen-15( 15N) etc. The compound of Chemical Formula 1 or Chemical Formula 2 according to the present application, optical isomers, stereoisomers or isotopic variants thereof can form pharmaceutically acceptable salts. The pharmaceutically acceptable salts include both acid or base addition salts and stereochemically isomeric forms thereof. The salts include any salts that maintain the activity of the parent compound in the subject to which they are administered and do not cause undesirable effects, and are not particularly limited thereto. Such salts include inorganic and organic salts, for example, acetic acid, nitric acid, aspartic acid, sulfonic acid, sulfuric acid, maleic acid, glutamic acid, formic acid, succinic acid, phosphoric acid, phthalic acid, tannic acid, tartaric acid, hydrobromic acid, propionic acid, benzenesulfonic acid, benzoic acid, stearic acid, esylic acid, lactic acid, bicarboxylic acid, bisulfuric acid, bitartaric acid, oxalic acid, butyric acid, calcium idetic acid, camsylic acid, carbonic acid, chlorobenzoic acid, citric acid, idetic acid, toluenesulfonic acid, edicilinic acid, esylinic acid, fumaric acid, gluceptic acid, pamoic acid, gluconic acid, glycolylarsanilic acid, methylnitric acid, polygalacturic acid , hexylisorcinonic acid, malonic acid, hydrabamic acid, hydrochloric acid, hydroiodoic acid, hydroxynaphtholic acid, isethionic acid, lactobionic acid, mandelic acid, estolinic acid, mucic acid, napsylic acid, muconic acid, p-nitromethanesulfonic acid, hexamic acid, pantothenic acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, salicylic acid, sulfamic acid, sulfanilinic acid, methanesulfonic acid, and teoclic acid. In addition, the basic salts include, for example, alkali and alkaline earth metal salts such as ammonium salts, lithium salts, sodium salts, potassium salts, magnesium salts and calcium salts, salts with organic bases such as benzathine, >methyl-Z>glucamine, hydrabamine salts and salts with amino acids such as arginine and lysine.In addition, the salt form can also be converted into the free form by treatment with a suitable base or acid. The term "addition salt" includes a compound of Formula 1 or Formula 2 and a solvate that a salt thereof can form. Such solvates are, for example, hydrates and alcoholates. The terms and abbreviations used herein have their original meanings unless otherwise defined. The present application also provides a method for preparing a compound of Formula 1 or Formula 2. Hereinafter, a method for preparing a compound of Formula 1 or Formula 2 will be described based on exemplary reaction schemes to help understanding the present application. However, a person skilled in the art to which the present application pertains can prepare a compound of Formula 1 or Formula 2 by various methods using known compounds or compounds that can be easily prepared therefrom based on the structure of Formula 1 or Formula 2, and all such methods should be construed as being included in the scope of the present application. That is, the compound of Chemical Formula 1 or Chemical Formula 2 can be manufactured by arbitrarily combining various synthetic methods described in this specification or disclosed in the prior art, and therefore, the following description related to the method for manufacturing the compound of Chemical Formula 1 or Chemical Formula 2 merely presents exemplary methods, and the order of unit operations, etc. can be selectively changed as needed, and the scope of the manufacturing method of the present application is not limited thereto [Reaction Scheme 1]. Step A: Compound 2 is obtained by adding phosphoryl trichloride and >ethyl->isopropylpropan-2-amine to compound 1 and heating. Step B: Compound 2 undergoes an SNAR reaction with a nucleophile having the formula H- Ri to synthesize compound 3 in the presence of a solvent such as dimethyl chloride and a base such as >ethyl->isopropylpropan-2-amine. Step C: Using a strong base such as sodium hydride in a nonpolar solvent such as tetrahydrofuran, the substituent -Y- R2 is introduced by the 2-chlorine substituent of the nucleophile of the compound having the formula H- Y- R2. Step D: In order to synthesize compound 5, the Suzuki reaction or Stilley reaction is used with compound 4 in step 1 and boronic acid or aryl stannane. According to another aspect of the present application, there is provided a pharmaceutical composition for preventing or treating a disease associated with a KRAS mutant protein comprising G12D, the pharmaceutical composition comprising a therapeutically effective amount of a compound of formula 1 or formula 2 or an optical isomer, stereoisomer, racemate, isotope variant, solvate, hydrate, or pharmaceutically acceptable salt thereof as an active ingredient. Specifically, the pharmaceutical composition may prevent or treat a disease associated with a KRAS mutant protein comprising G12D by inhibiting the activity of the KRAS mutant protein comprising G12D. According to an example of the present application, a compound of chemical formula 1 or chemical formula 2 or an optical isomer, stereoisomer, racemate, isotope variant, solvate, hydrate, or pharmaceutically acceptable salt thereof has a high binding ability to GDP- / GppNHp-KRAS mutant protein and can act as a KRAS mutant-specific inhibitor including G12D by inhibiting phosphorylation of extracellular signal-regulated kinases (Phospho-ERK, pERK) induced by KRAS mutation.Accordingly, one example of the present application relates to a composition for binding to a KRAS mutant protein, comprising a compound according to one example of the present application, an optical isomer, a stereoisomer, a racemate, an isotopic variant, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof. In addition, the compound of Chemical Formula 1 or Chemical Formula 2 according to one example of the present application can prevent, improve, or treat a disease or condition related to a KRAS mutant protein including G12D, specifically, a disease or condition caused by a KRAS mutant protein including KRAS G12D. For example, the compound of Chemical Formula 1 or Chemical Formula 2 according to the present application can effectively suppress growth signals of cancer cells due to KRAS mutations as an inhibitor of a KRAS mutant protein including G12D, and can be usefully used as a pharmaceutical composition for preventing or treating cancer. According to another aspect of the present application, a pharmaceutical composition for preventing or treating cancer is provided, which comprises a therapeutically effective amount of a compound of formula 1 or formula 2 or an optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate, or pharmaceutically acceptable salt thereof as an active ingredient. In addition, various forms of prodrugs that are converted into the compound of formula 1 or formula 2 in vivo as desired are also included in the scope of the present application. The pharmaceutical composition may further comprise one or more additives selected from the group consisting of pharmaceutically acceptable carriers, diluents, and adjuvants. As used herein, “treatment” means stopping, delaying, or alleviating the progression of a disease when used on a subject exhibiting symptoms of the disease. As used herein, “prevention” means reducing or eliminating the possibility of contracting a disease.As used herein, the term “pharmaceutical composition” may include other chemical components such as carriers, diluents, excipients, etc. in addition to the active compound according to the present application. Accordingly, the pharmaceutical composition may include a pharmaceutically acceptable carrier, diluent, excipient, or a combination thereof, as needed. Such a pharmaceutical composition facilitates administration of the active compound into a living organism. Various techniques for administering a pharmaceutical composition containing a compound are known, including, but not limited to, oral, injection, aerosol, parenteral, and topical administration. In addition, the pharmaceutical composition may be sterilized, or may further include auxiliary agents such as preservatives, stabilizers, wetting agents, emulsifying agents, salts for osmotic pressure control, and / or buffers, and may further include other therapeutically useful substances, and may be formulated according to conventional methods of mixing, granulating, or coating. As used herein, “carrier” means a compound that facilitates introduction of a compound into a cell or tissue. For example, dimethyl sulfoxide (DMSO) is a common carrier that facilitates the introduction of many organic compounds into the cells or tissues of living organisms. As used herein, a “diluent” is defined as a compound that not only stabilizes the biologically active form of the target compound, but is also diluted in water to dissolve the compound. Salts dissolved in buffers are used as diluents in the art. A commonly used buffer is phosphate buffered saline, which mimics the salt form of human body fluids. Because buffer salts can control the pH of a solution at low concentrations, buffered diluents rarely alter the biological activity of a compound. As used herein, “pharmaceutically acceptable” means a property that does not impair the biological activity and physical properties of a compound.In addition, the pharmaceutical composition may be a composition for preventing and / or treating a disease associated with a KRAS mutant protein including G12D. Here, the disease associated with the KRAS mutant protein including G12D may be, for example, cancer and may include any disease known to be associated with other KRAS mutations. The cancer may be angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyosarcoma, fibroma, lipoma, or teratoma; Squamous cell carcinoma, anaplastic small cell carcinoma, anaplastic multicellular carcinoma, adenocarcinoma, alveolar (bronchiolar) cancer, bronchiolar adenoma, sarcoma, lymphoma, chondromatosis, mesothelioma, esophageal cancer, stomach cancer, pancreatic cancer, small intestine cancer, colon cancer, kidney cancer, bladder cancer, urethral cancer, prostate cancer, testicular cancer, liver cancer, biliary tract cancer, hepatoblastoma, hepatocellular adenoma, hemangioma, gallbladder cancer, ampullary carcinoma, osteosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulocyte sarcoma), multiple myeloma, malignant giant cell tumor, osteochondroma, benign chondroma, chondromyxoid fibroma, chondroostoma, giant cell tumor, skull tumor, cranial hemangioma, cranial granuloma, cranial xanthoma, cranial osteitis deformans Meningioma, meningiosarcoma, glioblastoma, astrocytoma, medulloblastoma, ependymoma, germinomas, oligodendrogliomas, schwannomas, retinoblastomas, spinal neurofibromas, endometrial cancer, cervical cancer, ovarian cancer, hematological cancers, acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, monocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, mixed lineage leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, malignant melanoma, basal cell carcinoma, adenocarcinoma, neuroblastoma, but are not limited thereto. The pharmaceutical composition may be formulated into various oral dosage forms or parenteral dosage forms. For example, it can be in any oral dosage form such as tablets, pills, hard / soft capsules, liquids, suspensions, emulsions, syrups, granules, elixirs, etc.These oral administration dosage forms may, in addition to the active ingredient, contain, according to the typical composition of each dosage form, pharmaceutically acceptable carriers such as diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, or lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycol. In addition, when the oral administration dosage form is a tablet, it may contain binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, and, if desired, disintegrants such as starch, agar, alginic acid or its sodium salt, effervescent mixtures and / or absorbents, coloring agents, flavoring agents or sweeteners. The pharmaceutical composition may be formulated as a parenteral dosage form, in which case it is administered by parenteral administration methods such as subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. At this time, in order to formulate the pharmaceutical composition as a dosage form for parenteral administration, the active ingredient, i.e., the compound of Chemical Formula 1 or Chemical Formula 2 or an optical isomer, stereoisomer, isotopic variant, or a pharmaceutically acceptable salt thereof, is mixed in water with a stabilizer or buffer to prepare a solution or suspension, and such a solution or suspension can be prepared in a unit dosage form of an ampoule or vial. In addition, the pharmaceutical composition may be sterilized, or may further include auxiliary agents such as preservatives, stabilizers, wetting agents or emulsifying promoters, salts for osmotic pressure control, and / or buffers, and may further include other therapeutically useful substances, and may be formulated according to conventional methods of mixing, granulating, or coating. The above active ingredient, i.e., the compound of the above chemical formula 1 or chemical formula 2 or a pharmaceutically acceptable salt thereof, is administered to mammals including humans at a dose of 0.1 to 500 mg / kg (body weight) per day, preferably 0.The pharmaceutical composition may be included in an effective amount of 5 to 100 mg / kg (body weight), and the pharmaceutical composition may be administered orally or parenterally once a day or in divided doses of two or more times. In addition, the pharmaceutical composition may be used to treat cancer by additionally including a compound according to an example of the present application and at least one different therapeutic agent. The compound according to an example of the present application may exhibit synergistic effects when used in combination with different therapeutic agents. The term "synergistic" refers to a therapeutic combination that is more effective than the additive effect of two or more single agents. Combination therapy demonstrates "synergistic" and "synergistic", i.e., the effect achieved when the active ingredients are used together is greater than the sum of the effects resulting from the separate use of the compounds. A synergistic effect occurs when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined unit dosage form; Or (2) delivered as separate formulations by substitution. When delivered in an alternative therapy, a synergistic effect can be obtained when the compounds are administered or delivered sequentially, for example, by different injections in separate syringes. Typically, during an alternative therapy, effective doses of each active ingredient are administered sequentially, i.e., serially in time. In some embodiments, synergy is evidenced by lower toxicity of the combination compared to the same dose of any single ingredient at the same total dosage. For example, when a compound of Formula 1 or Formula 2 is co-administered with a different therapeutic agent, the toxicity of a 50:50 (w / w) combination comprising the compound of Formula 1 or Formula 2 and the different therapeutic agent can be less than the toxicity of 100% (w / w) of the compound of Formula 1 or Formula 2, and / or the toxicity of 100% (w / w) of the different therapeutic agent, wherein the combination has about the same or greater efficacy.That is, the toxicity of the combination of the compound of Chemical Formula 1 or Chemical Formula 2 and a different therapeutic agent is less than the toxicity of the individual components, and the efficacy of the combination is greater than the efficacy of the individual components. Furthermore, the purpose of combining the compound of Chemical Formula 1 or Chemical Formula 2 and a different therapeutic agent is not only to reduce toxicity and provide greater safety, but also to enhance efficacy to a greater extent than that provided by either agent alone. Increased efficacy is one of the benefits of combination therapy. The one or more therapeutic agents may include, but are not limited to, one or more additional combinations selected from the group consisting of RTK / Ras-MAPK pathway-related protein inhibitors (EGFR inhibitors, FGFR inhibitors, ALK inhibitors, ROS inhibitors, MET inhibitors, RAF inhibitors, ERK inhibitors, MEK inhibitors, SHP-2 inhibitors, PI3K inhibitors, KRAS inhibitors, KRAS-G12C inhibitors, S0S1 inhibitors), DNA damage inducers, EGFR antibody inhibitors, and immuno-oncology therapeutic agents.Examples of the one or more therapeutic agents include RTK / Ras-MAPK pathway inhibitors, including EGFR inhibitors (e.g., gefitinib, erlotinib, or lapatinib), FGFR inhibitors (e.g., pemigatinib or infigratinib (BGJ398)), ALK / ROS / MET inhibitors (e.g., crizotinib, cabozantinib, or foretinib), RAF inhibitors (e.g., vemurafenib, dabrafenib, or belvarafenib), ERK / MEK inhibitors (e.g., trametinib or cobimetinib), SHP-2 inhibitors (e.g., TN0155 and RMC4630), PI3K inhibitors (e.g., AMG 511 and bupalisib), KRAS inhibitors and KRAS-G12C inhibitors (e.g., sotorasib, adagrasib and divarasib), including but not limited to one or more inhibitors thereof.As an example of one or more of the above therapeutic agents, chemotherapy agents that induce DNA damage are alkylating agents (platinum chemotherapy agents: cisplatin, carboplatin, oxaliplatin / nitrogen mustard drugs: mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil / nitrosourea drugs: carmustine (BCNU), lomustine (CCNU), nimustine / others: altretamine, busulfan , Dacarbazine, Procarbazine, Temozolomide, Thiotepa, Lurbinectedin, etc.), antimetabolites (Fluorouracil (1,5-FU), Capecitabine, Cytarabine, Gemcitabine, Methotrexate, Mercaptopurine (6-MP), Leucovorin, Pemetrexed, etc.), Topoisomerase inhibitors (Epipodophyllotoxin: Etoposide), Teniphosa. 0]Tenoposide / Camptothecin: Topotecan, Irinotecan, SN-38 / Antitumor Antibiotics: Dactinomycin, Doxorubicin, Daunorubicin, Mitomycin, Bleomycin, etc.), Microtubule Inhibitors (Vinca Alkaloid: Vinblastine, Vincristine, Vinorelbine / Taxanes: Paclitaxel, Docetaxel, etc.), Hormone Antagonists (Tamoxifen, Flutamide) (Flutamide), leuprolide, etc.) and the like. Examples of the one or more therapeutic agents include, but are not limited to, EGFR antibody inhibitors, such as cetuximab, panitumumab, zalutumumab, nimotuzumab, and matuzumab. Examples of the one or more therapeutic agents include, but are not limited to, immunotherapy agents, such as AMG-404, pembrolizumab, or nivolumab.

[0643]

Effect of the invention

[0644]

Form for Embodiment of the Invention

[0645] Intermediate!. 4-Bromo-7,9-dichloro-2-methyl-2ff'pyrazolo[4,3- / 1quinazo! Synthesis of ine. Step 1: 7-Bromo-5-nitro-L6Hndazole (20 g, 82.6 mmol) was dissolved in THF (200 mL), and NaH (8.3 g, 124 mmol) was added at 0 °C under nitrogen, and the mixture was stirred at room temperature for 30 minutes. Mel (35.2 g, 248 mmol) was added to the reaction mixture, and the mixture was stirred for an additional 1 hour. The reaction was quenched by adding purified water, and the mixture was extracted with distilled water. The organic layer was washed with a saturated aqueous NaCl solution, dried over Na2S04, filtered, concentrated under reduced pressure, and stirred with hexane at room temperature for 30 minutes. The solid was filtered and dried to obtain 7-bromo-2-methyl-5-nitro-2indazole (20 g, 94% yield). LCMS (ES-API, m / z): [M+H] += 257.1. Step 2: 7-Bromo-2-methyl-5-nitro-2-type Hndazole (20 g, 78.1 mmol), Fe (21.8 g, 391 mmol), and NH4C1 (5.01 g, 93.7 mmol) were dissolved in a mixed solution of ethanol (120 mL), THF (120 mL), and purified water (40 mL), and stirred at 90 °C for 1 hour. The reaction mixture was filtered through celite, concentrated, and purified by silica gel column chromatography to obtain 7-bromo-2-methyl-2-indazole-5-amine (7 g, 40% yield) as a yellow solid. LCMS (ES- API, m / z): [M+H]+ = 227.1; Old NMR (400 MHz, CDCI3, ppm): 8 7.73 (s, 1H), 6.85 (s, 1H), 6.72 (s, 1H), 4.18 (s, 3H), 3.52 (br, 2H). Step 3: 7— Bromo— 2— methly— 27¥— indazole— 5— amine (6.67 g, 29.5 mmol), chloral hydrate (9.76 g, 29.5 mmol), Na2SC)4 (33.5 g, 236 mmol) were dissolved in purified water (70 mL), and then HC1 aqueous solution (4 mL) was slowly added and stirred at 90 °C for 30 minutes. 7-(7-bromo-2-methyl-2-hydroxy-1-amino-4-yl)-2-(A-amino-4-yl)-2-(trimethylammonium chloride ...Step 4: Concentrated sulfuric acid (60 mL) was slowly added to 7-bromo-2-methyl-2H-pyrazolo[3,2-e]indazole-5-yl-2-(hydroxyimino)acetamide (9 g, 30.3 mmol), and the mixture was stirred at 90 °C for 30 minutes. The reaction mixture was cooled to room temperature, ice was added, and the mixture was stirred for 30 minutes. The solid was filtered and dried to obtain 4-bromo-2-methyl-2H,6H,7H,8H-pyrazolo[3,2-e]indazole-7,8-dione (5.1 g, 60% yield). LCMS (ES-API, m / z): [M+H]+ = 281.1; 1H NMR (400 MHz, CD3OD, ppm): δ 8.30 (s, 1H), 8.14 (s, 1H), 7.74 (s, 1H), 7.61 (s, 1H), 4.24 (s, 3H). Step 5: 4-Bromo-2-methyl-2H,6H,7H,8H-pyrazolo[3,2-e]indazole-7,8-dione (5.1 g, 18.2 mmol) was dissolved in 2 M aqueous NaOH (7.28 g, 182 mmol), and then H2O2 (3.1 g, 91 mmol) was slowly added, and the mixture was stirred for 1 hour. Acetic acid was added to the reaction mixture at 0 °C to adjust the pH to 3, and the precipitated solid was filtered to obtain 5-amino-7-bromo-2-methyl-2H-pyrazole-4-carboxylic acid (3.08 g, 63% yield). LCMS (ES-API, m / z): [M+H]+ = 271.1; 1H NMR (400 MHz, DMSO-d6, ppm): δ 10.81 (s, 1H), 8.58 (s, 1H), 7.25 (s, 1H), 4.19 (s, 3H). Step 6: 5-Amino-7-bromo-2-methyl-2H-pyrazole-4-carboxylic acid (962 mg, 3.(56 mmol) was dissolved in methanol (14 mL) / toluene (42 mL), then 2 M (diazomethyl)trimethylsilane (488 mg, 4.27 mmol) was slowly added at 0 °C and stirred at room temperature for 5 minutes. The reaction was terminated by adding distilled water to the compound, and then extracted with EA (200 mL * 3). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain methyl 5-amino-7-bromo-2-methyl-2H-indazole-4-carboxylate (283 mg, 28% yield) as a white solid. LCMS (ES-API, m / z): [M + H]+ = 285.1;. NMR (400 MHz, CD3OD, ppm): δ 8.16 (s, 1H), 7.17 (s, 1H), 4.14 (s, 3H), 3.93 (s, 3H). Step 7: Methyl 5-amino-7-bromo-2-methyl-2H 2 -indazole-4-carboxylate (276 mg, 0.971 mmol) was dissolved in THF (13 mL), then trichloroethanecarbonyl isocyanate (220 mg, 1.17 mmol) was added at 0 °C and stirred for 5 minutes. The reaction mixture was concentrated under reduced pressure and the residue was suspended in ether. The solid was filtered to obtain methyl 7-bromo-2-methyl-5-[(2,2,2-trichloroacetyl)carbamoyl]amino]-2H-indazole-4-carboxylate (459 mg, 100% yield). LCMS (ES-API, m / z): [M + H] += 473.5. Step 8: Methyl 7-bromo-2-methyl-5[[(2,2,2-trichloroacetyl)carbamoyl]amino]-2H-indazole-4-carboxylate (459 mg, 0.971 mmol) was dissolved in NEU / MeOH (7 N, 100 mL) and stirred at 110 °C for 36 h under nitrogen. It was cooled to room temperature, the solvent was removed, and the mixture was filtered. The product was washed with ether and filtered to obtain 4-bromo-2-methyl-2H,6H,7H,8H,9H-pyrazolo[4,3-f]quinazoline-7,9-dione (287 mg, 100% yield, crude compound) as a white solid. LCMS (ES-API, m / z): [M+H] + = 296.1; 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.75 (s, 1H), 7.42 (s, 1H). Step 9: 4-Bromo-2-methyl-2H,6H,7H,8H,9H 2 -pyrazolo[4,3-f]quinazoline-7,9-dione (287 mg, 0.973 mmol) was slowly added with POCl3 (5.9 g, 38.9 mmol), DIPEA (377 mg, 2.92 mmol) and stirred at 110 °C for 20 h under nitrogen. The reaction mixture was concentrated under reduced pressure, toluene was added, and the pH was adjusted to 7 - 8 at 0 °C with saturated Na2CO3 solution. It was extracted with toluene, the organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain 4-bromo-7,9-dichloro-2-methyl-2H 2- pyr azo lo [ 4 , 3 - f]qui nazo line (124 mg, 38% yield) was obtained. LCMS (ES-API , m / z) : [M + H] + = 333.0.

[0646] Intermediate 2: 4-Bromo-7,9-dichloro-5— fluoro-2-methyl-2AFpyrazolo[4,3~

[0647] / Synthesis of Jquinazoline. Step 1: 7-Bromo-6-f luoro-2-methyl-Hndazole (40.0 g, 186 mmol) was dissolved in EA (500 mL), and Me30BF4 (41.3 g, 279 mmol) was added. The mixture was stirred at room temperature for 12 hours. Purified water was added to the reaction mixture to quench the reaction, and the mixture was extracted with distilled water. The organic layer was washed with a saturated aqueous NaCl solution, dried over Na2SC)4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 7-bromo-6-f luoro-2-methyl-2-methyl-Hndazole (37.3 g, 88% yield) as a yellow solid. NMR (400 MHz, DMSO- < ppm): S 8.54 (s, 1H), 7.78 (dd, J = 5.2, 8.8 Hz, 1H), 7.05 (t, J = 9.2 Hz, 1H), 4.19 (s, 3H). Step 2: After cooling H2S04 (370 mL) to 0 °C, 7-bromo-6-f luoro-2-methyl-2-indazole (37.0 g, 162 mmol) and KNO3 (19.8 g, 1,956 mmol) were slowly added at 0 °C and stirred at room temperature for 12 hours. Cold purified water was added to the reaction mixture to terminate the reaction, and saturated NaHC03 aqueous solution was slowly added at 0 °C to adjust the pH. The organic layer was extracted with a filtrate, washed with a saturated NaCl aqueous solution, dried over Na2S04, filtered, and concentrated under reduced pressure to obtain 7-bromo-6-fluoro-2-methyl-5-nitro-2-hydroxyl-Hndazole (38.0 g, 86% yield) as a yellow solid. NMR (400 MHz, DMSO- < ppm): S 8.91 (s, 1H), 8.85 (d, J = 7.2 Hz, 1H), 4.26 (s, 3H). Step 3: 7-Bromo-6-fluoro-2-methyl-5-nitro-2-hydroxyl-indazol-5-amine (30.0 g, 89% yield) was obtained as a yellow solid by dissolving 7-Bromo-6-fluoro-2-methyl-2-nitro-2-hydroxyl-indazol-5-amine (38.0 g, 139 mmol) and NH4Cl (59.3 g, 1.11 mol) in EtOH (400 mD / IfeO (200 mL). Fe (62.0 g, 1.11 mol) was added and stirred at 80 °C for 2 h. The resulting solid was filtered, washed with EtOH, and purified by silica gel column chromatography to obtain 7-bromo-6-fluoro-2-methyl-2-nitro-indazol-5-amine (30.0 g, 89% yield) as a yellow solid. Step 4: 2-((Benzyl oxy) imino)acetic acid (34.5 g, 193 mmol) in DMF (245 111 L) and HATU (54.9 g, 144 mmol), DI PEA (99.6 g, 770 mmol), 7— bromo— 6— f luoro— 2— methyl- 2j¥~indazol- 5-amine (23.5 g, 96.3 mmol) were added dropwise. The reaction mixture was stirred at room temperature for 2 hours and the reaction was quenched with cold purified water. The organic layer was extracted with a distilled water, washed with a saturated NaCl aqueous solution, dried over anhydrous Na2SO4, and concentrated. Solidified with petroleum ether / EA (5:1) to give G?)-2-((benzyloxy)imino)- (7— bromo— 6— f luoro— 2— methyl— 2-((benzyloxy)imino)-5-amine as a yellow solid. 2 - indazol— 5— yl )acetamide (35.5 g, 91% yield) was obtained. LCMS (ES-API , m / z): DMSO- < ppm): S 10.10 (s, 1H), 8.54 (s, 1H), 8.12 (d, J = 7.2 Hz, 1H) , 7.94 (s, 1H) , 7.54 - 7.27 (m, 5H), 5.27 (s, 2H) , 4.18 (s, 3H) . Step 5: G?)— 2— (( Benzy 1 oxy ) imino) ~N~ ( 7— bromo— 6 -f 1 uor 0— 2— me t hy 1 ~2H~ indazol-5- yl )acetamide (34.0 g, 83.9 mmol) was dissolved in H2SO4 (680 mL) and stirred at 90 °C for 2 hours. The reaction was stopped by cooling to room temperature and adding cold purified water. The organic layer was extracted with EA (1.0 L*5) and freeze-dried. Afterwards, the mixture was solidified with MeOH to obtain 4-bromo-5-fluoro— 2— methyl— 2,6— dihydropyrrolo[3, 2— e] indazole— 7,8— dione (11.0 g, 44% yield) as a red solid. LCMS (ES-API , m / z): [M+H] + = 320.1; Old NMR (400 MHz, DMSO- < ppm): S 11.42 (s, 1H) , 8.63 (s, 1H) , 4.18 (s, 3H) . Step 6: 4-Bromo-5 -f 1 uor 0— 2— me t hy 1 — 2 , 6— di hydr opyr rolo[3,2— e]indazole— 7,8— di one (10.5 g, 35.2 mmol) and NaOH (14.1 g, 352 mmol) were dissolved in 1,4-di oxane (200 mL), then H2O2 (20.5 g, 180 mmol) was added at 0 °C and stirred at room temperature for 1 hour. The reaction mixture was quenched by adding an aqueous solution of Na2S03, and the mixture was concentrated under reduced pressure to remove 1,4-dioxane. The pH was adjusted to 4 using 6 #HC1, and the resulting solid was filtered and dried to obtain 5— amino— 7— bromo— 6— f luoro— 2— methyl— 2-way2 - Indazole—4—carboxylic acid (8.80 g, 86.7% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + = 287.9; 1H NMR (400 MHz, DMSO— < ppm): δ 8.26 (s, 1H), 4.09 (s, 3H). Step 7: 5—Amino—7—bromo—6—fluoro—2—methyl—2H 2 - Indazole—4—carboxylic acid (9.00 g, 31.2 mmol) and K2CO3 (8.64 g, 62.5 mmol) were dissolved in DMF (90.0 mL), then CH3I (5.10 g, 35.9 mmol) was added slowly and stirred at room temperature for 2 hours. Saturated NH4Cl aqueous solution was added to the reaction mixture to terminate the reaction, and the organic layer was extracted with toluene. Dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain methyl 5 - amino - 7 - bromo - 6 - fluoro - 2 - methyl - 2H indazole - 4 - carboxylate (10.0 g, crude mixture) as a yellow solid. LCMS (ES-API, m / z): [M+H]+ = 303.9; 1H NMR (400 MHz, DMSO— < ppm): δ 8.31 (s, 1H), 7.15 (s, 2H), 4.11 (s, 3H), 3.89 (s, 3H). Step 8: Methyl 5—amino—7—bromo—6—fluoro—2—methyl—2H 2- Indazole-4-carboxylate (9.70 g, 32.1 mmol) was dissolved in THF (100 mL), and then 2,2,2-trichloroacetyl isocyanate (12.1 g, 64.2 mmol) was slowly added at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and dissolved in NH₃•H₂O (91.0 g, 727 mmol) and MeOH (100 mL), and further stirred at 40 °C for 2 hours. The reaction mixture was concentrated and solidified with MeOH to obtain 4-bromo-5-fluoro-2-methyl-2,6-dihydro-7H- 2 - Pyrazolo[4,3-c]quinazoline-7,9(8H)-dione (9.10 g, 90% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + = 314.8; ¹H NMR (400 MHz, DMSO-d₆, ppm): δ 8.72 (s, 1H), 4.19 (s, 3H). Step 9: 4-Bromo-5-fluoro-2-methyl-2,6-dihydro-7H- 2 - Pyrazolo[4,3-c]quinazoline-7,9(8H)-dione (8.10 g, 25.9 mmol) was dissolved in toluene (80.0 mL), and then POCl₃ (39.7 g, 259 mmol) and DIPEA (7.36 g, 56.9 mmol) were slowly added, and the mixture was stirred at 115 °C for 40 hours. The reaction mixture was cooled to room temperature, quenched with purified water, and the organic layer was extracted with toluene. The extracted organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain 4-bromo-7,9-dichloro-5-fluoro-2-methyl-2H- 2- py r az o 1 o [ 4 , 3 — / ] qu i naz o 1 i ne (9.00 g, 97% yield) was obtained as a yellow solid. LCMS (ES-API , m / z): [M+H] + = 350.8; Step 1: 7-Bromo-5-nitro-2-type Hndazole (300 mg, 1.24 mmol) was dissolved in DMF (5111 L), 2-iodoethanol (426.00 mg, 2.48 mmol), K2CO3 (514 mg, 3.72 mmol) were added, and the mixture was stirred at 140 °C for 3 h. Purified water was added to the reaction mixture to quench the reaction, and extraction was performed with distilled water. The organic layer was dried over MgS04, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 2-(7-bromo-5-nitro-2-type Hndazol-2-yl)ethan-1-ol (180 mg, 50.8% yield) as a light brown solid. LCMS (ES-API , m / z): [M+H] += 286.0; Old NMR (400 MHz, DMSO—⑦, ppm): δ 8.95 - 8.91 (m, 2H), 8.25 (d, J = 2.0 Hz, 1H), 5.07 (t, J = 5.3 Hz, 1H), 4.58 (t, J = 5.2 Hz, 2H), 3.89 (q, J = 5.2 Hz, 2H). Step 2: 2-(7-Bromo-5-nitro-2Hndazol-2-yl)ethan-1-ol (6.96 g, 24.3 mmol) was dissolved in a mixed solution of THF (37.4 mL), H20 (12.5 mL), and EtOH (37.4 mL), then Fe (6.79 g, 122 mmol) and NH4C1 (1.56 g, 29.2 mmol) were added and stirred at 90 °C for 1 hour. The reaction mixture was filtered through celite and the solvent was concentrated to obtain 2-(5-amino-7-bromo-2Hindazol-2-yl)ethan-1-ol (6.23 g, crude compound) as a brown solid. LCMS (ES-API, m / z): [M+H]+ = 256.0. Step 3: 2—(5—Amino—7—bromo—2H 2 -indazol—2—yl)ethan—1—ol (6.23 g, 24.3 mmol), (benzyloxyimino)acetic acid (3.63 g, 20.3 mmol), HATU (9.25 g, 24.3 mmol), DIPEA (7.86 g, 60.8 mmol) were dissolved in DMF (200 mL) and stirred at room temperature for 14 hours. Purified water was added to the reaction mixture to terminate the reaction and extracted with toluene. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain (±)-2-((benzyloxy)imino)-N-(7-bromo-2-(2-hydroxyethyl)-2Hindazol-5-yl)acetamide (8.46 g, crude compound) as a brown solid. LCMS (ES-API, m / z): [M+H]+ = 417.1. Step 4: (^)-2-( (Benzyl oxy ) imino) ~N~ ( 7- bromo- 2- ( 2-hydr oxye thyl ) - 2H- i ndazo 1-5- yl ) acetamide (8.46 g, 20.3 mmol) was dissolved in H2S04 (40.6 mL) and stirred at 90 °C for 30 minutes. The resulting solid was filtered, and the filtrate was mixed with distilled water to extract the organic layer. The organic layer was dried over NH2S04, filtered, and concentrated under reduced pressure. The filtered solids were combined to obtain 4— bromo— 2— ( 2-hydr oxyethyl )-2, 6-di hydr opyrrolo[3,2— e]indazole— 7,8— di one (6.29 g, crude compound) as a dark red solid. LCMS (ES-API, m / z): [M+H] += 310.0; NMR (400 MHz, DMSO— ⑦, ppm): S 10.83 (s, 1H) , 8.55 (s, 1H) , 7.26 (s, 1H), 7.21 - 6.77 (m, 1H) , 4.49 (t, J = 5.4 Hz, 2H) , 3.87 (t, J = 5.3 Hz, 2H). Step 5: 4-Bromo-2-(2-hydr oxyethyl)-2, 6-di hydr opyr rolo[3,2— e]indazole— 7,8— di one (5.0 g, 16.1 mmol) was dissolved in MeOH (150 mL), then ZerZ' butyl hydroperoxide (2.91 g, 32.2 mmol) and Cs2C03 (7.88 g, 24.2 mmol) were added and stirred at 70 °C for 2 hours. The reaction mixture was filtered and concentrated, and purified water was added to the obtained residue. The resulting solid was filtered again and dried to obtain methyl 5-amino-7-bromo-2-(2- hydr oxye t hy 1 ) ~2H~ i ndazo 1 e-4-car boxy late (1.79 g, 35.3% yield) as a brown solid. LCMS (ES-API, m / z): [M+H] + = 314.0; NMR (400 MHz, DMSO-⑦, ppm): S 8.22 (s, 1H), 7.22 (s, 1H), 7.15 (s, 2H), 4.97 (t, J = 5.3 Hz, 1H), 4.38 (t, J = 5.4 Hz, 2H), 3.89 - 3.79 (m, 5H). Step 6: To a suspension of NaH (229 mg, 9.55 mmol) in THF (10 mL), methyl 5— amino— 7— bromo— 2— (2— hydroxyethyl )— 2-propionyl group dissolved in THF (10 mL) was added. 2- Indazole—4—carboxylate (1.00 g, 3.18 mmol) and (bromomethyl)benzene (544 mg, 3.18 mmol) were slowly added and stirred at 70 °C for 2 hours. Purified water was added to the reaction mixture to terminate the reaction and extracted with toluene. The organic layer was dried over anhydrous MgSO₄, filtered, and concentrated under reduced pressure to obtain methyl 5-amino—2—(2—(benzyloxy)ethyl)—7—bromo—2H-indazole—4—carboxylate 2 - Indazole—4—carboxylate (390 mg, 30.3% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + = 404.1. Step 7: Methyl 5-amino-2-(2-(benzyloxy)ethyl)-7-bromo-2H-indazole-4-carboxylate (390 mg, 965 μmol) was dissolved in THF (10 mL), then 2,2,2-trichloro-1-isocyanato-1-ethanone (273 mg, 1.45 mmol) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent, dissolved in MeOH, and an excess of 7 N NH₃ solution was added and stirred at room temperature for 12 hours. The residue obtained by concentrating the reaction mixture was added to purified water and stirred at room temperature for 30 minutes, and then the product was filtered to obtain 2-(2-(benzyloxy)ethyl)—4—bromo—2,6-dihydro—7H-pyrazolo[4,3—f]quinazolin-7,9(8H)-dione 2 - (360 mg, 89.8% yield) was obtained as a light yellow solid. LCMS (ES-API, m / z): [M+H] + = 415.0. Step 8: 2-(2-(Benzyloxy)ethyl)-4-bromo-2,6-dihydro-7H-pyrazolo[4,3—f]quinazolin-7,9(8H)-dione 2- pyr azo lo [4, 3 -

[0648] / ]quinazol ine-7,9(8H,6H)-dione (360 mg, 866 μmol) was dissolved in POCl3 (5.32 g, 34.7 mmol), and then DIPEA (280 mg, 2.17 mmol) was slowly added at room temperature, and the mixture was stirred at 110 °C for 12 hours under nitrogen. The reaction mixture was cooled to room temperature and concentrated, then dissolved in EA (10 mL), and saturated aqueous NaHCO3 (30 mL) was slowly added while stirring. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, filtered, and concentrated. The residue obtained was put into MeOH (10 mL) and stirred at room temperature for 30 minutes, and then the product was filtered to obtain 2-(2-(benzyloxy)ethyl)-4-bromo-7,9-dichloro-2H 2 - pyr azo lo [4,3 - / ]quinazol ine (270 mg, 68.9% yield) as a yellow solid. LCMS (ES-API, m / z): [M+H] + = 451.0; 1H NMR (400 MHz, DMSO-d6, ppm): δ 9.35 (s, 1H), 8.13 (s, 1H), 7.26 - 7.19 (m, 5H), 4.83 (t, J = 5.1 Hz, 2H), 4.50 (s, 2H), 3.99 (t, J = 5.1 Hz, 2H).

[0649] Intermediate 4. 6-Bromo-1,3-dichloro-5-fluoro-8-methyl-6a,9a-dihydrofuro[3,2 - Step 1: Methyl 5—acetoxy—2—amino—4—bromobenzoate (20.0 g, 69.4 mmol) was dissolved in acetonitrile (1.0 L), then selectfluor (27.1 g, 76.4 mmol) was added and stirred at 80 °C for 24 hours. Saturated aqueous NaHCO3 solution was added to the reaction mixture to adjust the pH to 8, and then extracted with toluene. The organic layer was washed with saturated aqueous NaCl solution, dried over MgSO4, filtered, and concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain methyl 5-acetoxy-2-amino-4-bromo-3-fluorobenzoate (5.5 g, 26% yield). 1H NMR (400 MHz, DMSO-d6, ppm): δ 7.45 (d, J = 2.0 Hz, 1H), 6.74 (s, 2H), 3.83 (s, 3H), 2.29 (s, 3H). Step 2: Methyl 5—acetoxy—2—amino—4—bromo—3-fluorobenzoate (5.50 g, 18.0 mmol) was dissolved in methanol (275 mL), then K2CO3 (4.97 g, 35.9 mmol) was added and stirred at room temperature for 2 hours. 1 N aqueous HCl solution was added to the reaction mixture to acidify it, and then the organic layer was extracted with toluene and dried over MgSO4. The solvent was concentrated to obtain methyl 2-amino-4-bromo-3-fluoro-5-hydroxybenzoate (4.74 g, crude compound). XH NMR (400 MHz, DMSO—e, ppm):8 9.86 (s, 1H), 7.19 (d, J = 2.1 Hz, 1H), 6.07 (s, 2H), 3.81 (s, 3H). Step 3: Methyl 2—amino— 4—bromo— 3 -f 1 uor o-5-hydr oxybenzoate (2.00 g, 7.57 mmol) was dissolved in DMF (47.8 mL), and 9.2 M propargyl bromide (1.15 mL, 10.6 mmol) and K2C03 (2.09 g, 15.1 mmol) were sequentially added, and the mixture was stirred at room temperature for 1 day. Purified water was added to the reaction mixture to stop the reaction, and the mixture was extracted with distilled water. The organic layer was washed with saturated NaCl aqueous solution, dried over MgS04, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain methyl 2— amino— 4— bromo— 3— f luoro— 5— (prop— 2— yn— l-yloxy)benzoate (1.03 g, 45% yield). Eq. NMR (400 MHz, DMSO-e, ppm): 8 7.34 (d, J= 2.0 Hz, 1H), 6.42 (s, 2H), 4.82 (s, 2H), 3.84 (s, 3H), 3.61 (t, J = 2.3 Hz, 1H). Step 4: Methyl 2— amino— 4— bromo— 3— f luoro— 5— (prop— 2— yn— 1— yloxy)benzoate (1.02 g, 3.38 mmol) After dissolving in diethylaniline (10 mL), CsF (769 mg, 5.06 mmol) was added, heated to reflux, and stirred for 1 hour. The reaction mixture was cooled to room temperature and washed with doenjang and 1-Chuan HC1 aqueous solution. The organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain methyl 5-amino-7-bromo-6-f luoro-2-methylbenzofuran-4-carboxylate (910 mg, 89% yield). NMR (400 MHz, DMSO—Sha, ppm): 8 6.91 (s, 1H), 6.67 (s, 2H), 3.89 (s, 3H), 2.45 (s, 3H). Step 5: Methyl 5—amino—7—bromo—6—f luoro—2—methylbenzofuran—4—carboxylate (910 mg, 3.01 mmol) was dissolved in THF (30.3 mL), and trichloroacetyl isocyante (0.40 mL, 3.31 mmol) was added at 0 °C and stirred for 30 min. The reaction solvent was concentrated, and NHjMeOH (7 N, 8.62 mL, 60.3 mmol) was added to the residue, and the mixture was stirred at room temperature for 1 day. The residue was filtered with MeOH to obtain 6-bromo-5-f 1 uor o-8-methyl thylfuro[3,2-f ] qu i nazo 1 i ne-1 , 3 ( 2H, Mf ) -di one (863 mg, 91% yield) as a white solid. Old NMR (400 MHz, DMSO—< ppm): S 9.90 (s, 2H), 7.21 (s, 1H), 2.53 (s, 3H). Step 6: Bromo-5- fluoro- 8- methylfuro[3, 2- / ]quinazoline-l,3(2』7, 460- dione (750 mg, 2.40 mmol) with POCls (8.93 mL, 95.80 mmo 1 ) and DI PEA (1.04 mL, 5.99 mmol) was added and stirred at 110 °C for 7 hours. The reaction was terminated by adding saturated NaHC03 aqueous solution to the reaction mixture, and the toyo was extracted. The organic layer was dried over anhydrous MgS04, filtered, concentrated under reduced pressure, and then filtered with DCM to obtain a solid. The filtrate was concentrated and purified by silica gel column chromatography, and then combined with the solid to obtain 6-bromo-l,3-dichloro-5-f luoro-8-methyl- 6a,9a-dihydrofuro[3,2- / ]quinazoline (707 mg, 84% yield) as a white solid. DMSO—< ppm): S 7.64 (s, 1H) , 2.66 (s, 3H) .

[0650] Intermediate 5. Synthesis of 4-Bromo-7,9-dichloro-2-methyloxazolo[5,4-f]quinazoline. Step 1: 2-Amino-5-nitr opheno 1 (60 g, 389.30 mmol) was dissolved in ACN (600 111 L), NBS (69.29 g, 389.30 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Purified water was added to the reaction mixture to quench the reaction, and the organic layer was extracted by adding distilled water and dried over anhydrous NH2SO4. The resulting solid was filtered and dried under reduced pressure to obtain 2-amino-3-bromo-5-nitrophenol (90 g, 99.2% yield) as a brown solid. LCMS (ES-API , m / z): [M+H] += 234.8. Step 2: 2-amino-3-bromo-5-nitrophenol (25 g, 107.29 mmol) obtained in Step 1 was dissolved in toluene (250 111 L), 1,1,1-triethoxyethane (87.02 g, 536.44 mmol) was added, and the mixture was stirred at 100 °C for 12 hours. Ice water (250 mL) was added to the reaction mixture, and the reaction was terminated by stirring for 10 minutes, and then extracted with Toyo. The organic layer was dried over anhydrous NH2S04, filtered, and concentrated under reduced pressure. The residue was added to petronium ether (150 mL), stirred at room temperature for 60 minutes, and the product was filtered to obtain 4-bromo-2-methyl-6-nitrobenzo[(y]oxazole (17 g, 61.6% yield) as a brown solid. LCMS (ES-API , m / z): [M+H] + = 256.9; Medium NMR (400 MHz, DMSO—< ppm): S 8.68 (d, J= 2.0 Hz, 1H), 8.42 (d, J= 1.6 Hz, 1H), 2.73 (s, 3H). Step 3: 4-Bromo-2-methyl-6-nitrobenzo[(y]oxazole (12.5 g, 48.63 mmol) obtained in Step 2 was stirred in THF (250 mL) at room temperature until completely dissolved. The fixed bed {SS, 5 mL} containing the granular catalyst Pt / C (10.22 g, 486.30 ymol) was heated to 45 °C. The H2 back pressure controller was adjusted to 1 MPa. The solution was pumped into the fixed bed at a flow rate of 0.4 mL / min, and the resulting product was collected at a flow rate of 20 mL / min for 3.3 min. The reaction mixture was dried under reduced pressure to obtain 4-bromo-2-methylbenzo[(f]oxazol-6-amine (10.03 g, crude compound) as a purple solid. LCMS (ES-API , m / z): [M+H] += 226.9; Old NMR (400 MHz, DMSO- < ppm): S 6.79 (d, J = 1.6 Hz, 1H), 6.70 (d, J = 2.0 Hz, 1H), 5.59 - 5.33 (m, 2H), 2.49 (s, 3H). Step 4: 4-bromo-2-methylbenzo[(y]oxazol-6-amine (11 g, 48.45 mmol) obtained in Step 3 was dissolved in a mixed solution of THF (165 mL) and MeOH (165 mL), cooled to 5 °C, TS0H-H20 (921.52 mg, 4.84 mmol) and NIS (15.26 g, 67.82 mmol) were added, and stirred at room temperature for 1 hour. To the reaction mixture, a solution of NaHC03 (200 mL), EA (10 mL), and purified water (100 mL) were added to terminate the reaction, and the mixture was extracted with distilled water. The organic layer was dried over anhydrous Na2S04, filtered, concentrated under reduced pressure, and purified by silica gel chromatography to obtain 4-bromo-7- iodo-2-methyl-1 benzo[d\ oxazo 1 -6-ami ne (7.9 g, 40.2% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + = 354.9; NMR (400 MHz, DMSO—< ppm): S 6.96 (s, 1H), 5.58 (s, 2H), 2.54 (s, 3H). Step 5: 4-bromo-7-iodo-2-methylbenzo[(y]oxazole-6-amine (6.5 g, 18.42 mmol), TEA (5.59 g, 55.25 nmol), Pd(dppf KlrOfeCh (1.50 g, 1.84 mmol) obtained in Step 4 were dissolved in MeOH (135 mL) and stirred at 50 °C for 12 h under carbon monoxide. The reaction mixture was filtered and concentrated, and then purified by silica gel column chromatography to obtain methyl 6— amino— 4— bromo— 2— methylbenzo[(y]oxazole— 7— carboxylate (1.07 g, 18.2% yield) as a yellow solid. LCMS (ES-API , m / z): [M+H] += 287.0; Old NMR (400 MHz, DMSO—< ppm): S 7.04 (s, 1H), 7.02 (s, 2H), 3.86 (s, 3H), 2.55 (s, 3H). Step 6: Methyl 6-amino-4-bromo-2-methylbenzo[(y]oxazole-7-carboxylate (1.21 g, 4.24 mmol) obtained in Step 5 was dissolved in THF (12 mL), and 2, 2, 2-tri chloroacetyl isocyanate (1.60 g, 8.49 mmol) was slowly added at 0 °C under nitrogen, and stirred at room temperature for 1 hour. The reaction mixture was concentrated to obtain a white solid (1.8 g, crude compound). The obtained solid (1.8 g) was dissolved in THF (18 mL), and NH3•H20 (16.38 g, 130.87 mmol) was added at 0 °C, and stirred at room temperature for 2 hours. The residue obtained by concentrating the reaction mixture was dissolved in MeOH, stirred at room temperature for 30 minutes, and the product was filtered to obtain 4-bromo-2-methyl ... 1 oxazo 1 o [ 5 , 4 - / ] qu i nazo 1 i ne-7 , 9-dio 1 (1.1 g, 83.2% yield) was obtained as a white solid. LCMS (ES-API , m / z): [M+H] += 297.9; Old NMR (400 MHz, DMSO- < ppm): S 11.78 - 11.14 (m, 2H), 7.31 (s, 1H), 2.66 (s, 3H). Step 7: 4-bromo-2-niethyloxazok)[5,4- / ]quinazol ine-7,9-diol (1.2 g, 4.05 mmol) obtained in Step 6 was dissolved in POC13 (19.74 g, 128.74 mmol), then DI PEA (1.05 g, 8.11 mmol) was slowly added at room temperature under nitrogen, and stirred at 120 °C for 4 hours. The reaction mixture was cooled to room temperature, concentrated, dissolved in Toyo, and then NaHC03 aqueous solution was slowly added with stirring. The extract was added to the toyo, dried over anhydrous NH2SO4, filtered, concentrated under reduced pressure, and stirred with petroleum ether (6 mL) and EA (18 mL) at room temperature for 30 minutes. The product was filtered to obtain 4-bromo-7,9-dichloro-2-niethyloxazok)[5,4- / ]quinazol ine (1.06 g, 76.5% yield) as a yellow solid. LCMS (ES-API, m / z): [M+H] + = 333.7; Old NMR (400 MHz, DMSO—< ppm): 5 8.33 (s, 1H) , 2.83 (s, 3H) .

[0651] Intermediate 6. Synthesis of 6-Bromo-l,3-dichloroimidazo[l',2':l,6]pyrido[3,2-cdpyrimidine^]. Step 1: 6-Chloro-3-nitropicol inamide (10 g, 54.48 mmol) was dissolved in H2SO4 (276 g, 2.53 mol) and stirred at 70 °C for 3.5 hours. The reaction mixture was cooled to room temperature and ice water (1,200 mL) was added. The precipitate was filtered, washed with water, and dried to obtain 6-chloro-3-nitropicol inamide (9.85 g, crude compound) as a white solid. Step 2: 6-Chloro-3-nitropicol inamide (7.35 g, 36.46 mmol) was dissolved in ethanol (30111 L), and a saturated 28% ammonia solution (27.30 g, 218.09 mmol) was added and stirred in a sealed tube at 100 °C for 48 hours. The reaction mixture was cooled and concentrated under reduced pressure. After adding NH2C03 aqueous solution, the reaction was terminated by stirring at room temperature for 1 hour. The resulting solid was filtered, washed with distilled water, and dried to obtain 6-amino-3-nitro-pyridine-2-carboxamide (4.85 g, crude compound) as a yellow solid. ppm): S 8.11 (d, J = 9.2 Hz, 1H), 7.83 (brs, 1H), 7.57 (brs, 2H), 7.52 (brs, 1H), 6.50 (d, J = 9.2 Hz, 1H). Step 3: 6— Amino— 3— nitro— pyridine— 2— carboxamide (4.85 g, 26.63 mmol) was dissolved in DMF (49 mL), NBS (5.69 g, 31.95 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, purified water was added to stop the reaction, and the resulting solid was filtered and dried. After stirring with petroleum ether (45 mL) and EA (40 mL) at room temperature for 30 minutes, the solid was filtered and dried to obtain 6-am ino-3-nitr op i col inamide (5.6 g, 79.4% yield) as a yellow solid. LCMS (ES-API , m / z): [M+H] += 263.0; Old NMR (400 MHz, DMSO-d6, ppm): δ 8.48 (s, 1H), 7.90 (brs, 2H), 7.65 (brs, 2H). Step 4: 6-Amino-3-nitropicolylamide (5.9 g, 22.60 mmol) was dissolved in ethanol (59 mL) and distilled water (59 mL), then 2-bromo-1,1-diethoxyethane (6.68 g, 33.90 mmol) and HBr (9.14 g, 45.21 mmol) were added at room temperature and stirred at 100 °C for 16 h. The reaction mixture was concentrated to remove ethanol, and an aqueous NaHCO3 solution was added to adjust the pH to 8. The solid was precipitated, filtered, and dried to obtain 8-bromo-6-nitroimidazo[1,2-a]pyridine-5-carboxamide (5.28 g, 80.3% yield) as a gray solid. LCMS (ES-API, m / z): [M+H]+ = 287.0; Old NMR (400 MHz, DMSO-d6, ppm): δ 8.55 (d, J = 10.0 Hz, 2H), 8.34 (d, 1H), 8.09 (d, J = 1.6 Hz, 1H), 7.92 (d, J = 1.2 Hz, 1H). Step 5: 8-Bromo-6-nitroimidazo[1,2-a]pyridine-5-carboxamide (4.5 g, 15.79 mmol), Fe (3.53 g, 63.15 mmol) and NH4Cl (6.76 g, 126.29 mmol) were dissolved in a mixed solution of ethanol (90 mL) and water (18 mL), and then stirred at 85 °C for 16 h. The reaction mixture was filtered, and the solid was washed with EA / MeOH (10:1). The organic solvent was concentrated, washed with saturated aqueous NaHCO3 solution, filtered, and concentrated under reduced pressure to obtain 6-amino-8-bromoimidazo[1,2-a]pyridine-5-carboxamide (3.1 g, crude compound) as a green solid.LCMS (ES-API, m / z): [M+H]+= 254.9; NMR (400 MHz, DMSO— < ppm):S 8.21—7.61 (m, 3H), 7.57—7.20 (m, 2H), 6.02—5.40 (m, 2H). Step 6:6—Amino— 8—bromoimidazo[l, 2— a]pyridine— 5— carboxamide (10.47 g, 35.28 mmol) was added to 1,4-dioxane (100 mL), and the resulting suspension was stirred at 110 °C for 16 hours under nitrogen. The reaction mixture was cooled to room temperature, purified water was added, and the reaction was terminated by stirring for 10 minutes. The resulting solid was filtered, washed with distilled water, and dried to obtain 6-bromoimidazo[l ',2':l,6]pyrido[3,2—(f]pyrimidine—l,3(2j7, 460— dione (10.7 g, crude compound) as a yellow solid. LCMS (ES-API , m / z): [M+H] += 283.2; In NMR (400 MHz, DMSO - <ppm): δ 12.00 - 11.95 (m, 1H), 11.91 - 11.83 (m, 1H), 9.11 (d, J = 0.8 Hz, 1H), 8.02 - 7.94 (m, 1H), 7.84 - 7.74 (m, 1H). Step 7: To 6 - bromoimidazo[r,2':1,6]pyrido[3,2 - (f]pyrimidine - 1,3(2H,4H) - dione (5.4 g, 19.2 mmol) obtained in Step 6, POCl3(117.8 g, 768.5 mmol) and DIPEA (6.2 g, 48.0 mmol) were slowly added and stirred at 110 °C for 20 h under nitrogen. The reaction mixture was concentrated under reduced pressure at 40 °C, and after adding toluene, it was adjusted to pH 7 - 8 with saturated Na2CO3 solution at 0 °C. The organic layer extracted with toluene was dried over Na2SO4, filtered and concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 6 - bromo - 1,3 - dichloroimidazo[r,2':1,6]pyrido[3,2 - (f]pyrimidine (2.44 g, 37.7% yield) as a yellow solid. LCMS (ES - API, m / z): [M + H] + = 275.0; NMR (400 MHz, DMSO - d6, ppm): δ 9.28 (d, J = 1.2 Hz, 1H), 9.17 - 9.12 (m, 2H), 8.12 - 8.07 (m, 1H), 7.95 - 7.93 (m, 1H), 7.92 - 7.90 (m, 2H), 7.87 - 7.84 (m, 1H).

[0652] Intermediate 7. 4 - Bromo - 7,9 - dichloro - 5 - fluoro - 2 - methyl oxazolo[5,4 -

[0653] Synthesis of Zlquinazoline. Step 1: 2— Amino— 3— bromo— 4— f luorophenol (3 g, 14.56 mmol) was dissolved in toluene (30 mL), 1, 1, 1-triethoxyethane (11.81 g, 72.81 mmol) was added, and the mixture was stirred at 100 °C for 12 h. The solvent was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 4- bromo- 5- f luoro- 2-methylbenzo[(y]oxazole (3.2 g, 86.3% yield) as a yellow solid. LCMS (ES-API , m / z): [M+H] + = 229.9; NMR (400 MHz, CDC13, ppm): S 7.37 (dd, J = 8.8, 3.6 Hz, 1H), 7.11 (t, J = 9.2 Hz, 1H), 2.69 (s, 3H); 19F NMR (376 MHz, CDCI3, ppm): 5 -115.05. Step 2: 4-bromo-5 -f luoro-2-methy Ibenzo[d\ oxazo 1 e (4.2 g, 18.26 mmol) obtained in Step 1 was dissolved in H2S04 (21 mL) and pumped into flow reactor 1 (FLR1, PFA, coil reactor, 3.175(1 / 8”) mm, 20.036 mL, 80 °C) by pump 1 (SI, Pl, 3.649 mL / min), and HN03 (3.5 g) was pumped into flow reactor 1 by pump 2 (S2, P2, 0.358 mL / min). The residence time in flow reactor 1 was 5 min for FLR1, and the reaction mixture was collected in a bottle containing 20 mL of purified water at 0 °C by operating pumps 1 and 2 simultaneously for 15 min. The reaction mixture was added to the bottle containing 20 mL of purified water at 0 °C. Ice water was added to the reaction mixture. (100 mL) was added, and the resulting solid was filtered, washed with purified water (200 mL), and dried. The product was purified by silica gel column chromatography aphy to obtain 4-bromo-5-f 1 uor 0— 2— me t hy 1 — 6— nitrobenzo[( / ] oxazole (3.1 g, 62.0% yield) as a yellow solid. LCMS (ES-API , m / z): [M+H] + = 275.0;

[0654] NMR (400 MHz, CDCI3, ppm): S 8.21 (d, J = 5.6 Hz, 1H), 2.77 (s, 3H); 19 F NMR (376 MHz, CDCI3, ppm):S -115.66; 13C NMR (400 MHz, CDCI3, ppm): C7 107.023, (C{F}, d, J= 2.2 Hz). Step 3: 4-bromo-5-f luoro-2-methyl-6-nitrobenzo[(y]oxazole (3.1 g, 11.27 mmol) obtained in Step 2 was dissolved in EtOH (250 mL) and purified water (30 mL), and then Fe (2.52 g, 45.09 mmol) and NH4C1 (4.82 g, 90.17 mmol) were added, and the mixture was stirred at 50 °C for 2 h. The reaction mixture was filtered and concentrated, and then extracted with an aqueous solution of NaHC03 and distilled water. The organic layer was dried over anhydrous Na2SC)4, filtered, and concentrated under reduced pressure to give 4-bromo-5-fluoro-2-methylbenzo[(f]oxazol- 6-amine (2.6 g, crude compound) as a yellow solid. LCMS (ES-API , m / z): [M+H] + = 246.8; Old NMR (400 MHz, CDC13, ppm): S 6.84 (d, J = 6.8 Hz, 1H), 3.79 (s, 2H), 2.61 (s, 3H); 19F NMR (376 MHz, CDCI3, ppm): S - 134.49. Step 4: 4-bromo-5-f luoro-2-methylbenzo[(y]oxazol-6-amine (2.6 g, 10.61 mmol) obtained in Step 3 was dissolved in a mixed solution of THF (39 mL) and MeOH (39 mL), then Ts0H-H20 (201.82 mg, 1.06 mmol) and NIS (3.58 g, 15.92 mmol) were added at 0 °C, and the mixture was stirred at room temperature for 40 minutes. The reaction mixture was purified by adding NaHC03 aqueous solution and purified water to stop the reaction, and extracted with distilled water. The organic layer was dried over Na2S04, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give 4-bromo-5-fluoro-7-iodo-2-methylbenzo[(f]oxazol-6-amine (3.9 g, 98.1% yield) as a yellow solid. Obtained. LCMS (ES-API , m / z): [M+H]+ = 370.9; 4l NMR (400 MHz, CDCI3, ppm): S 4.31 (s, 2H) , 2.65 (s, 3H). Step 5: 4-bromo-5 -f 1 uor o-7 - iodo-2-methy 1 benzo [ d\ oxazo 1 -6- amine (3.9 g, 10.41 mmol), TEA (3.83 g, 37.85 mmol), Pd(dppf KlrCIfeCh (1.154 g, 1.56 mmol) obtained in Step 4 were dissolved in a mixed solution of MeOH (39 mL), 1,4-di oxane (19.5 mL), and DMF (19.5 mL), and then stirred at 50 °C under carbon monoxide. The mixture was stirred for 12 hours. The reaction mixture was filtered, concentrated, and purified by silica gel column chromatography to obtain methyl 6-amino-4-bromo- 5 -f 1 uor o-2-meth 2- 1 benzo [ ( / ] oxazo 1 e-7-carboxy late (700 mg, 21.(4% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H]. + = 304.9; Old NMR (400 MHz, CDC13, ppm): S 6.07 (s, 2H), 4.01 (s, 3H), 2.66 (s, 3H). Step 6: Methyl 6-amino-4-bromo-5-f luoro-2-methylbenzo[(y]oxazole-7-carboxylate (550 mg, 1.81 mmol) obtained in Step 5 was dissolved in THF (5.5111 L), and 2, 2, 2-tri chloroacetyl isocyanate (683.77 mg, 3.63 mmol) was slowly added at 0 °C under nitrogen, and stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the obtained yellow solid (820 mg, crude compound) was dissolved in MeOH (8.2 mL), and NH3-H20 (7.46 g, 59.61 mmol) was added at 0 °C, and stirred at room temperature under nitrogen for 2 hours. The reaction mixture was concentrated, stirred in MeOH (10 mL) for 30 minutes, and the product was filtered to obtain 4-bromo-5-f 1 uor o-2-me t hy 1 oxazo 10 [ 5 , 4 - / ] qu i nazo 1 i ne-7 , 9-di 01 (380 mg, 36.5% yield) was obtained as a gray solid. LCMS (ES-API, m / z): [M+H] + = 313.8; Old NMR (400 MHz, DMSO—< ppm): 2.66 (s, 3H); 19F NMR (376 MHz, DMSO— < ppm): S -128.31. Step 7: 4-bromo-5 -f 1 uor o-2-methy 1 oxazo 10 [ 5 , 4 - / ] qu i nazo 1 i ne- 7,9-diol (380 mg, 1.21 mmol) obtained in Step 6 was dissolved in POC13 (6.5 g, 42.17 mmol), then DI PEA (312.7 mg, 2.42 mmol) was slowly added at room temperature and stirred at 120 °C for 4 hours under nitrogen. The reaction mixture was cooled to room temperature and concentrated to remove P0C13, dissolved in Toyo, and then NaHC03 aqueous solution was slowly added with stirring. The organic layer was extracted with a solvent, dried over NH2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 4-bromo-7,9-dichloro-5-f luoro-2-methyloxazolo[5,4- / ]quinazol ine (260 mg, 54.1% yield) as a yellow solid. LCMS (ES-API , m / z): [M+H] + = 351.8; Old NMR (400 MHz, CDC13, ppm): S 2.88 (s, 3H); 19 F NMR (377 MHz, CDCI3, ppm): S — 119.19.

[0655] Intermediate 8. Synthesis of 'er,-Butyl l-vinyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. Step 1: Dissolve ZerZ” Butyl (17?, 5 S)-3, 8-diazabicyclo[3.2.1]octane-8-carboxylate (5 g, 23.55 mmol) in DCM (60 mL), then add TEA (2.38 g, 23.55 mmol) and Ph3CCl (7.22 g, 25.91 mmol), and stir at room temperature for 16 hours. Add purified water (200 mL) to the reaction mixture to terminate the reaction and extract with toluene. Dry the organic layer over anhydrous Na2SO4, filter, and concentrate under reduced pressure. Stir the residue with a petroleum ether / EA (10:1) solution at room temperature for 30 minutes and filter to obtain (1?,5S)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (9.64 g, 88.2% yield) as a white solid. LCMS (ES-API, m / z): [M+H] += 455.3; Old NMR (400 MHz, DMSO-⑦, ppm): δ 7.65 — 6.92 (m, 15H), 3.96 (br s, 2H), 2.85 (br d, J = 9.6 Hz, 2H), 2.29 (br d, J = 5.6 Hz, 2H), 1.89 (br s, 2H), 1.61 (br d, J = 10.8 Hz, 2H), 1.16 (s, 9H). Step 2: tert-Butyl (L?,5S)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4 g, 8.80 mmol) obtained in Step 1 and TMEDA (4.1 g, 35.20 mmol) were dissolved in THF (40 mL), and then —BuLi (1.3 M, 27.07 mL) was slowly added dropwise at -50 °C under nitrogen, and the mixture was stirred for 2.5 hours. Ethyl formate (1.96 g, 26.40 mmol) was added to the reaction mixture, and the mixture was further stirred at -20 °C for 2 hours. An aqueous NH4C1 solution was added to the reaction mixture at 0 °C to terminate the reaction, and the mixture was extracted with toluene. The organic layer was dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain tert-butyl 1-formyl-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.4 g, 48.0% yield) as a white solid. LCMS (ES-API, m / z): [M+H] += 482.3; Old NMR (400 MHz, DMSO-d6, ppm): δ 9.33 (s, 1H), 7.49 - 7.12 (m, 15H), 4.03 (q, J = 7.2 Hz, 1H), 3.27 - 3.15 (m, 1H), 2.93 - 2.81 (m, 1H), 2.35 (br d, J = 10.4 Hz, 2H), 2.20 - 2.02 (m, 2H), 1.76 - 1.66 (m, 2H), 1.13 - 1.00 (m, 9H). Step 3: MePPh3Br (2.07 g, 5.79 mmol) was dissolved in THF (16 mL), then -BuOK (714.3 mg, 6.37 mmol) was added, and the mixture was stirred at 0 °C for 10 minutes. tert-Butyl 1-formyl-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.33 g, 1.93 mmol) dissolved in THF (10 mL) was added, and the mixture was further stirred at room temperature for 2 hours. The reaction was terminated by adding purified water to the reaction mixture at 0 °C, and the mixture was extracted with toluene. The organic layer was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain tert-butyl 3-trityl-1-vinyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (840 mg, 88.8% yield) as a white solid. LCMS (ES-API, m / z): [M+H]+ = 480.3; DMSO - ⑦, ppm): S 7.60 - 7.10 (m, 15H), 6.08 (dd, J = 11.2, 18.0 Hz, 1H), 4.84 (d, J = 11.2 Hz, 1H), 4.77 - 4.66 (m, 1H), 4.05 (br s, 1H), 3.03 (br d, 7 = 11.2 Hz, 1H), 2.85 (br d, 7 = 10.4 Hz, 1H), 2.48 - 2.40 (m, 1H), 2.29 - 2.18 (m, 1H), 1.98 - 1.87 (m, 2H), 1.82 - 1.68 (m, 2H), 1.06 (s, 9H). Step 4: AcOH (17 mL) was added to tert-butyl 3-trityl-l-vinyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (840 mg, 1.75 mmol) obtained in Step 3, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain tert-butyl 1-vinyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (416 mg, 100% yield, crude compound) as a yellow solid. LCMS (ES-API, m / z): [M+H] + = 239.2.

[0656] Intermediate 9. Synthesis of tert-Butyl l-ethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. Step 1: MePPh3Br (2.22 g, 6.22 mmol) was dissolved in THF (22 mL), and then '-BuOK (767.28 mg, 6.84 mmol) was added and stirred at 0 °C for 10 minutes. To the reaction mixture, ZerZ' butyl l- / brmyl-3-tr ityl- 3 , 8-di az ab i eye 1 o [ 3.2.1 ] oct ane-8-car boxy late (1 g, 2.07 mmol) obtained in Step 2 of Intermediate 8 dissolved in THF (10 mL) was added and stirred at room temperature for 2 hours. The reaction was terminated by adding purified water to the reaction mixture at 0 °C, and extraction was performed with a ethanol extract. The organic layer was dried over anhydrous NH2S04, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain ZerZ" butyl 3-tr ityl-l-vinyl- 3 , 8-di az ab i eye 1 o [ 3.2.1 ] oct ane-8-car boxy late (631 mg, 62.7% yield) as a white solid. LCMS (ES-API, m / z): [M+H] + = 480.3; DMSO— (⑦, ppm): S 7.55 - 7.11 (m, 15H), 6.08 (dd, J = 11.2, 17.9 Hz, 1H), 4.84 (d, J = 11.2 Hz, 1H), 4.71 (d, J = 18.0 Hz, 1H), 4.11 - 3.94 (m, 1H), 3.03 (br d, J = 11.2 Hz, 1H), 2.89 - 2.79 (m, 1H), 2.48 - 2.39 (m, 1H), 2.29 - 2.16 (m, 1H), 2.04 - 1.85 (m, 2H), 1.81 — 1.63 (m, 2H), 1.06 (s, 9H). Step 2: tert-Butyl 3-trityl-1-vinyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (960 mg, 2.00 mmol) obtained in Step 1 was dissolved in MeOH (10 mL), then Pd / C (96 mg, 10% purity) was added under nitrogen, degassing and hydrogen purging were carried out 3 times, and then stirred at room temperature for 2 hours under hydrogen (15 Psi). The reaction mixture was filtered and concentrated under reduced pressure to obtain tert-Butyl 1-ethyl-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (930 mg, crude compound) as a white solid. LCMS (ES-API, m / z): [M+H]+ = 482.3. Step 3: AcOH (10 mL) was added to tert-Butyl 1-ethyl-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (930 mg, 1.93 mmol) obtained in Step 2, and stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain tert-Butyl 1-ethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (460 mg, crude compound) as a white solid. LCMS (ES-API, m / z): [M+H]+ = 241.1.

[0657] Synthesis of Intermediate 10. tert-Butyl 1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Step 1: Dissolve tert-Butyl 1-bromo-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.4 g, 2.90 mmol), obtained in Step 2 of Intermediate 8, in MeOH (10 mL), add NaBH4 (384.12 mg, 10.15 mmol), and stir at 0 °C for 1 hour under nitrogen. Add an aqueous NH4Cl solution to the reaction mixture at 0 °C, stir for 10 minutes to terminate the reaction, and extract with toluene. Dry the organic layer over anhydrous Na2SO4, filter, and concentrate under reduced pressure, then purify by silica gel column chromatography to obtain tert-Butyl 1-(hydroxymethyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.2 g, 85.4% yield) as a white solid. LCMS (ES-API, m / z): [M+H] + = 485.3; NMR (400 MHz, DMSO-d6, ppm): δ 7.51 - 7.10 (m, 15H), 4.64 (s, 1H), 4.02 (s, 1H), 3.67 (d, J = 10.4 Hz, 1H), 3.46 - 3.37 (m, 1H), 3.17 (s, 1H), 2.98 (d, J = 10.4 Hz, 1H), 2.83 (d, J = 11.2 Hz, 1H), 2.23 - 2.12 (m, 1H), 1.91 - 1.80 (m, 2H), 1.71 - 1.57 (m, 2H), 1.09 (s, 9H). Step 2: ZerZ” butyl l-(hydroxymethyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (600 mg, 1.24 mmol) obtained in Step 1 was dissolved in DMF (12 mL), and then Mel (527.19 mg, 3.71 mmol), NaH (59.42 mg, 1.49 mmol) were sequentially and slowly added at 0 °C under nitrogen, and the mixture was stirred for 1 hour. Saturated aqueous NH4C1 solution was added to the reaction mixture to terminate the reaction, and the mixture was extracted with toluene. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain tert'-butyl l-(methoxymethyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (490 mg, 79.4% yield) as a white solid. LCMS (ES-API, m / z): [M+H] + = 499.3; 1H NMR

[0658] (400 MHz, DMSO-d6, ppm): δ 7.51 - 7.06 (m, 15H), 4.06 - 3.99 (m, 1H), 3.67 -

[0659] 3.58 (m, 1H), 3.39 - 3.35 (m, 1H), 3.18 (s, 3H), 2.95 (d, J = 10.8 Hz, 1H),

[0660] 2.83 (d, J = 11.2 Hz, 1H), 2.47 - 2.42 (m, 1H), 2.19 - 2.12 (m, 1H), 1.96 -

[0661] 1.86 (m, 2H), 1.72 - 1.58 (m, 2H), 1.09 (s, 9H). Step 3: AcOH (13 mL) was added to tert-butyl l-(methoxymethyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (650 mg, 1.30 mmol) obtained in Step 2, and the mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain tert-butyl l-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (313 mg, 75.9% yield) as a white solid. LCMS (ES-API, m / z): [M+H] + = 257.2; 1H NMR (400 MHz, CDCl3, ppm): δ 4.19 (d, J = 6.4 Hz, 1H), 3.84 (d, J = 8.0 Hz, 1H), 3.67 (d, J = 9.2 Hz, 1H), 3.36 (s, 3H), 3.03 (d, J = 12.4 Hz, 1H), 2.97 (d, J = 12.4 Hz, 1H), 2.86 — 2.81 (m, 1H), 2.67 (dd, J = 12.8, 1.6 Hz, 1H), 2.44 (s, 2H), 2.04 - 1.99 (m, 2H), 2.03 - 1.69 (m, 1H), 1.48 (s, 9H).

[0662] Intermedi ate 11. Bert-Buty 1 Synthesis of 1-( (di f luoromethoxy)methy 1 )-3, 8- diazabicyclo[3,2.1]octaiie-8-carboxylate. Step 1: ZerZ」butyl l- / brmyl-3-trityl-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (2 g, 4.14 mmol) obtained in Step 2 of Intermediate 8 was dissolved in MeOH (20 mL), and then NaBH4 (548.70 mg, 14.50 mmol) was added and stirred at 0 °C for 3 h under nitrogen. NaBH4 (313.56 mg, 8.29 mmol) was further added and stirred at 0 °C for 30 min. Saturated NH4Cl aqueous solution was added to the reaction mixture, stirred for 10 min to terminate the reaction, and extracted with distilled water. The organic layer was dried over anhydrous NH2S04, filtered, and concentrated under reduced pressure to give ter'— butyl l-(hydroxymethyl)— 3— trityl— 3 ,8— diazabicyclo[3.2.1]octane- 8-carboxylate. l]octane— 8— carboxylate (1.92 g, crude compound) was obtained as a white solid. LCMS (ES-API , m / z): [M+H]+ = 485.3; ppm): S 7.53 - 7.11 (m, 15H), 4.64 (t, J = 5.6 Hz, 1H), 4.07 - 4.03 (m, 1H), 3.75 - 3.60 (m, 1H), 3.45 - 3.39 (m, 2H), 3.04 - 2.93 (m, 1H) , 2.88 - 2.78 (m, 1H) , 2.47 - 2.38 (m, 1H) , 2.24 - 2.11 (m, 1H), 1.87 (s, 2H), 1.72 - 1.56 (m, 2H) , 1.10 (s, 9H) . Step 2: ZerZ obtained in Step 1 was dissolved in DCM (5 mL) and purified water (5 mL) to form butyl l-(hydroxymethyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1 g, 2.06 mmol), then KOAc (1.24 g, 12.59 mmol) and (bromo(difluoro)methyl 1)-trimethylsilane (1.72 g, 8.46 mmol) were slowly added at 0 °C and stirred at room temperature for 12 hours. The reaction mixture was quenched by adding saturated NaHC03 aqueous solution and extracted with DCM. The organic layer was dried over anhydrous Na2S04, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain ter '-butyl 1-( (di f luoromethoxy)methy 1 )-3- trity 1 -3 , 8-di az ab i eye 1 o [ 3.2.1 ] octane-8-car boxy late (620 mg, 56.2% yield) as a white solid. LCMS (ES-API , m / z): [M+H] + = 535.3; (400 MHz, DMSO- ⑦, ppm): S 7.60 — 7.03 (m, 15H), 6.62 (t, J= 76.0 Hz, 1H), 4.20 — 4.08 (m, 1H),

[0663] 4.07 - 4.02 (m, 1H), 3.89 (d, J = 10.0 Hz, 1H), 2.96 (d, J = 10.8 Hz, 1H), 2.85

[0664] (d, J = 11.2 Hz, 1H), 2.51 - 2.43 (m, 1H), 2.25 - 2.14 (m, 1H), 1.99 - 1.87 (m, 2H), 1.75 - 1.58 (m, 2H), 1.10 (s, 9H). Step 3: 1-((Difluoromethoxy)methyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (620 mg, 1.16 mmol) obtained in Step 2 was dissolved in DCM (6.2 mL), then AcOH (13.01 g, 216.61 mmol) was added and stirred at room temperature for 12 hours. The reaction mixture was concentrated, then purified water and toluene were added to extract the aqueous layer. An aqueous NaHCO3 solution was added to the aqueous layer to titrate the pH to 8 - 9, then toluene was added to extract the organic layer, which was dried over anhydrous Na2SO4. The filtered solution was concentrated under reduced pressure to obtain 1-((Difluoromethoxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (220 mg, crude compound) as a white solid. LCMS (ES-API, m / z): [M+H] + = 293.2; 1H NMR (400 MHz, CDCl3, ppm): δ 6.67 (t, J = 76.0 Hz, 1H), 4.21 (s, 1H), 3.99 (d, J = 9.6 Hz, 2H), 2.85 - 2.65 (m, 3H), 2.57 (s, 1H), 2.47 (br s, 1H), 2.02 - 1.90 (m, 1H), 1.88 - 1.73 (m, 2H), 1.73 - 1.60 (m, 1H), 1.40 (s, 9H); 1919F NMR (376 MHz, DMSO-d6, ppm): δ -82.71. Intermediate 12. tert-Butyl 1-(tetrahydrofuran-2-yl)-3,8- Synthesis of diazabicyclo[3.2.1]octane-8-carboxylate. Step 1: tert-Butyl (1R,5S)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.5 g, 1.10 mmol) obtained in Step 1 of Intermediate 8, TMEDA (511.26 mg, 4.40 mmol), and THF (5 mL) were dissolved, and then n-BuLi (1.3 M, 3.38 mL) was added at -50 °C under nitrogen, and the mixture was stirred for 2.5 hours. 4-((tert-Butyldimethylsilyl)oxy)butanal (667.72 mg, 3.30 mmol) was added to the reaction mixture, and the mixture was further stirred at -50 °C for 2 hours. An aqueous NH4Cl solution (20 mL) was added to the reaction mixture at 0 °C to terminate the reaction, and the mixture was extracted with toluene. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain tert-butyl 1-(4-((tert-butyldimethylsilyl)oxy)-1-hydroxybutyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (658 mg, 45.5% yield). LCMS (ES-API, m / z): [M+H]+ = 657.4; DMSO— ⑦, ppm): S 7.58 — 7.07 (m, 15別, 4.21 (d, J = 5.6 Hz, 1H), 3.63 - 3.55 (m, 4H), 3.25 - 3.20 (m, 1H), 2.90 - 2.81 (m, 1H), 2.36 - 2.25 (m, 1H), 2.19 - 2.06 (m, 1H), 1.64 - 1.59 (m, 2H), 1.45 - 1.39 (m, 4H), 1.29 - 1.25 (m, 2H), 0.86 (s, 18H), 0.02 (s, 6H). Step 2: The ZerZ” butyl 1-(4-((Z'erZ'-butyldimethylsilyl)oxy)-1-hydroxybutyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.9 g, 3.53 mmol) obtained in Step 1 was dissolved in DMSO (30 mL), then CsF (5.36 g, 35.31 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Purified water (100 mL) was added to the reaction mixture to terminate the reaction, and the mixture was extracted with toluene. The organic layer was dried over anhydrous NH2SO4, filtered, and concentrated under reduced pressure, and purified by silica gel column chromatography to obtain ter'—butyl 1-(1,4-dihydroxybutyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (945 mg, 46.8% yield) as a white solid. LCMS (ES-API, m / z): [M+H] += 542.3; Old NMR (400 MHz, DMSO-(k, ppm): 5 7.59 - 7.06 (m, 15 / / ), 4.90 - 4.45 (m, 1H), 4.32 - 4.21 (m, 1H), 4.09 - 4.03 (m, 1H), 3.84 - 3.47 (m, 1H), 3.38 - 3.33 (m, 2H), 3.27 - 3.11 (m, 1H), 2.88 - 2.77 (m, 1H), 2.43 - 2.29 (m, 1H), 2.20 - 2.08 (m, 1H), 1.97 - 1.76 (m, 2H), 1.74 - 1.53 (m, 3H), 1.52 - 1.23 (m, 3H), 1.13 - 1.03 (m, 9H). Step 3: 8-Butyl l-(l,4-dihydroxybutyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane—8—carboxylate (1.59 g, 2.93 mmol) obtained in Step 2 was dissolved in pyridine (16 mL), then benzenesulfonyl chloride (1.55 g, 8.79 mmol) was added and stirred at room temperature for 16 hours. 1#HCl solution (50 mL) was added to the reaction mixture to terminate the reaction and extracted with toluene. The organic layer was dried over anhydrous NH2SO4, filtered and concentrated under reduced pressure, and then purified by silica gel column chromatography to 1-((R)-tetrahydrofuran-2-yl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (922 mg, 53.9% yield, Intermediate 12-1) and tert-butyl l-((S)-tetrahydrofuran-2-yl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (232 mg, 13.6% yield, Intermediate 12-2) were obtained.

[0665] Intermediate 12-1; LCMS (ES-API , m / z): [M+H] + = 524.3; ppm): S 7.66 - 7.24 (m, 15H) , 4.04 - 3.96 (m, 2H) , 3.77 - 3.75 (m, 1H) , 3.53 - 3.41 (m, 1H), 3.10 (d, J= 10.8 Hz, 1H), 2.89 - 2.74 (m, 1H) , 2.35 - 2.32 (m, 1H), 2.21 - 2.08 (m, 1H) , 1.85 - 1.83 (m, 2H) , 1.79 - 1.52 (m, 6H) , 1.08 (s, 9H);

[0666] Intermediate 12-2; LCMS (ES- API, m / z): [M+H] += 524.3; 1H NMR (400 MHz, DMSO-d6) δ 7.50 - 7.11 (m, 15H), 4.46 (s, 1H), 4.09 - 4.00 (m, 1H), 3.75 - 3.68 (m, 1H), 3.63 - 3.52 (m, 1H), 2.88 - 2.70 (m, 2H), 2.42 - 2.30 (m, 1H), 2.18 - 2.09 (m, 1H), 2.03 - 1.95 (m, 1H), 1.89 - 1.60 (m, 6H), 1.42 - 1.35 (m, 1H), 1.13 - 1.03 (m, 9H). Step 4: AcOH (5 mL) was added to tert-Butyl 1-(R)-tetrahydrofuran-2-yl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 457.41 μmol) obtained in Step 3, and the mixture was stirred at 30 °C for 16 hours. Purified water (10 mL) was added to the reaction mixture to terminate the reaction, and ethyl acetate was added to extract the aqueous layer. Saturated aqueous NaHCO3 (15 mL) was added to adjust the pH of the aqueous layer, followed by extraction with ethyl acetate, drying over anhydrous Na2SO4, filtration, and concentration under reduced pressure to obtain tert-Butyl 1-(R)-tetrahydrofuran-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (101 mg, crude compound). LCMS (ES-API, m / z): [M+H]+ = 283.2; DMSO-d6, δ, ppm): δ 4.27 (s, 1H), 3.99 - 3.90 (m, 1H), 3.78 - 3.69 (m, 1H), 3.61 - 3.51 (m, 1H), 2.79 - 2.65 (m, 3H), 2.49 - 2.41 (m, 1H), 1.89 - 1.58 (m, 9H), 1.40 (s, 9H).

[0667] Intermediate 13. Synthesis of 'er,~Butyl 1-( (5)~tetrahydrof uran-2-y 1)-3, 8~ diazabicyclo[3.2.1]octaiie-8-carboxylate.

[0668] AcOH (2 mL) was added to ZerZ」butyl 1-(( S)-tetrahydrofuran-2-y 1 )-3- trity 1 -3 , 8-di az ab i eye 1 o [ 3.2.1 ] oct ane-8-car boxy late (232 mg, 442.16 uniol) obtained in step 3 of Intermediate 12, and the mixture was stirred at 30 °C for 16 h. Purified water (10 mL) was added to the reaction mixture to terminate the reaction, and the mixture was extracted with a distilled water bath. The pH of the aqueous layer was adjusted by adding saturated NaHC03 aqueous solution (15 mL) to the water layer, and then extraction was performed using a distilled water bath. The organic layer was dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure to obtain ferf-butyl l-((S)-tetrahydrofuran-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (98 mg, crude compound). LCMS (ES-API, m / z): [M+H]+ = 283.2; Old NMR (400 MHz, DMS0—⑦, ppm): S 4.39 — 4.28 (m, 1H), 4.04 - 3.93 (m, 1H), 3.82 - 3.75 (m, 1H) , 3.73 - 3.66 (m, 1H) , 3.65 - 3.56 (m, 1H), 2.71 (d, J= 12.4 Hz, 2H) , 2.48 - 2.43 (m, 1H) , 2.37 (d, J= 12.0 Hz, 1H), 1.88 — 1.56 (m, 8H) , 1.39 (s, 9H) .

[0669] Intermediate 14. 'er'-Butyl l-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]octane~8~ carboxyl ate의 합성 . Step 1: (Methoxymethyl)triphenylphosphonium bromide (1.93 g, 4.97 mmol) was dissolved in THF (20 mL), and r-BuOK (1 M, 5.47 mL) was added at 0 °C under nitrogen and stirred for 1 hour. To the reaction mixture, tert-butyl (1 ^,5S)-3-trityl-3,8- di az ab i eye 1 o [ 3.2.1 ] oct ane-8-car boxy 1 at e (800 mg, 1.66 mmol) obtained in Step 1 was added dissolved in THF (8 mL), and stirred at 0 °C for 1 hour under nitrogen and then at room temperature for 12 hours. The reaction was terminated by adding purified water (50 mL) at 0 °C and extracted with distilled water. The organic layer was dried over anhydrous NH2S04, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain ZerZ」butyl G?)—l—(2—methoxyvinyl)—3—trityl—3,8— diazabicyclo[3.2.1]octane- 8- carboxylate (0.74 g, 87.4% yield) as a yellow oil. NMR (400 MHz, DMSO— ⑦, ppm): S 7.59 — 7.14 (m, 15H) , 6.39 — 6.28 (m, 0.5H), 5.85 - 5.76 (m, 0.5H), 5.31 - 5.05 (m, 1H) , 3.48 - 3.44 (m, 1.5H), 3.43 (s, 1H), 3.32 - 3.24 (m, 0.5H), 3.08 - 2.99 (m, 0.5H), 2.91 - 2.74 (m, 1.5H), 2.32 - 2.16 (m, 1H) , 2.13 - 2.05 (m, 0.5H), 2.01 - 1.91 (m, 1.5H), 1.85 (d, J = 11.2 Hz, 0.5H), 1.79 - 1.66 (m, 1.5H), 1.18 - 1.04 (m, 9H).Step 2: ZerZ” butyl G?)-l-(2-methoxyvinyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.74 g, 1.45 mmol) obtained in Step 1 was dissolved in MeOH (15 mL), then Pd / C (1.54 g, 1.45 mmol) was added and the mixture was stirred at room temperature for 2 hours under hydrogen. The reaction mixture was filtered and concentrated, and then purified by silica gel column chromatography to obtain ZerZ” butyl l-(2-methoxyethy1)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.76 g, crude mixture) as a yellow oil. NMR (400 MHz, DMSO—⑦, ppm): S 7.40 (s, 3H), 7.33 — 7.27 (m, 7H), 7.21 - 7.07 (m, 5別, 4.03 - 3.98 (m, 1H), 3.15 - 3.10 (m, 3H), 2.89 - 2.83 (m, 1H), 2.82 - 2.75 (m, 1H), 2.43 - 2.36 (m, 1H), 2.21 - 2.12 (m, 1H), 2.05 - 1.94 (m, 2H), 1.94 - 1.88 (m, 1H), 1.87 - 1.78 (m, 2H), 1.73 - 1.58 (m, 3H), 1.13 - 1.04 (m, 9H). Step 3: AcOH (10 mL) was added to ZerZ”-butyl l-(2-methoxyethyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (760 mg, 1.48 mmol) obtained in Step 2, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to remove AcOH, purified water was added, and then washed with toluene.After adding saturated aqueous NaHCO₃ solution to the aqueous layer to adjust the pH to 7 - 8, extraction was carried out with toluene. The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain tert'-butyl 1-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (211 mg, 52.7% yield) as a yellow oil. ¹H NMR (400 MHz, DMSO-d₆, ppm): δ 3.98 — 3.92 (m, 1H), 3.37 — 3.34 (m, 2H), 3.20 — 3.17 (m, 3H), 2.77.

[0670] - 2.64 (m, 2H), 2.47 - 2.40 (m, 2H), 2.13 - 2.00 (m, 2H), 1.91 - 1.80 (m, 3H),

[0671] 1.77 - 1.68 (m, 1H), 1.67 - 1.58 (m, 1H), 1.40 (s, 9H). Synthesis of Intermediate 15, tert-Butyl l-(1-methoxyethyl)-3,8-diazabicyclo[3,2.1]octane-8-carboxylate.

[0672] Boc Boc I Boc I Boc i

[0673] 《r 。 - 하애 - 石 1Step 1: Dissolve ZerZ” butyl (17?,5S)-3-trityl-3,8-diazabicyclo[3.2.1]octane—8—carboxylate (1.2 g, 2.49 mmol), obtained in Step 2 of Intermediate 8, in THF (12 mL), then add MeMgBr (3 M, 4.14 mL) under nitrogen at 0 °C and stir for 1 hour. Terminate the reaction by adding saturated aqueous NH4C1 and extract with toluene. Wash the organic layer with saturated aqueous NaCl, dry over anhydrous Na2S04, filter, and concentrate to obtain 化八- butyl 1-(1-hydroxyethyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.77 g, crude mixture) as a white solid. ppm): δ 7.52 - 7.12 (m, 15H), 4.72 (s, 1H), 4.00 (s, 1H), 3.37 - 3.34 (m, 1H), 3.24 - 3.16 (m, 1H), 2.87 - 2.76 (m, 1H), 2.39 - 2.29 (m, 1H), 2.19 - 2.09 (m, 1H), 1.97 - 1.90 (m, 1H), 1.89 - 1.78 (m, 1H), 1.71 - 1.56 (m, 2H), 1.08 (s, 9H), 0.98 (d, J = 5.6 Hz, 3H). Step 2: ZerZ” butyl l-(l-hydroxyethyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (470 mg, 942.54 μmol) obtained in Step 1 was dissolved in DMF (4 mL), and then Mel (176.03 μL, 2.83 mmol) and NaH (45.24 mg, 1.13 mmol) were slowly added sequentially, and the mixture was stirred at 0 °C for 1 hour. An aqueous NH4C1 solution was added to the reaction mixture to terminate the reaction, and the mixture was extracted with toluene. The organic layer was washed with a saturated aqueous NaCl solution, dried over anhydrous NH2SO4, filtered, and concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain tert-butyl 1-(1-methoxyethyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (420 mg, 86.9% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6, ppm): δ 7.47 — 7.11 (m, 15H), 4.01 — 3.97 (m, 1H), 3.75 — 3.64 (m, 1H), 3.16 (d, J = 11.2 Hz, 1H), 3.08 (s, 3H), 2.83 - 2.75 (m, 2H), 2.17 - 2.10 (m, 1H), 1.93 - 1.76 (m, 2H), 1.70 (d, J = 10.(8 Hz, 1H), 1.64 (d, J = 11.2 Hz, 1H), 1.08 (s, 9H), 0.99 (d, J = 6.0 Hz, 3H). Step 3: AcOH (7 mL) was added to tert-butyl l-(l-methoxyethyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (660 mg, 1.29 mmol) obtained in Step 2, and the mixture was stirred at room temperature for 16 hours. Purified water was added to the reaction mixture to terminate the reaction, and the mixture was washed with EA. After adjusting the pH of the aqueous layer to 8 - 9, the mixture was extracted with EA, and the organic layer was washed with saturated aqueous NaCl solution and dried over anhydrous Na2SO4. The filtered solution was concentrated under reduced pressure to obtain tert-butyl l-(l-methoxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (211 mg, 52.7% yield) as a yellow oil. NMR (400 MHz, DMSO-⑦, ppm): δ 3.98 - 3.92 (m, 1H), 3.37 - 3.34 (m, 2H), 3.20 — 3.17 (m, 3H), 2.77 — 2.64 (m, 2H), 2.47 — 2.40 (m, 2H), 2.13 — 2.00 (m, 2H), 1.91 - 1.80 (m, 3H), 1.77 - 1.68 (m, 1H), 1.67 - 1.58 (m, 1H), 1.40 (s, 9H).

[0674] Synthesis of Intermediate 6. tert-Butyl l-(ethoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. Step 1: The ZerZ” butyl (17?,5S)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.0 g, 2.07 mmol) obtained in Step 2 of Intermediate 8 was dissolved in MeOH (10 mL), then NaBH4 (230 mg, 6.08 mmol) was added at 0 °C and stirred for 1 hour. An aqueous NH4C1 solution was added at 0 °C and stirred for 10 minutes to terminate the reaction, followed by extraction with DCM. The organic layer was washed with a saturated aqueous NaCl solution, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure to obtain ZerZ” butyl l-(hydroxymethyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.0 g, crude mixture) as a white solid. NMR (400 MHz, DMSO—⑦, ppm): S 7.51 — 7.05 (m, 15別, 4.64 (t, J = 5.6 Hz, 1H), 3.73 - 3.62 (m, 1H), 3.45 - 3.38 (m, 2H), 2.98 (d, J = 10.8 Hz, 1H), 2.83 (d, J = 10.8 Hz, 1H), 2.47 - 2.44 (m, 1H), 2.21 - 2.12 (m, 1H), 1.92 - 1.79 (m, 2H), 1.71 - 1.56 (m, 2H), 1.09 (s, 9H). Step 2: The ZerZ” butyl l-(hydroxymethyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (700 mg, 1.44 mmol) obtained in Step 1 was dissolved in DMF (7 mL), then EtI (346.58 uL, 4.33 mmol) and NaH (69.32 mg, 1.73 mmol) were sequentially added slowly at 0 °C and stirred for 1 hour. An aqueous NH4C1 solution was added to the reaction mixture to terminate the reaction, followed by extraction with toluene.The organic layer was washed with water and saturated aqueous NaCl solution, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain tert'-butyl 1-(ethoxymethyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (640 mg, 86.4% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3, ppm): δ 7.49 (bs, 5H), 7.29 - 7.23 (m, 8H), 7.18 - 7.10 (m, 3H), 3.65 (s, 2H), 3.49 - 3.36 (m, 2H), 3.11 (d, J = 10.8 Hz, 1H), 2.92 (d, J = 11.2 Hz, 1H), 2.61 - 2.52 (m, 1H), 2.25 - 2.17 (m, 1H), 2.14 - 2.06 (m, 2H), 2.05 - 1.97 (m, 1H), 1.81 (d, J = 11.2 Hz, 1H), 1.76 - 1.67 (m, 1H), 1.17 (s, 9H), 1.11 (t, J = 6.8 Hz, 3H). Step 3: AcOH (7.3 mL) was added to tert'-butyl 1-(ethoxymethyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (730 mg, 1.42 mmol) obtained in Step 2, and the mixture was stirred at room temperature for 16 hours. Purified water was added to the reaction mixture to terminate the reaction, and then extracted with toluene. The organic layer was dried over anhydrous NH2SO4, filtered, and concentrated under reduced pressure to obtain tert'-butyl 1-(ethoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (350 mg, crude mixture) as a yellow oil. 1H NMR (400 MHz, DMSO—d6, ppm): δ 3.98 - 3.92 (m, 1H), 3.37 - 3.34 (m, 2H) , 3.20 - 3.17 (m, 3H) , 2.77 - 2.64 (m, 2H) , 2.47 - 2.40 (m, 2H), 2.13 - 2.00 (m, 2H) , 1.91 - 1.80 (m, 3H), 1.77 - 1.68 (m, 1H) , 1.67 - 1.58 (m, 1H) , 1.40 (s, 9H) .

[0675] Intermediate 17. Synthesis of 3-(Difluoromethyl)-3-methylpiperidine hydrochloride. Step 1: ZerZ」 Butyl 3- formylpiperidine-1-carboxylate (8 g, 37.51 mmol) was dissolved in DCM (80 mL), and CH3I (15.97 g, 112.53 mmol) and r-BuOK (6.31 g, 56.27 mmol) were added sequentially at 0 °C under nitrogen, and the mixture was stirred at room temperature for 3 hours. Distilled water was added to the reaction mixture to stop the reaction, and the mixture was extracted with distilled water. The organic layer was washed with saturated NaCl aqueous solution, dried over anhydrous Na2S04, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain ZerZ」 butyl 3— formyl— 3— methylpiper idine— 1— carboxylate (6.6 g, crude) as a yellow oil. NMR (400 MHz, DMSO-d6, ppm): δ 9.46 (s, 1H), 3.86 (d, J = 13.6 Hz, 1H), 3.51 (td, J = 8.8, 4.4 Hz, 1H), 3.03 - 2.94 (m, 2H), 1.91 - 1.86 (m, 1H), 1.52 - 1.49 (m, 1H), 1.38 (s, 11H), 0.94 (s, 3H). Step 2: ZerZ” butyl 3-formyl-3-methylpiperidine-1-carboxylate (4.2 g, 18.48 mmol) obtained in Step 1 was dissolved in DCM (40 mL), then DAST (8.94 g, 55.43 mmol) was added at -15 °C under nitrogen and stirred for 1 hour. Saturated aqueous NaHCO3 was added to the reaction mixture to terminate the reaction and extracted with DCM. The organic layer was washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain tert-butyl 3-(difluoromethyl)-3-methylpiperidine-1-carboxylate (1.8 g, crude) as a colorless oil. 1H NMR (400 MHz, CDCl3, ppm): δ 5.56 (t, J = 56.0 Hz, 1H), 3.69 (s, 1H), 3.31 - 3.08 (m, 3H), 2.18 - 2.06 (m, 1H), 1.71 - 1.69 (m, 3H), 1.56 - 1.42 (m, 12H). Step 3: tert-Butyl 3-(difluoromethyl)-3-methylpiperidine-1-carboxylate (600 mg, 2.41 mmol) obtained in Step 2 was dissolved in DCM (4 mL), then HCl / 1,4-dioxane (2 M, 8.00 mL) was added at room temperature and stirred for 1 hour. It should be noted that there are some unclear notations like "ZerZ" in the original text which might be typos. The translation has been done as accurately as possible based on the existing text.The reaction mixture was concentrated under reduced pressure to obtain 3-(difluoromethyl)-3-methylpiperidine hydrochloride (720 mg, crude) as a white solid. NMR (400 MHz, CDCI3, ppm): δ 9.90 - 9.23 (m, 2H), 5.77 (t, J = 55.6 Hz, 1H), 3.85 — 2.95 (m, 3H), 2.10 — 1.50 (m, 3H), 1.29 (s, 3H).

[0676] Intermediate 18. Synthesis of (1R,5S)-3-Methyl-3,8-diazabicyclo[3.2.1]octane trifluoroacetate. Step 1: tert-Butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.5 g, 7.07 mmol) was dissolved in THF (15 mL), then K2CO3 (2.93 g, 21.20 mmol) was added and stirred at room temperature for 1 hour. CH3I (3.01 g, 21.20 mmol) was slowly added to the reaction mixture and further stirred at room temperature for 12 hours. Distilled water (30 mL) was added to the reaction mixture to terminate the reaction, and the mixture was extracted with EA (30 mL×3). The organic layer was washed with saturated aqueous NaCl (30 mL×3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain tert-butyl (1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.5 g, crude) as a yellow oil. NMR (400 MHz, CDCI3, ppm): δ 4.24 - 4.07 (m, 2H), 2.62 (dd, J = 10.8, 2.4 Hz, 2H), 2.30 — 2.10 (m, 5H), 1.86 (d, J = 1.4 Hz, 4H), 1.47 (s, 9H). Step 2: The tert-butyl (1S, 5S)-3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1 g, 4.42 mmol) obtained in Step 1 was dissolved in DCM (10 mL), then TFA (10.00 mL) was added and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain (1S, 5S)-3-methyl-3,8-diazabicyclo[3.2.1]octane 2,2,2-trifluoroacetate (541 mg, crude) as a yellow oil. LCMS (ES-API, m / z): [M+H]+ = 127.1.

[0677] Synthesis of Intermediate 19. tert-Butyl (1S, 5S)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate. Step 1: Dissolve ZerZ” Butyl (17?, 5S)-3, 8-diazabicyclo[3.2.1]octane-3-carboxylate (5 g, 23.55 mmol) in DCM (60 mL), then add Et3N (2.38 g, 23.55 mmol) and [chloro(diphenyl)methyl]benzene (7.22 g, 25.91 mmol), and stir at room temperature for 12 hours. Add distilled water (80 mL) to the reaction mixture to terminate the reaction, and extract with DCM (50 mL * 3). Wash the organic layer with saturated aqueous NaCl solution, dry over anhydrous NH2SO4, filter, and concentrate under reduced pressure, then purify by silica gel column chromatography to obtain tert-butyl (17?, 5S)-8-trityl-3, 8-diazabicyclo[3.2.1]octane-3-carboxylate (7.66 g, 71.5% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6, ppm): δ 7.60 - 7.46 (m, 5H), 7.32 - 7.14 (m, 10H), 3.67 - 3.48 (m, 5H), 3.46 - 3.42 (m, 1H), 1.38 (s, 9H), 1.09 (d, J = 4.8 Hz, 2H), 0.70 - 0.56 (m, 2H). Step 2: Dissolve ethyl formate (977.71 mg, 13.20 mmol) and TMEDA (2.05 g, 17.60 mmol) in THF (30 mL), then slowly add —BuLi (1.3 M, 13.54 mL) under nitrogen at -50 °C, and stir at -50 °C for 2.5 hours. Add the tert-butyl (17?, 5S)-8-trityl-3, 8-diazabicyclo[3.2.1]octane-3-carboxylate obtained in Step 1 (2.00 g, 4.A solution of 40 mmol) dissolved in THF (15 mL) was added dropwise under nitrogen at -50 °C and stirred at -20 °C for 2 hours. At 0 °C, saturated aqueous NH4C1 solution (90 mL) was added to the reaction mixture to terminate the reaction and extracted with toluene. The organic layer was washed with saturated aqueous NaCl solution, dried over NH2S04, filtered and concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain (IS, 5’?)-2-formyl-8-trityl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (1.29 g, 60.7% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6, ppm): δ 9.44 - 9.12 (m, 1H), 7.64 - 7.15 (m, 15H), 4.15 (s, 1H), 3.73 - 3.51 (m, 3H), 3.42 (d, J = 10.8 Hz, 1H), 1.53 - 1.35 (m, 9H), 1.32 - 1.22 (m, 2H), 0.89 - 0.67 (m, 2H). Step 3: (IS, 57?)-2-formyl-8-trityl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (1.29 g, 2.67 mmol) obtained in Step 2 was dissolved in EtOH (13 mL), then NaBH4 (252.81 mg, 6.68 mmol) was added under nitrogen at 0 °C and stirred at room temperature for 1 hour. Saturated aqueous NH4C1 solution (25 mL) was added to the reaction mixture to terminate the reaction and extracted with EA (25 mL * 3).The organic layer was washed with saturated NaCl aqueous solution (50 mL*2), dried over anhydrous Na2S04, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain ZerZ」butyl (IS, 57?) -2- ( hydr oxymeth y 1 ) -8- 1 ri tyl-3 , 8- diazabicyclo[3.2.1]octane- 3-carboxylate (1.28 g, crude) as a white solid. ppm): S 7.52 (s, 5H), 7.34 — 7.09 (m, 10H), 4.65 — 4.55 (m, 1H), 4.07 - 4.02 (m, 1H), 3.78 - 3.63 (m, 2H), 3.57 - 3.50 (m, 1H) , 3.35 - 3.28 (m, 2H) , 3.27 - 3.19 (m, 1H) , 1.42 (s, 9H) , 1.11 - 0.97 (m, 1H) , 0.93 - 0.77 (m, 1H) , 0.71 - 0.58 (m, 1H) , 0.57 - 0.41 (m, 1H). Step 4: AcOH (4.5 mL) was added to ZerZ」butyl (IS, 57?) -2- (hydr oxymethyl )-8-tri ty 1-3 , 8-diazabicyclo[3.2.1]octane— 3— carboxylate (450 mg, 928.55 u niol) obtained in Step 3, and the mixture was stirred at room temperature for 12 h. After completion of the reaction, the mixture was dried under reduced pressure to obtain tert-butyl (IS, 57?) -2 - ( hydr oxymethy 1 )-3 , 8-di azabi eye lo[3.2.1] octane-3-carboxylate

[0678] (225 mg, crude) was obtained as a white solid. LCMS (ES-API, m / z): [M+H] + = 243.1.

[0679] Intermediate 20. -3-Methyl-3,8-diazabicyclo[3.2.1]octane-2,2,4,4-d| synthesis Step 1: ZerZ」 Butyl ( 17?, 5 S) -3 , 8-di az ab i eye 1 o [ 3 .2. 1 ] oct ane-8-car boxy late (10 g, 47.11 mmol) was dissolved in THF (100 mL), then K2C03 (19.53 g, 141.32 mmol) was added, and CH3I (19.99 g, 140.85 mmol) was slowly added dropwise at room temperature for 1 hour. The reaction mixture was stirred at room temperature for 3 hours. Distilled water (200 mL) was added to the reaction mixture to stop the reaction, and the mixture was extracted with EA (100 mL*3). The organic layer was washed with saturated NaCl aqueous solution (100 mL*3), dried over Na2SC)4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain ZerZ" butyl (17?, 5S)-3-methyl 1-3, 8-diazabicyclo[3.2.1]octane- 8-carboxylate (10.4 g, 97.5% yield) as a yellow oil. NMR (400 MHz, CDC13, ppm):S 4.23 — 4.11 (m, 2H) , 2.64 — 2.55 (m, 2H), 2.27 — 2.12 (m, 5H) , 1.89 — 1.78 (m, 4H) , 1.45 (s, 9H) . Step 2: Ter'-butyl (17?, 5S)-3-methy 1-3, 8-diazabicyclo[3.2.1]octane— 8— carboxylate (5.2 g, 22.98 mmol) and ruthenium oxide hydrate (712.83 mg, 4.60 mmol) obtained in Step 1 were dissolved in EA (265 mL), and then NaICU aqueous solution (10% wt, 265.49 mL) was slowly added at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes and then at room temperature for 16 hours. This was repeated in another batch.The two batches were combined, saturated Na2S03 aqueous solution (500 mL) was slowly added dropwise at 0 °C, stirred for 30 minutes at 0 °C, and then stirred for an additional 30 minutes at room temperature. The reaction mixture was filtered, and the filtrate was extracted with EA (200 mL*3). The organic layer was washed with saturated NaCl aqueous solution (200 mL*2), dried over Na2SC)4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain ZerZ" butyl (17?, 5 S) -3-methyl-2,4-dioxo-3,8- diazabicyclo[3.2.1]octane- 8-carboxylate (3.2 g, 27.3% yield) as a white solid. NMR (400 MHz, CDCI3, ppm):S 4.89 — 4.73 (m, 2H) , 3.07 (s, 3H) , 2.40 - 2.28 (m, 2H), 2.02 - 1.91 (m, 2H) , 1.45 (s, 9H) . Step 3: To (1 ^,5S)-3-methyl-2,4-dioxo-3,8-diazabicyclo[3.2.1]octane— 8— carboxylate (3.2 g, 12.58 mmol) obtained in Step 2, HCl / l,4-di oxane (2 M, 90 mL) was added at room temperature and stirred for 12 hours. After the reaction was completed, the mixture was dried under reduced pressure to obtain (17?, 5 S) -3-me t hy 1 -3 , 8-di az ab i eye 10 [ 3.2.1 ] octane-2 , 4-dione (2.6 g, crude) as a white solid. Old NMR (400 MHz, MeOD, ppm): S 4.75 - 4.69 (m, 2H), 3.11 (s, 3H), 2.58 — 2.45 (m, 2H) , 2.36 — 2.27 (m, 2H) . Step 4: (17?, 5 S) -3-me t hy 1 -3 , 8-di az ab i eye 10 [ 3.2.1 ] octane-2 , 4- dione (2.0 g, 10.After dissolving NaBH(0Ac)3 (6.67 g, 31.48 mmol) and PhCHO (3.34 g, 31.48 mmol) in DCM (20 mL), NaBH(0Ac)3 (6.67 g, 31.48 mmol) AcOH (6.30 mg, 104.92 umol) was added and stirred at room temperature for 2 hours. Saturated NaHC03 (10 mL) was added to the reaction mixture to terminate the reaction and extracted with DCM (10 mL*3). The organic layer was washed with saturated NaCl aqueous solution (10 mL*3), dried over Na2SC)4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography {reverse phase-MPLC (FA condition, column: 330 g Flash Column Welch Ultimate XB_C18 20-40 um, 120 A; Mobile phase: H20 (0.225% FA) - ACN; Gradient B%: 10-100%, 100 mL / min, 60 min) to obtain ( \R, 5 S)-8-benzy 1-3-methoxy 1-3,8- diaz ab i eye 1 o [ 3.2.1 ] octane-2 , 4-di one (2.0 g, 74.1% yield) as yellow oil.

[0680] NMR (400 MHz, CDC13, ppm): δ 7.38 — 7.26 (m, 5H), 3.89 — 3.80 (m, 2H), 3.73 (s, 2H), 3.13 (s, 3H), 2.41 - 2.27 (m, 2H), 1.96 - 1.88 (m, 2H). Step 5: (17?, 5 S)-8-benzy 1 -3-me thyl-3,8- d i az ab i eye 10 [3.2.1] octane-2, 4-d i one (2 g, 8.19 mmol) obtained in Step 4 was dissolved in THF (40111L), and then LiAlD4 (2 M, 24.56 mL) was slowly added thereto at 0 °C under nitrogen. The reaction mixture was stirred at room temperature for 30 minutes, then heated to 66 °C and stirred for an additional 8 hours. Water (1.86 mL), 15% aqueous NaOH solution (1.86 mL), and water (5.58 mL) were sequentially added to the reaction mixture at 0 °C to terminate the reaction, and then concentrated under reduced pressure to obtain (1 ^,5S)-8-benzyl-3- methyl- 3,8- diazabicyclo[3.2. l]octane- 2, 2,4,4- (么 (1.66 g, 92.2% yield) as a yellow oil, and it was confirmed by deuterated ratio test that the ratio of 4D label product was 93.7% and that of 3D label product was 6.1%. NMR (400 MHz, CDCI3, ppm): δ 7.43 - 7.29 (m, 5H), 3.53 (s, 2H), 3.13 - 3.06 (m, 2H), 2.23 (s, 3H), 2.00 - 1.92 (m, 2H), 1.85 - 1.78 (m, 2H). Step 6: (17?, 5S)-8-benzyl-3-methyl-3,8-diazabicyclo[3.2.1]octane-2,2,4,4- (obtained in Step 5 (800 mg, 3.63 mmol) was dissolved in EtOH (20 mL), and then wet Pd / C (772.75 mg, 726.13 μmol) and HC00NH4 (1.14 g, 18.15 mmol) were sequentially added at room temperature and stirred at 90 °C for 3 hours under nitrogen. The reaction mixture was cooled to room temperature, EtOH (10 mL) was added, and after filtration, the resulting solid was washed with EtOH (10 mL*3). HC1 / 1,4-dioxane (2 M, 10 mL) was added to the filtrate at room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, dissolved in water (10 mL), and washed with MTBE (10 mL*2). An aqueous NaOH solution (15% wt.) was slowly added to the aqueous layer at room temperature to basify it, and then extracted with DCM (20 mL*3). The resulting organic layer was dried over Na2SO4 and filtered, and then HC1 / 1,4-dioxane (2 M, 20 mL) was added to the resulting filtrate and stirred at room temperature for 1 hour. The reaction mixture was dried under reduced pressure to obtain (1^,5S)-3-methyl-3,8-diazabicyclo[3.2.1]octane-2,2,4,4- (235 mg, crude) as a pink solid. 4l NMR (400 MHz, D2O, ppm): δ 4.43 — 4.29 (m, 2H), 2.92 (s, 3H), 2.36 — 2.29 (m, 2H), 2.24 — 2.13 (m, 2H).

[0681] Intermediate 21: Synthesis of (1R,5S)-3-(Methyl-cis-7)-3,8-diazabicyclo[3.2.1]octane Step 1: Dissolve tert-butyl (1ʹ?,55)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2 g, 9.42 mmol) in THF (80 mL), add K2C03 (3.91 g, 28.26 mmol), and stir at room temperature for 1 hour. Slowly add trideuterio(iodo)methane (1.37 g, 9.42 mmol) to the reaction mixture at room temperature and stir for an additional 12 hours. Filter the reaction mixture to remove solids, concentrate the filtrate under reduced pressure, and purify by silica gel column chromatography to obtain tert-butyl (1ʹ?,55)-3-(methyl-ʹ?)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.95 g, 90.3% yield) as a yellow liquid. 1H NMR (400 MHz, CDCI3, ppm): 84.28 - 3.99 (m, 2H), 2.61 (dd, J = 10.8, 2.4 Hz, 2H), 2.32 - 2.17 (m, 2H), 1.85 (s, 4H), 1.47 (s, 9H). Step 2: Dissolve tert-butyl (1ʹ?,55)-3-(methyl-ʹ?)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (600 mg, 2.62 mmol) obtained in Step 1 in DCM (6 mL), add TFA (4.61 g, 40.40 mmol), and stir at 20 °C for 4 hours. After completion of the reaction, concentrate the reaction mixture under reduced pressure to obtain (1ʹ?,5S)-3-(Methyl-ʹ?)-3,8-diazabicyclo[3.2.1]octane (636 mg, crude) as a white solid. LCMS (ES-API, m / z): [M+H]+ = 130.2.

[0682] Synthesis of Intermediate 22: -2,2,3-Trimethyl-3,8-diazabicyclo[3.2.1]octane. Step 1: (1S,5S)-Butyl 3-methyl-2-oxo-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (700 mg, 2.91 mmol) and 2,6-di-tert-butyl-4-methylpyridine (717.80 mg, 3.50 mmol) were dissolved in DCM (35 mL), then Tf2O (986.3 mg, 3.50 mmol) was added at -65 °C under nitrogen and stirred for 2 hours. Then MeMgBr (3 M, 3.88 mL) was added at -65 °C and stirred for an additional 2 hours. Distilled water was added to the reaction mixture to terminate the reaction, and then extracted with toluene. The organic layer was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain (1S,5S)-tert-butyl 2,2,3-trimethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (477 mg, 57.9% yield) as a pale yellow oil. NMR (400 MHz, CDCl₃, ppm): δ 4.20 (d, J = 44.4 Hz, 1H), 3.76 (dd, J = 49.2, 6.0 Hz, 1H), 2.56 (t, J = 12.0 Hz, 1H), 2.36 (d, J = 10.0 Hz, 1H), 2.14 (s, 3H), 2.05 - 1.94 (m, 1H), 1.80 - 1.66 (m, 3H), 1.46 (s, 9H), 1.06 (s, 3H), 0.93 (s, 3H). Step 2: tert-Butyl (1S,5R)-2,2,3-trimethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (477 mg, 1.88 mmol) obtained in Step 1 was dissolved in DCM (4.2 mL), and then TFA (1.92 g, 16.8 mmol) was added at room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and then TFA was removed together with MeCN (10 mL). The reaction mixture was washed with i-Pr₂O (10 mL), filtered, and concentrated under reduced pressure to obtain (1S,5R)-2,2,3-trimethyl-3,8-diazabicyclo[3.2.1]octane (589 mg, crude) as a yellow oil. LCMS (ES-API, m / z): [M+H]+ = 155.2; ¹H NMR (400 MHz, D₂O, ppm): δ 4.37 - 4.26 (m, 1H), 4.11 (d, J = 6.4 Hz, 1H), 3.56 (d, J = 2.4 Hz, 2H), 2.81 (s, 3H), 2.42 - 2.24 (m, 3H), 2.18 - 2.05 (m, 1H), 1.55 (s, 3H), 1.49 (s, 3H).

[0683] Intermediate 23. Synthesis of 2-(Difluoromethyl)-6-azaspiro[3.5]nonane. Step 1: (Methoxymethyl)triphenylphosphonium chloride (8.59 g, 25.07 mmol) was dissolved in THF (80 mL), and r-BuOK (1 M, 27.58 mL) was added at 0 °C under nitrogen, and stirred for 1 hour. ZerZ」Butyl 2- 0x0- 6- azaspiro[3.5]nonane- 6-carboxylate (2 g, 8.36 mmol) was dissolved in THF (20 mL), added to the reaction mixture, and stirred at 20 °C for 12 hours. Distilled water was added to the reaction mixture to terminate the reaction, and extraction was performed with a tungsten nitrate. The organic layer was washed with saturated NaCl aqueous solution, dried over Na2S04, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain ZerZ" butyl 2- (methoxymethylene )-6- azasp iro [ 3.5 ] nonane-6-carboxy 1 at e (2.6 g, crude) as a colorless oil. 4l NMR (400 MHz, CDCI3, ppm):S 5.78 (s, 1H) , 3.49 (s, 3H) , 3.36 — 3.25 (m, 2H) , 3.24

[0684] - 3.13 (m, 2H), 2.42 - 2.13 (m, 4H), 1.55 - 1.51 (m, 2H), 1.45 - 1.40 (m, 2H), 1.39 (s, 9H). Step 2: ZerZ」butyl 2- (methoxymeth y 1 ene) -6-azasp ir 0 [ 3.5 ] nonane- 6-car boxy late (2.25 g, 8.42 mmol) obtained in Step 1 was dissolved in MeCN (22 mL) and H2O (5.5 mL), and TFA (1.38 g, 12.12 mmol) was added and stirred at 20 °C for 2 hours. The reaction mixture was quenched by adding saturated NaHC03 aqueous solution, extracted with distilled water, and concentrated under reduced pressure to obtain ter'— butyl 2-formy 1 -6-azasp ir 0 [ 3.5 ] nonane-6-car boxy 1 at e (1.77 g, crude) as a yellow oil. Old NMR (400 MHz, CDCI3, ppm): S 9.75 (d, J = 1.6 Hz, 1H), 3.37 (s, 1H), 3.35 — 3.28 (m, 2H), 3.22 (s, 1H), 2.14 — 2.06 (m, 1H), 2.04 - 1.85 (m, 3H) , 1.67 - 1.61 (m, 2H) , 1.55 - 1.48 (m, 3H) , 1.47 (d, J = 2.8 Hz, 9H). Step 3: ZerZ」butyl 2-formyl 1-6-azasp ir 0 [ 3.5 ] nonane-6-carboxylate (1.77 g, 6.99 mmol) obtained in Step 2 was dissolved in DCM (18 mL), and DAST (2.25 g, 13.97 mmol) was added at 0 °C and stirred for 2 hours. Saturated NaHC03 aqueous solution was added to the reaction mixture to stop the reaction, and the mixture was extracted with DCM and washed with saturated NaCl aqueous solution.The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure, and purified by silica gel column chromatography to obtain ZerZ” butyl 2-(difluoromethyl)-6-azaspiro[3.5]nonane-6-carboxylate (1.27 g, 66.0% yield) as a colorless oil.

[0685] NMR (400 MHz, CDCl3, ppm): δ 5.95 — 5.58 (m, 1H), 3.38 — 3.25 (m, 4H), 2.81

[0686] - 2.57 (m, 1H), 1.93 - 1.84 (m, 2H), 1.83 - 1.68 (m, 2H), 1.66 - 1.60 (m, 1H), 1.55 - 1.49 (m, 3H), 1.48 - 1.46 (m, 9H). Step 4: The ZerZ” butyl 2-(difluoromethyl)-6-azaspiro[3.5]nonane-6-carboxylate (1.22 g, 4.43 mmol) obtained in Step 3 was dissolved in DCM (12 mL), then HCl / 1,4-dioxane (2 M, 24.40 mL) was added, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain 2-(difluoromethyl)-6-azaspiro[3.5]nonane (770 mg, crude) as a yellow oil. LCMS (ES-API, m / z): [M+H] + = 176.1;

[0687] Intermediate 24. Synthesis of 3-Chloro-凡』¥"dimethyl-5,6,7,8-tetrahydro-0T)yrazolo[1,5 - 3][1,4]diazepine-2-carboxamide hydrochloride. Step 1: Diethyl 1H-pyrazole-3,5-dicarboxylate (5 g, 23.56 mmol) was dissolved in AcOH (90 mL), then NaClO (80.18 g, 75.40 mmol) was added and stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to remove acetic acid, the residue was dissolved in distilled water, then 1 M HCl was added to adjust the pH to 4 and extracted with toluene. The organic layer was washed with water and saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain diethyl 4-chloro-1H-pyrazole-3,5-dicarboxylate (4.88 g, 79.8% yield) as a white solid. 1H NMR (400 MHz, MeOH-d4, ppm): δ 4.40 (q, J = 7.2 Hz, 4H), 1.40 (t, J = 7.2 Hz, 6H). Step 2: Diethyl 4-chloro-1H-pyrazole-3,5-dicarboxylate (3.88 g, 15.73 mmol) obtained in Step 1 was dissolved in DMF (24 mL), then N-tert-butyl (3-bromopropyl)carbamate (5.62 g, 23.60 mmol), Cs2CO3 (25.63 g, 78.65 mmol) and KI (130.57 mg, 786.55 μmol) were added and stirred at room temperature for 16 h. Distilled water was added to the reaction mixture to terminate the reaction, then extracted with toluene. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure and purified by silica gel column chromatography to obtain diethyl 1-(3-((tert-butoxycarbonyl)amino)propyl)-4-chloro-1H-pyrazole-3,5-dicarboxylate (3.11 g, 46.5% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3, ppm): δ 4.83 (s, 1H), 4.65 (t, J = 6.8 Hz, 2H), 4.48 - 4.39 (m, 4H), 3.13 (q, J = 6.0 Hz, 2H), 2.08 - 2.03 (m, 2H), 1.45 - 1.40 (m, 15H). Step 3: Diethyl 1-(3-((tert-butoxycarbonyl)amino)propyl)-4-chloro-1H-pyrazole-3,5-dicarboxylate (3.11 g, 7.70 mmol) obtained in Step 2 was dissolved in 1,4-dioxane (15 mL), then HC1 / 1,4-dioxane (2 M, 45 mL) was added and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain diethyl l-(3-aminopropyl)-4-chloro-1H-pyrazole-3,5-dicarboxylate hydrochloride (2.6 g) as an off-white solid. Step 4: Diethyl 1-(3-aminopropyl)-4-chloro-1H-pyrazole-3,5-dicarboxylate hydrochloride (2.6 g, 7.64 mmol) obtained in Step 3 was dissolved in MeOH (50 mL), then TEA (3.87 g, 38.21 mmol) was added and stirred at 80 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to remove methanol, dissolved in toluene, and washed with distilled water. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain ethyl 3-chloro-4-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate and methyl 3-chloro-4-oxo—.

[0688] 5.6.7.8 - tetrahydro - 4H - pyrazolo[1,5 - b][1,4]diazepine - 2 - carboxylate mixture (2.25 g) was obtained as a white solid. Step 5: The ethyl 3 - chloro - 4 - oxo - 5,6,7,8 - tetrahydro - 4H - pyrazolo[1,5 - b][1,4]diazepine - 2 - carboxylate and methyl 3 - chloro - 4 - oxo - 5,6,7,8 - tetrahydro - 4H - pyrazolo[1,5 - b][1,4]diazepine - 2 - carboxylate mixture (1.80 g, 3.62 mmol) obtained in Step 4 was dissolved in THF (26 mL), and BH3 - Me2S (10 M, 1.57 mL) was added under nitrogen at 0 °C. After stirring at room temperature for 2 hours, the mixture was further stirred at 45 °C for 12 hours. Distilled water was added to the reaction mixture to terminate the reaction, and then the mixture was extracted with toluene. The organic layer was washed with saturated aqueous NaCl solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain ethyl 3 - chloro -

[0689] A mixture of 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate and methyl 3-chloro-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate (766 mg) was obtained as a colorless oil. Step 6: The mixture of ethyl 3-chloro-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate and methyl 3-chloro-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate (861 mg, 3.53 mmol) obtained in Step 5 was dissolved in DCM (10 mL), then DMAP (43.16 mg, 353.32 μmol), TEA (1.07 g, 10.60 mmol) and BOC20 (1.70 g, 7.77 mmol) were sequentially added, and the mixture was stirred at room temperature for 2 hours. Distilled water was added to the reaction mixture to terminate the reaction, and then extracted with toluene. The organic layer was washed with saturated aqueous NaCl solution, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain a mixture of 5-(tert-butyl) 2-ethyl 3-chloro-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate and 5-(tert-butyl) 2-methyl 3-chloro-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate (1.4 g, crude) as a white solid. _ 5-(tert-butyl) 2-methyl 3-chloro-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate mixture (1.4 g, crude) was obtained as a white solid. NMR (400 MHz, DMSO—2, ppm): 5 4.60 — 4.45 (m, 4H), 4.27 (q, J = 7.2 Hz, 0.6H), 3.71 (s, 0.4H), 3.66 (s, 2H), 1.81 (s, 2H), 1.35 (s, 9H), 1.17 (t, J= 7.2 Hz, 1H). Step 7: After dissolving Me2NH (2 M, 9.45 mL) in DCM (26 mL), AlMe3 (2 M, 9.45 mL) was added at 0 °C under nitrogen and stirred for 20 min. To the reaction mixture, 5- (ter'— butyl ) 2-ethyl 3— chloro— 7,8— dihydro— 4-butyl-2-methyl-2-(2-chloro-7,8-dihydro-4-yl) obtained in Step 6 was added. 2 - pyrazolo[l,5— a] [l,4]diazepine—

[0690] 2, 5(6-dicarboxylate and 5-(ZerZ」butyl)2-methyl 3-chloro- 7,8-dihydro- 46 The mixture of pyrazolo[l,5-a][l,4]diazepine- 2,5(6』60-dicarboxylate (1.3 g, 3.94 mmol) was dissolved in DCM (26 mL), slowly added dropwise at 0 °C, and stirred at room temperature for 16 hours. Distilled water was added to the reaction mixture to stop the reaction, and the mixture was extracted with distilled water. The organic layer was washed with a saturated NaCl aqueous solution, dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography to give ZerZ」butyl 3-chloro- 2-(dimethyl carbamoyl)— 7,8— dihydro— 4-dicarboxylate. 2- Pyrazolo[1,5 - a][1,4]diazepine - 5(6H)-carboxylate (763 mg, 55.9% yield) was obtained as a colorless oil. 1H NMR (400 MHz, DMSO-d6, ppm): δ 4.51 (s, 2H), 4.45 - 4.37 (m, 2H), 3.66 (s, 2H), 2.96 (s, 6H), 1.80 (s, 2H), 1.36 (s, 9H). Step 8: tert-Butyl 3-chloro-2-(dimethylcarbamoyl)-7,8-dihydro-4H-pyrazolo[1,5 - a][1,4]diazepine - 5(6H)-carboxylate (113 mg, 329.62 μmol) obtained in Step 7 was dissolved in 1,4-dioxane (1 mL), then HCl / 1,4-dioxane (2 M, 1 mL) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain 3-chloro-2-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5 - a][1,4]diazepine - 2-carboxamide hydrochloride (91 mg, crude) as a white solid. LCMS (ES-API, m / z): [M+H] + = 243.1.

[0691] Intermediate 25. ((1R,7aS)-2,2-Difluorodihydro-1 1 3,3'-Spiro[cyclopropane - pyrrolizidine-1(2a'H)-yl]methanol synthesis. Step 1: Ethyl 2—methylene—5—oxotetrahydro—1H—pyrrolizine—7a(5H)0—carboxylate (8.0 g, 38.2 mmol) was dissolved in toluene (100 mL), then TMSCF2Br (23.3 g, 115 mmol) and TBAB (370 mg, 1.15 mmol) were added, and the mixture was stirred at 110 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain ethyl 2, 2-difluoro-5'-oxodihydro-1'H, 3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)0—carboxylate (4.80 g, 48.4% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3, ppm): δ 4.26 (q, J = 7.2 Hz, 2H), 4.04 (d, J = 12.0 Hz, 1H), 3.07 (d, J = 12.0 Hz, 1H), 2.80 (td, J = 16.8, 9.6 Hz, 1H), 2.66 - 2.54 (m, 1H), 2.53 - 2.42 (m, 1H), 2.37 - 2.26 (m, 1H), 2.23 - 2.04 (m, 2H), 1.49 - 1.26 (m, 5H). Step 2: Ethyl 2,2-difluoro-5'-oxodihydro-1'H, 3'H-spiro[cyclopropane—1,2'-pyrrolizine]—7a'(5'H)0—carboxylate (3.0 g, 11.6 mmol) obtained in Step 1 was dissolved in THF (30 mL), then LAH (2.5 M, 27.8 mL) was added under nitrogen at 0 °C, and the mixture was stirred at 60 °C for 2 h. H2O (2.6 mL), 15% aq. NaOH (2.6 mL), H2O (7.9 mL) was sequentially added to terminate the reaction, and extraction was carried out with toluene. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain (2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5'H)-yl)methanol as a yellow solid, which is a racemic mixture. LCMS (ES-API, m / z): [M+H]+ = 204.1. Step 3: (2,2-Difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5'H)-yl)methanol (1.9 g, 9.35 mmol) obtained in Step 2 was dissolved in DMF (10 mL), then TBDPSC1 (3.08 g, 11.2 mmol) and imidazole (1.27 g, 18.7 mmol) were added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure to remove DMF and purified by silica gel column chromatography to obtain 7a'-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluorotetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine] (2.65 g, 63.3% yield) as a racemic mixture. LCMS (ES-API, m / z): [M+H]+ = 442.3. Step 4: The racemic mixture 7a'-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluorotetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine] (1.20 g) was subjected to SFC (column: DAICEL CHIRALPAK IC (250 mm * 50 mm, 10 μm); mobile phase: [CO2 - EtOH(0.Using [l% NH3H2O)]: B%: 12%, isocratic elution mode, chiral isomers were separated. As a result, (L?,7a’』?)- 7a’- (((比 rz」 butyldiphenylsi ly 1 )oxy)methy 1 )-2, 2- dif luorotetrahydro— 1’月, 3’月— spiro[cyclopropane— l,2’-pyrrolizine] (563 mg, 1.27 mmol) and (IS, 7a’S)- 7a’- (((比 r'- butyldiphenylsi ly 1 )oxy)methy 1 )-2, 2- dif luorotetrahydro— 1’月, 3’月— spiro[cyclopropane— l,2’-pyrrolizine] (593 mg, 1.34 mmol) were obtained as a colorless oil. Step 5: (M,7a' / ?)-=- (((tert- Butyl di phenylsi ly 1 )oxy)methy 1 )-2, 2-di f luorotetrahydro-1. spi rot cyclopropane-1,2'-pyrrol i zine] (563 mg, 1.27 mmol) was dissolved in MeOH (5111L), then KHF2 (2.10 g, 26.9 mmol) was added and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure to remove MeOH and purified by silica gel column chromatography to obtain ((L?, 7a'』?)— 2,2— di fluorodihydro— 1'乃, 3 '方 2- spiro[cyclopropane— 1,2 '-pyrrol iz in]- 7a'(5'^)-yl)methanol (185 mg, 67.8% yield) was obtained as a colorless oil. Old NMR (400 MHz, CDCI3, ppm): S 3.47 - 3.28 (m, 2H), 3.13 (dd, J = 12.0, 7.2 Hz, 2H), 2.82 (d, J= 12.0 Hz, 1H), 2.73 - 2.58 (m, 1H), 2.07 -1.95 (m, 1H) , 1.92 - 1.88 (m, 3H) , 1.84 - 1.78 (m, 2H), 1.38 - 1.21 (m, 2H) .

[0692] Intermediate 26. Synthesis of (3,3-Dif luoro-l-azabicyclo[3.2.0]heptan-5— yl)methan. Step 1: 1-(ZerZ」Butyl)2-methyl (5)-4,4-difluoropyrrolidine-1,2-dicarboxylate (8 g, 30.16 mmol)OHHMPA (7.03 g, 39.21 mmol) was dissolved in THF (120 mL), then LiHMDS (1 M, 39.21 mL) was added at -60 °C under nitrogen, and the mixture was stirred for 1.5 h. 1-Bromo-2-chloroethane (21.63 g, 150.80 mmol) was added to the reaction mixture, and the mixture was stirred for an additional 12 h at room temperature. Distilled water was added to the reaction mixture to quench the reaction, and extraction was performed with a distilled water bath. The organic layer was washed with a saturated NaCl aqueous solution, dried over Na2SC)4, filtered, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography to obtain 1-(ZerZ」butyl)2-methyl 2-(2-chloroethyl)-4,4-difluoropyrrolidine-1,2-dicarboxylate (2.92 g, 29.5% yield) as a yellow oil. NMR (400 MHz, CDC13, ppm): S 4.05 — 3.81 (m, 2H), 3.77 (d, J = 6.4 Hz, 3H), 3.72 - 3.51 (m, 2H), 2.80 - 2.55 (m, 3H), 2.53 - 2.40 (m, 1H) , 1.54 - 1.40 (m, 9H). Step 2: 1-(ZerZ」butyl)2-methyl 2-(2-ch lor oethyl)-4,4- di f luoropyrrol idine-1,2-di carboxylate (1.9 g, 5.80 mmol) obtained in Step 1 was dissolved in DCM (19111L), and then TFA (5.83 g, 51.16 mmol) was added at room temperature and stirred for 2 hours.The reaction mixture was depressurized to remove DCM and methyl 2-(2-chloroethyl)-4,4-difluoropyrrolidine-2-carboxylate TFA was obtained as a yellow solid. 4l NMR (400 MHz, CDCI3, ppm):S 3.94 (s, 3H), 3.92 - 3.71 (m, 2H) , 3.61 (t, J = 6.4 Hz, 2H) , 3.04 (td, J = 14.0, 2.4 Hz, 1H) , 2.66 (s, 3H) . Step 3: Methyl 2-(2-chloroethyl)-4,4-difluoropyrrolidine-2-carboxylate (2.2 g, 6.44 mmol), the TFA salt obtained in Step 2, was dissolved in MeCN (33 111 L), and K2C03 (2.67 g, 19.32 mmol) was added at room temperature. The mixture was stirred at 85 °C for 12 h under nitrogen. The reaction mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain methyl 3,3-difluoro-l-azabicyclo[3.2.]heptane-5-carboxylate as a yellow oil. Old NMR (400 MHz, CDCI3, ppm): S 3.81 (s, 3H), 3.73 - 3.64 (m, 1H), 3.37 (d, J = 8.8 Hz, 1H), 3.31 - 3.18 (m, 1H), 3.17 - 3.07 (m, 1H), 2.87-2.78 (m, 1H) , 2.77 - 2.58 (m, 2H) , 2.47 - 2.37 (m, 1H) . Step 4: After dissolving methyl 3,3-difluoro- l-azabicyclo[3.2]heptane- 5-carboxylate (790 mg, 4.13 mmol) obtained in Step 3 in THF (16 mL), LAH (2.5 M, 4.96 mL) was slowly added dropwise under nitrogen at 0 °C and stirred at room temperature for 12 hours. To the reaction mixture, H2O (0.47 mL), 15% aqueous NaOH (0.47 mL), H2O (1.4 mL) were sequentially added to terminate the reaction, followed by filtration and concentration under reduced pressure to obtain (3,3-difluoro-1-azabicyclo[3.2.1]heptan-5-yl)methanol as a yellow solid. 1H NMR (400 MHz, CDCI3, ppm): δ 3.84 - 3.53 (m, 3H), 3.39 (d, J = 12.0 Hz, 1H), 3.29 (q, J = 9.2 Hz, 1H), 3.15 - 3.01 (m, 2H), 2.47 - 2.21 (m, 4H).

[0693] Intermediate 27. (2 1 ,2’-Difluoro-1-aj.'- cyclopropan]-5-yl)methanol synthesis. Step 1: Dissolve tert-butyl 2-methyl (5)-4-methylenepyrrolidine-1,2-dicarboxylate (10 g, 41.45 mmol) in THF (140 mL), then add TMSCF3 (20.63 g, 145.06 mmol) and NaI (3.11 g, 20.72 mmol) under nitrogen at 0 °C and stir at 60 °C for 8 hours. Concentrate the reaction mixture under reduced pressure to remove THF, then extract with distilled water and DCM. Wash the organic layer with saturated aqueous NaCl solution, dry over Na2SO4, filter and concentrate under reduced pressure, and purify the residue by prep-HPLC to obtain 5-(tert-butyl) 6-methyl (65)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (9.58 g, 79.4% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6, ppm): δ 4.45 - 4.31 (m, 1H), 3.75 - 3.61 (m, 3H), 3.60 - 3.36 (m, 2H), 2.61 - 2.52 (m, 1H), 1.96 - 1.81 (m, 1H), 1.71 - 1.61 (m, 1H), 1.61 - 1.52 (m, 1H), 1.46 - 1.31 (m, 9H). Step 2: Dissolve 5-(tert-butyl) 6-methyl (6S)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (5 g, 17.17 mmol) obtained in Step 1 and HMPA (4.00 g, 22.31 mmol) in THF (125 mL), then add LiHMDS (1 M, 22.31 mL) under nitrogen at -40 °C and stir for 1 hour. Then add 1-bromo-2-chloroethane (12.31 g, 85.83 mmol) at -40 °C, and stir the reaction mixture at room temperature for 12 hours.After terminating the reaction by adding a saturated aqueous solution of NH4C1 to the reaction mixture, extraction was carried out with toluene. The organic layer was washed with a saturated aqueous solution of NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 5-(tert-butyl) 6-methyl 6-(2-chloroethyl)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (2.17 g, 35.8% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6, ppm): δ 3.89 - 3.76 (m, 1H), 3.70 - 3.44 (m, 6H), 2.69 - 2.51 (m, 2H), 2.42 - 2.30 (m, 1H), 2.12 - 2.01 (m, 1H), 1.73 - 1.62 (m, 1H), 1.61 - 1.52 (m, 1H), 1.47 - 1.27 (m, 9H). Step 3: 5-(tert-butyl) 6-methyl 6-(2-chloroethyl)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (2.17 g, 6.14 mmol) obtained in Step 2 was dissolved in DCM (22 mL), and then TFA (7.70 g, 67.54 mmol) was added at room temperature and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain methyl 6-(2-chloroethyl)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylate (1.56 g, crude) as a yellow oil. 1H NMR (400 MHz, DMSO-d6, ppm): δ 7.33 - 7.07 (m, 1H), 3.80 (s, 3H), 3.77 - 3.64 (m, 2H), 3.62 - 3.52 (m, 1H), 3.43 - 3.32 (m, 1H), 2.67 - 2.52 (m, 2H), 2.43 - 2.40 (m, 1H), 2.37-2.30 (m, 1H), 1.90 - 1.73 (m, 2H). Step 4: Methyl 6— (2— chloroethyl )—1 , 1— di f luoro— 5— azaspiro[2.4]heptane- 6-carboxylate (1.56 g, 6.15 mmol) obtained in Step 3 was dissolved in MeCN (85 mL), and TEA (3.11 g, 30.75 mmol) was added at room temperature and stirred at 85 °C for 6 hours. The reaction mixture was concentrated under reduced pressure and purified through silica gel column chromatography to obtain methyl 2',2'—di f luoro— 1— azaspiro [bi cyclo [3.2.0]heptane— 3 , 1 ' -eye 1 opr opane ] -5 - carboxylate (351 mg, 26.3% yield) as a yellow oil. Old NMR (400 MHz, DMSO-d6, ppm): S 3.64 (s, 3H), 3.40 - 3.36 (m, 1H), 3.26 - 3.18 (m, 1H), 3.04 (d, J = 12.8 Hz, 1H), 2.77 - 2.69 (m, 1H) , 2.64 - 2.55 (m, 1H), 2.40 - 2.33 (m, 1H), 2.31 - 2.22 (m, 2H) , 1.80 (t, J = 8.8 Hz, 2H) . Step 5: Methyl 2',2'-difluoro-l- azaspiro[bicyclo[3.2.0]heptane— 3,1'— cyclopropane]— 5— carboxylate (350 mg, 1.61 mmol) obtained in Step 4 was dissolved in THF (20 mL), LAH (2.5 M, 1.29 mL) was added at 0 °C under nitrogen, and the mixture was stirred at room temperature for 30 minutes. Saturated Na2S04 aqueous solution was added to the reaction mixture at 0 °C to terminate the reaction, and the mixture was extracted with Toyo.The organic layer was washed with saturated NaCl aqueous solution, dried over Na2S04, filtered and concentrated under reduced pressure to obtain (2',2'-difluoro-l- az asp iro [ bi eye 1 o [ 3.2.0 ] hep t ane-3 , 1 ' — cyclopropan]— 5— yl ) methanol (226 mg, crude) as a yellow solid. Old NMR (400 MHz,. ppm): S 3.39 - 3.33 (m, 2H), 3.32 - 3.22 (m, 2H) , 3.20 - 3.11 (m, 1H) , 2.98 (d, J = 12.8 Hz, 1H) , 2.62 - 2.54 (m, 1H) , 2.25 - 2.11 (m, 2H), 2.11 - 2.02 (m, 1H), 1.92 - 1.83 (m, 1H), 1.78 - 1.69 (m, 2H).

[0694] Intermediate 28. Synthesis of (l-Methyloctahydro-Lff-cyclopentaL6]pyr idin-4-yl )methan()l. Step 1: NaH (3.07 g, 76.84 mmol) was added to a mixture of THF (100 mL) and DMA (100 mL), and ethyl 2-oxocyc 1 opent ane-l-carboxy 1 at e (10 g, 64.03 mmol) was stirred at 0 °C for 30 minutes under nitrogen. 2-(3-bromopropyl ) iso indo 1 ine-1,3- dione (18.88 g, 70.43 mmol) dissolved in THF (100 mL) was slowly added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes and then at 70 °C for an additional 12 hours. After cooling the reaction mixture to room temperature, saturated NH4C1 aqueous solution was added to quench the reaction, and the mixture was extracted with a distilled water. The organic layer was washed with saturated NaCl aqueous solution, dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography to obtain ethyl l-(3-(l,3-dioxoisoindol in-2-yl )propyl ) -2-oxocyc 1 opent ane-l-carboxy late (10.15 g, 44.9% yield) as a white solid. LCMS (ES-API, m / z): [M+H] += 344.1; Old NMR (400 MHz, CDCI3, ppm): 5 7.86 — 7.80 (m, 2H), 7.73 — 7.69 (m, 2H), 4.23 — 4.05 (m, 2H), 3.67 (t, J= 6.8 Hz, 2H), 2.57 - 2.46 (m, 1H) , 2.45 - 2.34 (m, 1H) , 2.31 - 2.17 (m, 1H), 2.07 - 1.82 (m, 4H) , 1.82 - 1.71 (m, 1H) , 1.70 - 1.54 (m, 2H) , 1.22 (t, J= 7.2 Hz, 3H). Step 2: Ethyl 1-( 3-( 1 ,3-di oxo iso indo 1 in-2-yl )propyl )-2- oxocyc 1 opent ane-l-car boxy 1 at e (10.1 g, 29.41 mmol) obtained in Step 1 was dissolved in EtOH (100 111 L), and MeNH2 (9.26 g, 89.44 mmol) was slowly added at room temperature and stirred at 85 °C for 3 hours. After cooling the reaction mixture to room temperature, the generated solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was stirred with EA (50 mL) at room temperature for 30 minutes, the organic solvent was filtered and concentrated under reduced pressure to obtain ethyl 3, 4, 4a, 5, 6, 7-hexahydro- 2-yl 1-opent a [ b\ pyr idi ne-4-car boxy late (6.1 g, crude) as a yellow oil. LCMS (ES-API, m / z): [M+H]+ = 196.0; 4l NMR (400 MHz, CDCI3, ppm): S 4.26 - 4.09 (m, 2H), 3.73 - 3.50 (m, 2H), 2.72 - 2.65 (m, 1H), 2.47 - 2.28 (m, 3H) , 1.85 - 1.66 (m, 2H), 1.65 - 1.39 (m, 3H) , 1.30 - 1.23 (m, 4H) .Step 3: Ethyl 3, 4, 4a, 5, 6, 7-hexahydro- 2-min“ eye 1 opent a [ b\ pyr idi ne-4-car boxy late (4.6 g) obtained in Step 2 was dissolved in TFE (115 111 L) and injected into a fixed-bed reactor (a fixed-bed reactor (5 mL) was filled with particle catalyst {14% Ni / Al2O3, 2 a, H2 back pressure controller 3.5 MPa, H2 flow rate 20 mL / min, reaction temperature 125 °C) through a pump, and the reaction mixture was collected for 40 min, and then the fixed-bed reactor was washed with TFE (115 mL). The reaction mixture was washed with saturated NaCl aqueous solution, dried over Na2S04, filtered and concentrated to give ethyl octahydro- L¥-cyclopentaL as pyr idine- 4-carboxylate (4.1 g, crude) was obtained as a yellow oil. LCMS (ES-API, m / z): [M+H]. + = 198.0; (400 MHz, MeOH-S, ppm): S 4.24 - 4.10 (m, 2H) , 2.97 - 2.86 (m, 1H) , 2.77 - 2.56 (m, 1H), 2.35 - 2.11 (m, 1H) , 2.02 - 1.67 (m, 6H) , 1.66 - 1.35 (m, 4H) , 1.28 - 1.24 (m, 3H). Step 4: After dissolving ethyl octahydro- L¥-cyclopentaL obtained in Step 3 in MeOH (4.4 g, 22.30 mmol) and HCHO aqueous solution (5.43 g, 66.91 mmol) in MeOH (88 mL), NaBH3CN (1.54 g, 24.53 mmol) was added at room temperature and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure, and saturated NH4Cl aqueous solution was added, followed by extraction with distilled water. The organic layer was washed with saturated NaCl aqueous solution, dried over Na2S04, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give ethyl 1— methyloctahydro— L¥-cyclopentaL6]pyr idine— 4— carboxylate (3.1 g, 65.7% yield) as a yellow oil. LCMS (ES-API, m / z): [M+H] += 212.0; Old NMR (400 MHz, CDCI3, ppm): S 4.25 - 4.08 (m, 2H), 3.32 - 2.97 (m, 1H), 2.61 - 2.40 (m, 1H), 2.38 - 2.09 (m, 4H), 2.02 - 1.88 (m, 2H) , 1.88 - 1.57 (m, 7H) , 1.55 - 1.43 (m, 1H) , 1.32 - 1.22 (m, 3H) . Step 5: Ethyl 1-methyloctahydro- L¥-cyclopentaL obtained in Step 4 was dissolved in THF (56 mL) and LAH (2.5 M, 13.81 mL) was slowly added at 0 °C under nitrogen. The mixture was stirred at room temperature for 12 h. To the reaction mixture, water (1.31 mL), 15 wt% NaOH aqueous solution (1.31 mL), and water (3.93 mL) were sequentially added at 0 °C to terminate the reaction. The residue was filtered and concentrated under reduced pressure to obtain (1-methyloctahydro- lff-cyclopentaL-pyridine-4-carboxylate) (2.14 g, crude) as a yellow oil. LCMS (ES-API, m / z): [M+H] + = 170.0; ppm): S 3.66 — 3.37 (m, 2H), 3.36 - 2.92 (m, 1H), 2.90 - 2.74 (m, 1H), 2.47 - 2.37 (m, 1H), 2.34 - 2.25 (m, 1H), 2.09 (s, 3H) , 1.96 - 1.62 (m, 4H) , 1.60 - 1.46 (m, 3H) , 1.45 - 1.20 (m, 3H) . intermediate 29. Synthesis of ((35:4S)-4-(Dif luoromethyl)-l,3-dimethylpiperidin-3-yl)methanol. Step 1: 1—( ter'— Butyl ) 3-methyl 4-oxop i per i di ne-1 , 3-dicarboxylate (10 g, 38.87 mmol ), K2CO3 (8.06 g, 58.30 mmol ) were dissolved in acetone (100 mL), Mel (8.28 g, 58.30 mmol ) was added, and the mixture was stirred at 40 °C for 12 h under nitrogen. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The organic layer was washed with saturated NaCl solution (100 mL), dried over Na2S04, filtered, concentrated under reduced pressure, and purified through si li ca gel column chromatography to obtain 1- (ZerZ」butyl) 3-methyl 3-methyl-4-oxop i per idi ne-1, 3-dicarboxylate (10.4 g, 98.6% yield) as a colorless oil. LCMS (ES-API, m / z): [M+H] += 172.1; 4l NMR (400 MHz, CDC13, ppm): 5 4.50 (d, J = 13.6 Hz, 1H), 4.22 - 4.05 (m, 1H), 3.73 (s, 3H), 3.40 - 3.29 (m, 1H), 3.09 (d, J = 13.6 Hz, 1H), 2.80 - 2.69 (s, 1H) , 2.49 (td, J = 14.8, 4.4 Hz, 1H) , 1.49 (s, 9H), 1.32 (s, 3H) . Step 2: 1-(ZerZ」Butyl)3-methyl 3-methyl-4-oxopiper idine-1,3-dicarboxylate (9.2 g, 33.91 mmol) and 2-(di f luoromethylsulfonyl)pyr idine (19.66 g, 101.64 mmol) obtained in Step 1 were dissolved in DMF (92 mL), and then BuOK (11.4 g) was added at -40 °C under nitrogen, and the mixture was stirred for 1 hour while maintaining the temperature at -10 to -20 °C. Then, HC1 (3 M, 92.00 mL) was slowly added dropwise at -40 °C, and the reaction mixture was stirred at room temperature for 12 hours. The pH of the reaction mixture was adjusted to 8–9 with NaHC03, and then Boc20 (11.10 g, 50.86 mmol) was added and stirred at room temperature for 2 hours. Distilled water was added to the reaction mixture to quench the reaction, and extraction was performed with a distilled water bath. The organic layer was washed with a saturated NaCl aqueous solution, dried over Na2SC)4, filtered, concentrated under reduced pressure, and purified through silica gel column chromatography to obtain 1- (ZerZ」butyl) 3-methyl 4-(difluoromethylene)-3-methylpiper idine-1, 3-dicarboxylate (3.8 g, 12.45 mmol, 36.7% yield) as a yellow oil. LCMS (ES- API, m / z): [M+H]+= 250.0; 4l NMR (400 MHz, CDCl3, ppm): S 3.96 (d, J= 11.6 Hz, 1H), 3.72 (s, 3H), 3.63 - 3.52 (m, 1H), 3.37 - 3.26 (m, 1H), 3.18 (d, J = 13.6 Hz, 1H), 2.33 (s, 2H), 1.46 (s, 9H) , 1.39 (d, J= 3.2 Hz, 3H) . Step 3: 1- ( ZerZ」butyl ) 3-methyl 4-(difluoromethylene)-3- methylpiper idine-1 ,3-dicarboxylate (1.5 g, 1.64 mmol) obtained in Step 2 was dissolved in MeOH (12.5111 L), and wet Pd / C (175 mg, 164.44 umol) was added under nitrogen, and the mixture was stirred at room temperature for 4 h under H2 (15 psi). The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give 1- ( ter'— butyl ) 3-methyl (3S, 4S)— 4— (dif luoromethyl )— 3— methylpiper idine— 1 ,3— dicarboxylate (1.4 g, 92.7% yield) as a colorless oil. LCMS (ES-API, m / z): [M+H]+= 252.0; NMR (400 MHz, CDCI3, ppm): S 6.40 - 5.97 (m, 1H), 4...

Claims

【Scope of Claims】 【Claim 11 A compound of the following chemical formula 1, an optical isomer, a stereoisomer, a racemate, an isotopic variant, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] Coming C or N; Ri is hydrogen, halogen, Ci-3 alkyl, or Ci-3 alkoxy; L is a direct bond, 0, or NR6; R2 is C1-6 alkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C2-6 alkoxyalkyl, C1-6 haloalkyl, Rx and Ry are independently a 3- to 10-membered cycloalkyl, a 3- to 12-membered heterocyclyl, a 6- to 20-membered aryl, or a 6- to 20-membered heteroaryl, which may be optionally substituted with one or more R7; R7 is in each case independently H, D, halogen, hydroxy, Ci-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 hydroxyalkyl, C1-4 haloalkyl, C2-4 haloalkenyl, C2-4 haloalkynyl, C1-4 alkoxy, C1-4 alkyl - N(R16)2, =C-(R16)2, cyano, C(0)R16, C(=0)0R16, C(=O)N(R16)2, - NHC(O)- 6 to 20 membered aryl, -N(R16)2, (C1-4 alkoxy) C1-4 alkyl, oxo, -0R16, -SR16, - (C1-4 alkyl) C(O)R16, 3 to 10 membered cycloalkyl, 3 to 10-membered heterocycloalkyl, 6- to 20-membered aryl, 6- to 20-membered heteroaryl, - Z3- 3- to 10-membered cycloalkyl, - Z3- 3- to 10-membered heterocycloalkyl, - Z3- 6- to 20-membered aryl, - Z3- 6- to 20-membered heteroaryl, - Z3- 0C(0)N(Ri6)2, or - Z『 0C(0)- 3- to 10-membered heterocyclyl; wherein R7 is 1 to 3 cyano, halogen, Ci-6 haloalkyl, amino, -0Ri4, -SR14, or - N(R M )2 can be replaced by ; 362 R15 is independently in each case H, C1-6 alkyl, C1-6 haloalkyl, 3- to 10-membered cycloalkyl, or 3- to 10-membered heterocycloalkyl; wherein said cycloalkyl or said heterocycloalkyl may be substituted with 1 to 4 halogens or Ci-6 alkoxy; R16 is independently H, halogen, or Ci-6 alkyl in each case; Zi to Z3 are independently Ci-4 alkyl; optionally substituted with D, hydroxy, Ci-4 hydroxyalkyl, or 6- to 20-membered heteroaryl; R6, R14, R17, R18, R20, R22, R23, R24 and R25 are each independently H or C1-6 alkyl; R3 is a 3- to 10-membered cycloalkyl, a 3- to 10-membered heterocycloalkyl, a 6- to 20-membered aryl, or a 6- to 20-membered heteroaryl, which may be optionally substituted with one or more R8; R8 and R21 are each independently H, halogen, hydroxy, -N(R18)2, 0Ri8, 0C(=0)N(Ri8)2, SH, S(CI-3 alkyl), S(Ci-3 haloalkyl), S(=0)(Ci-6 alkyl), S(=0)2(Ci-6 alkyl), C(=0)(Ci-6 alkyl), C(=O)OH, C(=O)N(R18)2, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 haloalkyl, C1-3 hydroxyalkyl, C1-3 alkoxyalkyl, C1-4 alkyl - N(R18)2, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 cyanoalkyl, cyano, oxo, 3- to 10-membered cycloalkyl, 3-membered A 6- to 20-membered heterocycloalkyl, a 6- to 20-membered aryl, or a 6- to 20-membered heteroaryl; Y1 is H, halogen, C1-4 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl- C1-4 alkyl, 6- to 20-membered aryl, 6- to 20-membered aryl- C1-4 alkyl, 6- to 20-membered heteroaryl, 6- to 20-membered heteroaryl-Ci-4 alkyl, 3- to 6-membered heterocycle, or 3- to 6-membered heterocycle-Ci-4 alkyl, which may be optionally substituted with one or more R21; Y2 is H, CD3, C1-4 alkyl, or Ci-4 haloalkyl; or Yi and Y2 are linked to form a 3- to 10-membered heterocycloalkyl, or a 3- to 10-membered heterocycloalkenyl, which may be optionally substituted with one or more R9; R9 is, in each case, independently of one another, H, hydroxy, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkenyl, -NH-R17, -N(R17)2, C1-3 alkyl - N(R17)2, oxo, -Yi(C1-3 alkyl), - (C1-3 alkyl)-OH, -(C1-3 alkyl)-O-(C1-3 alkyl), -(C1-3 alkyl)-O-(C1-3 haloalkyl), -C(O)OH, -C(0)O(C1-3 alkyl), -C(0)NH2, -C(O)N(R17)2, cyano, C1-3 cyanoalkyl, a 3- to 10-membered heterocyclyl, a 6- to 20-membered aryl, or a 6- to 20-membered heteroaryl; two R9s that are the same or different from one another may form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycle on the same atom, and may optionally be substituted with one or more halogens, hydroxy, oxo, C1-3 alkyl, C1-3 haloalkyl, or -O-C1-3 alkyl; two R9s that are the same or different from one another may be directly bonded at adjacent atoms, or may form a fused ring with a 3- to 6-membered cycloalkyl, a 3- to 6-membered heterocycloalkyl, a 6- to 20-membered aryl, or a 6- to 20-membered heteroaryl, and may optionally be substituted with one or more R10s; R10 is, in each case, independently of one another, H, C1-3 alkyl, hydroxy, halogen, -N(R22)2, -CH2N(R 22 )2, oxo, -O-(C1-3 alkyl), -(C1-3 alkyl)-OH, -C(O)OH, -C(0)O(C1-3 alkyl), -C(0)N(R22)2, cyano, C1-3 cyanoalkyl, or a 3- to 10-membered heterocyclyl; Rn is H, CD3, Ci-6 alkyl, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocycloalkyl, - C(=0)Ri3, or N(RW)2; When Rii is 3- to 12-membered cycloalkyl, or 3- to 12-membered heterocycloalkyl, optionally one or more D, hydroxy, cyano, halogen, oxo (=0), Ci-3 alkyl, hydroxy C1-3 alkyl, C1-3 haloalkyl, - 0- C1-3 alkyl, - C1-3 alkyl- 0- R19, - N(R19)2, C1-3 alkyl- N(R19)2, -C(O)R19, -C(O)O-R19, - C(0)NH2, -C(O)NH(R19)2, Co-2 alkyl- 3- to 6-membered cycloalkyl, Co-2 alkyl- 3- to 6-membered heterocycloalkyl, Co-2 alkyl- 6- to 20-membered aryl, or Co-2 alkyl- 6- to 20-membered may be substituted with heteroaryl; R no] In case of C1-6 alkyl, optionally one or more halogen, hydroxy, cyano, - N(R19)2, C1-3 alkyl, halo C1-3 alkyl, CD3C1-3 alkyl, hydroxy C1-3 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered heterocycloalkenyl, 5-6 membered aryl, 5-6 membered heteroaryl, - C(0)N(R19)2, - C(0)R19, - S- C1-3 alkyl, - S(0)2- C1-3 alkyl, - S(0)2- N(R19)2, — N(R19)— S(0)2— R19, — NHC(O)R19, — NHC(O)N(R19)2, -0-C(0)N(RI9)2, — o— CI-3alkyl, - o-halo Ci-3alkyl, - o- CD3, -0-(CI-3alkyl)- 0-C1-3alkyl, - o- Ci-3alkyl- OH, - o- C(0)- Ci-3alkyl, - o- P(0)(- o- R19)- R19, or - P(0)2- o- R19; which may be substituted with the 3- to 6-membered cycloalkyl, the 3- to 6-membered heterocycloalkyl, the 3- to 10-membered Cycloalkenyl, 3-10 membered heterocycloalkenyl, 5-6 membered aryl, or 5-6 membered heteroaryl may be optionally substituted with one or more D, hydroxy, cyano, halogen, C1-3 alkyl, C1-3 haloalkyl, hydroxy C1-3 alkyl, - O- C1-3 alkyl, C1-3 alkyl- O- C1-3 alkyl, oxo (=0), or N(R19)2; R19 is independently H, C1-6 alkyl, or C1-6 haloalkyl in each case; R12 is independently in each case D, halogen, hydroxy, C1-3 alkyl, C1- 3-haloalkyl, C1-3hydroxyalkyl, C1-3alkenyl, C1-3alkynyl, C1-3alkyl-0-R20, C1-3alkyl-0-C1- 3-haloalkyl, C1-3 alkyl - S(0)2R20, - N(R20)2, -CH2N(R20)2, oxo (=0), cyano, cyano Cl~ 3-alkyl, Co-3-alkyl-3 to 10-membered cycloalkyl, or Co-3-alkyl-3 to 10-membered heterocyclyl; R13 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-3 alkyl-0- C1-6 alkyl, - N(R23)2, - OR23, -SR23, 3 to 10 membered cycloalkyl, 3 to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclyl, 6- to 20-membered aryl, 6- to 20-membered heteroaryl, or -Cl- 6-Alkyl-3 to 10-membered cycloalkyl; 3 to 10-membered cycloalkyl, 3 to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclyl, 6- to 20-membered aryl, 6- to 20-membered heteroaryl, or -C1- 6-alkyl- 3- to 10-membered cycloalkyl may be optionally substituted with one or more D, hydroxy, halogen, Ci-3 alkyl, halo Ci-3 alkyl, 3- to 6-membered cycloalkyl, - N(R24)2 or oxo (=0); n is an integer from 0 to 4; m is an integer from 0 to 4; R5 is H, halogen, Ci-6 alkyl, Ci-3 haloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, cyano, cyano Ci-3 alkyl, hydroxy, Ci-3 hydroxyalkyl, C(0)(NR25)2, 6-20 membered aryl, - Ci-3 alkyl- 3-6 membered cycloalkyl, - Ci-3 alkyl- 3-6 membered heterocycloalkyl, - Ci-3 alkyl- 6-20 membered aryl, - Ci-3 alkyl- 0- Ci-3 alkyl- 6-20 membered aryl, or - Ci-3 alkyl- 6-20 membered heteroaryl.

2. In claim 1, provided that, if Y2 is visible, A compound, an optical isomer, a stereoisomer, a racemate, an isotopic variant, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof, wherein Yi is H, halogen, Ci-4 alkyl, a 6- to 20-membered aryl, a 6- to 20-membered aryl-Ci-4 alkyl-, a 6- to 20-membered heteroaryl, or a 6- to 20-membered heteroaryl-Ci-4 alkyl-, which may be optionally substituted with one or more R21.

3. In claim 1, provided that, if Rii is shown, R12 is independently in each case D, halogen, Ci-3 haloalkyl, Ci-3 hydroxyalkyl, C1-3 alkenyl, C1-3 alkynyl, C1-3 alkyl- 0- R20, C1-3 alkyl- 0- C1-3 haloalkyl, C1-3 alkyl- S(0)2R20, oxo (=0), cyano C2-3 alkyl, Co-3 alkyl- 3 to 10 membered cycloalkyl, or Co-3 alkyl-tetrahydrofuran; Rx is pyridinyl, piperazinyl, diazepanyl, oxaazabicyclohexanyl, oxaazabicyclooctanyl, oxaazabicyclononanyl, azabicyclohexanyl, azabicycloheptanyl, azaspirohexanyl, azaspiroheptanyl, oxaazaspiroheptanyl (oxaazaspir ohep t any 1), oxaazaspirooctanyl, oxaazaspirononanyl, oxaazasp ir ononany 1, oxaazaspirodecanyl, oxaazaspiroundecanyl, oxaazaspirododecanyl, octahydropyrrolo[3,4-c]pyrrolyl, hexahydro-1H-furo[3,4-c]pyrrolyl, octahydro- 1 minute “cyclopenta [way] pyridinyl (octahydro- L¥-cyc lopent a L pyridinyl ), hexahydro- 1 way 2-pyrrolo[2, 1-c][1,4]oxazinyl (hexahydro-lj¥-pyrrolo[2, 1-c][l,4]oxazinyl), spiro[cyclopropane-1,2'-pyrrolizidinyl] (spiro[eye 1 opr opane-1,2'-pyrrolizidinyl]), or 1-azaspiro[bicyclo[3.2.heptane-3,1'-cyclopropanyl] (1-azaspiro[bieye lo[3.2.heptane-3,1'-cyclopropanyl]); or A compound, an optical isomer, a stereoisomer, a racemate, an isotopic variant, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof, wherein R5 is - Ci-3alkyl- 0- Ci-3alkyl- 6- to 20-membered aryl.

4. In the first paragraph, provided that R11 is - C(=O)R13, R13 is a 3- to 10-membered cycloalkyl substituted with one or more selected from the group consisting of D, hydroxy, halogen, Ci-3 alkyl, halo Ci-3 alkyl, 3- to 6-membered cycloalkyl, -N(R24)2 and oxo (=0), a 3- to 10-membered cycloalkenyl, a 3- to 10-membered cycloalkynyl, a 3- to 10-membered heterocyclyl, a 6- to 20-membered aryl, or a 6- to 20-membered heteroaryl; or A compound, an optical isomer, a stereoisomer, a racemate, an isotopic variant, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof, wherein R13 is C1-4 haloalkyl, C1-6 cyanoalkyl, C1-3 alkyl- 0- C1-6 alkyl, or - C1-6 alkyl- 3- to 10-membered cycloalkyl.

5. In claim 1, R11 is CD3, substituted C1-4 alkyl, substituted or unsubstituted C5-9 alkyl, substituted or unsubstituted C5-9 haloalkyl, substituted cyclopropyl, substituted or unsubstituted 4- to 12-membered cycloalkyl, substituted or unsubstituted 3- to 12-membered heterocycloalkyl, or - C(=0)Ri3, wherein R13 is C5-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C5-6 haloalkyl, C1-6 cyanoalkyl, C1-3 alkyl-0- C1-6 alkyl, -SR23, substituted 3-membered cycloalkyl, substituted or unsubstituted 4- to 10-membered cycloalkyl, substituted or unsubstituted 3- to 10-membered cycloalkenyl, substituted or unsubstituted 3- to 10-membered cycloalkynyl, substituted or unsubstituted 3- to A compound comprising a 10-membered heterocyclyl, a substituted or unsubstituted 6- to 20-membered aryl, a substituted or unsubstituted 6- to 20-membered heteroaryl, or a substituted or unsubstituted -Ci-6alkyl- 3- to 10-membered cycloalkyl, an optical isomer, a stereoisomer, a racemate, an isotopic variant, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.

6. In claim 5, provided that, if Rn is cycloalkyl or heterocycloalkyl, Rn is 4- to 12-membered cycloalkyl, or 3- to 12-membered heterocycloalkyl, and optionally one or more D, hydroxy, cyano, halogen, oxo (=0), C1-3 alkyl, hydroxy C1-3 alkyl, C1-3 haloalkyl, - 0- C1-3 alkyl, - C1- 3-alkyl— o— R19, -N(R19)2, CI-3-alkyl — N(R19)2, — C(O)R W , — C(0)0— RW, -C(0)NH 2I-C(0)NH(RI9)2, Co-2alkyl- 3-6 membered cycloalkyl, Co-2alkyl- 3-6 membered heterocycloalkyl, Co-2alkyl- 6-20 membered aryl, or Co-2alkyl- 6-20 membered heteroaryl; or Rn is cyclopropyl, one or more D, hydroxy, cyano, halogen, oxo (=0), C1-3 alkyl, hydroxy C1-3 alkyl, C1-3 haloalkyl, - O- C1-3 alkyl, -Ci- 3 alkyl— 0— R19, — N(R19)2, CI-3 alkyl — N(R19)2, — C(O)R W , — C(0)0— R19, -C(0)NH 2I A compound, an optical isomer, a stereoisomer, a racemate, an isotopic variant, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof, which is substituted with -C(0)NH(R19)2, Co-2 alkyl- 3-6 membered cycloalkyl, Co-2 alkyl- 3-6 membered heterocycloalkyl, Co-2 alkyl- 6-20 membered aryl, or Co-2 alkyl- 6-20 membered heteroaryl.

7. In claim 5, provided that, if Rii is alkyl, Rn is Ci-4 alkyl, one or more CD3C1-3 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered heterocycloalkenyl, 5-6 membered aryl, 5-6 membered heteroaryl, - C(0)N(Ri9)2, - C(0)RW, - S- C1-3 alkyl, - S(0)2- Ci-3 alkyl, - S(0)2- N(R19)2, - N(R19)- S(0)2- R19, - NHC(0)N(R19)2, - 0- C(0)N(R19)2, -O-CD3, - 0-( Cl-3 alkyl)- 0- Ci-3 alkyl, -0- Cl-3 alkyl- OH, -0-C(0)- C1-3 alkyl, - o- P(0)(- o- R19)- R19, or - P(0)2- o- R19; Rll is C5-6 alkyl, optionally one or more halogen, hydroxy, cyano, - N(R19)2, C1-3 alkyl, halo Cl-3 alkyl, CD3C1-3 alkyl, hydroxy C1-3 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered heterocycloalkenyl, 5-6 membered aryl, 5-6 membered heteroaryl, - C(0)N(Ri9)2, - C(0)RW, - S- C1-3 alkyl, -S(0)2- Ci-3 alkyl, - S(0)2- N(R19)2, — N(R19)— S(0)2— R19, — NHC(O)R19, — NHC(O)N(R19)2, -0-C(0)N(RI9)2, —0— C1-3 alkyl, -o-halo Cl-3 alkyl, - o- CD3, -0- (C1-3 alkyl)- 0- C1-3 alkyl, -o- Cl-3 alkyl- OH, -0-C(0)- C1-3 alkyl, - o- P(0)(- o- R19)- R19, or - P(0)2- o- R19; wherein the 3- to 6-membered cycloalkyl, the 3- to 6-membered heterocycloalkyl, the 3- to 10-membered cycloalkenyl, the 3- to 10-membered heterocycloalkenyl, the 5- to 6-membered aryl, or the 5- to 6-membered heteroaryl is optionally substituted with one or more D, hydroxy, A compound, an optical isomer, a stereoisomer, a racemate, an isotopic variant, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof, which may be substituted with cyano, halogen, C1-3 alkyl, C1-3 haloalkyl, hydroxy C1-3 alkyl, -0- C1-3 alkyl, C1-3 alkyl-0- C1-3 alkyl, or N(R19)2.

8. In claim 5, provided that, if R11 is - C(=O)R13, R13 is C5-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C5-6 haloalkyl, C1-6 cyanoalkyl, C1-3 alkyl-0-C1-6 alkyl, -SR23, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-20 membered aryl, 6-20 membered heteroaryl, or -Ci-6 alkyl- 3-10 membered cycloalkyl; 3-membered cycloalkyl is substituted with one or more D, hydroxy, halogen, C1-3 alkyl, halo C1-3 alkyl, 3-6 membered cycloalkyl, -N(R19)2 or oxo; A compound, an optical isomer, a stereoisomer, a racemate, an isotopic variant, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof, wherein the 4- to 10-membered cycloalkyl, a 3- to 10-membered cycloalkenyl, a 3- to 10-membered cycloalkynyl, a 3- to 10-membered heterocyclyl, a 6- to 20-membered aryl, a 6- to 20-membered heteroaryl, or - Ci-6 alkyl- 3- to 10-membered cycloalkyl may be optionally substituted with one or more D, hydroxy, halogen, Ci-3 alkyl, halo Ci-3 alkyl, 3- to 6-membered cycloalkyl, - N(R24)2, or oxo (=0). 【In the claim 1, Ri is hydrogen, halogen, or Ci-3 alkoxy, compound, optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate, or pharmaceutically acceptable salt thereof.

10. In claim 1, L is a direct bond or 0, a compound, an optical isomer, a stereoisomer, a racemate, an isotopic variant, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.

11. In claim 1, 369 A compound, an optical isomer, a stereoisomer, a racemate, an isotopic variant, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof, wherein Rx and Ry are independently a 3- to 12-membered cycloalkyl, a 3- to 12-membered heterocyclyl, or a 6- to 20-membered heteroaryl, which may be optionally substituted with one or more R7.

12. In claim 1, A compound, an optical isomer, a stereoisomer, a racemate, an isotopic variant, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof, wherein Rx is a 3- to 12-membered heterocyclyl or a 6- to 20-membered heteroaryl, Ry is a 3- to 10-membered cycloalkyl, and wherein Rx and Ry may be optionally substituted with one or more R7.

13. The compound of claim 1, R7 is in each case independently H, D, halogen, hydroxy, Ci-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 hydroxyalkyl, C1-4 haloalkyl, C2-4 haloalkenyl, C2-4 haloalkynyl, C1-4 alkoxy, C1-4 alkyl - N(R16)2, =CH2, =CHF, =CF2, C(=0)N(R16)2, -N(R16)2, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, - Z3- 3- to 10-membered cycloalkyl, or - Z3- 3- to 10-membered heterocycloalkyl; A compound, an optical isomer, a stereoisomer, a racemate, an isotopic variant, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof, wherein R7 may be substituted with 1 to 3 cyano, halogen, haloalkyl, amino, -0R14, -SR14, or -N(R14)2.

14. In claim 1, R3 is a monocyclic or bicyclic aryl of 6 to 20 members, or a monocyclic or bicyclic heteroaryl of 6 to 20 members, and may be optionally substituted with one or more R8s, R8 is, in each case independently of one another, H, halogen, hydroxy, -NH2, 0C(=0)NH2, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 haloalkyl, C1-3 hydroxyalkyl, C1-3 cyanoalkyl, or cyano, a compound, an optical isomer, a stereoisomer, a racemate, an isotope variant, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof. 370

15. According to claim 1, Y1 is C1-4 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-4 alkyl-, a 3- to 6-membered heterocycle, or a 3- to 6-membered heterocycle-C1-4 alkyl-, and may be optionally substituted with one or more R21s; Y2 is C1-4 alkyl, or C1-4 haloalkyl; or Y1 and Y2 are linked to form piperidine, pyrrolidine, piperazine, azepane, azetidine, morpholine, oxazepane, dihydropyridine, tetrahydroazepine, or hexahydrodiazepine and may be optionally substituted with one or more R9s; R9 is, in each case independently of one another, H, hydroxy, halogen, C1-3alkyl, C1-3haloalkyl, C1-3alkenyl, -NH-R17, -N(R17)2, C1-3alkyl -N(R17)2, oxo, -C(═O)(C1-3alkyl), -(C1-3alkyl)-OH, -(C1-3alkyl)-O-(C1-3alkyl), -(C1-3alkyl)-O-(C1-3haloalkyl), -C(O)OH, -C(O)O(C1-3alkyl), -C(O)NH2, -C(O)N(R17)2, cyano, C1-3cyanoalkyl, a 3- to 10-membered heterocyclyl, a 6- to 20-membered aryl, or a 6- to 20-membered heteroaryl; two R9s that are identical or different from one another form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycle on the same atom, such that a spiro ring is formed with the ring formed by the connection of Y1 and Y2, and may optionally be substituted with one or more halogens, hydroxy, oxo, C1-3alkyl, C1-3haloalkyl, or -O-C1-3alkyl; two R9s that are identical or different from one another are connected on adjacent atoms to form a 3- to 6-membered heterocycloalkyl, such that a fused ring is formed with the ring formed by the connection of Y1 and Y2, and may optionally be substituted with one or more R10. 1 — a compound, an optical isomer, a stereoisomer, a racemate, an isotopic variant, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.

16. According to claim 14, R3 is phenyl, biphenyl, naphthyl, toluyl, naphthalenyl, pyridinyl, anthracenyl, indenyl, dihydroindenyl, indanyl 371 A compound, an optical isomer, a stereoisomer, a racemate, an isotopic variant, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof, wherein the compound is (indanyl), quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzothiophenyl, benzofuranyl, indazolyl, or thienopyridinyl, and which may be optionally substituted with one or more R8.

17. In claim 1, R5 is H, C1-3 alkyl, C1-3 hydroxyalkyl, or - C1-3 alkyl- 0- C1-3 alkyl- 6 membered to A 20-membered aryl compound, an optical isomer, a stereoisomer, a racemate, an isotopic variant, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.

18. In claim 11, wherein Rx and Ry are independently 3- to 5-membered cycloalkyl, pyridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, diazepanyl, morphol inyl, pyrrolizidinyl, or methylenepyrrolizidinyl. (methylenepyrrolidinyl), oxaazabicyclohexanyl, oxaazabicycloheptanyl, oxaazabicyclooctanyl, oxaazabicyclononanyl, azabicyclohexanyl, azabicycloheptanyl, azaspirohexanyl (azaspirohexanyl), azaspiroheptanyl, azaspirooctanyl (azaspirooctanyl), oxaazaspiroheptanyl, oxaazaspirooctanyl, oxaazaspirononanyl, oxaazaspirodecanyl, oxaazaspiroundecanyl, oxaazaspirododecanyl, octahydropyrrolo[3,4 - c]pyrrolyl, hexahydro - 1H - furo[3,4 - c]pyrrolyl, octahydro - 1H - cyclopenta[b]pyridinyl, tetrahydro - 1',3'H - 372 Spiro[cyclopropane-1,2'-pyrrolidinyl](tetrahydro-1'H-spiro[cyclopropane-1,2'-pyrrolidinyl]), hexahydro-1'H-pyrrolo[2,1-c][1,4]oxazinyl, spiro[cyclopropane-1,2'-pyrrolidinyl](spiro[cyclopropane-1,2'-pyrrolidinyl]), 1-azaspiro[bicylco[3.2.0]heptane-3,1'-cyclopropanyl] (1-azaspiro[bicylco[3.2.0]heptane-3,1'-cyclopropanyl]), quinolizidinyl, indolinyl, benzimidazolyl, benzotriazolyl(benztr iazolyl), thioxanthinyl, carbazolyl, carbolinyl, or acridinyl, and optionally may be substituted with one or more R7, a compound, an optical isomer, a stereoisomer, a racemate, an isotope variant, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.

19. According to claim 11, wherein Rx and Ry are independently of each other a 3- to 5-membered cycloalkyl, pyridinyl, azetidinyl, pyrrolidinyl, piperidinyl (piperidinyl), piperazinyl, diazepanyl, morpholinyl (morpholinyl), oxaazabicyclo[2.2.1]heptanyl (oxaazabicyclo[2.2.1]heptanyl), oxaazabicyclo[3.1.1]heptanyl, oxaazabicyclo[4.1.0]heptanyl, oxaazabicyclo[2.2.2]octanyl, oxaazabicyclo[3.2.1]octanyl, oxaazabicyclo[3.3.0]octanyl, oxaazabicyclo[3.3.1]nonanyl, azabicyclo[3.1.0]hexanyl, azabicyclo[3.2.0]heptanyl, azabicyclo[2.2.1]heptanyl, azabicyclo[4.1.0]heptanyl (azabicyclo[4.1.0]heptanyl), pyrrolidinyl, methylenepyrrolidinyl, octahydro-1H-cyclopenta[b]pyridinyl (octahydro-1H-cyclopenta[b]pyridinyl), tetrahydro-1’H,3’H-spiro[cyclopropane-1,2’-pyrrolidinyl]), azaspiro[2.3]hexanyl 373 ( az asp iro [ 2.3 ] hexany 1 ), azaspiro [2.4]heptanyl , azaspiro [2.5]octanyl ( az asp iro [ 2.5 ] oct any 1 ), oxaazaspiro [3.3]heptanyl ( oxaazaspiro [ 3.3 ] hep t any 1 ), oxaazaspiro [2.5] octanyl ( oxaazasp i ro [ 2.5] oct any 1 ), oxaazaspiro [3.4] octanyl ( oxaazaspiro [3.4]octanyl ), oxaazaspiro [2.5] octanyl ( oxaazasp i ro [ 2.5] oct any 1 ), oxaazaspiro [4.4] nonanyl ( oxaazaspiro [4.4 J nonanyl ), oxaazaspiro [4.5] decanyl ( oxaazaspiro [4.5 J decanyl ), oxaazaspiro [5.5] undecanyl ( oxaazaspiro [5.5 Jundecanyl ), Octahydropyrrolo[3,4— c]pyrrolyl, hexahydro— lH—furo[3,4— c]pyrrolyl, hexahydro- l-upyrrololo[2,1— c][l,4]oxazinyl, spiro[cyclopropane- 1,2'-pyrrolizidinyl], 1-azaspiro[bicyclo[3.2.heptane- 3,1'-cyclopropanyl] 3.2.0] heptane-3,1'-cyclopropanyl), quinolizidinyl, indolinyl, benzimidazolyl, benzotriazolyl, thioxanthinyl, carbazolyl, carbolinyl, or acridinyl, optionally substituted with one or more R7, a compound, its optical isomers, stereoisomers, racemates, isotope variants, solvates, hydrates, or pharmaceutically acceptable salts thereof.

20. According to claim 12, The Rx is pyridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, diazepanyl, morpholinyl, 1-azabicyclo[3.2.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2-oxa-5-azabicyclo[2.2.2]octanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 6-oxa-1— 374 Azabicyclo[3.3.0]octanyl (6—oxa—1—azabicyclo[3.3.0]octanyl), 6—oxa—2—azaspiro[3.4]octanyl, 7—oxa—4—azaspiro[2.5]octanyl, 6—oxa—3—azabicyclo[3.1.1]heptanyl, 2—oxa—5—azabicyclo[4.1.0]heptanyl, 3—oxa—7—azabicyclo[3.3.1]nonanyl, 3—azabicyclo[3.1.0]hexanyl, 1—azabicyclo[3.2.0]heptanyl, 2—azabicyclo[2.2.1]heptanyl, 3—azabicyclo[4.1.0]heptanyl, pyrrolizidinyl, octahydro—1H—cyclopenta[b]pyridinyl, tetrahydro—1’H,3’H—spiro[cyclopropane—1,2’—pyrrolizidinyl] H~ sp iro [ eye 1 opr opane-1 , 2 ' -pyrrol izidinyl ] ), 5 -azaspiro [2.3]hexanyl (5- az asp iro [2.3]hexanyl 1 ), 5 -azaspiro [2.4]heptanyl (5- azaspiro [2.4]hept any 1 ), 6 -azaspiro [2.5]octanyl, 2 -oxa- 6 -azaspiro [3.4]octanyl (2-oxa~6- azaspiro[3.4]octanyl ), 4 -oxa- 7 -azaspiro [2.5]octanyl (4-oxa~7- az asp iro[2.5]octanyl 1 ), 6 -oxa- 2 -azaspiro [3.4]octanyl (6-oxa~2- azaspiro[3.4]octanyl), 7-oxa- 4 -azaspiro[2.5]octanyl (7-oxa~4- azaspiro[2.5]octanyl), 2-oxa- 6 -azaspiro[3.3]heptanyl (2-oxa~6- azaspiro[3.3]heptanyl), 1-oxa- 7 -azaspiro[4.4]nonanyl, 7-oxa- 1-azaspiro[4.4]nonanyl, 1-oxa- 8 -azaspiro[ 4.5 ]decanyl (l-oxa-8- az asp iro [4.5] decany 1 ), 2 -oxa- 8 -azaspiro [4.5] decanyl (2— oxa— 8— az asp iro [4.5] decany 1 ), 2 -oxa- 8 -azaspiro [5.5] undecanyl (2— oxa— 8— az asp iro [5.5] unde cany 1 ), octahydropyrrolo [3,4- c]pyrrole- 2(1-yl) (octahydropyrrolo[3,4- c]pyrro l-2(L60- yl) , hexahydro- 1H-furo [3,4- c]pyrrolyl (hexahydro-1H-furo[3,4-c]pyrrolyl), hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl, spiro[cyclopropane-1,2'-pyrrolizidinyl], or 1-azaspiro[bicylco[3.2.1]heptane-3,1'-cyclopropanyl], and Ry is a 3- to 5-membered cycloalkyl, 375 Rx and Ry may optionally be substituted with one or more R7s, and each R7 is independently of the others in each case H, D, halogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C2-4 haloalkenyl, C2-4 haloalkynyl, C1-4 alkoxy, =O(R16)2, -N(R16)2, (C1-4 alkoxy)C1-4 alkyl, or a 3- to 10-membered cycloalkyl, which may be substituted with 1 to 3 halogens, a compound, its optical isomers, stereoisomers, racemates, isotopic variants, solvates, hydrates, or pharmaceutically acceptable salts thereof.

21. According to claim 1, - L-R2 is selected from the following structures, a compound, its optical isomers, stereoisomers, racemates, isotopic variants, solvates, hydrates, or pharmaceutically acceptable salts thereof: 376 People.; px°, People.;조 ☆ People 0 ; P9〈 F People 0 ; P9 each People 0 ; F9으, People유介己다 People유〈'heart. People 0; p illusion, people 0 ; p of, people 0 ; po〈> people 0 ; pa> people.; p you 377  people% love people% Yu people* 1 ©, people%© people.※ ⑦ people.= Nian people. Ling rQ< people. WQ.'people.으0-』 people.〜조 people.? rq people. Ai' q eight hearts warehouse factory de people 0 으 jie丄factory 0 people.으 r / 즈 0 people.스시저 people.※ / you se丄factory people ◎ <

22. According to claim 1, - R3 is selected from the following structures, a compound, its optical isomer, stereoisomer, racemate, isotope variant, solvate, hydrate, or a pharmaceutically acceptable salt thereof: 379 According to claim 1, - R4 is selected from the following structures, a compound, its optical isomer, stereoisomer, racemate, isotope variant, solvate, hydrate, or a pharmaceutically acceptable (ner 1그..

24. According to claim 1, the compound of Formula 1 is selected from the group consisting of the following (1) to (506), a compound, its optical isomer, stereoisomer, racemate, isotope variant, solvate, hydrate, or a pharmaceutically acceptable salt thereof: (1) 1-(4-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-7-(((2'R,7aS)-2-fluorotetrahydro-1'H-pyrrolizin-7a(5'H)-yl)methoxy)-2-methyl-2'H-pyrazolo[4,3-f]quinazolin-9-yl)azepane-4-carbonitrile; (2) 1-(4-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-7-(((2'R,7aS)-2-fluorotetrahydro-1'H-pyrrolizin-7a(5'H)-yl)methoxy)-2-methyl-2'H-pyrazolo[4,3-f]quinazolin-9-yl)azepane-4-carboxamide; (3) 1-(4-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1'H-pyrrolizin-7a(5'H)-yl)methoxy)-2-methyl-2'H-pyrazolo[4,3-f]quinazolin-9-yl)azepane-4-carbonitrile; 383 pyrrolizin-7a(5'H)-yl)methoxy)-2-methyl-9-(2,3,6,7-tetrahydro-1'H-azepirrl-yl)-2'H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (5) (R)-1-(4-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-7- (((2β,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5βH)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3-methylpiperidin-3-ol; (6) 4-(4-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-7-(((2β,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5βH)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-6-methyl-1,4-oxazepan-6-ol; (7) 4-(9-(2,5-Diazabicyclo[2.2.2]octan-2-yl)-5-fluoro-7-(((2β,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5βH)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (8) (R)-1-(4-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-7- (((2β,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5βH)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3-methylpiperidin-3-ol; (9) 4—(9—(3,6 - Dihydropyridin - 1(2H)-yl)-5 - fluoro - 7 - (((2R,7aS)-2 - fluorotetrahydro - 1H - pyrrolizin - 7a(5H)-yl)methoxy)-2 - methyl - 2H - pyrazolo[4,3 - f]quinazolin - 4 - yl)-5 - ethynyl - 6 - fluoronaphthalen - 2 - ol; (10) 5 - Ethynyl - 6 - fluoro - 4-(5 - fluoro - 9-(5 - fluoro - 3,6 - dihydropyridin - 1(2H)-yl)-7 - (((2R,7aS)-2 - fluorotetrahydro - 1H - pyrrolizin - 7a(5H)-yl)methoxy)-2 - methyl - 2H - pyrazolo[4,3 - f]quinazolin - 4 - yl)naphthalen - 2 - ol; (11) 5 - Ethynyl - 6 - fluoro - 4 - (5 - fluoro - 7 - (((2R,7aS)-2 - fluorotetrahydro - 1H - pyrrolizin - 7a(5H)-yl)methoxy)-2 - methyl - 9 - (4,7 - diazaspiro[2.5]octan - 7 - yl)- 2H - pyrazolo[4,3 - f]quinazolin - 4 - yl)naphthalen - 2 - ol; (12) 5 - Ethynyl - 6 - fluoro - 4 - (5 - fluoro - 7 - (((2R,7aS)-2 - fluorotetrahydro - 1H - Pyrrolizin - 7a(5'H)-yl)methoxy)-2-methyl-9-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (13) 2-((R)-1-(4-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2'R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5'H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)piperazin-2-yl)acetonitrile; (14) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2'R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5'H)-yl)methoxy)-2-methyl-9-morpholino-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; 384 (15) 4-(9-((1'R,5'S)-3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-fluoro-7-(((2'R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5'H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (16) 4-(4-(8-Ethynyl-7-fluoronaphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)morpholine; (17) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-((1R,5S)-8-((R)-2-hydroxypropyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-methyl-5a,9a-dihydro-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (18) 4-(8-Ethynyl-7-fluoronaphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-((1R,5S)-8-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazoline; (19) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)-8-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (20) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1 J 6 i -pyrrolizin-7a(5 J 60 _ yl)methoxy)-9-((1R,5S)-8-(2-(2-methoxyethoxy)ethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (21) 4-(2-(2-(Benzyloxy)ethyl)-9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethyl-6-fluoronaphthalen-2-ol; (22) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-((1R,5S)-8-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (23) 1-(4-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3-methylazetidin-3-ol; 385 (24) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)-8-(oxetan-2-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (25) 4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (26) 4-(9-((1R,4R)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (27) 4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-(2-hydroxyethyl)-2H-pyrazolo[4,3-i]quinazolin-4-yl)-5-ethyl-6-fluoronaphthalen-2-ol; (28) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-(piperidin-1-yl)-2H-pyrazolo[4,3-i]quinazolin-4-yl)naphthalen-2-ol; (29) 1— ((1S, 5S)— 3— (4— (8— ethynyl— 7— fluoro— 3— hydroxynaphthalen— 1— yl )—5 — fluoro— 7— (((2S, 7aS)— 2— fluorotetrahydro— 1H— pyrrolizin— 7a(5H)-yl)methoxy)— 2— methyl-2H-pyrazolo[4,3-f]quinazol in-9-y 1)-3, 8-diazabicyclo [3.2.1] octan-8-yl)- 2,2, 2-trifluoroethan-l-one; (30) 5— Ethynyl— 6— fluoro— 4— (5— fluoro— 7— (((2S, 7aS)— 2— fluorotetrahydro— 1H-pyrrolizin- 7a(5H)-yl)methoxy)- 2- methyl- 9- ((1S, 5S)-l-vinyl-3,8-diazabicyclo [3.2.1] octan-3-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl )naphthalen- 2-ol; (31) 5— Ethynyl— 6— fluoro— 4— (5— fluoro— 7— (((2S, 7aS)— 2— fluorotetrahydro— 1 J 6 i -pyrrolizin-7a(5 J 60 _ yl)methoxy)-2-methyl-9-((lS,5S)-l-vinyl-3,8-diazabicyclo [3.2.1] octan-3-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl )naphthalen- 2-ol; (32) 4-(9-((』?)-3-Amino-3-methylpiperidin-1-yl)-5-fluoro-7-(((2』?,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (33) 3-((1』?,5S)-3-(4-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2』?,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2- 386 methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propanenitrile; (34) 4-(9-((1』?,4』?)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-5-fluoro-7-(((2』?,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-amine; (35) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2ʹ,7aS)-2-fluorotetrahydro-1ʹH-pyrrolizin-7a(5ʹH)-yl)methoxy)-2-methyl-9-(6ʹH)-3-(methylamino)pyrrolidin-1-yl)-2ʹH-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (36) 5-Ethynyl-6-fluoro-4-(5-fluoro-9-((1ʹ,5ʹ)-8-(2-fluoroethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2ʹ,7aS)-2-fluorotetrahydro-1ʹH-pyrrolizin-7a(5ʹH)-yl)methoxy)-2-methyl-2ʹH-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (37) 6-(4-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2ʹ,7aS)-2-fluorotetrahydro-1ʹH-pyrrolizin-7a(5ʹH)-yl)methoxy)-2-methyl-2ʹH-pyrazolo[4,3-f]quinazolin-9-yl)-6-azaspiro[3.5]nonan-2-ol; (38) (3R,4S)—1—(4—(8—Ethynyl—7—fluoro—3—hydroxynaphthalen—1—yl)—5—fluoro—7—(((2R,7aS)—2—fluorotetrahydro—1H—pyrrolizin—7a(5H)—yl)methoxy)—2—methyl—2H—pyrazolo[4,3—f]quinazolin—9—yl)pyrrolidine—3,4—diol; (39) 2—Amino—7—fluoro—4—(5—fluoro—7—(((2R,7aS)—2—fluorotetrahydro—pyrrolizin-7a(5H _ yl)methoxy)-9-((1R,5S)-8-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]octan—3—yl)—2—methyl—2H—pyrazolo[4,3—f]quinazol in—4—yl)benzo[b]thiophene—3—carbonitrile; (40) (S)-4-(9-((1S,5R)-1-Ethyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro—7—(((2R,7aS)—2—fluorotetrahydro—1H—pyrrolizin—7a(5H)—yl)methoxy)—2—methyl—2H—pyrazolo[4,3—f]quinazolin—4—yl)—5—ethynyl—6—fluoronaphthalen—2—ol; (41) (Nai a)-4-(9-((1S,5S)-1-Ethyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (42) (5a)-4-(9-((1S,5S)-1-Ethyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (43) (A , (Nai a)-4-(9-((1S,5S)-1-Ethyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 387 (44) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1 J 6 i -pyrrolizin-7a(5 J 60 _yl)methoxy)-9-((17?,5S)-8-(2-methoxyethyl)-3,8- diazabicyclo[3.

2. l]octan— 3— yl )— 2— methyl— 2月— pyrazolo[4,3— / ]quinazol in— 4— yl )naphthalen— 2— ol; (45) 5— Ethynyl— 6— fluoro— 4— (5— fluoro— 7— (((2』?, 7aS)— 2— fluorotetrahydro— 1月— pyrrol izin— 7a(5方 0— yl )methoxy)— 2— methyl— 9— ((5)— 3— (methylamino)pyrrol idin— 1— yl )— 2月— pyrazolo[4,3— / ]quinazol in— 4— yl )naphthalen— 2— ol; (46) 4— (7— (((5)— 2— (Di f luoromethylene)tetrahydro— 1月— pyrrol izin— 7a(5方 0— yl )methoxy)-5-f luoro— 9— ( (1』?, 5 S) -8 - ( 3-me t hoxypr opy 1 )-3 , 8- diazabicyclo[3.

2. l]octan— 3— yl )— 2— methyl— 2月— pyrazolo[4,3— / ]quinazol in— 4— yl )—5— ethynyl-6-f luoronaphthalen— 2— ol; (47) 4- (9- ((1乃 ,55)- 3,8- Diazabicyclo[3.2.1]octan- 3- yl)- 7- (((2乃 ,7aS)- 2- f luorotetrahydro— 1月— pyrrol izin— 7a(5方 0— yl )me t hoxy ) -2 - ( 2-hydr oxye t hy 1 )— 2月— pyrazolo[4,3— / ]quinazol in— 4— yl )— 5— ethynyl— 6— f luoronaphthalen— 2— ol; (48) 5-Ethynyl-6-fluoro-4-(5-fluoro-9-((1S,5S)-8-(3-fluoropropyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2S,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (49) 7-(9-((1S,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2S,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-1-ethyl-2,3-dihydro-1H-inden-5-ol; (50) 4-(7-(((5)-2-(Difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluoro-2-methyl-9-((1S,5S)-8-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (51) 4-(9-(3,6-Diazabicyclo[3.1.1]heptan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H))-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (52) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1 J 6 i -pyrrolizin-7a(5 J 60 _ yl)methoxy)-2-methyl-9-((1R,5S)-8-(2,2,2-trifluoroethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; 388 (53) (R)-1-(4-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H))-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3-methylpiperidin-3-ol; (54) (』?)-1-(7-((1-((1,1-Difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methoxy)—4—(8-ethynyl-7—fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro—2-methyl—2月—pyrazolo[4,3— / ]quinazolin-9-yl)—3-methylpiperidin-3-ol; (55) 5-Ethynyl—6-fluoro—4-(5-fluoro-7-(((2』?,7aS)-2-fluorotetrahydro—1月—pyrrolizin-7a(5方0-yl)methoxy)—2-methyl—9-(1-oxa-6-azaspiro[3.5]nonan-6-yl)—2月—pyrazolo[4,3— / ]quinazolin-4-yl)naphthalen-2-ol; (56) 4-(9-((1乃,55)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(((1乃,7a'乃)-2,2-difluorodihydro-1’月,3’月-spiro[cyclopropane-1,2’-pyrrolizin]-7a’(5\60~yl)methoxy)-5-fluoro—2-methyl—2月—pyrazolo[4,3— / ]quinazolin-4-yl)—5-ethynyl—6—fluoronaphthalen-2-ol; (57) 4-(9-((1α,5β)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(((1α,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-c]quinazol-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (58) 4-(7-(((5)-2-(Difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5'H)-yl)methoxy)-5-fluoro-9-((1α,5β)-8-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-methyl-2H-pyrazolo[4,3-c]quinazol-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (59) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2α,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5'H)-yl)methoxy)-9-(1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-methyl-2H-pyrazolo[4,3-c]quinazol-4-yl)naphthalen-2-ol; (60) 4-(9-(Dimethylamino)-5-fluoro-7-(((2α,7aS)-2-fluorotetrahydro- 1H - Pyrrolizin - 7a(5H - 0 - yl)methoxy) - 2 - methyl - 2H - pyrazolo[4,3 - f]quinazolin - 4 - yl) - 5 - ethynyl - 6 - fluoronaphthalen - 2 - ol; (61) (』&)- 4 - (9 - ((1』?, 5』?)- 2,6 - Diazabicyclo[3.2J3]heptan - 2 - yl)-5 - fluoro - 7—(((2』?, 7aS)— 2 - fluorotetrahydro— 1H - pyrrolizin— 7a(5H - 0 - yl)methoxy)— 2 - methyl— 2H - pyrazolo[4,3 - f]quinazolin - 4 - yl )—5 - ethynyl— 6 - fluoronaphthalen - 2 - ol 389 (62) (5》)- 4 - (9 - ((1』?, 5』?)- 2,6 - Diazabicyclo[3.2J3]heptan - 2 - yl)-5 - fluoro - 7—(((2』?, 7aS)— 2 - fluorotetrahydro— 1H - pyrrolizin— 7a(5H - 0 - yl)methoxy)— 2 - methyl— 2H - pyrazolo[4,3 - f]quinazolin - 4 - yl )— 5 - ethynyl— 6 - fluoronaphthalen - 2 - ol (63) 5— Ethynyl— 6— fluoro— 4— (5— fluoro— 7—(((2』?, 7aS)— 2— fluorotetrahydro— l J 6 i -pyrrolizin-7a(5 J 60 _ yl)methoxy)-2-methyl-9-((17?,5S)-8-methyl-3,8- di azabi cyclo [3.2.1] oct an-3-yl)-2^pyr azo lo [4,3- / ] quinazolin-4-yl )naphthalen- 2-ol; (64) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-(6-(oxetan-3-ylmethyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen- 2-ol; (65) 3-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-chloro-4-(trifluoromethyl)aniline; (66) 4-(7-((1-((1,1-Difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methoxy)-5-fluoro-2-methyl-9-((1R,5S)-8-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (67) 4— (7— (((IS, 7a’ 5)— 2,2— Difluorodihydro— 1’β, 3 ’β— spiro [cyclopropane— 1,2’ -pyrrolizin]-7a' (5 ’β 0—yl)methoxy )—5— fluoro— 2— methyl— 9—((1’R, 5’S)— 8— (oxetan— 3- ylmethyl)— 3,8— diazabicyclo [3.2.1] octan— 3— yl)—2β— pyrazolo [4,3— f]quinazolin— 4-yl )—5— ethynyl— 6— fluoronaphthalen— 2— ol; (68) 5— Ethynyl— 6— fluoro— 4— (5— fluoro— 7— (((2’R, 7aS)— 2— fluorotetrahydro— l J 6 i -pyrrolizin-7a(5 J 60 _ yl)methoxy)-2-methyl-9-((1’R,5’S)-3-methyl-3,8- diazabicyclo [3.2.1] octan-8-yl)-2β-pyrazolo [4,3-f] quinazolin-4-yl )naphthalen- 2-ol; (69) 4- (9- (1- ((Difluoromethoxy)methyl)- 3,8-diazabicyclo[3.2.1]octan- 3— yl)— 5— fluoro— 7— (((2’R, 7aS)— 2— fluorotetrahydro— 1β— pyrrolizin— 7a(5β 0— yl )methoxy)— 2— methyl— 2β— pyrazolo [4,3— f]quinazolin— 4— yl )— 5— ethynyl— 6 — fluoronaphthalen-2-ol; (70) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2ʹ,7aS)-2-fluorotetrahydro-1ʹH-pyrrolizin-7a(5ʹH)-yl)methoxy)-2-methyl-9-(1-((R)-tetrahydrofuran-2-yl)- 390 3,8-diazabicyclo[3.2.1]octan-3-yl)-2ʹH-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (71) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2ʹ,7aS)-2-fluorotetrahydro-1ʹH-pyrrolizin-7a(5ʹH)-yl)methoxy)-2-methyl-9-(1-((S)-tetrahydrofuran-2-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2ʹH-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (72) 4-(9-(4,4-Difluoropiperidin-1-yl)-5-fluoro-7-(((2ʹ,7aS)-2-fluorotetrahydro-1ʹH-pyrrolizin-7a(5ʹH)-yl)methoxy)-2-methyl-2ʹH-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (73) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2ʹ,7aS)-2-fluorotetrahydro-1 J 6 i -pyrrolizin-7a(5 J 60 _yl)methoxy)-2-methyl-9-((17?,5S)-8-(methyl-^)-3,8- di azabi cyclo [3.2.1] oct an-3-yl)-2^pyr azo lo [4,3- / ] quinazolin-4-yl )naphthalen- 2-ol; pyrrolizin-7a(5750 _ yl)methoxy)-9-((17?,5S)-8-(2-methoxyethyl)-3,8- diazabicyclo[3.

2. l]octan— 3— yl )— 2— methyl— 2月— pyrazolo[4,3— / ]quinazol in— 4— yl )—4— (trif luoromethyl )ani line; (75) 9- ((1』?, 55)- 3,8- Diazabicyclo[3.2.1]octan- 3- yl)- 4- (5- ethynyl- 6 - f luoroi soqui noli n—4—y 1)—5— fluoro— 7— (((2』?, 7aS)— 2— fluor otetrahydro—L¥— pyrrol izin— 7a(5方 0— yl )methoxy)— 2— methyl— 2月— pyrazolo[4,3— / ]quinazol ine; (76) 4- (9- ((1』?, 55)- 3,8- Diazabicyclo[3.2.1]octan- 3- yl)- 5- f luoro- 7- (((2』?, 7aS)— 2— f luorotetrahydro— 1月— pyrrol izin— 7a(5方 0— yl)methoxy)— 2— methyl— 2月— pyrazolo[4,3— / ]quinazol in— 4— yl)— 2— amino— 7— fluorobenzofuran— 3— carboni tri le; (77) 4-(9-((1^5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2』?, 7aS)—2—fluorotetrahydro—1月—pyrrolizin—7a(5方0—yl)methoxy)—2—methyl—2月—pyrazolo[4,3— / ]quinazol in—4—yl)—2—amino—5—fluorobenzofuran—3—carbonitrile; (78) 5—Ethynyl—6—fluoro—4—(5—fluoro—7—(((2』?, 7aS)—2—fluorotetrahydro—1月—pyrrolizin—7a(5方0—yl)methoxy)—2—methyl—9—(2—oxa—6—azaspiro[3.5]nonan—6—yl)—2月—pyrazolo[4,3— / ]quinazol in—4—yl)naphthalen—2—ol; (79) 5—Ethynyl—6—fluoro—4—(5—fluoro—7—(((2』?, 7aS)—2—fluorotetrahydro—1月-pyrrolizin—7a(5方0—yl)methoxy)—9—(1—(2—methoxyethyl)—3,8—diazabicyclo[3.

2. l]octan—3—yl)—2—methyl—2月—pyrazolo[4,3— / ]quinazol in—4—yl)naphthalen—2—ol; 391 (80) 5—Ethynyl—6—fluoro—4—(5—fluoro—7—(((2』?, 7aS)—2—fluorotetrahydro— 1H-Pyrrolizin-7a((5S,0S)-yl)methoxy)-9-(1-(1-methoxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-4-yl)naphthalen-2-ol; (81) 4-(9-(1-(Ethoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a((5S,0S)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (82) 7-(4-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a((5S,0S)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-9-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one; (83) 6-(4-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a((5S,0S)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-9-yl)-1,6-diazaspiro[3.5]nonan-2-one; (84) 1 - (4 - (8 - Ethynyl - 7 - fluoro - 3 - hydroxynaphthalen - 1 - yl)-5 - fluoro - 7 - (((2'S, 7aS)-2 - fluorotetrahydro - 1'H - pyrrolizin - 7a(5'H)) - yl)methoxy)-2 - methyl - 2'H - pyrazolo[4,3 - f]quinazolin - 9 - yl)-3 - (fluoromethyl)piperidin - 3 - ol; (85) 4 - (9 - ((1'R, 5'S)-3,8 - Diazabicyclo[3.2.1]octan - 3 - yl)-5 - fluoro - 7 - (((6S,8aS)-hexahydro - 1'H - pyrrolo[2,1 - c][1,4]oxazin - 6 - yl)methoxy)-2 - methyl - 2'H - pyrazolo[4,3 - f]quinazolin - 4 - yl)-5 - ethynyl - 6 - fluoronaphthalen - 2 - ol; (86) (R)-4 - (9 - ((1'R, 5'S)-3,8 - Diazabicyclo[3.2.1]octan - 3 - yl)-5 - fluoro - 7 - (((6R, 8aR)-hexahydro - 1'H - pyrrolo[2,1 - c][1,4]oxazin - 6 - yl)methoxy)-2 - methyl - 2'H - pyrazolo[4,3 - f]quinazolin - 4 - yl)-5 - ethynyl - 6 - fluoronaphthalen - 2 - ol; (87) (S)-4 - (9 - ((1'R, 5'S)-3,8 - Diazabicyclo[3.2.1]octan - 3 - yl)-5 - fluoro - 7 - (((6R, 8aR)-hexahydro - 1'H - pyrrolo[2,1 - c][1,4]oxazin - 6 - yl)methoxy)-2 - methyl - February — pyrazolo[4,3- / ]quinazol in-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (88) (2J?, 4r)-6-(7-(((5)-2-(Difluoromethylene)tetrahydro-1J?-pyrrolizin—7a(5J?0-yl)methoxy)—4-(8-ethynyl-7-f1uoro-3-hydroxynaphthalen-1-yl)-5-fluoro—2-methyl—2J?-pyrazolo[4,3- / ]quinazolin-9-yl)—6-azaspiro [3.5] nonan-2-o1; (89) (2S, 45)-6-(7-(((5)-2-(Difluoromethylene)tetrahydro-1J?-pyrrolizin—7a(5J?0-yl)methoxy)—4-(8-ethynyl-7-f1uoro-3-hydroxynaphthalen-1-yl)-5-fluoro—2-methyl—2J?-pyrazolo[4,3- / ]quinazolin-9-yl)—6-azaspiro [3.5] nonan-2-o1; 392 (90) Methyl (1J?,55)-3-(4-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)—5-fluoro—7-(((2J?, 7aS)-2-fluorotetrahydro-1J?-pyrrolizin—7a(5J?0-yl)methoxy)—2-methyl—2J?-pyrazolo[4,3- / ]quinazolin-9-yl)—3,8-diazabicyclo[3.2.1] octane-8-carboxylate; (91) 1— ((1』?, 55)— 8— (4— (8— Ethynyl— 7— f luoro— 3— hydroxynaphthalen— 1— yl )—5 — f luoro— 7— (((2』?, 7aS)— 2— f luorotetrahydro— 1月— pyrrol izin— 7a(5方 0— yl)methoxy)— 2— methyl-2^pyrazolo[4,3- / ]quinazol in-9-y 1)-3, 8~di azabi cyclo [3.2.1] oct an-3-yl)- 2,2, 2~tr i f luoroethan-l-one; (92) 1—(6— (8— Ethyl— 7— f luoro— 3— hydroxynaphthalen— 1—yl )-5 -f luoro-3- (((2』?, 7aS)— 2— f luorotetrahydro— 1月— pyrrol izin— 7a(5方 0— yl)methoxy)— 8— methylfuro[3,2— / ] quinazol in— 1—yl)— 3,3— di fluor opi peri din— 4—o 1; (93) (3』?)— 1—(6— (8— Ethyl— 7— f luoro— 3— hydroxynaphthalen— 1—yl )-5 -f luoro- 3— (((2』?, 7aS)— 2— f luorotetrahydro— 1月— pyrrolizin— 7a(5方 0— yl)methoxy)— 8— methylfuro[3,2— / ] quinazol in— 1—yl)— 3— methyip i per i din— 3—o 1; (94) (3』?)— 1— (6— (8— Ethynyl— 7— f luoro— 3— hydroxynaphthalen— 1—yl )—5 — f luoro— 3— (((2』?, 7aS)— 2— f luorotetrahydro— 1月— pyrrol izin— 7a(5方 0— yl)methoxy)— 8— methylfuro[3,2— / ] quinazol in— 1—yl)— 3— methyip i per i din— 3—o 1; (95) 6- (8- Ethynyl- 7- f luoronaphthalen- 1- yl)- 5- f luoro- 3- (((2』?, 7aS)- 2 - f luorotetrahydro— 1月— pyrrol izin— 7a(5方 0— yl )methoxy)—8—methyl—l— morphol inof uro [3 ,2- / ] quinazol ine; (96) 4- (1- ((1』?, 55)- 3,8- Diazabicyclo[3.2.1]octan- 8- yl)- 5- f luoro- 3- (((2』?, 7aS)— 2— f luorotetrahydro— 1月— pyrrol izin— 7a(5方 0— yl)methoxy)— 8— methylfuro[3,2— / ]quinazol in— 6— yl)— 5— ethynyl— 6— f luoronaphthalen— 2— amine; (97) 2— Amino— 7— f luoro— 4— (5— f luoro— 3— (((2』?, 7aS)— 2— f luorotetrahydro— pyrrol iz in- 7a(5方 0-yl)methoxy)- 1-((L?,5S)- 8- (2- methoxyethyl)- 3,8~ diazabicyclo[3.2.1]octan— 3— yl)— 8— methylfuro[3,2— / ]quinazolin— 6— yl )benzo[b] thiophene— 3— carboni tri le; (98) 5-Ethynyl-6-fluoro-4-(5-fluoro-3-(((2'R,7aS)-2-fluorotetrahydro-1 J 6 i -pyrrolizin-7a(5 J 60 _ yl)methoxy)-1-((1'R,5S)-8-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-methylfuro[3,2-f]quinazolin-6-yl)naphthalen-2-ol; 393 (99) 5-Ethynyl-6-fluoro-4-(5-fluoro-3-(((2'R,7aS)-2-fluorotetrahydro-1'H-pyrrolizin-7a(5'H)-yl)methoxy)-8-methyl-1-((1'R,5S)-8-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)furo[3,2-f]quinazolin-6-yl)naphthalen-2-ol; (100) 4-(1-(3,6-Diazabicyclo[3.1.1]heptan-6-yl)-5-fluoro-3-(((2'R,7aS)-2-fluorotetrahydro-1'H-pyrrolizin-7a(5'H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; (101) 5-Ethynyl-6-fluoro-4-(5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-1-((R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)furo[3,2-f]quinazolin-6-yl)naphthalen-2-ol; (102) 5-Ethynyl-6-fluoro-4-(5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1-(3-(3-methoxypropyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)-8-methylfuro[3,2-f]quinazolin-6-yl)naphthalen-2-ol; (103) 2-Amino-7-fluoro-4-(5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-1-((R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)furo[3,2-f]quinazolin-6-yl)benzo[b]thiophene-3-carbonitrile; (104) 5-Ethynyl-6-fluoro-4-(5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1-(3-(2-methoxyethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)-8-methylfuro[3,2-f]quinazolin-6-yl)naphthalen-2-ol; (105) 4-(1-(((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile; (106) 4-(1-(((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (107) 5-Ethynyl-6-fluoro-4-(5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-1-((1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)furo[3,2-f]quinazolin-6-yl)naphthalen-2-ol; (108) 4-(1-((1R,5S)-3-(Cyclopropylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H- 394 pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (109) 4-(1-(3,6-Diazabicyclo[3.1.1]heptan-6-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile; (110) 2-Amino-7-fluoro-4-(5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-pyrrolizin-7a(5H)0 _yl)methoxy)-l-((17?,5S)-3-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]octan—8—yl)—8—methylfuro[3,2— / ]quinazolin—6—yl)benzoL이thiophene—3—carbonitr i le; (111) 1—((1』?, 55)—3—(6—(8—Ethynyl—7—fluoro—3—hydroxynaphtha len—l—yl )—5 —fluoro—3—(((2』?, 7aS)—2—fluorotetrahydro—1月—pyrrol izin—7a(5方0—yl)methoxy)—8—methylfuro[3,2- / ]quinazol in-l-y 1)-3, 8~diazabi cyclo [3.2.1] oct an-8-y 1)-2, 2,2-trif luoroethan-l-one; (112) 2—Amino—7—fluoro—4—(5—fluoro—3—(((2』?, 7aS)—2—fluorotetrahydro—pyrrol iz in—7a(5方0—yl)methoxy)—1—((1』?, 55)—8—(3—methoxypropyl)—3, 8 —diazabicyclo[3.2.1]octan—3—yl)—8—methylfuro[3,2— / ]quinazolin—6—yl)benzoL이thiophene—3—carbonitr i le; (113) 4-(l-((1^5S)-3-Ethyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-5- fluoro—3—(((2』?, 7aS)—2—fluorotetrahydro—1月—pyrrol izin—7a(5方0—yl)methoxy)—8—methylfuro[3,2— / ]quinazol in—6—yl )—5—ethynyl—6—fluoronaphthalen—2—ol; (114) 5-Ethynyl-6-fluoro-4-(5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-1-((1R,5S)-3-(oxetan-3-ylmethyl)- 3,8-diazabicyclo[3.2.1]octan-8-yl)furo[3,2-f]quinazolin-6-yl)naphthalen-2-ol; (115) 5-Ethynyl-6-fluoro-4-(5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1 J 6 i -pyrrolizin-7a(5 J 60 _ yl)methoxy)-1-((1R,5S)-3-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-8-methyl furo[3,2-f]quinazolin-6-yl)naphthalen-2-ol; (116) 5-Ethynyl-6-fluoro-4-(5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1 J 6 i -pyrrolizin-7a(5 J 60 _ yl)methoxy)-1-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-8-methyl furo[3,2-f]quinazolin-6-yl)naphthalen-2-ol; (117) 5-Ethynyl-6-fluoro-4-(5-fluoro-1-((1R,5S)-3-(3-fluoropropyl)- 3.8-Diazabicyclo[3.2.1]octan-8-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H- 395 pyrrolizin—7a(5H)-yl)methoxy)—8-methylfuro[3,2-f]quinazolin—6-yl)naphthalen-2-ol; (118) 4-(1-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-3-(((R)-3,3-difluoro—1-azabicyclo[3.2.0]heptan-5-yl)methoxy)—5-fluoro—8-methylfuro[3,2-f]quinazolin—6-yl)—5-ethynyl—6-fluoronaphtha1en-2-ol; (119) 4-(1-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-3-(((R)-3,3-difluoro—1-azabicyclo[3.2.0]heptan-5-yl)methoxy)—5-fluoro—8-methylfuro[3,2-f]quinazolin—6-yl)—5-ethynyl—6-fluoronaphthalen-2-ol; (120) 2-Amino—7-fluoro—4-(5-fluoro—3-(((2R,7aS)-2-fluorotetrahydro—pyrrolizin—7a(5H)-yl)methoxy)—8-methyl—1-(3-methyl—3,6-diazabicyclo[3.1.1]heptan-6-yl)furo[3,2-f]quinazolin—6-yl)benzo[b]thiophene-3-carbonitrile; (121) 5-Ethynyl-6-fluoro-4-(5-fluoro-1-((1R,5S)-8-(3-fluoropropyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy))-8-methylfuro[3,2-f]quinazolin-6-yl)naphthalen-2-ol; (122) 5-Ethynyl-6-fluoro-4-(5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1 J 6 i -pyrrolizin-7a(5 J 60 _ yl)methoxy)-1-((1R,5S)-8-(3-hydroxypropyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-methylfuro[3,2-f]quinazolin-6-yl)naphthalen-2-ol; (123) 4-(1-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-3-(((S)-2,2-difluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy))-5-fluoro-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (124) 5-Ethynyl-6-fluoro-4-(5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1 J 6 i -pyrrolizin-7a(5 J 60 _yl)methoxy)-8-methyl-l-((17?,5S)-8-(3,3,3-trifluoropropyl)—3,8—diazabicyclo[3.2.1]octan—3—yl)furo[3,2— / ]quinazolin—6—yl)naphthalen—2—ol; (125) 5—Ethynyl—6—fluoro—4—(5—fluoro—3—(((2』?, 7aS)—2—fluorotetrahydro—l J 6 i -pyrrolizin-7a(5 J 60 _ yl)methoxy)-l-((17?,5S)-8-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-methyl furo[3,2- / ]quinazolin-6-yl)naphthalen-2-ol; (126) 5—Ethynyl—6—fluoro—4—(5—fluoro—3—(((2』?, 7aS)—2—fluorotetrahydro—1月—pyrrolizin—7a(5方0—yl)methoxy)—1—(3—(3—hydroxypropyl)—3,6— 396 diazabicyclo[3.

1. l]heptan—6—yl)—8—methylfuro[3,2— / ]quinazolin—6—yl)naphthalen—2—ol; (127) 4-(1-((1R,5S)-8-(Cyclopropylmethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (128) 1-((1R,5S)-3-(6-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2-difluoropropan-1-one; (129) 1-((1R,5S)-3-(6-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)ethan-1-one; (130) 4-(3-(((1R,7a′R)-2,2-Difluorodihydro- 3'-spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5'-hydroxy)methoxy)-5-fluoro-1-((1S,5S)-8-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (131) 1-((1S,5S)-3-(3-(((1S,7a'S)-2,2-difluorodihydro-1S,3'S-spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5'-hydroxy)methoxy)-6-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethanone; (132) 4-(1-((1S,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-3-(((1S,7a'S)-2,2-difluorodihydro-1S,3'S-spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5'-hydroxy)methoxy)-5-fluoro-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (133) 4 - (3 - (((1α, 7aα)-2,2 - Difluorodihydro - 1α, 3α - spiro[cyclopropane - 1,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)-5 - fluoro - 1 - ((1α, 5S)-8 - (2 - methoxyethyl)-3,8 - diazabicyclo[3.2.1]octan - 3 - yl)-8 - methylfuro[3,2 - f]quinazolin - 6 - yl)-5 - ethynyl - 6 - fluoronaphthalen - 2 - ol; (134) 4 - (3 - (((1α, 7aα)-2,2 - Difluorodihydro - 1α, 3α - spiro[cyclopropane - 1,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)-5 - fluoro - 8 - methyl - 1 - ((1α, 5S)-8-(oxetan - 397 3 - ylmethyl)-3,8 - diazabicyclo[3.2.1]octan - 3 - yl)furo[3,2 - f]quinazolin - 6 - yl)-5 - ethynyl - 6 - fluoronaphthalen - 2 - ol; (135) 5 - Ethynyl - 6 - fluoro - 4 - (5 - fluoro - 3 - (((2α, 7aS)-2 - fluorotetrahydro - 1 J 6 i -pyrrolizin - 7a(5 J 60 _ yl)methoxy)-1 - ((1α,5S)-8 - (2 - hydroxyethyl)-3,8 - diazabicyclo[3.2.1]octan - 3 - yl)-8 - methylfuro[3,2 - f]quinazolin - 6 - yl)naphthalen - 2 - ol; (136) 5-Ethynyl-6-fluoro-4-(5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1 J 6 i -pyrrolizin-7a(5 J 60 _ yl)methoxy)-1-((1R,5S)-8-((S)-2-hydroxypropyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-methylfuro[3,2-f]quinazolin-6-yl)naphthalen-2-ol; (137) 4-(6-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1R-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-1-methylpiperazin-2-one; (138) 4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1R-pyrrolizin-7a(5H)-yl)methoxy)-2-methyloxazolo[5,4-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (139) 5-Ethynyl-6-fluoro-4-(7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)-8-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)oxazolo[5,4-f]quinazolin-4-yl)naphthalen-2-ol; (140) 5-Ethynyl-6-fluoro-4-(3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H) _ yl)methoxy)-1-((1R,5S)-3-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)imidazo[1',2':1,6]pyrido[3,2-b]pyrimidin-6-yl)naphthalen-2-amine; (141) tert-Butyl (1R,5S)-8-(6-(3-amino-8-ethynyl-7-fluoronaphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-b]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate; (142) 3-((1ʹ,5ʹ)-8-(6-(3-Amino-8-ethynyl-7-fluoronaphthalen-1-yl)-3-(((2ʹ,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1ʹ,2ʹ:1,6]pyrido[3,2-b]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)propan-1-ol; (143) 5-Ethynyl-6-fluoro-4-(3-(((2ʹ,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1-((1ʹ,5ʹ)-3-methyl-3,8~ 398 diazabicyclo[3.2.1]octan-8-yl)imidazo[1ʹ,2ʹ:1,6]pyrido[3,2-b]pyrimidin-6-yl)naphthalen-2-amine; (144) 4-(9-((1ʹ,5ʹ)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2ʹ,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyloxazolo[5,4-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (145) 5-Ethyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)-3-(oxetan-2-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (146) 5-Ethyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)-3-((tetrahydrofuran-3-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (147) 1-((1R,5S)-3-(7-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)-4-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethan-1-one; (148) 4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((S,2)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethyl-6-fluoronaphthalen-2-ol; (149) 4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-2-aminobenzofuran-3-carbonitrile; (150) 4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-2-amino-7-fluorothieno[3,2-c]pyridine-3-carbonitrile; (151) 4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(((S)-1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-i]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (152) 3-Chloro-5-(4-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2- 399 methyl-2H-pyrazolo[4,3-i]quinazolin-9-yl)-1-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide; (153) 4-(1-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-3-((2',2'-difluoro-1-azaspiro[bicylco[3.2.0]heptane-3,1'-cyclopropan]-5-yl)methoxy)-5-fluoro-8-methylfuro[3,2-i]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (154) 4-(1-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (155) 4-(1-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((6R,8aR)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (156) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (157) 4-(1-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-3-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)-5-fluoro-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (158) 5-Ethynyl-6-fluoro-4-(5-fluoro-3-(((2'R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5'H)-yl)methoxy)-8-methyl-1-((1'R,5S)-3-(methyl-sulfonyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)furo[3,2-f]quinazolin-6-yl)naphthalen-2-ol; (159) 5-Ethynyl-6-fluoro-4-(5-fluoro-3-(((2'R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5'H)-yl)methoxy)-8-methyl-1-((1'R,5S)-8-(methyl-sulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)furo[3,2-f]quinazolin-6-yl)naphthalen-2-ol; (160) 1-((1'R,5S)-3-(3-(((1'S,7a'S)-2,2-Difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)-6-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethan-one; _ y1)methoxy)-6-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-8-niethylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroetharrl-one; (161) 4—(3—(((1S,7a′S)-5)-2,2-Difluorodihydro-1′H,3′H-spiro[cyclopropane-1,2′-pyrrolizin]-7a′(5′H)-yl)methoxy)-5-fluoro-8-methyl-1-((1R,5S)-8-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)furo[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 400 (162) (2,2-Difluorocyclopropyl)(1R,5S)-3-(6-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone; (163) ((1R,5S)-3-(6-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(oxiran-2-yl)methanone; (164) 2-Amino-7-fluoro-4-(5-fluoro-3-(((2′,7aS)-2-fluorotetrahydro-pyrrolizin-7a(5′H)-yl)methoxy)-8-methyl-1-((1′,5′S)-8-(methyl-sulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)furo[3,2-f]quinazolin-6-yl)benzo[b]thiophene-3-carbonitrile; (165) 9-((1′,5′S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-4-(3- (difluoromethyl)-8-ethynyl-7-fluoronaphthalen-1-yl)-5-fluoro-7-(((2′,7aS)-2-fluorotetrahydro-1′H-pyrrolizin-7a(5′H)-yl)methoxy)-2-methyl-2′H-pyrazolo[4,3-f]quinazoline; (166) 4-(9-((1′,5′S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-fluoro-2-methyl-2′H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (167) 4—(1—(3—(Difluoromethyl)—3—methylpiperidin—1—yl)-5 -fluoro-3-(((2R, 7aS)—2—fluorotetrahydro—1H—pyrrolizin—7a(5H)-yl)methoxy)—8—methylfuro[3,2—f]quinazolin—6—yl)—5—ethynyl—6—fluoronaphthalen—2—ol; (168) 4—(1—(2—(Difluoromethyl)—6—azaspiro[3.5]nonan—6—yl)-5 -fluoro-3-(((2R, 7aS)—2—fluorotetrahydro—1H—pyrrolizin—7a(5H)-yl)methoxy)—8—methylfuro[3,2—f]quinazolin—6—yl)—5—ethynyl—6—fluoronaphthalen—2—ol; (169) 4-(3-((1-((3-Azabicyclo [3.1.0]hexan-3 -yl)methyl)cyclopropyl)methoxy)-1-((1R, 5S)-3,8-diazabicyclo [3.2.1]octan-3-yl)- 5-fluoro—8—methylfuro[3,2—f]quinazolin—6—yl)—5—ethynyl—6—fluoronaphtha 1 en~2 -ol; (170) 5-(1-((1R, 5S)- 3,8-Diazabicyclo[3.2.1]octan- 3-yl)- 5- fluoro- 3-(((2R, 7aS)—2—fluorotetrahydro—1H—pyrrolizin—7a(5H)-yl)methoxy)—8—methylfuro[3,2—f]quinazolin—6—yl)-2 -fluoro—3—methyl—4— (trifluoromethyl)aniline; (171) 4-(1-((1S,5S)-8-((3,3-Difluorocyclobutyl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (172) 5-(9-((1S,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-2-fluoro-3-methyl-4-(trifluoromethyl)aniline; (173) 4-(7-(((R)-1-((Dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-2-methyl-9-((1S,5S)-8-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (174) Aziridin-2-yl((17?,5S)-3-(6-(8-ethynyl-7-fluoro-3-hydroxynaphthalen—1—yl)—5—fluoro—3—(((2』?,7aS)—2—fluorotetrahydro—1月—pyrrolizin-7a(5方0-yl)methoxy)-8-methylfuro[3,2- / ]quinazolin-1-yl)-3,8~diazabicyclo[3.2.1]octan—8—y1)methanone; (175) 1—((1』?,55)—3—(6—(8—Ethynyl—7—fluoro—3—hydroxynaphthalen—1—yl)—5—fluoro—3—(((2』?,7aS)—2—fluorotetrahydro—1月—pyrrolizin—7a(5方0-yl)methoxy)—8—methylfuro[3,2- / ]quinazolin-l-y1)-3,8~diazabicyclo[3.2.1]octan-8-y1)-3,3,3-trifluoropropan-l-one; (176) 4-(1-((1』?,55)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-8-methyl—3—(((4aS,7a』?)—1—methyloctahydro—4a月—cyclopenta[b]pyridin—4a-yl)methoxy)furo[3,2— / ]quinazolin—6—yl)—5—ethynyl—6—fluoronaphthalen—2—ol; (177) 4-(1-((1S,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-8-methyl-3-(((4aR,7aS)-1-methyl octahydro-4aR,7aR-cyclopenta[b]pyridin-4a-yl)methoxy)furo[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (178) 4-((S)-1-((1S,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1R-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-2-amino-5-fluorobenzo[b]thiophene-3-carbonitrile; (179) 5-Ethynyl-6-fluoro-4-(5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1R-pyrrolizin-7a(5H)-yl)methoxy)-1-(1-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-methyl furo[3,2-f]quinazolin-6-yl)naphthalen-2-ol; (180) 4— ((1』?, 55)— 3— (6— (8— Ethynyl— 7— f luoro— 3— hydroxynaphthalen— 1— yl )—5 — f luoro— 3— (((2』?, 7aS)— 2— f luorotetrahydro— 1月— pyrrol izin— 7a(5方 0— yl)methoxy)— 8— methy If uro [3,2- / ] quinazolin-l-y 1)-3, 8~di azabi cyclo [3.2.1] oct an-8-yl)butane- 1,2-diol; (181) 4- (1- ((1』?, 55)- 3,8- Diazabicyclo[3.2.1]octan- 3- yl)- 5- f luoro- 3- (((2』?, 7aS)— 2— f luorotetrahydro— 1月— pyrrol izin— 7a(5方 0— yl)methoxy)— 8— methylfuro[3,2— / ]quinazolin— 6— yl)— 5— ethynyl— 1,6— dif luoronaphthalen— 2— ol; (182) 4— (7— (((IS, 7a’ 5)— 2,2— Dif luorodi hydro— 1’月, 3 ’月— spiro [cyclopropane— 1,2’ -pyrrol izin]-7a' (5\60—yl)methoxy)—5—fluoro—2—methyl—9—((l』?,5S)—3—methyl — 3.8—diazabicyclo[3.2.1]octan-8-yl)-2^pyrazolo[4,3- / ]quinazolin-4-yl)-5- ethynyl-6-f luoronaphthalen— 2— ol; (183) 5-Ethynyl-6-fluoro-4-(5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1-((1R,5S)-8-(3-(hydroxymethyl)cyclobutyl)- 3,8-diazabicyclo[3.2.1]octan-3-yl)-8-methylfuro[3,2-f]quinazolin-6-yl)naphthalen-2-ol; (184) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)-8-(oxetan-3-ylmethyl)- 3,8-diazabicyclo[3.2.1]octan-3-yl)oxazolo[5,4-f]quinazolin-4-yl)naphthalen-2-ol; (185) 1-((1R,5S)-3-(6-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-4,4,4-trifluorobutan-1-one; (186) 4-(9-((1^5S)-3-Ethyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro—7—(((2』?, 7aS)—2-fluorotetrahydro—1月—pyrrolizin—7a(5方0—yl)methoxy)—2-methyl—2月—pyrazolo[4,3— / ]quinazolin—4-yl )—5—ethynyl—6—fluoronaphthalen—2—ol; (187) 5—Ethynyl—6—fluoro—4—(5—fluoro—7—(((2』?, 7aS)—2-fluorotetrahydro—l J 6 i -pyrrolizin-7a(5 J 60 _ yl)methoxy)-9-((17?,5S)-3-isopropyl-3,8-diazabicyclo[3.

2. l]octan—8—yl )—2—methyl—2月—pyrazolo[4,3— / ]quinazolin—4-yl )naphthalen—2—ol; (188) 5—Ethynyl—6—fluoro—4—(5—fluoro—7—(((2』?, 7aS)—2-fluorotetrahydro—l^pyrrolizin-7a(5750 _ yl)methoxy)-2-methyl-9-((17?, 5S)-3-(oxetan-3-yl)-3,8- 403 diazabi cyclo [3.2.1] octan-8-yl)-2^pyr azolo [4,3- / ] quinazolin-4-yl )naphthalen- 2-ol; (189) (2,2-Difluorocyclopropyl)(1R,5S)-3-(4-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone; (190) ((1R,5S)-3-(4-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(1-(trifluoromethyl)cyclopropyl)methanone; (191) (2,2-Difluorocyclopropyl)(1R,5S)-8-(4-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methanone; (192) 1— ((1』?, 55)— 3— (4— (8— Ethynyl— 7— f luoro— 3— hydroxynaphthalen— 1—yl )—5 — f luoro— 7— (((2』?, 7aS)— 2— f luorotetrahydro— 1月— pyrrol izin— 7a(5方 0— yl)methoxy)— 2— methyl-2^pyrazolo[4,3- / ]quinazol in-9-y 1)-3, 8~di azabi cyclo [3.2.1] oct an-8-yl)- 3,3, 3~tr i f luoropropan-l-one; (193) Az i r i d i n-2-y 1 ( ( 17?, 5 S) -3- ( 4- ( 8-e t hyny 1 -7 -f 1 uoro-3- hydroxynaphthalen— 1— yl)— 5— f luoro— 7— (((2』?, 7aS)— 2— f luorotetrahydro— 1月— pyrrol izin— 7a(5方 0— yl )methoxy)— 2— methyl— 2月— pyrazolo[4,3— / ]quinazol in— 9— yl )- 3 , 8~d i azabi eye lo[3.2.1]oct an— 8— y 1 )met hanone; (194) ((』?)- Azir idin- 2- yl)((L?, 55)- 3- (4- (8- ethynyl- 7- f luoro- 3- hydroxynaphthalen— 1—yl)— 5— fluoro— 7— (((2』?, 7aS)— 2— fluorotetrahydro—1月— pyrrol izin— 7a(5方 0— yl )methoxy)— 2— methyl— 2月— pyrazolo[4,3— / ]quinazol in— 9— yl )- 3 , 8~d i azabi eye lo[3.2.1]oct an— 8— y 1 )met hanone; (195) 4-(7-((1-((4-(Difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-fluoro-2-methyl-9-((1R,5S)-3-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (196) 4-(9-((1R,5S)-8-((2,2-Difluorocyclopropyl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H- 404 pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (197) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1 J 6 i -pyrrolizin-7a(5 J 60 _ yl)methoxy)-2-methyl-9-((1R,5S)-8-(4,4,4-trifluorobutyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (198) 3—((1R,5S)—3—(4—(8—Ethynyl—7—fluoro—3—hydroxynaphthalen—1—yl)—5—fluoro—7—(((2R,7aS)—2—fluorotetrahydro—1H—pyrrolizin—7a(5H)—yl)methoxy)—2—methyl—2H—pyrazolo[4,3—f]quinazol—9—yl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—3—oxopropanenitrile; (199) 1—((1R,5S)—3—(4—(8—Ethynyl—7—fluoro—3—hydroxynaphthalen—1—yl)—5—fluoro—7—(((2R,7aS)—2—fluorotetrahydro—1H—pyrrolizin—7a(5H)—yl)methoxy)—2—methyl—2H—pyrazolo[4,3—f]quinazol—9—yl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—4,4,4—trifluorobutan—1—one; (200) ((1R,5S)—3—(4—(8—Ethynyl—7—fluoro—3—hydroxynaphthalen—1—yl)—5—fluoro—7—(((2R,7aS)—2—fluorotetrahydro—1H—pyrrolizin—7a(5H)—yl)methoxy)—2—methyl—2H—pyrazolo[4,3—f]quinazolin—9—yl)—3,8—diazabicyclo[3.2.1]octan—8—yl)(oxetan—3—yl)methanone; (201) 4-(1-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-8-methyl-3-(((4aR,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)furo[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (202) 4-(1-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-8-methyl-3-(((4aR,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)furo[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (203) (5)-7-(4-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione; (204) (』?)— 7— (4— (8— Ethynyl— 7— f luoro— 3— hydroxynaphthalen— 1—yl )-5 -f luoro- 7— (((2』?, 7aS)— 2— f luorotetrahydro— 1月— pyrrolizin— 7a(5方 0— yl)methoxy)— 2— methyl— 2月— pyrazolo[4,3- / ]quinazol in- 9- yl)- 1,3,7- triazaspiro[4.5]decane- 2,4- dione; (205) 2- (((1』?, 55)- 3- (6- (8- Ethynyl- 7- fluoro- 3- hydroxynaphthalen- 1-yl)- 5— f luoro— 3— (((2』?, 7aS)— 2— f luorotetrahydro— 1月— pyrrol izin— 7a(5方 0— yl)methoxy)— 8— 405 methylfuro[3,2- / ]quinazol in-l-y 1)-3, 8~di azabi cyclo [3.2.1] oct an-8- yl )methyl )propane— 1, 3-diol; (206) 4- (9- ((1乃,55)- 3,8- Diazabicyclo[3.2.1]octan- 3- yl)- 7- (((乃 )- 2,2- di f luoro— 1—( ((5)—3— f luoropyrrol idin-l-yl )methyl )cyclopropyl )methoxy)— 5 — f luoro— 2— methyl— 2月— pyrazolo[4,3— / ]quinazol in— 4— yl )— 5— ethynyl— 6 — f luoronaphthalen-2-ol; (207) 5-Ethynyl-6-fluoro-4-(5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1-((1R,5S)-8-((2- (hydroxymethyl)cyclopropyl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-methylfuro[3,2-f]quinazolin-6-yl)naphthalen-2-ol; (208) 5-Ethynyl-6-fluoro-4-(5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-1-((1R,5S)-8-((1-methylazetidin-3-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)furo[3,2-f]quinazolin-6-yl)naphthalen-2-ol; (209) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1 J 6 i -pyrrolizin-7a(5 J 60 _ yl)methoxy)-2-methyl-9-((1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-amine; (210) 4-(9-((1α,5α)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(((R)-3-Fluoropyrrolidin-1-yl)methyl)cyclobutyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-c]quinazol-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (211) 2-((1α,5α)-3-(4-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2α,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H))yl)methoxy)-2-methyl-2H-pyrazolo[4,3-c]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)_ N,N-Dimethyl acetamide; (212) 4-(9-((1α,5α)-8-((2,2-Difluorocyclopropyl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((R)-1-((dimethyl amino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-c]quinazol-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (213) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2α,7aS)-2-fluorotetrahydro-1 J 6 i-pyrrolizin-7a(5 J 60 _ yl)methoxy)-2-methyl-9-((17?,5S)-8-(3,3,3-trifluoropropyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2H-pyrazolo[4,3-i]quinazol-4-yl)naphthalen-2-ol; 406 (214) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2H-pyrazolo[4,3-i]quinazol-4-yl)naphthalen-2-ol; (215) (1-(Dimethylamino)cyclopropyl)(CR,5S)-8-(4-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-i]quinazol-9-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methanone; (216) ((1S,5S)-3-(4-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2S,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(oxetan-2-yl)methanone; (217) (2,2-Difluorocyclopropyl)((1S,5S)-3-(7-(((1R)-1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-4-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone; (218) ((1S,5S)-3-(4-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2S,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(2-(trifluoromethyl)cyclopropyl)methanone; (219) ((1R,5S)-3-(4-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-c]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(3-methyloxetan-3-yl)methanone; (220) ((1R,5S)-3-(4-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-c]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(1H-1,2,4-triazol-3-yl)methanone; (221) ((1R,5S)-3-(4-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-c]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(1-hydroxycyclopropyl)methanone; (222) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)-8-(2- 407 (trifluoromethoxy)ethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2H-pyrazolo[4,3-c]quinazol-4-yl)naphthalen-2-ol; (223) 4-(9-((1R,5S)-8-((2,2-Difluorocyclobutyl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-c]quinazol-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (224) 4-(9-((1R,5S)-8-(2-(2,2-Difluorocyclopropyl)ethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-c]quinazol-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (225) 5-Ethynyl-6-fluoro-4-(5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1 J 6i -pyrrolizin-7a(5 J 60 _ yl)methoxy)-1-((1R,5S)-8-(3-(methoxy-ι-propyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-methyl furo[3,2-f]quinazolin-6-yl)naphthalen-2-ol; (226) 4—(9—((1R,5S)—3—((2,2-Difluorocyclopropyl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)—5-fluoro-7—(((2R,7aS)—2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)—2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)—5-ethynyl-6-fluoronaphthalen-2-ol; (227) 5—Ethynyl—6-fluoro—4—(5-fluoro-7—(((2R,7aS)—2-fluorotetrahydro— 1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)-8-((1-methyl-1H-imidazol-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (228) 5—Ethynyl—6-fluoro—4—(5-fluoro-7—(((2R,7aS)—2-fluorotetrahydro—1 J 6 i -pyrrolizin-7a(5 J 60 _yl)methoxy)-2-methyl-9-((17?,5S)-3-propyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-2^pyrazolo[4,3- / ]quinazolin-4-yl)naphthalen-2-ol; (229) 4-(9-((1^5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(((S)-l-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-2-methyl- 2H—pyrazolo[4,3— / ]quinazolin—4—yl)—5—ethynyl—6—fluoronaphthalen—2—ol; (230) (』?)- 4- ((1』?, 55)- 3- (4- (8-Ethynyl- 7-fluoro- 3-hydroxynaphthalen- 1-yl)—5—fluoro—7—(((2』?, 7aS)—2—fluorotetrahydro—1H—pyrrolizin—7a(5H0—yl)methoxy)—2—methyl—2H—pyrazolo[4,3— / ]quinazolin—9—yl)—3,8—diazabicyclo[3.2.1]octane-8-carbonyl) oxetan—2—one; 408 (231) (5)-4-((1R,5S)-3-(4-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl))-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)oxetan-2-one; (232) 4-(7-((1-((3-Azabicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methoxy)-9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (233) 4-(7-((1-((3-Azabicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methoxy)-5-fluoro-2-methyl-9-((1R,5S)-8-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (234) (IS, 5』?)— 8— (4— (8— Ethynyl— 7— f luoro— 3— hydroxynaphthalen— 1— yl )—5 — f luoro— 7— (((2』?, 7aS)— 2— f luorotetrahydro— 1月— pyrrol izin— 7a(5方 0— yl)methoxy)— 2— methyl- 2月- pyr azo lo [4, 3- / ] quinazol in- 9- yl)- 3,8- di azabi cyclo [3.2.1] oct an- 2- one; (235) ((5)- 2,2- Dif luorocyclopropyl)(CL / ?, 55)- 3- (4- (8- ethynyl- 7- f luoro- 3— hydroxynaphthalen— 1—yl)— 5— fluoro— 7— (((2』?, 7aS)— 2— fluorotetrahydro—1月— pyrrol izin— 7a(5方 0— yl )methoxy)— 2— methyl— 2月— pyrazolo[4,3— / ]quinazol in— 9— yl )- 3, 8~d i azabi eye lo[3.2.1]oct an— 8— y 1 )met hanone; (236) 5— Ethynyl— 6— fluoro— 4— (5— fluoro— 7— (((2』?, 7aS)— 2— fluorotetrahydro— 1月- pyrrol izin— 7a(5方 0— yl )methoxy)-2-methy 1-9-( (17?, 5S)-8-((5- (trif luoromethyl)furan— 2— yl)methyl)— 3,8— diazabicyclo[3.2.1]octan— 3— yl)— 2月— pyrazolo[4,3— / ]quinazol in— 4— yl )naphthalen— 2— ol; (237) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1 J 6 i -pyrrolizin-7a(5 J 60 _ yl)methoxy)-2-methyl-9-((1R,5S)-8-(5,5,5-trifluoropentyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2H-pyrazolo[4,3-c]quinazol-4-yl)naphthalen-2-ol; (238) 4-(9-((1R,5S)-8-((4,5-dihydro-1H-imidazol-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-c]quinazol-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (239) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)0-yl)methoxy)-9-((1R,5S)-3-(3-methoxypropyl)-3,8~ 409 diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-c]quinazol-4-yl)naphthalen-2-ol; (240) 4-(9-((1^5S)-3-((2,2-Difluorocyclobutyl)methyl)-3,8- diazabicyclo[3.2.1]octan—8—yl)—5—fluoro—7—(((2』?,7aS)—2—fluorotetrahydro—1月—pyrrolizin—7a(5方0—yl)methoxy)—2—methyl—2月—pyrazolo[4,3— / ]quinazolin—4—yl)—5—ethynyl-6-fluoronaphthalen—2—ol; (241) 5—Ethynyl—6—fluoro—4—(5—fluoro—7—(((2』?, 7aS)—2—fluorotetrahydro—1月-pyrrolizin-7a(5方0-yl)methoxy)- 2-methyl- 9- ((L?, 5S)- 3- (oxetan- 3-ylmethyl)- 3,8—diazabicyclo[3.2.1]octan—8—yl)—2月—pyrazolo[4,3—f]quinazolin-4_ yl )naphthalen—2—ol; (242) 5—Ethynyl—6—fluoro—4—(5—fluoro—7—(((2』?, 7aS)—2—fluorotetrahydro— 1月-pyrrolizin- 7a(5方0-yl)methoxy)- 2-methyl- 9- ((L?, 5S)- 3- (oxetan- 2-ylmethyl)- 3.8—diazabicyclo[3.2.1]octan—8—yl)—2月—pyrazolo[4,3—f]quinazolin-4_ yl )naphthalen—2—ol; (243) 5-Ethynyl-6-fluoro-4-(5-fluoro-9-((1R,5S)-3-(2-fluoroethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-4-yl)naphthalen-2-ol; (244) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1 J 6 i -pyrrolizin-7a(5 J 60 _ yl)methoxy)-2-methyl-9-((1R,5S)-3-(3,3,3-trifluoropropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-i]quinazolin-4-yl)naphthalen-2-ol; (245) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1 J 6 i -pyrrolizin-7a(5 J 60 _ yl)methoxy)-2-methyl-9-((1R,5S)-3-(4,4,4-trifluorobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-i]quinazolin-4-yl)naphthalen-2-ol; (246) 2-(2,2-Difluorocyclopropyl)-1-((1ʹR,5S)-3-(4-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2ʹR,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5ʹH)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-9-yl)- 3,8-diazabicyclo[3.2.1]octan-8-yl)ethan-1-one; (247) 1-((1ʹR,5S)-3-(4-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2ʹR,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5ʹH)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5,5,5-trifluoropentan-1-one; 410 (248) Aziridin-2-yl ((1ʹR,5S)-8-(4-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2ʹR,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5ʹH)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methanone; (249) 4—(9—((1R,5S)—3—(Cyclopropylmethyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—5—fluoro—7—(((2R,7aS)—2—fluorotetrahydro—1H—pyrrolizin—7a(5H)—yl)methoxy)—2—methyl—2H—pyrazolo[4,3—f]quinazolin—4—yl)—5—ethyl—6—fluoronaphthalen—2—ol; (250) 5—Ethynyl—6—fluoro—4—(5—fluoro—7—(((2R,7aS)—2—fluorotetrahydro—1H—pyrrolizin—7a(5H)—yl)methoxy)—2—methyl—9—((1R,5S)—8—(4,4,4—trifluoro—2—hydroxybutyl)—3,8—diazabicyclo[3.2.1]octan—3—yl)—2H—pyrazolo[4,3—f]quinazolin—4—yl)naphthalen—2—ol; (251) 5—Ethynyl—6—fluoro—4—(5—fluoro—7—(((2R,7aS)—2—fluorotetrahydro—1H—pyrrolizin—7a(5H)—yl)methoxy)—9—((1R,5S)—3—((R)—2—hydroxypropyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2H—pyrazolo[4,3—f]quinazolin—4—yl)naphthalen—2—ol; (252) 5—Ethynyl—6—fluoro—4—(5—fluoro—7—(((2R,7aS)—2—fluorotetrahydro—1 J 6 i -pyrrolizin-7a(5J 60 _ yl)methoxy)-9-((17?,5S)-3-(2-methoxyethyl)-3,8-diazabicyclo[3.

2. l]octan—8—yl)—2—methyl—2月—pyrazolo[4,3— / ]quinazol in—4—yl)naphthalen—2—ol; (253) 4-(7-(((』?)-2,2-Difluoro-1-(((5)-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)—5—fluoro—2—methyl—9—((1』?,55)—8—(oxetan—3—ylmethyl)—3,8—diazabi cyclo[3.2.1]octan—3—yl)—2月—pyrazolo[4,3— / ]quinazol in—4—yl)—5—ethynyl—6—fluoronapht ha1en-2-o1; (254) 4-(9-((1^5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-((l-((4-(fluoromethylene)piperidin-l-yl)methyl)cyclopropyl)methoxy)—2—methyl—2月—pyrazolo[4,3— / ]quinazol in—4—yl)—5—ethynyl—6—fluoronaphthalen—2—ol; (255) ((1R,5S)-3-(7-((1U)-2,2-Difluoro-1-(((5)-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)—4—(8—ethynyl—7—fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro—2—methyl—2H—pyrazolo[4,3—i]quinazol-9-yl)—3,8-diazabicyclo[3.2.1]octan-8-yl)(2-(trifluoromethyl)cyclopropyl)methanone; (256) 1-((1R,5S)-3-(7-((1U)-2,2-Difluoro-1-(((5)-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)—4—(8—ethynyl—7—fluoro-3-hydroxynaphthalen-1- 411 yl)-5-fluoro—2—methyl—2H—pyrazolo[4,3—i]quinazol-9-yl)—3,8-diazabicyclo[3.2.1]octan-8-yl)—4,4,4-trifluorobutan-1-one; (257) 1-((M,5S)-3-(7-((1U)-1-((Dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-4-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro—2—methyl—2H—pyrazolo[4,3—i]quinazol-9-yl)—3,8-diazabicyclo[3.2.1]octan-8-yl)—4,4,4-trifluorobutan-1-one; (258) 4— (7— (((IS, 7a’ 5)— 2,2— Difluorodihydro— 1’β, 3 ’β— spiro [cyclopropane— 1,2’ -pyrrolizin]-7a' (5'750-yl)methoxy)-5-fluoro-2-methyl-9-((17?,5S)-3-(oxetan- 3- ylmethyl)— 3,8— diazabicyclo[3.2.1]octan— 8— yl)— 2β— pyrazolo[4,3— / ]quinazolin— 4-yl )— 5— ethynyl— 6— fluoronaphthalen— 2— ol; (259) 5— Ethynyl— 6— fluoro— 4— (5— fluoro— 7— (((2β, 7aS)— 2— fluorotetrahydro— 1β— pyrrolizin— 7a(5β 0— yl )methoxy)-2-methyl-9-((17?,5S)-3-((tetrahydrofuran-2- yl)methyl)— 3,8— diazabicyclo[3.2.1]octan— 8— yl)— 2β- pyrazolo[4,3— / ]quinazolin— 4— yl )naphthalen— 2— ol; (260) 4- (7- (((IS, 7a’ 5)- 2,2- Difluorodihydro- 3 ’β- spiro [cyclopropane- 1,2’ -pyrrolizin]-7a' (5 ] )methoxy)-5-fluoro-9-( (17?, 5S)-3-(3- methoxypropyl)— 3,8— diazabicyclo[3.2.1]octan— 8— yl)— 2— methyl— 2β— pyrazolo[4,3 — / ]quinazolin— 4— yl )—5— ethynyl— 6— fluoronaphtha 1 en-2-o 1; (261) (2,2-Difluorocyclopropyl)(CL / ?, 55)-3-(4-(8-ethynyl-7-fluoro-3-hydroxynaphthalen—1—yl)—5—fluoro—7—(((2』?, 7aS)-2-fluorotetrahydro—1月—pyrrolizin—7a(5 J 60-yl)methoxy)—2—methyloxazolo[5,4— / ]quinazolin—9—yl)—3,8—diazabicyclo[3.2.1]octan—8—y1)methanone; (262) 4-(7-((C / ?)-l-((Dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)—5—fluoro—9—((1』?, 55)—3—(3—methoxypropyl)—3,8—diazabicyclo[3.

2. l]octan—8—yl)—2—methyl—2月—pyrazolo[4,3— / ]quinazolin—4—yl)—5—ethynyl-6-fluoronaphthalen-2-ol; (263) ((1』?, 55)-3-(7-(((』?)-1-((Dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)—4—(8—ethynyl—7—fluoro-3-hydroxynaphtha1en-l-y1)- 5-fluoro—2—methyl—2月—pyrazolo[4,3— / ]quinazolin—9—yl)—3,8—diazabicyclo[3.2.1]octan—8—yl)(2—(trifluoromethyl)cyclopropyl)methanone; (264) 4-(7-(((』?)-1-((Dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)—5—fluoro—2—methyl—9—((1』?,55)—3—(oxetan—3— 412 ylmethyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2月—pyrazolo[4,3— / ]quinazol in—4—yl)—5—ethynyl—6—f1uoronapht ha1en-2-o1; (265) 5—Ethynyl—6—fluoro—4—(5—fluoro—7—(((2』?,7aS)—2—fluorotetrahydro—1月—pyrrol izin—7a(5方0—yl)methoxy)-2-methy 1-9-((1』?,5S)-8-((2- (trifluoromethyl)cyclopentyl)methyl)—3,8—diazabicyclo[3.2.1]octan—3—yl)—2月—pyrazolo[4,3— / ]quinazol in—4—yl)naphthalen—2—ol; (266) 5—Ethynyl—6—fluoro—4—(5—fluoro—7—(((2』?,7aS)—2—fluorotetrahydro— 1月—pyrrol iz in-7a(5方0-yl)methoxy)-2-methyl-9-((1』?,55)-8-(((L?,2』?)-2- (trifluoromethyl)cyclobutyl)methyl)—3,8—diazabicyclo[3.2.1]octan—3—yl)—2H—pyrazolo[4,3— / ]quinazol in—4—yl)naphthalen—2—ol; (267) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)-3-((2- (trifluoromethyl)cyclopentyl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-i]quinazolin-4-yl)naphthalen-2-ol; (268) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)- -3-(((1R,2R)-2- (trifluoromethyl)cyclobutyl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-i]quinazolin-4-yl)naphthalen-2-ol; (269) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-((1-((4-(fluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-methyl-9- ((1R,5S)-8-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2H-pyrazolo[4,3-i]quinazolin-4-yl)naphthalen-2-ol; (270) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2ʹ,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-((1R,5S)-3-(3-hydroxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (271) 4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-((1-(((Z)-3-(fluoromethylene)pyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (272) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2ʹ,7aS)-2-fluorotetrahydro-1 J 6 i -pyrrolizin-7a(5 J 60 _ yl)methoxy)-9-((1R,5S)-3-(4-methoxybutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; 413 (273) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)-3-((tetrahydro-2H-pyran- 3-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-i]quinazolin- 4-yl)naphthalen-2-ol; (274) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)-3-((tetrahydrofuran-3-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-i]quinazolin-4-yl)naphthalen-2-ol; (275) 4-(7-((Cis)-1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-isobutyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (276) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1 J 6 i -pyrrolizin-7a(5 J60 _ yl)methoxy)-9-((17?,5S)-3-(2-hydroxy-2-methylpropyl)-3,8- diazabicyclo[3.

2. l]octan— 8— yl )— 2— methyl— 2月— pyrazolo[4,3— / ]quinazol in— 4— yl )naphthalen— 2— ol; (277) 5— Ethynyl— 6— fluoro— 4— (5— fluoro— 7— (((2』?, 7aS)— 2— fluorotetrahydro— 1月— pyrrol izin— 7a(5方 0— yl )methoxy)-2-methyl-9-((17?,5S)-3-((2-methyloxetan-2- yl)methyl)— 3,8— diazabicyclo[3.2.1]octan— 8— yl)— 2月- pyrazolo[4,3— / ]quinazolin— 4— yl )naphthalen— 2— ol; (278) 4- (7- (((5)- 2- (Di f luoromethylene)tetrahydro- 1月- pyrrol izin- 7a(5方 0- yl )methoxy)-5-f luoro— 9— ( (1』?, 5 S) - 3 - ( 3 -me t hoxyp r opy 1 )-3 , 8- diazabicyclo[3.

2. l]octan— 8— yl )— 2— methyl— 2月— pyrazolo[4,3— / ]quinazol in— 4— yl )—5— ethynyl-6-f luoronaphthalen— 2— ol; (279) 4-(7-((C / ?)-l-((Dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-2-methyl-9-((1』?, 55)-8-(( (1』?, 2S)-2-(trifluoromethyl)cyclopropyl)methyl)—3,8—diazabicyclo[3.2.1]octan—3—yl)—2月—pyrazolo[4,3— / ]quinazol in—4—yl )—5—ethynyl—6—fluoronaphthalen—2—ol; (280) 5—Ethynyl—6—fluoro—4—(5—fluoro—7—(((2』?, 7aS)—2—fluorotetrahydro— 1月-pyrrol iz in-7a(5方0-yl)methoxy)-2- methyl-9-((1』?, 55)-3-(( (1』?, 2』?)-2- (trifluoromethyl)cyclopropyl)methyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2月—pyrazolo[4,3— / ]quinazol in—4—yl )naphthalen—2—ol; 414 (281) 1- ((M,5S)-8-(7- ((U)-l-((Dimethylamino)methyl)-2,2-difluorocyclopropyl ) me t hoxy ) -4 - ( 8-ethyny 1 -7 -fluoro-3-hydroxynaphtha 1 en-l-y 1 )- 5-fluoro—2—methyl—2月—pyrazolo[4,3— / ]quinazol in—9—yl )—3,8—diazabicyclo[3.

2. l]octan—3—yl )—3—methoxypropan—1—one; (282) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2ʹ,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5ʹH)-yl)methoxy)-9-((1S,5R)-2-(hydroxymethyl)-3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-c]quinazolin-4-yl)naphthalen-2-ol; (283) 4-(9-((1S,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-((1-(((1S,5S,6S)-6-fluoro-3-azabicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methoxy)-2-methyl-2H-pyrazolo[4,3-c]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (284) 4-(9-((1S,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(((S)-4- (difluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-c]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (285) 4-(9-((1S,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(((S)-4- ((Difluoromethylene)-1,3—dimethylpiperidin—3—yl)methoxy)—5—fluoro—2—methyl—2H—pyrazolo[4,3—f]quinazol—4—yl)—5—ethynyl—6—fluoronaphthalen—2—ol; (286) 4-(7-((Cis)-1-((Dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)—9—((1R,5S)—3—ethyl—3,8—diazabicyclo[3.2.1]octan—8-yl)-5-fluoro—2—methyl—2H—pyrazolo[4,3—f]quinazol—4—yl)—5—ethynyl—6-fluoronaphthalen-2-ol; (287) 5-Ethyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H))-yl)methoxy)-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2H—pyrazolo[4,3—f]quinazol—4—yl)naphthalen—2—ol; (288) 4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(((R)-2,2-difluoro—1—((3-fluoroazetidin-1-yl)methyl)cyclopropyl)methoxy)—5—fluoro-2-methyl—2H—pyrazolo[4,3—f]quinazol—4—yl)—5—ethynyl—6-fluoronaphthalen—2—ol; (289) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyloxazolo[5,4-i]quinazolin-4-yl)naphthalen-2-ol; 415 (290) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)-3-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)oxazolo[5,4-i]quinazolin-4-yl)naphthalen-2-ol; (291) 4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-i]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (292) 4-(9-((1S,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-c]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (293) 4-(9-((1S,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-2-methyl-7-(((1-(((1R,5S,6R)-6-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methoxy)-2H-pyrazolo[4,3-c]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (294) 4-(9-((1S,5S)-3,8-Diazabicyclo[3.2.1]octan-8-yl)-7-(((S)-1-((4-(difluoromethylene)piperidin-1-yl)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-c]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (295) 4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-8-yl)-7-(((R)-1-((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (296) 4-(9-((1R,5S)-3-((3-(Difluoromethyl)oxetan-3-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7-(((R)-1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (297) 4-(7-(((R)-1-((1,1-Difluoro-6-azaspiro[2.5]octan-6-yl)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (298) 4-(7-((C / ?)-1-((4-(Difluoromethylene)piperidin-1-yl)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-9-((17?,5S)-3-(3-methoxypropyl)-3,8 - 416 diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2月—pyrazolo[4,3— / ]quinazol in—4—yl)—5—ethynyl-6-fluoronaphthalen—2—ol; (299) 4-(7-((C / ?)-1-((Dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)—5—fluoro—9—((1』?,55)—3—(3-methoxybutyl)—3,8 —diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2月—pyrazolo[4,3— / ]quinazol in—4—yl)—5—ethynyl-6-fluoronaphthalen—2—ol; (300) 4-(7-(((』?)-1-((Dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)—5—fluoro—9—((l』?,5S)—3—(3-methoxy—2—methylpropyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2月—pyrazolo[4,3 — / ]quinazol in—4—yl)—5—ethynyl—6—fluoronaphtha 1 en-2-o 1; (301) 3— ((1ʹ,5ʹ)— 8— (4— (8— Ethynyl— 7— fluoro— 3— hydroxynaphthalen— 1— yl )—5 — fluoro— 7— (((2ʹ,7aS)— 2— fluorotetrahydro— 1ʹH— pyrrolizin— 7a(5ʹH)— yl)methoxy)— 2— methyl— 2ʹH— pyrazolo[4,3— f]quinazolin— 9— yl)— 3,8— diazabicyclo[3.2.1]octan-3_ yl )propyl carbamate; (302) 4- (9- ((1ʹ,5ʹ)- 3,8- Diazabicyclo[3.2.1]octan- 8- yl)- 7- (((1ʹ)-2,2- difluoro-l-(((1ʹ,5ʹ,6ʹ)-6—(trifluoromethyl)—3— azabicyclo[3.1.0]hexan— 3— yl )methyl )cyclopropyl )methoxy)— 5— fluoro— 2— methyl— 2ʹH— pyrazolo[4,3 — f]quinazolin— 4— yl )—5— ethynyl— 6— fluoronaphtha 1 en-2-ol; (303) 4- (9- ((1ʹ,5ʹ)- 3,8- Diazabicyclo[3.2.1]octan- 8- yl)- 7- (((1ʹ)-2,2- difluoro-l-(((1ʹ,5ʹ,6ʹ)-6 -fluoro-3-azabicyclo [3.1.0]hexan-3- yl )methyl )cyclopropyl )methoxy)— 5— fluoro— 2— methyl— 2ʹH— pyrazolo[4,3 — f]quinazolin— 4— yl )—5— ethynyl— 6— fluoronaphtha 1 en-2-ol; (304) 4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-8-yl)-7-((U)-1-((3-(difluoromethylene)pyrrolidin-1-yl)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (305) 4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-8-yl)-7-(((R)-2,2-difluoro-1-((3-fluoroazetidin-1-yl)methyl)cyclopropyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (306) 4-(7-(((?)-1-((3-(Difluoromethylene)pyrrolidin-1-yl)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-9-((1?,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 417 (307) 4-(7-((C / ?)-2,2-Difluoro-l-((3-fluoroazetidin-l-yl)methyl)cyclopropyl)methoxy)— 5— fluoro— 9—((1』?, 55)— 3— (3— methoxypropyl)— 3, 8 — diazabicyclo[3.

2. l]octan— 8— yl )— 2— methyl— 2月— pyrazolo[4,3— / ]quinazol in— 4— yl )—5— ethynyl-6-f luoronaphthalen— 2— ol; (308) 4- (9- ((1乃,55)- 3,8- Diazabicyclo[3.2.1]octan- 8- yl)- 7- (((乃)-1- ((diethylamino)methyl)— 2,2— dif luorocyclopropyl)methoxy)— 5— f luoro— 2— methyl— 2月— pyrazolo[4,3— / ]quinazol in— 4— yl )— 5— ethynyl— 6— f luoronaphthalen— 2— ol; (309) 4- (9- ((1乃,55)- 3,8- Diazabicyclo[3.2.1]octan- 8- yl)- 7- (((乃 )- 2,2- di f luoro— 1— ((methylamino)methyl )cyclopropyl )methoxy)— 5— f luoro— 2— methyl— 2月— pyrazolo[4,3— / ]quinazol in— 4— yl )—5— ethynyl— 6— f luoronaphthalen— 2— ol; (310) 4-(7-(((1S)-2,2-difluoro-1-((6-fluoro-3-azabicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1S,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (311) 4-(7-(((1R)-2,2-difluoro-1-(((1R,5S,6R)-6-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (312) 4-(7-(((1R)-1-(((1R,5S)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (313) 4-(7-((1-((3-oxa-8-aza-bicyclo[3.2.1]octan-8-yl)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-c]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (314) 4-(7-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-c]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (315) 4-(7-((cis)-1-((diethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-c]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 418 (316) 4-(7-(((』?)-1-((Ethyl (2, 2, 2-trifluoroethyl) amino)methyl)-2, 2-difluorocyclopropyl)methoxy)—5—fluoro—9—(((1』?, 55)-3-(3-methoxypropyl)—3, 8-diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2月—pyrazolo[4,3— / ]quinazol in—4—yl)—5—ethynyl-6-fluoronaphthalen—2—ol; (317) 4-(7-((l-((4-Oxa-7-azaspiro[2.5]octan-7-yl)methyl)cyclopropyl)methoxy)—5—fluoro—9—(((1』?, 55)-3-(3-methoxypropyl)—3, 8-diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2月—pyrazolo[4,3— / ]quinazol in—4—yl)—5—ethynyl-6-fluoronaphthalen—2—ol; (318) 4-(7-((l-((Diethylamino)methyl ) cyclopropyl )methoxy)—5—fluoro-9-(((L?, 5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-y 1)-2-methyl-2月—pyrazolo[4,3— / ]quinazol in—4—yl)—5—ethynyl—6—fluoronaphthalen—2—ol; (319) 4-(7-(((^)-2,2-Difluoro-1-((methylamino)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (320) 5-Ethynyl-6-fluoro-4-(5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-7-((1-((6-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methoxy)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (321) 4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-8-yl)-7-(((R)-1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (322) 4-(7-((1-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (323) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5R)-2,2,3-trimethyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (324) 4-(7-((1-((4-(Difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8- 419 diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (325) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-2-methyl-7-((1-((6-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methoxy)-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (326) 4-(7-(((R)-1-((Dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-9-((1R,5S)-3-(3-ethoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (327) 4-(7-((R)-1-((Dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-((3-(methoxymethyl)oxetan-3-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (328) 5-Ethynyl-6-fluoro-4-(5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-7-(((R)-4-methylmorpholin-2-yl)methoxy)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (329) 4-(7-((S)-3-(Dimethylamino)pyrrolidin-1-yl)-5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (330) 4-(7-((1-((1,1-Difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (331) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1 J 6 i -pyrrolizin-7a(5 J 60 _yl)methoxy)-2-methyl-9-((17?,5S)-3-methyl-3,8-diazabicyclo[3.2.1]octan—8—yl—2,2,4,4—d4)—2月—pyrazolo[4,3—f]quinazol in-4-yl)naphthalen—2—ol; (332) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2』?,7a』?)-2-fluoro-6- pyrrol iz in—7a(5方0—yl)methoxy)-9-((17?,5S)-3-(4-methoxybutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2月—pyrazolo[4,3~ / ]quinazol in—4—yl)naphthalen—2—ol; 420 (333) 5—Ethynyl—6—f luoro—4—(5—f luoro—7—((1—((3—methoxy—3—methylazet idin-l-yl)methyl)cyclopropyl)methoxy)—9—((L?,5S)—3—(3—methoxypropyl)—3,8—di azabi cyclo [3.2.1] oct an—8—y 1)—2—methyl—2月—pyr azo lo [4, 3 — / ]quinazol in—4—yl)naphthalen—2—ol; (334) 4-(7-((1-(((4,4- Di f luorocyclohexyl)(methyl)amino)methyl)cyclopropyl)methoxy)—5—fluoro-9- ((L?, 5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (335) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2S, 7a』?)-2-fluoro-6- pyrrolizin-7a(5S)-yl)methoxy)-9-((1R, 5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3 -i]quinazolin-4-yl)naphthalen-2-ol; (336) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2』?, 7aS)-2-fluorotetrahydro-1 J 6 i -pyrrolizin-7a(5 J 60 _ yl)methoxy)-9-((1R,5S)-8-(3-methoxybutyl)-3,8-diazabicyclo[3.

2. l]octan-3-yl)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-4-yl)naphthalen-2-ol; (337) 4-(9-((1S,5S)-8-(3-Ethoxypropyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2S,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)yl)methoxy)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (338) (A , a)-(2,2-Difluorocyclopropyl)((1S,5S)-3-(7-(((S)-1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-4-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-5-fluoro-2-methyl-2H-pyrazolo[4,3-i]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone; (339) (5a)-(2,2-Difluorocyclopropyl)((1S,5S)-3-(7-(((S)-1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-4-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-5-fluoro-2-methyl-2H-pyrazolo[4,3-i]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone; (340) (7&)-((17?, 5S)-3-(7-(( (7?)-l-( (Dimethyl ami no)methyl )-2,2- di f luorocyclopropyl )methoxy)— 4— (8— ethynyl— 7— f 1 uor o-3-hydr oxynaphtha 1 en-l-y 1 )- 5-f luoro— 2— methyl— 2月— pyrazolo[4,3— / ]quinazol in— 9— yl )—3,8— diazabicyclo[3.2.1]octan— 8— yl )(2— (tri fluoromethyl) cyclopropyl )methanone; 421 (341) (5a)-((17?, 5S)-3-(7-(( (7?)-l-( (Dimethyl ami no)methyl )-2,2- di f luorocyclopropyl ) me t hoxy ) -4 - ( 8-e t hyny 1 -7 -f 1 uor o-3-hydr oxynaphtha 1 en-l-y 1 )- 5-f luoro— 2— methyl— 2月— pyrazolo[4,3— / ]quinazol in— 9— yl )—3,8— diazabicyclo[3.2.1]octan— 8— yl )(2— (tri fluoromethyl) cyclopropyl )methanone; (342) (Sa)— 5— Ethynyl— 6— fluoro— 4— (5— fluoro— 7— (((2 ^,7aS)—2 — f luorotetrahydro- 1月- pyrrol izin- 7a(5方 0- yl)methoxy)- 9- ((L?, 5S)_3_(3_ methoxypropyl)— 3,8— di azabi cyclo [3.2.1] oct an— 8— y 1)—2— methyl— 2月— pyr azo lo [4, 3 — / ]quinazol in— 4— yl )naphthalen— 2— ol; (343) (is a)—5—Ethynyl—6—fluoro—4—(5—fluoro—7—(((2^,7aS)—2—fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-((1R,5S)_3_(3_methoxypropyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2H-pyrazolo[4,3—f]quinazolin-4-yl)naphthalen-2-ol; (344) 4-(7-((l-(((S)-3-(Dimethylamino)pyrrolidin-l-yl)methyl)cyclopropyl)methoxy)—5—fluoro—9—((1R,5S)—3—(3—methoxypropyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2H-pyrazolo[4,3—f]quinazolin-4-yl)—5—ethynyl-6-fluoronaphthalen-2-ol; (345) 5—Ethynyl—6—fluoro—4—(5—fluoro-7-((l-((3- (methoxymethyl)pyrrolidin-l-yl)methyl)cyclopropyl)methoxy)—9—((1R,5S)—3—(3—methoxypropyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2H-pyrazolo[4,3—f]quinazolin-4-yl)naphthalen-2-ol; (346) 4-(7-((C / ?)-1-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-2,2-difluorocyclopropyl)methoxy)—5—fluoro—9—((1』?, 55)—3—(3-methoxypropyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2H—pyrazolo[4,3— / ]quinazolin—4—yl)—5—ethynyl-6-fluoronaphthalen—2—ol; (347) 4-(7-((1-((6,6-Difluoro-3-azabicyclo[3.1.3]hexan-3-yl)methyl)cyclopropyl)methoxy)—5—fluoro—9—((1』?, 55)—3—(3-methoxypropyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2H—pyrazolo[4,3— / ]quinazolin—4—yl)—5—ethynyl-6-fluoronaphthalen—2—ol; (348) 5—Ethynyl—6—fluoro—4-(5—fluoro—7—((1-((3-(fluoromethyl)azetidin—1-yl)methyl)cyclopropyl)methoxy)—9—((1』?, 55)—3—(3-methoxypropyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2H—pyrazolo[4,3— / ]quinazolin—4—yl)naphthalen—2—ol; 422 (349) 4-(7-(((1S, 27?)-1-((Dimethylamino)methyl)-2- ((trifluoromethyl)cyclopropyl)methoxy)—5—fluoro—9—((1ʹR,5S)—3—(3—methoxypropyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2H—pyrazolo[4,3—f]quinazolin—4—yl)—5—ethynyl—6—fluoronaphthalen—2—ol; (350) 4-(9-((1ʹR,5S)-3,8-Diazabicyclo[3.2.1]octan-8-yl)-7-(((1ʹR,2S)-1-((dimethylamino)methyl)-2-(trifluoromethyl)cyclopropyl)methoxy)—5—fluoro-2—methyl—2H—pyrazolo[4,3—f]quinazolin—4—yl)—5—ethynyl—6—fluoronaphthalen—2—ol; (351) 4-(9-((1ʹR,5S)-3,8-Diazabicyclo[3.2.1]octan-8-yl)-7-(((1ʹR,2S)-1-((dimethylamino)methyl)-2-(trifluoromethyl)cyclopropyl)methoxy)—5—fluoro-2—methyl—2H—pyrazolo[4,3—f]quinazolin—4—yl)—5—ethynyl—6—fluoronaphthalen—2—ol; (352) 4-(7-(((1ʹR,2S)-1-((Dimethylamino)methyl)-2- ((trifluoromethyl)cyclopropyl)methoxy)—5—fluoro—9—((1ʹR,5S)—3—(3—methoxypropyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2H—pyrazolo[4,3—f]quinazolin—4—yl)—5—ethynyl—6—fluoronaphthalen-2-ol; (3S,3) 4-(7-(((3S,4S)-4-(Difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-5-fluoro—9—((1ʹR,5S)—3—(3—methoxypropyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2H—pyrazolo[4,3—f]quinazolin—4—yl)—5—ethynyl-6—fluoronaphthalen-2-ol; (3R,4R) 4-(7-(((3ʹR,4ʹR)-4-(Difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-5-fluoro—9—((1ʹR,5S)—3—(3—methoxypropyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2H—pyrazolo[4,3—f]quinazolin—4—yl)—5—ethynyl-6—fluoronaphthalen-2-ol; (355) 5-Ethynyl-6-fluoro-4-(5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-7-((1-(((R)-2-methylmorpholino)methyl)cyclopropyl)methoxy)-2H-pyrazolo[4,3-f]quinazol-4-yl)naphthalen-2-ol; (356) 4-(7-((1-(((2R,6S)-2,6- Dimethylmorpholino)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazol-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (357) 4-(7-((1-(((3S,5R)-3,5-Difluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8- 423 diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazol-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (358) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-((1-(((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)methyl)cyclopropyl)methoxy)-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (359) 4-(7-((1-((2-oxa-5-azabicyclo[2.2.2]octan-5-yl)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (360) 4-(7-((1-((6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (361) 4-(7-((1-(((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)cyclopropyl)methoxy))-5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-b]quinazol-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (362) 5-Ethynyl-6-fluoro-4-(5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)- 3,8-diazabicyclo[3.2.1]octan-8-yl)-7-((1-(((5)-3-methoxypyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-2-methyl-2H-pyrazolo[4,3-b]quinazol-4-yl)naphthalen-2-ol; (363) 5-Ethynyl-6-fluoro-4-(5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)- 3,8-diazabicyclo[3.2.1]octan-8-yl)-7-((1-(((R)-3-methoxypyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-2-methyl-2H-pyrazolo[4,3-b]quinazol-4-yl)naphthalen-2-ol; (364) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-((1-(((5)-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-9-((1ʹ,5ʹ)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (365) 5-Ethynyl-6-fluoro-4-(5-fluoro-9-((1ʹ,5ʹ)-3-(3-methoxypropyl)- 3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-7-((1-((4- 424 (trifluoromethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (366) 4-(7-(((1-(((3-oxa-7-azabicyclo[3.3.1]nonan-7-yl)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1ʹ,5ʹ)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (367) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-((1-((3-fluoro-3-methylazetidin-1-yl)methyl)cyclopropyl)methoxy)-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (368) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-((1-((3-isopropoxyazetidin-1-yl)methyl)cyclopropyl)methoxy)-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (369) 5-Ethynyl-6-fluoro-4-(5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-7-((1-((3-methylazetidin-1-yl)methyl)cyclopropyl)methoxy)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (370) 1—((1— (((4— (8— Ethynyl— 7— fluoro— 3— hydroxynaphthalen—l—yl )—5 — f luoro— 9— ((L?, 55)— 3— (3— methoxypropyl)— 3,8— di azabi cyclo [3.2.1] oct an-8-y 1)-2- methyl— 2月— pyrazolo[4,3— / ]quinazol in— 7— yl ) oxy ) me t hy 1 ) eye 1 op r opy 1 )methyl )-3- (trif luoromethyl )azet idin-3-ol; (371) 4-(7-((l-((8-0xa-3-azabicyclo[3.2.1]octan-3- yl)methyl)cyclopropyl)methoxy)— 5— fluoro— 9—((1』?, 55)— 3— (3— methoxypropyl)— 3, 8 — diazabicyclo[3.

2. l]octan— 8— yl )— 2— methyl— 2月— pyrazolo[4,3— / ]quinazol in— 4— yl )—5— ethynyl-6-f luoronaphthalen— 2— ol; (372) 4- (7-(((乃 )-2, 2- Di fluoro- 1-(((1乃 ,55,65)-6- fluoro- 3- azabi cyclo [3.1.0]hexan— 3— yl )methyl )cyclopropyl )methoxy)— 5— f luoro—2—methyl—9— ((1』?, 55)- 3- (oxetan- 3- ylmethyl)- 3,8- diazabicyclo[3.2.1]octan- 8- yl)- 2月- pyrazolo[4,3— / ]quinazol in— 4— yl )—5— ethynyl— 6— f luoronaphthalen— 2— ol; (373) 4 - (7 - (((』?)-1 - ((3 - (Difluoromethylene)pyrrolidin - 1 - yl)methyl)-2,2 - difluorocyclopropyl)methoxy) - 5 - fluoro - 2 - methyl - 9 - ((1』?,55) - 3 - (oxetan - 3— 425 ylmethyl) - 3,8 - diazabicyclo[3.2.1]octan - 8 - yl) - 2H - pyrazolo[4,3 - f]quinazolin - 4 - yl) - 5 - ethynyl - 6 - fluoronaphthalen - 2 - ol; (374) 5 - Ethynyl - 6 - fluoro - 4 - (5 - fluoro - 2 - methyl - 9 - ((1』?,5S) - 3 - (oxetan - 3—ylmethyl)-3,8 - diazabicyclo[3.2.1]octan - 8 - yl)-7 - ((1 - (((1』?,55\ 67?) - 6 - (trifluoromethyl) - 3 - azabicyclo[3.1.0]hexan - 3 - yl)methyl)cyclopropyl)methoxy)-2H - pyrazolo[4,3 - f]quinazolin - 4 - yl)naphthalen - 2 - ol; (375) 4 - (7 - (((』?)-1 - ((4 - (Difluoromethylene)piperidin - 1 - yl)methyl)-2,2 - difluorocyclopropyl)methoxy) - 5 - fluoro - 2 - methyl - 9 - ((1』?,55) - 3 - (oxetan - 3 - ylmethyl) - 3,8 - diazabicyclo[3.2.1]octan - 8 - yl) - 2H - pyrazolo[4,3 - f]quinazolin - 4 - yl) - 5 - ethynyl - 6 - fluoronaphthalen - 2 - ol; (376) 4-(7-(((3ʹ,4ʹ)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-5-fluoro-2-methyl-9-((1ʹ,5S)-3-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (377) 4-(7-(((5)-4-(Difluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)-5-fluoro-2-methyl-9-((1ʹ,5S)-3-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (378) 4-(7-(((ʹ)-2,2-Difluoro-1-((3-fluoroazetidin-1-yl)methyl)cyclopropyl)methoxy)-5-fluoro-2-methyl-9-((1ʹ,5S)-3-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; (379) 5-Ethynyl-6-fluoro-4-(5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-7-((1-((3-(oxetan-3-ylmethyl)azetidin-1-yl)methyl)cyclopropyl)methoxy)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (380) 4-(7-((1-((7-oxa-1-azaspiro[4.4]nonan-1-yl)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (381) 4-(7-((1-((6-oxa-2-azaspiro[3.4]octan-2-yl)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8 - 426 diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (382) 5-Ethynyl-6-fluoro-4-(5-fluoro-9-((1ʹ,5ʹ)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-7-((1-((tetrahydro-1,7-oxa[3,4-c]pyrrol-5(3H)-yl)methyl)cyclopropyl)methoxy)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (383) 4-(7-((1-((2-Oxa-5-azabicyclo[4.1.0]heptan-5-yl)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1ʹ,5ʹ)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (384) 4-(7-((1-((7,7-Difluoro-3-azabicyclo[4.1.0]heptan-3-yl)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1ʹ,5ʹ)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (385) 4-(7-((1-((6,6-Difluoro-2-azabicyclo[2.2.1]heptan-2-yl)methyl)cyclopropyl)methoxy)—5—fluoro—9—((1R,5S)—3—(3-methoxypropyl)—3,8 —diazabicyclo[3.2.1]octan—8—yl)—2-methyl—2H—pyrazolo[4,3—f]quinazolin—4—yl)—5—ethynyl-6-fluoronaphthalen—2—ol; (386) 4-(7-(((R)-1-((Diethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)—5—fluoro—2—methyl—9—((1R,5S)—3—(oxetan—3-ylmethyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2H—pyrazolo[4,3—f]quinazolin—4—yl)—5—ethynyl—6—fluoronaphthalene-2-ol; (387) 4-(9-((1R,5S)-3-(2-oxaspiro[3.3]heptan-6-yl)-3,8-diazabicyclo[3.2.1]octan—8—yl)—5—fluoro—7—(((2R,7aS)—2-fluorotetrahydro—1H—pyrrolizin—7a(5H))-yl)methoxy)—2—methyl—2H—pyrazolo[4,3—f]quinazolin—4—yl)—5—ethynyl-6-fluoronaphthalen—2—ol; (388) 5-Ethynyl-6-fluoro-4-(5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-7-((1-((2- (trifluoromethyl)morpholino)methyl)cyclopropyl)methoxy)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (389) (2,2-Difluorocyclopropyl)((1R,5S)-3-(7-(((1S)-1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-4-(8-ethynyl-7- 427 fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-2-methyloxazolo[5,4-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone; (390) 4-(7-((1-((3-(Diethylamino)azetidin-1-yl)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (391) 1—((1— (((4—(8—Ethynyl—7—fluoro—3—hydroxynaphthalen—1—yl)—5—fluoro—9—((L?,55)—3—(3—methoxypropyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)-2—methyl—2H—pyrazolo[4,3— / ]quinazol in—7—yl)oxy)methyl)cyclopropyl)methyl)—N,N—dimethylazetidine—3—carboxamide; (392) 5—Ethynyl—6—fluoro—4—(5—fluoro—7—((l—((3—(2—hydroxypropan—2—yl)azetidin—l—yl)methyl)cyclopropyl)methoxy)—9—((1』?,55)—3—(3—methoxypropyl)- 3,8—diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2H—pyrazolo[4,3— / ]quinazo1in—4—yl)naphthalen—2—ol; (393) 4-(7-((l-((3-((Dimethylamino)methyl)azetidin—l—yl)methyl)cyclopropyl)methoxy)—5—fluoro—9—((1』?,55)—3—(3—methoxypropyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2H—pyrazolo[4,3— / ]quinazol in—4—yl)—5—ethynyl-6—fluoronaphthalen—2—ol; (394) 5—Ethynyl—6—fluoro—4—(5—fluoro—9—((1』?,55)—3—(3—methoxypropyl)- 3.8— Diazabicyclo[3.2.1]octan— 8— yl)— 2— methyl— 7— ((1— ((3,3,4— trimethylpiperazin— 1-yl )methyl )cyclopropyl )methoxy)— 2H— pyrazolo[4,3— f]quinazol in— 4— yl )naphthalen— 2— ol; (395) 4- (7- (((R)- 2,2- Dif luoro- 1-((3- fluor oazeti din- 1- yl )methyl )cyclopropyl )methoxy)— 5— f luoro— 2— methyl— 9—((1R, 5S)— 3— (oxetan— 3— ylmethyl )— 3,8— di azabi cyclo [3.2.1] oct an— 8— yl )— 2H— pyrazolo[4,3— f]quinazol in— 4— yl )—5— ethynyl— 6— f 1 uor onapht ha 1 en-2-o 1; (396) 5- Ethyl- 6- fluoro- 4- (5- fluoro- 7- (((S,Z)- 2- (f luoromethylene)tetrahydro— 1H— pyrrol izin— 7a(5H0— yl ) me t hoxy ) -2~me t hy 1 -9- ((1R, 5S)- 8- (oxetan- 3- ylmethyl)- 3,8- di azabi cyclo [3.2.1] oct an- 3- y 1)-2H- pyrazolo[4,3— f]quinazol in— 4— yl )naphthalen— 2— ol; (397) 4- (7- (((5)- 2- (Di f luoromethylene)tetrahydro- 1H- pyrrol iz in- 7a(5H60- yl)methoxy)- 5- fluoro- 2- methyl- 9- ((L?,5S)- 8- (oxetan- 3- ylmethyl)- 3,8- 428 (3,8-diazabicyclo[3.2.1]octan-3-yl)-2H-pyrazolo[4,3-c]quinazolin-4-yl)-5-ethyl-6-fluoronaphthalen-2-ol; (398) 4-(7-((1-((1,1-Difluoro-5-azaspiro[2.4]heptan-5-yl)methyl)cyclopropyl)methoxy)-5-fluoro-2-methyl-9-((1R,5S)-3-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-c]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (399) 1-((1-(((4-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-2-methyl-9-((1R,5S)-3-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-c]quinazolin-7-yl)oxy)methyl)cyclopropyl)methyl)-3-methylazetidin-3-ol; (400) 4-(7-((1-((1,1-Difluoro-5-azaspiro[2.3]hexan-5-yl)methyl)cyclopropyl)methoxy)-5-fluoro-2-methyl-9-((1R,5S)-3-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (401) 4-(7-((1-((7-Oxa-4-azaspiro[2.5]octan-4-yl)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (402) 4-(7-((1-((4-Ethyl-1,4-diazepan-1-yl)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (403) (5a)-4-(9-((1^5S)-3-Ethyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro—7—(((2』?, 7aS)—2-fluorotetrahydro—1月—pyrrolizin—7a(5方0—yl)methoxy)—2-methyl—2月—pyrazolo[4,3— / ]quinazolin—4-yl)—5-ethynyl—6-fluoronaphthalen—2—ol; (404) (A , a)-4-(9-((1^5S)-3-Ethyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro—7—(((2』?, 7aS)—2-fluorotetrahydro—1月—pyrrolizin—7a(5方0—yl)methoxy)—2-methyl—2月—pyrazolo[4,3— / ]quinazolin—4-yl)—5-ethynyl—6-fluoronaphthalen—2—ol; (405) 5—Ethynyl—6-fluoro—4-(5-fluoro—9-((1』?, 55)—3-(3-methoxypropyl)-3, 8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl -7-(((1-(((4-(2, 2,2-trifluoroethyl)piperazin—1—yl)methyl)cyclopropyl)methoxy)—2』¥—pyrazolo[4,3 — / ]quinazolin—4-yl)naphthalen—2—ol; 429 (406) 4—(7—((1—(((3,3—Dimethylmorpholino)methyl)cyclopropyl)methoxy)—5—fluoro—9—((L?,55)—3—(3—methoxypropyl)—3,8—diazabicyclo[3.2.1]octan-8-yl)-2-methyl—2H—pyrazolo[4,3— / ]quinazolin—4-yl)—5—ethynyl—6—fluoronaphthalen—2—ol; (407) 4—(7—((1—(((2,2—Dimethylmorpholino)methyl)cyclopropyl)methoxy)—5—fluoro—9—((L?,55)—3—(3—methoxypropyl)—3,8—diazabicyclo[3.2.1]octan-8-yl)-2-methyl—2H—pyrazolo[4,3— / ]quinazolin—4-yl)—5—ethynyl—6—fluoronaphthalen—2—ol; (408) ((1’?,55)-3-(7-((((R)-1—((Dimethylamino)methyl)-2,2—difluorocyclopropyl)methoxy)—4—(8—ethynyl—7—fluoro-3-hydroxynaphthalen-1-yl)-5—fluoro—2—methyloxazolo[5,4— / ]quinazolin—9-yl)—3,8—diazabicyclo[3.2.1]octan—8-yl)(2—(trifluoromethyl)cyclopropyl)methanone; (409) 5-Ethynyl-6-fluoro-4-(5-fluoro-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-7-((1-((3-morpholinoazetidin-1-yl)methyl)cyclopropyl)methoxy)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (410) 2-Amino-5-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)-3-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)benzo[b]thiophene-3-carbonitrile; (411) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)-3-(2-(methylsulfonyl)ethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (412) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)-3-(3-(methylsulfonyl)propyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-c]quinazol-4-yl)naphthalen-2-ol; (413) 2-Amino-5-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-((1R,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-c]quinazol-4-yl)benzothiophene-3-carbonitrile; (414) (1a)-5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)-3- 430 (oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-c]quinazol-4-yl)naphthalen-2-ol; (415) (Sa)—5—Ethynyl—6—fluoro—4—(5—fluoro—7—(((2^,7aS)—2—fluorotetrahydro—1ʹH—pyrrolizin—7a(5ʹH)—yl)methoxy)—2—methyl—9—((1ʹR,5ʹS)—3—(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2ʹH—pyrazolo[4,3-ʹf]quinazolin-4-yl)naphthalen-2—ol; (416) 5—Ethynyl—6—fluoro—4—(5—fluoro—9—((1ʹR,5ʹS)—3—(3-methoxypropyl)-3,8—diazabicyclo[3.2.1]octan-8-yl)—2—methyl—7—((1—((3—(pyrrolidin-1-yl)azetidin-1-yl)methyl)cyclopropyl)methoxy)—2ʹH—pyrazolo[4,3-ʹf]quinazolin-4-yl)naphthalen-2—ol; (417) 4-(9-((1ʹR,5ʹS)-3,8-Diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-7-(((2ʹR,7aS)—2—fluorotetrahydro—1ʹH—pyrrolizin—7a(5ʹH)—yl)methoxy)—2—methyl—2ʹH—pyrazolo[4, 3-ʹf] quinazo1in-4-yl)-2-amino-5 -fluorobenzo[b]thiophene-3-carbonitrile; (418) 5—Ethynyl—6—fluoro—4—(5—fluoro—7—((1—((3—fluoro-3- ((methoxymethyl)pyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-2-methyl-9-((1R,5S)-3-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (419) 4-(7-((1-((1-oxa-7-azaspiro[4.4]nonan-7-yl)methyl)cyclopropyl)methoxy)-5-fluoro-2-methyl-9-((1R,5S)-3-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (420) 4-(9-((1R,5S)-3-(2-oxaspiro[3.3]heptan-6-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7-(((S)-1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (421) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)-3-(3-(methylthio)propyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (422) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)-3-(3-(methylthio)butyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-f]quinazolin-4- 431 yl)naphthalen-2-ol; (423) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((1R,5S)-3-(thietan-3-ylmethyl)- 3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (424) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-(((1R,5S)-3-(thietan-2-ylmethyl)- 3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (425) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-(((1R,5S)-3-((tetrahydrothiophen- 3-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-f]quinazolin- 4-yl)naphthalen-2-ol; (426) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-(((1R,5S)-3-((tetrahydro-2H-pyran-2-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (427) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-((1R,5S)-3-(3-(methoxymethyl)cyclobutyl)- 3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (428) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-((1R,5S)-3-(3-methoxycyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (429) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-((1R,5S)-3-((3-methoxycyclobutyl)methyl)- 3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol; (430) 4-(9-((1^5S)-3-(6-oxaspiro[3.4]octan-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-7-(((2』?,7aS)-2-fluorotetrahydro-1月-pyrrolizin-7a(5方0-yl)methoxy)-2-methyl-2H-pyrazolo[4,3— / ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 432 (431) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-((((2』?,7aS)-2-fluorotetrahydro-1月-pyrrolizin-7a(5方0-yl)methoxy)-9-((17?,5S)-3-(6-methoxyspiro[3.3]heptan-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2月-pyrazolo[4,3- / ]quinazolin_4-yl)naphthalen-2-ol; (432) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-((((2』?,7aS)-2-fluorotetrahydro-1月-pyrrolizin-7a(5方0-yl)methoxy)-9-((1』?,55)-3-(2-(methoxymethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2月-pyrazolo[4,3— / ]quinazo1in-4-yl)naphthalen-2-ol; (433) 4—(7—((1—((2—Oxa—8—azaspiro[5.5]undecan—8—yl)methyl)cyclopropyl)methoxy)—5—fluoro—2—methyl—9—((1′R,5′S)—3—(oxetan—3—ylmethyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2H—pyrazolo[4,3—f]quinazolin—4—yl)—5—ethynyl—6—fluoronaphthalen-2-ol; (434) 4-(7-((1-(((5)-3-(Dimethylamino)pyrrolidin-1-yl)methyl)cyclopropyl)methoxy)—5—fluoro—2—methyl—9—((1′R,5′S)—3—(oxetan—3—ylmethyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2H—pyrazolo[4,3—f]quinazolin—4—yl)—5—ethynyl—6—fluoronaphthalen-2-ol; (435) 5—Ethynyl—6—fluoro—4—(5—fluoro-7-((l-((3- (methoxymethyl)pyrrolidin-l-yl)methyl)cyclopropyl)methoxy)-2~methyl-9-((1′R,5′S)—3—(oxetan-3—ylmethyl)-3,8—diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3—f]quinazolin—4—yl)naphthalen—2—ol; (436) 4-(9-((1^5S)-3-(6-0xaspiro[3.4]octan-2-yl)-3,8- diazabicyclo[3.2.1]octan— 8— yl)— 5— f luoro— 7— (((2』?,7aS)— 2— f luorotetrahydro— 1月— pyrrol izin— 7a(5方 0— yl )methoxy)— 2— methyl— 2月— pyrazolo[4,3— / ]quinazol in— 4— yl )—5— ethynyl-6-f luoronaphthalen— 2— ol; (437) 4-(7-((C / ?)-l-((Dimethylamino)methyl)-2,2- difluorocyclopropyl)methoxy)— 5— fluoro— 9—((1』?, 55)— 3— (3— methoxycyclobutyl)— 3, 8 — diazabicyclo[3.

2. l]octan— 8— yl )— 2— methyl— 2月— pyrazolo[4,3— / ]quinazol in— 4— yl )—5— ethynyl-6-f luoronaphthalen— 2— ol; (438) 5— Ethynyl— 6— fluoro— 4— (5— fluoro— 7— ((1— (((』?)— 3— fluoropyrrol i din— 1— yl )methyl )cyclopropyl )methoxy)— 9— ((L?,5S)— 3— (3— (methoxymethyl )cyclobutyl )- 3,8— di azabi cyclo [3.2.1] oct an— 8— y 1)—2— methyl— 2月— pyr azo lo [4,3— / ]quinazo 1 in— 4— yl )naphthalen— 2— ol; (439) 5- Ethynyl- 6- f luoro- 4-(5- f luoro- 9-( (1乃, 55)- 3-(3- 433 ((methoxymethyl)(ethylbutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-7-(((3R,4R)-1-methyl-4-(trifluoromethyl)pyrrolidin-3-yl)methoxy)-2H-pyrazolo[4,3-i]quinazolin-4-yl)naphthalen-2-ol; (440) 4-(7-((((R)-1-((Dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3- ((methoxymethyl)(ethylbutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (441) 5-Ethyl-6-fluoro-4-(5-fluoro-7-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- _ yl)methoxy)-9-((1R,5S)-3-(3-(methoxymethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-4-yl)naphthalen-2-ol; (442) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((3′,4′)-4-methoxy-1,3-dimethylpiperidin-3-yl)methoxy)-2-methyl-9-((1′,5S)-3-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-i]quinazolin-4-yl)naphthalen-2-ol; (443) 4-(7-(((5)-4,4-Difluoro-1,3-dimethylpiperidin-3-yl)methoxy)-5-fluoro-2-methyl-9-((1′,5S)-3-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-i]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (444) 4-(7-(((5)-4,4-Difluoro-1,3-dimethylpiperidin-3-yl)methoxy)-5-fluoro-2-methyl-9-((1′,5S)-3-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-i]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (445) 4-(7-(((』?)-1-((Dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)—5—fluoro—2—methyl—9—((1』?, 5,5)—3—(oxetan—3—ylmethyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2H—pyrazolo[4,3— / ]quinazolin—4—yl)—5—ethyl—6—fluoronaphthalen-2-ol; (446) 5-Ethyl-6-fluoro-4-(5-fluoro-7-(((2』?, 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-((L?, 5$)-3-(oxetan-2-ylmethyl)-3,8~diazabicyclo[3.2.1]octan—8—yl)—2H—pyrazolo[4,3— / ]quinazolin—4—yl)naphthalen—2-ol; (447) 4-(7-((( ^)-2,2-Difluoro-l-(((3- (methoxymethyl)cyclobutyl)(methyl)amino)methyl)cyclopropyl)methoxy)—5—fluoro- 434 9-((1』?, 55)-3-(3-(methoxymethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8 - yl)—2—methyl—2H—pyrazolo[4,3— / ]quinazolin—4—yl)—5—ethynyl—6—fluoronaphthalene-2-ol; (448) 5-Ethynyl-6-fluoro-4-(5-fluoro-9-(((1R,5S)-3-(3- (methoxymethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7-(((1-(((S)-3-methoxypyrrolidin-1-yl)methyl)cyclopropyl)methoxy)—2—methyl—2H—pyrazolo[4,3—f]quinazolin-4-yl)naphthalen-2-ol; (449) 4-(7-((((R)-2,2-Difluoro-1-(((3- (methoxymethyl)cyclobutyl)amino)methyl)cyclopropyl)methoxy)—5—fluoro-9-((1R,5S)-3-(3-(methoxymethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2—methyl—2H—pyrazolo[4,3—f]quinazolin-4-yl)—5—ethynyl—6—fluoronaphthalen-2-ol; (450) 4-(7-((((1R,7a'S)-2,2-Difluorodihydro- 3'H-spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5 ] )methoxy)-5-fluoro-9-((1R,5S)-3-(3- ((methoxymethyl)(cyclobutyl))-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-c]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (451) 4-(7-(((R)-1-((4-(Difluoromethylene)piperidin-1-yl)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3- ((methoxymethyl)(cyclobutyl))-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-c]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (452) 4-(7-(((3S,4S)-4-(Difluoromethyl)-1-ethyl-3-methylpiperidin-3-yl)methoxy)-5-fluoro-2-methyl-9-((1R,5S)-3-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-c]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (453) 4-(7-(((3R,4R)-4-(Difluoromethyl)-1-ethyl-3-methylpiperidin-3-yl)methoxy)-5-fluoro-2-methyl-9-((1R,5S)-3-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-c]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (454) 4-(7-(((3S,4S)-4-(Difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-5-fluoro-2-methyl-9-((1R,5S)-3-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-c]quinazolin-4-yl)-5-ethyl-6-fluoronaphthalen-2-ol; (455) 4-(7-(((3S,4S)-4-(Difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-5-fluoro-2-methyl-9-((1R,5S)-3-(oxetan-3-ylmethyl)-3,8- 435 diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-c]quinazolin-4-yl)-5-ethyl-6-fluoronaphthalen-2-ol; (456) 4-(7-((1-((1-Oxa-8-azaspiro[4.5]decan-8-yl)methyl)cyclopropyl)methoxy)-5-fluoro-2-methyl-9-((1R,5S)-3-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (457) 4-(7-((1-((2-Oxa-8-azaspiro[4.5]decan-8-yl)methyl)cyclopropyl)methoxy)-5-fluoro-2-methyl-9-((1R,5S)-3-(oxetan-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (458) 4-(7-(((5)-2-(Difluoromethylene)tetrahydro-1R-pyrrolizin-7a(5'H,6'H)-yl)methoxy)-5-fluoro-9-((1R,5S)-3-(3-(methoxymethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (459) 4-(9-((1^5S)-3-(2-oxaspiro[3.3]heptan-6-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7-(((7?)-1-(((2-oxaspiro[3.3]heptan-6-yl)amino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3- / ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (460) 4-(9-((1^5S)-3-(2-oxaspiro[3.3]heptan-6-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7-((C / ?)-2,2-difluoro-1-((methyl(2-oxaspiro[3.3]heptan—6-yl)amino)methyl)cyclopropyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3- / ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (461) 4-(7-((1-(((3-(Difluoromethyl)pyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1』?,5S)-3-(3- (methoxymethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3- / ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (462) 5-Ethynyl-6-fluoro-4-(5-fluoro-9-((1R,5S)-3-(3-(methoxymethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-7-((1-((5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)cyclopropyl)methoxy)-2H-pyrazolo[4,3-f]quinazol-4-yl)naphthalen-2-ol; (463) 4-(7-((1-((2-Oxa-6-azaspiro[3.4]octan-6-yl)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3- (methoxymethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H- 436 pyrazolo[4,3-f]quinazol-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (464) 4-(7-((((R)-1-((Dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3- (methoxymethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazol-4-yl)-5-ethynyl-6-fluoronaphthalen-2-amine; (465) 4-(9-((1^5S)-3-(2-oxaspiro[3.3]heptan-6-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7-(((7?)-1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-i]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-amine (466) 4-(9-((17?,5S)-3-(2-oxaspiro[3.3]heptan-6-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7-(((7?)-1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-i]quinazolin-4-yl)-2-amino-5-fluorobenzo[b]thiophene-3-carbonitrile (467) 2-Amino-4-(7-(((7?)-1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-9-((17?,5S)-3-(3- (methoxymethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-4-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (468) 4-(7-(((』?)-1-((Dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)—5—fluoro—9—((1』?,5S)-3-(3- (methoxymethyl)cyclobutyl)—3,8-diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2月-pyrazolo[4,3— / ]quinazolin—4—yl)—5—ethyl—6—fluoronaphthalen—2—ol; (469) 4-(9-((1^5S)-3-(2-oxaspiro[3.3]heptan-6-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7-(((7?)-l-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)—5—fluoro—2—methyl—2月—pyrazolo[4,3— / ]quinazolin— 4-yl)—5—ethyl—6—fluoronaphthalene-2-ol; (470) 2-(((1』?,55)-8-(4-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)- 5-fluoro—7—((((2』?,7aS)—2—fluorotetrahydro—1月—pyrrolizin—7a(5方0—yl)methoxy)—2—methyl—2月—pyrazolo[4,3— / ]quinazolin—9—yl)—3,8—diazabicyclo[3.2.!]octan-3_yl)methyl)cyclobutan-1-one: (471) 4-(9-((1^5S)-3-(l-0xaspiro[3.3]heptan-6-yl)-3,8-diazabicyclo[3.2.1]octan—8—yl)—5—fluoro—7—(((2』?,7aS)—2—fluorotetrahydro—1月—pyrrolizin—7a(5方0—yl)methoxy)—2—methyl—2月—pyrazolo[4,3— / ]quinazolin—4—yl)—5—ethynyl-6-fluoronaphthalen-2-ol; 437 (472) 5-Ethyny1-6-fluoro-4-(5-fluoro-7-((((2』?,7aS)-2-fluorotetrahydro-1月—pyrrolizin—7a(5方0—yl)methoxy)—9—((L?,5S)—3—(3—(methoxymethyl)cyclobutyl)-3,8—diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2月—pyrazolo[4,3— / ]quinazolin—4—yl)naphthalen—2—yl carbamate; (473) 4-(7-((((』?)-2,2-Difluoro-1-((methyl(2-oxaspiro[3.3]heptan-6-yl)amino)methyl)cyclopropyl)methoxy)—5—fluoro—9—((1』?,5S)-3-(3- (methoxymethyl)eyelobutyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2月-pyrazolo[4,3— / ]quinazolin—4—yl)—5—ethynyl—6—fluoronaphtha1en-2-o1; (474) 5-Ethynyl-1,6-difluoro-4-(5-fluoro-7-(((2β,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-((1β,5S)-3-((3- (methoxymethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-c]quinazol-4-yl)naphthalen-2-ol; (475) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2β,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-((1β,5S)-3-((3-methoxybicyclo[1.1.1]pentan-1-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-c]quinazol-4-yl)naphthalen-2-ol; (476) 3-((1β,5S)-8-(4-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2β,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-c]quinazol-9-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)cyclobutan-1-one; (477) 5— (4— (8— Ethynyl— 7— fluoro— 3— hydroxynaphthalen— 1— yl )— 5— fluoro-9- ( (1ʹ, 5ʹ)- 3- (3- (methoxymethyl )cyclobutyl )- 3, 8- diazabicyclo[3.2.1]octan- 8- yl )- 2— methyl— 2ʹ— pyrazolo[4, 3— f]quinazol in— 7— yl )—#,쑤 dimethy Ip i col inamide; (478) 4- (7- (2- (Dimethylamino)ethyl )-5-fluoro-9-( (1ʹ, 5ʹ)-3-(3- ( methoxyme t hy 1 ) eye 1 obu t y 1 )— 3, 8— di azabi cyclo [3.

2. 1] oct an— 8— yl )—2— methyl— 2ʹ- pyrazolo[4, 3— f]quinazol in— 4— yl )—5— ethynyl— 6— fluoronaphtha 1 en-2-o 1; (479) 4- (7- ( ( (3S, 4S)- 4- (Difluoromethyl )-1- methylpyrrol i din- 3- yl )methoxy)- 5- fluoro- 9-( (1ʹ, 5ʹ)- 3- (3- (methoxymethyl )cyclobutyl )-3, 8 - diazabicyclo[3.

2. l]octan— 8— yl )— 2— methyl— 2ʹ— pyrazolo[4, 3— f]quinazol in— 4— yl )—5— ethynyl-6-fluoronaphtha len-2-ol; (480) 4-(7-(((3ʹ,4ʹ)-4-(Difluoromethyl)-1-methylpyrrolidin-3-yl)methoxy)-5-fluoro-9-(((1ʹ,5ʹ)-3-(3-(methoxymethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5- 438 ethynyl-6-fluoronaphthalen-2-ol; (481) 4-(7-(((1-((Dimethylamino)methyl)cyclopropyl)methoxy)-5-fluoro-9-(((1ʹ,5ʹ)-3-(3-(methoxymethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (482) 4-(7-(((1-((Diethylamino)methyl)cyclopropyl)methoxy)-5-fluoro-9-(((1ʹ,5ʹ)-3-(3-(methoxymethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (483) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-((((2ʹ,7aS)-2-fluorotetrahydro-1 J 6 i -pyrrolizin-7a(5J 60 _ yl)methoxy)-2-methyl-9-((17?,5S)-8-methyl-3,8-diazabicyclo[3.

2. l]octan—3—yl)oxazolo[5,4— / ]quinazol in—4—yl)naphthalen—2—ol; (484) 4-(7-((C / ?)-l-((Dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)—5—fluoro—2—methyl—9—((l』?,5S)—8—methyl—3,8-diazabicyclo[3.

2. l]octan—3—yl)oxazolo[5,4— / ]quinazol in—4—yl)—5—ethynyl—6—fluoronaphthalen-2-ol; (485) 5—Ethynyl—6—fluoro—4—(5—fluoro—7—(((2』?,7aS)—2—fluorotetrahydro-1月-pyrrolizin-7a(5方0-yl)methoxy)-9-((1』?,55)-3-(3-methoxy cyclobutyl)-3,8 -diazabicyclo[3.

2. l]octan—8—yl)—2—methyl—2月-pyrazolo[4,3— / ]quinazol in—4—yl)naphtha 1 err 2—amine; (486) 4- (7-(((』?)-1-((Diethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)—5—fluoro—9—((1』?,5S)-3-(3- ((methoxymethyl)ethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (487) 4-(9-((1R,5S)-3-(2-oxaspiro[3.3]heptan-6-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H))-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-4-yl)-5-ethyl-6-fluoronaphthalen-2-ol; (488) 4-(7-(((R)-1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-((3-methoxycyclobutyl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3-i]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (489) 4-(7-((1-((7-oxa-2-azaspiro[3.5]nonan-2-yl)methyl)cyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3- (methoxymethyl)ethyl) - 3,8 - diazabicyclo[3.2.1]octan - 8 - yl) - 2 - methyl - 2H - 439 pyrazolo[4,3 - f]quinazolin - 4 - yl) - 5 - ethynyl - 6 - fluoronaphthalen - 2 - ol; (490) 4 - (7 - (((S) - 4 - (Difluoromethylene) - 1,3 - dimethylpiperidin - 3 - yl)methoxy) - 5 - fluoro - 9 - ((1R,5S) - 3 - (3 - (methoxymethyl)cyclobutyl) - 3,8 - diazabicyclo[3.2.1]octan - 8 - yl) - 2 - methyl - 2H - pyrazolo[4,3 - f]quinazolin - 4 - yl) - 5 - ethynyl - 6 - fluoronaphthalen - 2 - ol; (491) 4 - (7 - (((R) - 4 - (Difluoromethylene) - 1,3 - dimethylpiperidin - 3 - yl)methoxy) - 5 - fluoro - 9 - ((1R,5S) - 3 - (3 - (methoxymethyl)cyclobutyl) - 3,8 - diazabicyclo[3.2.1]octan - 8 - yl) - 2 - methyl - 2H - pyrazolo[4,3 - f]quinazolin - 4 - yl) - 5 - ethynyl - 6 - fluoronaphthalen - 2 - ol; (492) 5 - Ethynyl - 6 - fluoro - 4-(5 - fluoro - 7 - (((3S,4S) - 4 - methoxy - 1,3 - dimethylpiperidin - 3 - yl)methoxy) - 2 - methyl - 9 - ((1R,5S) - 3 - (oxetan - 3 - ylmethyl)- (3.8—diazabicyclo[3.2.1]octan—8—yl)—2H—pyrazolo[4,3 - f]quinazolin - 4 - yl)naphthalen—2—ol; (493) 5 - Ethynyl - 6 - fluoro - 4-(5 - fluoro - 7 - (((2R,7aS)-2 - fluorotetrahydro - 1H - pyrrolizin—7a(5H)-yl)methoxy)—2—methyl—9—((1R,5S)-3 - (((R)-tetrahydrofuran— 3—yl)methyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2H—pyrazolo[4,3—f]quinazolin— 4—yl)naphthalen—2—ol; (494) 5 - Ethynyl - 6 - fluoro - 4-(5 - fluoro - 7 - (((2R,7aS)-2 - fluorotetrahydro - 1H—pyrrolizin—7a(5H)-yl)methoxy)—2—methyl—9—((1R,S^-S-CCC^-tetrahydrofur arr 3—yl)methyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2H—pyrazolo[4,3—f]quinazolin— 4—yl)naphthalen—2—ol; (495) 4-(7-((C / ?)-1-((Dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)—5—fluoro—9—((1』?, 55)—3—(3—methoxycyclobutyl)—3,8—diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2月—pyrazolo[4,3— / ]quinazol in—4—yl)—5—ethyl-6-fluoronaphthalen-2-ol; (496) 5-Ethynyl-6-fluoro-4-(5-fluoro-9-((1乃, 5S)-3-(3-(methoxymethyl)cyclobutyl)-3,8~diazabicyclo[3.2.1]octan-8-yl)-2,7-dimethyl- 2月—pyrazolo[4,3— / ]quinazol in—4—yl)naphthalen—2—ol; (497) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2』?, 7aS)-2-fluorotetrahydro-1月-pyrrolizin—7a(5方0—yl)methoxy)—9—((L?,5S)—3—(3—(methoxymethyl)cyclobutyl)- 3.8—diazabicyclo[3.2.1]octan—8—yl)—2—methyl—2月—pyrazolo[4,3— / ]quinazo 1 in—4—yl)naphtha 1 err 2—amine; (498) 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2』?, 7aS)-2-fluorotetrahydro- 440 1H-Pyrrolo[3,2-c]pyridin-7a(5H)-yl)methoxy)-9-((1R,5S)-3-((1S,2S)-2- (methoxymethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]oct-8-yl)-2-methyl-2H-pyrazolo[4,3-c]quinazol-4-yl)naphthalen-2-ol; (499)(5S)-(4-(7-(((R)-1-((Dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3- (methoxymethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]oct-8-yl)-2-methyl-2H-pyrazolo[4,3-c]quinazol-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (500)(R)-4-(7-(((R)-1-((Dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-9-((1R,5S)-3-(3- (methoxymethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]oct-8-yl)-2-methyl-2H-pyrazolo[4,3-c]quinazol-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (501) (5a)-(4-(9-((1^5S)-3-(2-oxaspiro[3.3]heptan-6-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7-(((7?)-1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3- / ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (502) (A , a)-4-(9-((1^5S)-3-(2-oxaspiro[3.3]heptan-6-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7-(((7?)-1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3- / ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (503) 4-(7-((((^)-2,2-Difluoro-1-(((3-(methoxymethyl)cyclobutyl)amino)methyl)cyclopropyl)methoxy)-5-fluoro-9- (((1'R,5S)-3-(3-(methoxymethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl-2H-pyrazolo[4,3- / ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (504) 2-Amino-7-fluoro-4-(5-fluoro-3-(((2S,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1-((1S,5S)-3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-8-methylfuro[3,2-f]quinazolin-6-yl)benzothiophene-3-carbonitrile; (505) 4-(9-((1S,5S)-3-(2-oxaspiro[3.3]heptan-6-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7-((1- ((dimethylamino)methyl)cyclopropyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; (506) 4-(3-(((R)-1-((Dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-1-((1S,5S)-3-(3- 441 (methoxymethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. 【

25. A compound of the following chemical formula 2, an optical isomer, a stereoisomer, a racemate, an isotopic variant, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof: [Chemical Formula 2] In the above chemical formula 2, Ri is hydrogen, halogen, Ci-3 alkyl, or Ci-3 alkoxy; L is a direct bond, 0, or NR6; R2 is C1-6 alkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C2-6 alkoxyalkyl, C1-6 haloalkyl, R x , — Zi— R x , — Zi— R y — R x , — Zi— R y — Z2— N(Ri5)2, — ZI— R y — Z2— R x , — N(Ri5)2, — ZI— N(Ri5)2, — ZI— C(O)N(R15)2, or - Zi- 0R15 ; Rx and Ry are independently a 3- to 10-membered cycloalkyl, a 3- to 12-membered heterocyclyl, a 6- to 20-membered aryl, or a 6- to 20-membered heteroaryl, which may be optionally substituted with one or more R7; R7 is in each case independently H, D, halogen, hydroxy, Ci-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 hydroxyalkyl, C1-4 haloalkyl, C2-4 haloalkenyl, C2-4 haloalkynyl, C1-4 alkoxy, C1-4 alkyl - N(R16)2, =C-(R16)2, cyano, C(0)R16, C(=0)0R16, C(=O)N(R16)2, - NHC(O)- 6 to 20 membered aryl, -N(R16)2, (C1-4 alkoxy) C1-4 alkyl, oxo, -0R16, -SR16, - (C1-4 alkyl) C(O)R16, 3 to 10 membered cycloalkyl, 3 to 10-membered heterocycloalkyl, 6- to 20-membered aryl, 6- to 20-membered heteroaryl, - Z3- 3- to 10-membered cycloalkyl, - Z3- 3- to 10-membered heterocycloalkyl, - Z3- 6- to 20-membered aryl, - Z3- 6- to 20-membered heteroaryl, - Z3- 0C(0)N(Ri6)2, or - Z『 0C(0)- 3- to 10-membered heterocyclyl; wherein R7 is 1 to 3 cyano, halogen, Ci-6 haloalkyl, amino, -0Ri4, -SR14, or - N(R M )2 can be replaced by ; R15 is independently in each case H, Ci-6 alkyl, Ci-6 haloalkyl, 3- to 10-membered cycloalkyl, or 3- to 10-membered heterocycloalkyl; wherein said cycloalkyl or said heterocycloalkyl may be substituted with 1 to 4 halogens or Ci-6 alkoxy; R16 is independently H, halogen, or Ci-6 alkyl in each case; 442 Z1 to Z3 are independently C1-4 alkyl; optionally substituted with D, hydroxy, C1-4 hydroxyalkyl, or 6- to 20-membered heteroaryl; R6, R14, R17, R18, R20, R22, R23, R24 and R25 are each independently H or C1-6 alkyl; R3 is a 3- to 10-membered cycloalkyl, a 3- to 10-membered heterocycloalkyl, a 6- to 20-membered aryl, or a 6- to 20-membered heteroaryl, which may be optionally substituted with one or more R8; R8 and R21 are each independently H, halogen, hydroxy, -N(R18)2, 0Ri8, 0C(=0)N(Ri8)2, SH, S(CI-3 alkyl), S(Ci-3 haloalkyl), S(=0)(Ci-6 alkyl), S(=0)2(Ci-6 alkyl), C(=0)(Ci-6 alkyl), C(=O)OH, C(=O)N(R18)2, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 haloalkyl, C1-3 hydroxyalkyl, C1-3 alkoxyalkyl, C1-4 alkyl - N(R18)2, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 cyanoalkyl, cyano, oxo, 3- to 10-membered cycloalkyl, 3-membered A 6- to 20-membered heterocycloalkyl, a 6- to 20-membered aryl, or a 6- to 20-membered heteroaryl; Y1 is H, halogen, C1-4 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl- C1-4 alkyl, 6- to 20-membered aryl, 6- to 20-membered aryl- C1-4 alkyl, 6- to 20-membered heteroaryl, 6- to 20-membered heteroaryl-Ci-4 alkyl, 3- to 6-membered heterocycle, or 3- to 6-membered heterocycle-Ci-4 alkyl, which may be optionally substituted with one or more R21; Y2 is H, CD3, C1-4 alkyl, or Ci-4 haloalkyl; or Yi and Y2 are linked to form a 3- to 10-membered heterocycloalkyl, or a 3- to 10-membered heterocycloalkenyl, which may be optionally substituted with one or more R9; R9 is in each case independently H, hydroxy, halogen, Ci-3 alkyl, Ci-3 haloalkyl, C1-3 alkenyl, -NH-R17, -N(R17)2, C1-3 alkyl - N(R17)2, oxo, -I (C1-3 alkyl), - (C1-3 alkyl)- OH, -(C1-3 alkyl)- 0-(Ci-3 alkyl), -(C1-3 alkyl)- 0-(Ci-3 haloalkyl), -C(O)OH, - C(0)0(Ci-3 alkyl), -C(0)NH2, -C(0)N(Ri7)2, cyano, Ci-3 cyanoalkyl, 3-10 membered heterocyclyl, 6-20 membered aryl, or 6-20 membered heteroaryl; Two R9s, which are the same or different, may form a 3- to 6-membered cycloalkyl, or a 3- to 6-membered heterocycle from the same atom, which may be optionally substituted with one or more halogens, hydroxy, oxo, C1-3 alkyl, C1-3 haloalkyl, or -0- C1-3 alkyl; Two R9s, which are the same or different, may be directly bonded to adjacent atoms, or may form a condensed ring with a 3- to 6-membered cycloalkyl, a 3- to 6-membered heterocycloalkyl, a 6- to 20-membered aryl, or a 6- to 20-membered heteroaryl, which may be optionally substituted with one or more Rio; Rio is independently H, Ci-3 alkyl, hydroxy, halogen, - N(R22)2, -CH2N(R in each case 22 )2, oxo, - o- (C1-3 alkyl), - (C1-3 alkyl)- OH, -C(O)OH, - C(0)0(Ci-3 alkyl), - C(0)N(R22)2, cyano, C1-3 cyanoalkyl, or 3- to 10-membered heterocyclyl; Rn is H, CD3, Ci-6 alkyl, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocycloalkyl, - C(=0)Ri3, or N(RW)2; When Rii is 3- to 12-membered cycloalkyl, or 3- to 12-membered heterocycloalkyl, optionally one or more D, hydroxy, cyano, halogen, oxo, Ci-3 alkyl, hydroxy Ci-3 alkyl, C1-3 haloalkyl, - 0- C1-3 alkyl, - C1-3 alkyl- 0- R19, - N(R19)2, C1-3 alkyl - N(R19)2, - C(0)R19, -C(O)O-R19, - C(0)NH2, -C(O)NH(R19)2, Co-2 alkyl- 3- to 6-membered cycloalkyl, Co-2 alkyl- 3- to 6-membered heterocycloalkyl, Co-2 alkyl- 6- to 20-membered aryl, or Co-2 alkyl- 6- to 20-membered may be substituted with heteroaryl; R n o] In case of Ci-6 alkyl, optionally one or more halogen, hydroxy, cyano, - N(R19)2, C1-3 alkyl, halo C1-3 alkyl, CD3C1-3 alkyl, hydroxy C1-3 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered heterocycloalkenyl, 5-6 membered aryl, 5-6 membered heteroaryl, - C(0)N(R19)2, — C(0)R19, — S— C1-3 alkyl, — S(0)2— C1-3 alkyl, — S(0)2— N(R19)2, — N(R19)— S(0)2— R19, -NHC(O)R19, -NHC(O)N(R19)2, -OC(O)N(R19)2, - 0- C1-3 alkyl, - o-halo Ci-3 alkyl, - o- CD3, - 0-(Ci-3 alkyl)- 0- C1-3 alkyl, - o- Ci-3 alkyl- OH, - 0- C(0)- C1-3 alkyl, - o- P(0)(- o- R19)- R19, or - P(0)2- o- R19; The above 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered heterocycloalkenyl, 5- to 6-membered aryl, or 5- to 6-membered heteroaryl optionally comprises one or more D, hydroxy, cyano, halogen, Ci-3 alkyl, Ci-3 haloalkyl, hydroxy C1-3 alkyl, - 0- C1-3 alkyl, C1-3 alkyl- 0- C1-3 alkyl, oxo (= 0), or It can be substituted with N(R19)2; 444 R19 is independently H, Ci-6 alkyl, or Ci-6 haloalkyl in each case; R12 is independently in each case D, halogen, hydroxy, Ci-3 alkyl, Ci-3 haloalkyl, C1-3 hydroxyalkyl, C1-3 alkenyl, C1-3 alkynyl, C1-3 alkyl- 0- R20, C1-3 alkyl- 0- C1-3 haloalkyl, C1-3 alkyl - S(0)2R20, - N(R20)2, -CH2N(R2O)2, oxo (=0), cyano, cyano Cl~ 3 alkyl, Co-3 alkyl- 3 to 10 membered cycloalkyl, or Co-3 alkyl- 3 to 10 membered heterocyclyl; R13 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-3 alkyl-0- C1-6 alkyl, - N(R23)2, -OR23, - SR23, 3 to 10 membered cycloalkyl, 3 to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclyl, 6- to 20-membered aryl, 6- to 20-membered heteroaryl, or -Ci- 6-Alkyl-3 to 10-membered cycloalkyl; 3 to 10-membered cycloalkyl, 3 to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclyl, 6- to 20-membered aryl, 6- to 20-membered heteroaryl, or -Ci- 6-alkyl- 3- to 10-membered cycloalkyl may be optionally substituted with one or more D, hydroxy, halogen, Ci-3 alkyl, halo Ci-3 alkyl, 3- to 6-membered cycloalkyl, - N(R24)2 or oxo (=0); n is an integer from 0 to 4; m is an integer from 0 to 4; R5 is H, halogen, Ci-6 alkyl, Ci-3 haloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, cyano, cyano Ci-3 alkyl, hydroxy, Ci-3 hydroxyalkyl, C(0)(NR25)2, 6-20 membered aryl, - Ci-3 alkyl- 3-6 membered cycloalkyl, - Ci-3 alkyl- 3-6 membered heterocycloalkyl, - Ci-3 alkyl- 6-20 membered aryl, - Ci-3 alkyl- 0- Ci-3 alkyl- 6-20 membered aryl, or - Ci-3 alkyl- 6-20 membered heteroaryl. 【

26. A pharmaceutical composition comprising a compound according to any one of claims 1 to 25, an optical isomer, a stereoisomer, a racemate, an isotopic variant, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof. 【

27. ​​A pharmaceutical composition according to claim 26, further comprising a pharmaceutically acceptable carrier.

28. 445 A pharmaceutical composition according to claim 26, wherein the pharmaceutical composition is an antagonist of a KRAS mutant protein including a G12D mutation. 【Claim 2: A pharmaceutical composition according to claim 26, wherein the pharmaceutical composition is for the prevention or treatment of a disease associated with a KRAS mutant protein including a G12D mutation. 【

30. A pharmaceutical composition according to claim 26, wherein the pharmaceutical composition is for the prevention or treatment of cancer. 【

31. A pharmaceutical composition according to claim 26, wherein the composition is administered by at least one selected from the group consisting of oral administration, intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, intradermal administration, topical administration, intranasal administration, intrapulmonary administration, and rectal administration. 【

32. A pharmaceutical composition according to claim 26, wherein the composition is formulated with at least one selected from the group consisting of tablets, pills, hard / soft capsules, liquids, suspensions, emulsifiers, syrups, granules, and elixirs. 【

33. A pharmaceutical composition according to claim 26, wherein the pharmaceutical composition further comprises at least one selected from the group consisting of an RTK / Ras-MAPK pathway-related protein inhibitor, a DNA damage-inducing agent, an EGFR antibody inhibitor, and an immuno-oncology therapeutic agent.

34. A pharmaceutical composition according to claim 33, wherein the RTK / Ras-MAPK pathway-related protein inhibitor is at least one selected from the group consisting of an EGFR inhibitor, an FGFR inhibitor, an ALK inhibitor, a ROS inhibitor, a MET inhibitor, a RAF inhibitor, an ERK inhibitor, a MEK inhibitor, a SHP-2 inhibitor, a PI3K inhibitor, a KRAS inhibitor, a KRAS-G12C inhibitor, and an S0S1 inhibitor. 【

35. In claim 30, the cancer is angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyosarcoma, fibroma, lipoma, teratoma; squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated multicellular carcinoma, adenocarcinoma, alveolar (bronchiolar) cancer, bronchiolar adenoma, sarcoma, lymphoma, chondrosarcoma, mesothelioma, esophageal cancer, stomach cancer, pancreatic cancer, small intestine cancer, colon cancer, kidney cancer, bladder cancer, urethral cancer, prostate cancer, testicular cancer, liver cancer, biliary tract cancer, hepatoblastoma, hepatocellular adenoma, hemangioma, gallbladder cancer, ampullary cancer, osteosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant 446 Lymphoma (reticulocyte cell sarcoma), multiple myeloma, malignant giant cell tumor, osteochondroma, benign chondroma, chondromyxoid fibroma, chondroostoma, giant cell tumor, cranioma, cranial hemangioma, cranial granuloma, cranial xanthoma, cranial osteitis deformans, meningioma, meningiosarcoma, glioblastoma, astrocytoma, medulloblastoma, ependymoma, germinoma, oligodendroglioma, schwannoma, retinoblastoma, spinal neurofibroma, endometrial cancer, cervical cancer, ovarian cancer, blood cancer, acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, monocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, mixed lineage leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, malignant melanoma, A pharmaceutical composition comprising at least one selected from the group consisting of basal cell carcinoma, adenocarcinoma, and neuroblastoma. 【

36. A composition for binding to a KRAS mutant protein including a G12D mutation, comprising a compound according to any one of claims 1 to 25, an optical isomer, a stereoisomer, a racemate, an isotopic variant, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof. 447

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