KRAS inhibitors

Abstract

The present disclosure relates to KRAS inhibitors, and also provides methods of treating cancer using such compounds.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority to U.S. Provisional Application No. 63 / 160,436 filed on 12 March 2021 and U.S. Provisional Application No. 63 / 288,965 filed on 13 December 2021, the entirety of which disclosures are incorporated herein by reference.

[0002] This disclosure provides a KRAS inhibitor and a method for treating cancer using said compound.

[0003] (Technical field) The KRAS oncogene is part of the Ras family of GTPases, which are involved in signal transduction in many cells. KRAS mutations are gain-of-function mutations and are present in up to 30% of all tumors, and as high as 90% of pancreatic cancers. KRAS G12D mutations are found in 28% of all pancreatic ductal adenocarcinoma patients, 13% of all colorectal cancer patients, 4% of all non-small cell lung cancer patients, and 3% of all gastric cancer patients (see, for example, https: / / www.mycancergenome.org / content / alteration / kras-g12d / ). Due to the clinical importance of this protein, many attempts have been made to develop Ras inhibitors, but most of these attempts have been unsuccessful. This is mainly because KRAS is difficult to bind to in the intracellular KRAS binding pocket due to competition with GTP, and because the allosteric site is unknown. Therefore, there is a need for drugs that inhibit KRAS G12D. [Overview of the project]

[0004] In a first embodiment, this disclosure relates to formula (I): [ka] [In the formula, R 1is aryl or heteroaryl, wherein said aryl and heteroaryl may be optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, amino C1-C3 alkyl, C3-C4 cycloalkyl, halogen, halo C1-C3 alkoxy, halo C1-C3 alkyl, hydroxy, and hydroxy C1-C3 alkyl; R 2 and R 3 are independently selected from hydrogen, C1-C3 alkoxy, C1-C3 alkyl, cyano, halogen, halo C1-C3 alkyl, and hydroxy; R 4 is selected from Chemical Formula ; wherein R a is hydrogen or C1-C3 alkyl; n is 0, 1, 2, 3, or 4; each R b is independently selected from C1-C3 alkyl, C3-C6 cycloalkyl, halogen, and hydroxy; or two R b groups may together with the carbon atoms to which they are attached form a 3- to 6-membered cycloalkyl ring; and Chemical Formula represents a point of attachment to a portion of the parent molecule; R 5 is -(C1-C3 alkyl)-R 6 or -(C1-C6 alkyl)NR c R d ; wherein R 6 is NR c R dA C3-C6 cycloalkyl group substituted with (C1-C3 alkyl); and a 5- to 10-membered monocyclic, dicyclic, or tricyclic ring comprising one nitrogen atom and a second heteroatom optionally selected from oxygen or nitrogen, wherein the ring contains 0-3 double bonds and may optionally be substituted with 1, 2, or 3 groups independently selected from C1-C3 alkoxy, C1-C3 alkyl, halogen, halo-C1-C3 alkoxy, halo-C1-C3 alkyl, and hydroxyl; where R c and R d These, together with the nitrogen atom to which they are bonded, form a 5-10 membered monocycle or dicycle that further includes one heteroatom appropriately selected from nitrogen, oxygen, and sulfur, wherein the ring may be appropriately substituted with one, two, or three groups independently selected from C1-C3 alkoxy, C1-C3 alkoxyC1-C3 alkyl, C1-C3 alkyl, benzyl, halogen, haloC1-C3 alkyl, hydroxy, hydroxyC1-C3 alkyl, and oxo; or R c and R d One of the elements is selected from hydrogen and C1-C3 alkyl, and the other is selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxycarbonyl, and C1-C3 alkylcarbonyl. The present invention provides compounds of or pharmaceutically acceptable salts thereof.

[0005] In one embodiment, n is 0. In another embodiment, n is 1, 2, 3, or 4. In one embodiment, n is 1. In another embodiment, n is 2. In yet another embodiment, n is 3. In yet another embodiment, n is 4.

[0006] In some embodiments, R 4 teeth, [ka] Selected from.

[0007] In some embodiments, R 4 teeth, [ka] Selected from; and R 6 This is a 5- to 10-membered monocyclic, dicyclic, or tricyclic ring containing one nitrogen atom and a second heteroatom optionally selected from oxygen or nitrogen, wherein the ring contains 0-3 double bonds and may optionally be substituted with 1, 2, or 3 groups independently selected from C1-C3 alkoxy, C1-C3 alkyl, halogen, halo-C1-C3 alkoxy, halo-C1-C3 alkyl, and hydroxyl.

[0008] In some embodiments, R 2 and R 3 These are halogens, respectively. In some embodiments, R 2 is chloroform, R 3 is fluoro. In some embodiments, R 2 is hydrogen, R 3 It is fluoro.

[0009] In some embodiments, R 4 teeth, [ka] And here R a It is either hydrogen or a C1-C3 alkyl group.

[0010] In some embodiments, R 4 teeth, [ka] And here R a It is either hydrogen or a C1-C3 alkyl group.

[0011] In some embodiments, R 4 teeth, [ka] And here R aIt is either hydrogen or a C1-C3 alkyl group.

[0012] In some embodiments, R 4 teeth, [ka] And here R a It is either hydrogen or a C1-C3 alkyl group.

[0013] In some embodiments, R 5 is -(C1-C3 alkyl)-R 6 That is the case.

[0014] In some embodiments, R 5 teeth, [ka] Selected from; each ring may be appropriately substituted with one or two groups independently selected from C1-C3 alkoxy, C1-C3 alkyl, halogen, halo-C1-C3 alkyl, and hydroxyl.

[0015] In some embodiments, R 5 teeth, [ka] And here p is 0, 1, or 2; and Each R x The element is independently selected from C1-C3 alkoxy, C1-C3 alkyl, halogen, halo-C1-C3 alkyl, and hydroxyl.

[0016] In some embodiments, R 5 teeth, [ka] And here q and r are independently either 0 or 1; R x and R yThe element is independently selected from C1-C3 alkoxy, C1-C3 alkyl, halogen, halo-C1-C3 alkyl, and hydroxyl.

[0017] In some embodiments, R 5 teeth, [ka] That is the case.

[0018] In some embodiments, R 5 teeth, [ka] And here q and r are independently either 0 or 1; R x and R y These are independently selected from C1-C3 alkoxy, C1-C3 alkyl, halogen, halo-C1-C3 alkyl, and hydroxyl; R z It is hydrogen or fluoro.

[0019] In some embodiments, R 5 teeth, [ka] And here s is either 0 or 1; where R x The elements are selected from C1-C3 alkoxy, C1-C3 alkyl, halogen, halo-C1-C3 alkyl, and hydroxyl.

[0020] In some embodiments, R 5 teeth, [ka] That is the case.

[0021] In some embodiments, R 5 teeth, [ka] And here q and r are independently either 0 or 1; R x and R y The element is independently selected from C1-C3 alkoxy, C1-C3 alkyl, halogen, halo-C1-C3 alkyl, and hydroxyl.

[0022] In some embodiments, R 5 teeth, [ka] And here q, r, and d are each independently either 0 or 1; R x , R y , and R p The element is independently selected from C1-C3 alkoxy, C1-C3 alkyl, halogen, halo-C1-C3 alkyl, and hydroxyl.

[0023] In some embodiments, R 5 teeth, [ka] That is the case.

[0024] In some embodiments, R 1 The compound is naphthyl, which is substituted with a hydroxyl group and may be further substituted with one or two groups selected from C1-C3 alkyl, C2-C4 alkynyl, and halogen groups.

[0025] In some embodiments, R 1 teeth, [ka] That is the case.

[0026] In some embodiments, R 1 teeth, [ka] That is the case.

[0027] In some embodiments, R 1 teeth, [ka] That is the case.

[0028] In some embodiments, R 1 teeth, [ka] That is the case.

[0029] In some embodiments, this disclosure relates to formula (I) [wherein, R 2 is hydrogen; R 3 is fluoro; R 1 teeth, [ka] Selected from; and R 5 teeth, [ka] Selected from; here [ka] [This represents a point that connects to a part of the parent molecule.] The present invention provides compounds of the same, or pharmaceutically acceptable salts thereof.

[0030] In some embodiments, this disclosure relates to formula (I) [wherein, R 2 is chloro; R 3 is fluoro; R 1 teeth, [ka] Selected from; and R 5 teeth, [ka] Selected from; here [ka] The present invention provides compounds of [where is a point that connects to a part of the parent molecule], or pharmaceutically acceptable salts thereof.

[0031] In some embodiments, this disclosure uses formula (II): [ka] [In the formula, R 1 teeth, [ka] Selected from; [ka] This represents a point connected to a part of the parent molecule; R 4 teeth, [ka] Selected from; here R a is hydrogen or C1-C3 alkyl; and [ka] represents a point connected to a part of the parent molecule; and R 5 teeth, [ka] Selected from; here [ka] [This represents a point that connects to a part of the parent molecule.] The present invention provides compounds of or pharmaceutically acceptable salts thereof.

[0032] In one embodiment, this disclosure relates to formula (IIa): [ka] [In the formula, R 1 teeth, [ka] Selected from; here [ka] represents a point connected to a part of the parent molecule; and R 4 teeth, [ka] Selected from; here R a is hydrogen or C1-C3 alkyl; and [ka] [This represents a point that connects to a part of the parent molecule.] The present invention provides compounds of or pharmaceutically acceptable salts thereof.

[0033] In some embodiments, R 4 teeth, [ka] And here R a It is either hydrogen or a C1-C3 alkyl group.

[0034] In some embodiments, R 4 teeth, [ka] And here R aIt is either hydrogen or a C1-C3 alkyl group.

[0035] In some embodiments, R 4 teeth, [ka] And here R a It is either hydrogen or a C1-C3 alkyl group.

[0036] In some embodiments, R 4 teeth, [ka] And here R a It is either hydrogen or a C1-C3 alkyl group.

[0037] In some embodiments, the disclosure provides atropisomers of any compound of the embodiments described herein. In some embodiments, the compound is a stable atropisomer as described herein.

[0038] In some embodiments, the Disclosure provides a pharmaceutical composition comprising a compound of formula (I), (II), or (IIa), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0039] In some embodiments, the Disclosure provides oral formulations comprising a compound of formula (I), (II), or (IIa), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0040] In one embodiment, the present disclosure relates to a method for treating cancer expressing the KRAS G12D mutation in a target subject, wherein formula (I): [ka] [In the formula, R 1is aryl or heteroaryl, wherein said aryl and heteroaryl may be optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, aminoC1-C3 alkyl, C3-C4 cycloalkyl, halogen, haloC1-C3 alkoxy, haloC1-C3 alkyl, hydroxy, and hydroxyC1-C3 alkyl; R 2 and R 3 are independently selected from hydrogen, C1-C3 alkoxy, C1-C3 alkyl, cyano, halogen, haloC1-C3 alkyl, and hydroxy; R 4 is selected from ## STR ## ; wherein R a is hydrogen or C1-C3 alkyl; n is 0, 1, 2, 3, or 4; each R b is independently selected from C1-C3 alkyl, C3-C6 cycloalkyl, halogen, and hydroxy; or two R b groups may together with the carbon atoms to which they are attached form a 3- to 6-membered cycloalkyl ring; and ## STR ## represents a point of attachment to a portion of the parent molecule; R 5 is -(C1-C3 alkyl)-R 6 or -(C1-C6 alkyl)NR c R d ; wherein R 6 is NR c R dA C3-C6 cycloalkyl group substituted with (C1-C3 alkyl); and a 5- to 10-membered monocyclic, dicyclic, or tricyclic ring comprising one nitrogen atom and a second heteroatom optionally selected from oxygen or nitrogen, wherein the ring contains 0-3 double bonds and may optionally be substituted with 1, 2, or 3 groups independently selected from C1-C3 alkoxy, C1-C3 alkyl, halogen, halo-C1-C3 alkoxy, halo-C1-C3 alkyl, and hydroxyl; where R c and R d These, together with the nitrogen atom to which they are bonded, form a 5-10 membered monocycle or dicycle that further includes one heteroatom appropriately selected from nitrogen, oxygen, and sulfur, wherein the ring may be appropriately substituted with one, two, or three groups independently selected from C1-C3 alkoxy, C1-C3 alkoxyC1-C3 alkyl, C1-C3 alkyl, benzyl, halogen, haloC1-C3 alkyl, hydroxy, hydroxyC1-C3 alkyl, and oxo; or R c and R d One of the elements is selected from hydrogen and C1-C3 alkyl, and the other is selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxycarbonyl, and C1-C3 alkylcarbonyl. The present invention provides a method characterized by administering a compound or a pharmaceutically acceptable salt thereof to a target.

[0041] In one embodiment, n is 0. In another embodiment, n is 1, 2, 3, or 4. In one embodiment, n is 1. In another embodiment, n is 2. In yet another embodiment, n is 3. In yet another embodiment, n is 4.

[0042] In some embodiments of the method, R 4 teeth, [ka] Selected from.

[0043] In some embodiments of the method, R 4 teeth, [ka] Selected from; and R 6 This is a 5- to 10-membered monocyclic, dicyclic, or tricyclic ring containing one nitrogen atom and a second heteroatom optionally selected from oxygen or nitrogen, wherein the ring contains 0-3 double bonds and may optionally be substituted with 1, 2, or 3 groups independently selected from C1-C3 alkoxy, C1-C3 alkyl, halogen, halo-C1-C3 alkoxy, halo-C1-C3 alkyl, and hydroxyl.

[0044] In some embodiments of the method, R 2 and R 3 These are halogens, respectively. In some embodiments, R 2 is chloroform, R 3 is fluoro. In some embodiments of the method, R 2 is hydrogen, R 3 It is fluoro.

[0045] In some embodiments of the method, R 4 teeth, [ka] And here R a It is either hydrogen or a C1-C3 alkyl group.

[0046] In some embodiments of the method, R 4 teeth, [ka] And here R a It is either hydrogen or a C1-C3 alkyl group.

[0047] In some embodiments of the method, R 4 teeth, [ka] And here R a It is either hydrogen or a C1-C3 alkyl group.

[0048] In some embodiments of the method, R 4 teeth, [ka] And here R a It is either hydrogen or a C1-C3 alkyl group.

[0049] In some embodiments of the method, R 5 is -(C1-C3 alkyl)-R 6 That is the case.

[0050] In some embodiments of the method, R 5 teeth, [ka] Selected from; each ring may be appropriately substituted with one or two groups independently selected from C1-C3 alkoxy, C1-C3 alkyl, halogen, halo-C1-C3 alkyl, and hydroxyl.

[0051] In some embodiments of the method, R 5 teeth, [ka] And here p is 0, 1, or 2; Each R x The element is independently selected from C1-C3 alkoxy, C1-C3 alkyl, halogen, halo-C1-C3 alkyl, and hydroxyl.

[0052] In some embodiments of the method, R 5 teeth, [ka] And here q and r are independently either 0 or 1; R x and R y The element is independently selected from C1-C3 alkoxy, C1-C3 alkyl, halogen, halo-C1-C3 alkyl, and hydroxyl.

[0053] In some embodiments of the method, R 5 teeth, [ka] That is the case.

[0054] In some embodiments of the method, R 5 teeth, [ka] And here q and r are independently either 0 or 1; R x and R y These are independently selected from C1-C3 alkoxy, C1-C3 alkyl, halogen, halo-C1-C3 alkyl, and hydroxyl; R z It is hydrogen or fluoro.

[0055] In some embodiments of the method, R 5 teeth, [ka] And here s is either 0 or 1; R x The elements are selected from C1-C3 alkoxy, C1-C3 alkyl, halogen, halo-C1-C3 alkyl, and hydroxyl.

[0056] In some embodiments of the method, R 5 teeth, [ka] That is the case.

[0057] In some method aspects, R 5 is

化

[0058] In some method aspects, R 5 is

化

[0059] In some method aspects, R 5 is

化

[0060] In some method aspects, R 1 is naphthyl, wherein said naphthyl is substituted with a hydroxy group, and may be optionally further substituted with 1 or 2 groups selected from C1-C3 alkyl, C2-C4 alkynyl, and halogen.

[0061] In some method aspects, R 1 is

化

[0062] In some embodiments of the method, R 1 teeth, [ka] That is the case.

[0063] In some embodiments of the method, R 1 teeth, [ka] That is the case.

[0064] In some embodiments of the method, R 1 teeth, [ka] That is the case.

[0065] In some embodiments of the method, R 2 is hydrogen; R 3 is fluoro; R 1 teeth, [ka] Selected from; and R 5 teeth, [ka] Selected from; here [ka] This represents a point that connects to a part of the parent molecule.

[0066] In some embodiments of the method, R 2 is chloroform; R 3 is fluoro; R 1 teeth, [ka] Selected from; and R5 ,

Chem.

Chem.

[0067] In some method aspects, the compound is an atropisomer of any compound of the foregoing aspects. In one embodiment, the compound is a stable atropisomer as described herein.

[0068] In another aspect, the present disclosure provides a method of inhibiting KRAS G12D activity in a cell, comprising contacting the cell with a compound of Formula (I), Formula (II), or Formula (IIa) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some aspects, the contacting is performed in vitro. In certain embodiments, the contacting is performed in vivo.

[0069] In another aspect, the present disclosure provides a method of inhibiting cell proliferation in vitro or in vivo, comprising contacting a cell with an effective amount of a compound of Formula (I), Formula (II), or Formula (IIa) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0070] In another aspect, the present disclosure provides a method of treating a KRAS G12D-associated disease or disorder in a patient in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), Formula (II), or Formula (IIa) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0071] In another aspect, the present disclosure provides a compound of Formula (I), Formula (II), or Formula (IIa), or a pharmaceutically acceptable salt thereof, for use in inhibiting KRAS G12D.

[0072] In another embodiment, the Disclosure provides compounds of formula (I), formula (II), or formula (IIa) as defined herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in the treatment of KRAS G12D-related diseases or disorders.

[0073] In another embodiment, the Disclosure provides the use of compounds of formula (I), formula (II), or formula (IIa) as defined herein, or pharmaceutically acceptable salts thereof, in the manufacture of pharmaceuticals for the treatment of cancer.

[0074] In another embodiment, the present disclosure provides the use of compounds of formula (I), formula (II), or formula (IIa) as defined herein, or pharmaceutically acceptable salts thereof, in the manufacture of pharmaceuticals for inhibiting KRAS G12D activity.

[0075] In another embodiment, the Disclosure provides the use of compounds of formula (I), formula (II), or formula (IIa) as defined herein, or pharmaceutically acceptable salts thereof, in the manufacture of pharmaceuticals for the treatment of KRAS G12D-related diseases or disorders.

[0076] In some embodiments, this disclosure is, [ka] [ka] [ka] [ka] [ka] The present invention provides compounds selected from or pharmaceutically acceptable salts thereof.

[0077] In some embodiments, this disclosure is, 4-(6-chloro-4-{3,9-diazabicyclo[4.2.1]nonan-9-yl}-8-fluoro-2-{[(2S)-1-methylpyrrolidine-2-yl]methoxy}quinazoline-7-yl)naphthalene-2-ol; 4-(6-chloro-4-{1,4-diazabicyclo[3.2.2]nonan-4-yl}-8-fluoro-2-{[(2S)-1-methylpyrrolidine-2-yl]methoxy}quinazoline-7-yl)naphthalene-2-ol; 6-(6-chloro-4-{3,9-diazabicyclo[4.2.1]nonan-3-yl}-8-fluoro-2-{[(2S)-1-methylpyrrolidine-2-yl]methoxy}quinazoline-7-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine; 6-(6-chloro-4-{3,6-diazabicyclo[3.2.2]nonan-3-yl}-8-fluoro-2-{[(2S)-1-methylpyrrolidine-2-yl]methoxy}quinazoline-7-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine; 6-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine; 6-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine; 6-(2-{[(2S,7aR)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine; 6-(2-{[(2R,7aR)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine; 6-{6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonan-3-yl]-8-fluoro-2-{[(2S,4R)-4-methoxy-1-methylpyrrolidine-2-yl]methoxy}quinazoline-7-yl}-4-methyl-5-(trifluoromethyl)pyridine-2-amine; 6-(2-{[(2S,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine; 6-(2-{[(2S,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (isomer 1); 6-(2-{[(2S,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (isomer 2); 4-{6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonan-3-yl]-8-fluoro-2-{[(2S)-1-methylpyrrolidine-2-yl]methoxy}quinazoline-7-yl}naphthalene-2-ol; 4-(2-{[(2R,7aR)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)naphthalene-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-5-ethylnaphthalene-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-5-ethylnaphthalene-2-ol (isomer 1); 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-5-ethylnaphthalene-2-ol (isomer 2); 4-(2-{[(2S,7aR)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-5-ethylnaphthalene-2-ol; 4-(2-{[(2S,7aR)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-5-ethylnaphthalene-2-ol (isomer 1); 4-(2-{[(2S,7aR)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-5-ethylnaphthalene-2-ol (isomer 2); 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-5-fluoronaphthalene-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-5-fluoronaphthalene-2-ol (isomer 1); 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-5-fluoronaphthalene-2-ol (isomer 2); 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)naphthalene-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)naphthalene-2-ol (isomer 1); 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)naphthalene-2-ol (isomer 2); 4-(2-{[(2S,7aR)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)naphthalene-2-ol; 4-(2-{[(2S,7aR)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)naphthalene-2-ol (isomer 1); 4-(2-{[(2S,7aR)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)naphthalene-2-ol (isomer 2); 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)naphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-5-fluoronaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-5-ethylnaphthalene-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 6-{6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonan-3-yl]-2-({1-[(dimethylamino)methyl]cyclopropyl}methoxy)-8-fluoroquinazoline-7-yl}-4-methyl-5-(trifluoromethyl)pyridine-2-amine; 6-{6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonan-3-yl]-8-fluoro-2-{[1-({3-oxa-8-azabicyclo[3.2.1]octan-8-yl}methyl)cyclopropyl]methoxy}quinazoline-7-yl}-4-methyl-5-(trifluoromethyl)pyridine-2-amine; 6-{6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonan-3-yl]-8-fluoro-2-({1-[(3-fluoropiperidine-1-yl)methyl]cyclopropyl}methoxy)quinazoline-7-yl}-4-methyl-5-(trifluoromethyl)pyridine-2-amine; 6-{6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonan-3-yl]-8-fluoro-2-[(1-{[(3R)-3-fluoropyrrolidine-1-yl]methyl}cyclopropyl)methoxy]quinazolin-7-yl}-4-methyl-5-(trifluoromethyl)pyridine-2-amine; 6-(2-{[(2S,7aS)-2-(difluoromethoxy)-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine; 6-(2-{[(2S,7aS)-2-(difluoromethoxy)-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine; 6-{6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonan-3-yl]-8-fluoro-2-({1-[(morpholine-4-yl)methyl]cyclopropyl}methoxy)quinazoline-7-yl}-4-methyl-5-(trifluoromethyl)pyridine-2-amine; 6-{6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonan-3-yl]-8-fluoro-2-({1-[(piperidine-1-yl)methyl]cyclopropyl}methoxy)quinazoline-7-yl}-4-methyl-5-(trifluoromethyl)pyridine-2-amine; 6-{6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonan-3-yl]-8-fluoro-2-({1-[(3-fluoropiperidine-1-yl)methyl]cyclopropyl}methoxy)quinazoline-7-yl}-4-methyl-5-(trifluoromethyl)pyridine-2-amine; 6-{6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonan-3-yl]-8-fluoro-2-({1-[(3-fluoropiperidine-1-yl)methyl]cyclopropyl}methoxy)quinazoline-7-yl}-4-methyl-5-(trifluoromethyl)pyridine-2-amine; 6-{6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonan-3-yl]-8-fluoro-2-({1-[(4-fluoropiperidine-1-yl)methyl]cyclopropyl}methoxy)quinazoline-7-yl}-4-methyl-5-(trifluoromethyl)pyridine-2-amine; 4-{4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-2-({1-[(dimethylamino)methyl]cyclopropyl}methoxy)-8-fluoroquinazoline-7-yl}-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-5-fluoronaphthalene-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-4-[(1R,6S)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-5-fluoronaphthalene-2-ol; 4-{4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoro-2-{[1-({3-oxa-8-azabicyclo[3.2.1]octan-8-yl}methyl)cyclopropyl]methoxy}quinazoline-7-yl}-5-ethylnaphthalene-2-ol; 1-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-8-fluoroisoquinoline-3-amine; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-5-ethylnaphthalene-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)naphthalene-2-ol; 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-7-(8-ethylnaphthalene-1-yl)-8-fluoroquinazoline; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-5-fluoronaphthalene-2-ol; 6-(2-{[(2R,7aR)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine; 6-(2-{[(2S,7aR)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine; 6-{4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonan-3-yl]-2-[(2,2-difluoro-hexahydro-1H-pyrrolidine-7a-yl)methoxy]-8-fluoroquinazoline-7-yl}-4-methyl-5-(trifluoromethyl)pyridine-2-amine; and 6-(2-{[(6'R,7'aR)-6'-fluoro-hexahydrospiro[cyclopropane-1,2'-pyrrolidine]-7'a-yl]methoxy}-6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine; The present invention provides compounds selected from or pharmaceutically acceptable salts thereof.

[0078] In some embodiments, the Disclosure provides a pharmaceutical composition comprising any of the compounds described in the above embodiments, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0079] In another embodiment, the present disclosure provides a method for treating a target cancer, the method comprising administering a therapeutically effective amount of any compound or pharmaceutical composition of the above embodiments, or a pharmaceutically acceptable salt thereof, to the target subject.

[0080] In another embodiment, the present disclosure provides a method for treating a cancer susceptible to KRAS G12D inhibition of a subject, characterized by administering a therapeutically effective amount of any compound or pharmaceutical composition of the above embodiment, or a pharmaceutically acceptable salt thereof, to the subject of interest.

[0081] In another embodiment, the present disclosure provides a method for treating cancer exhibiting KRAS G12D inhibition of a target, the method comprising administering a therapeutically effective amount of any compound or pharmaceutical composition of the above embodiment, or a pharmaceutically acceptable salt thereof, to the target subject. [Modes for carrying out the invention]

[0082] Unless otherwise specified, any atom whose valence is not met is assumed to contain enough hydrogen atoms to satisfy the valence requirement.

[0083] The singular forms "a," "an," and "the" include the plural form unless explicitly stated otherwise in the sentence.

[0084] As used herein, the term "or" means logical disjunction (i.e., and / or) and does not mean exclusive disjunction unless expressed by terms such as "either," "unless," "alternatively," or similar terms.

[0085] As used herein, the phrase "or a pharmaceutically acceptable salt thereof" refers to at least one compound, a salt of at least one compound, or a combination thereof. For example, "a compound of formula (I) or a pharmaceutically acceptable salt thereof" includes, but is not limited to, one compound of formula (I), two compounds of formula (I), a pharmaceutically acceptable salt of one compound of formula (I), a pharmaceutically acceptable salt of one compound of formula (I) and one or more compounds of formula (I), and pharmaceutically acceptable salts of two or more compounds of formula (I).

[0086] As used herein, the term "C2-C4 alkenyl" refers to a group derived from a straight-chain or branched-chain hydrocarbon containing two to four carbon atoms and one double bond.

[0087] As used herein, the term "C1-C3 alkoxy" refers to a C1-C3 alkyl group that is connected to the parent molecule via an oxygen atom.

[0088] As used herein, the term "C1-C3 alkoxycarbonyl" refers to a C1-C3 alkoxy group that is connected to the parent molecule via a carbonyl group.

[0089] As used herein, the term "C1-C3 alkyl" refers to a group derived from a straight-chain or branched-chain saturated hydrocarbon containing one to three carbon atoms.

[0090] As used herein, the term "C1-C6 alkyl" refers to a group derived from a straight-chain or branched-chain saturated hydrocarbon containing one to three carbon atoms.

[0091] As used herein, the term "C1-C3 alkylcarbonyl" refers to a C1-C3 alkyl group that is connected to the parent molecule via a carbonyl group.

[0092] As used herein, the term "C2-C4 alkynyl" refers to a group derived from a straight-chain or branched-chain hydrocarbon containing two to four carbon atoms and one triple bond.

[0093] As used herein, the term "amino" refers to -NH2.

[0094] As used herein, the term "amino C1-C3 alkyl" refers to an amino group that is connected to the parent molecule via a C1-C3 alkyl group.

[0095] As used herein, the term "aryl" refers to a phenyl group, or a bicyclic fused ring in which one or both rings are phenyl groups. A bicyclic fused ring consists of a phenyl group fused with a 4- to 6-membered aromatic or non-aromatic carbon ring. The aryl groups of this disclosure may be attached to the parent molecule via any substitutable carbon atom in the group. Representative examples of aryl groups include, but are not limited to, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl.

[0096] In this specification, the term "cyano" refers to -CN.

[0097] As used herein, the term "C3-C4 cycloalkyl" refers to a saturated monocyclic hydrocarbon ring having three or four carbon atoms and containing no heteroatoms.

[0098] As used herein, the terms "halo" and "halogen" refer to F, Cl, Br, or I.

[0099] As used herein, the term "halo-C1-C3 alkoxy" refers to a halo-C1-C3 alkyl group that is connected to the parent molecule via an oxygen atom.

[0100] As used herein, the term "halo-C1-C3 alkyl" refers to a C1-C3 alkyl group substituted with one, two, or three halogen atoms.

[0101] As used herein, the term “heteroaryl” refers to a five- or six-membered aromatic ring in which at least one atom is selected from N, O, and S, and the remaining atoms are carbon. The term “heteroaryl” also includes bicyclic rings in which a heteroaryl ring is fused with a four- to six-membered aromatic or non-aromatic ring further containing 0, 1, or 2 heteroatoms selected from N, O, and S; and tricyclic rings in which a bicyclic ring is fused with a four- to six-membered aromatic or non-aromatic ring further containing 0, 1, or 2 heteroatoms selected from N, O, and S. The heteroaryl group is connected to the parent molecule via any substitutable carbon or nitrogen atom in the group. Representative examples of heteroaryl groups include, but are not limited to, alloxazine, benzo[1,2-d:4,5-d']bisthiazole, benzoxadiazolyl, benzoxazolyl, benzofuranil, benzothienyl, furanil, imidazolyl, indazolyl, indolyl, isoxazolyl, isoquinolinil, isothiazolyl, naphthilidinyl, oxadiazolyl, oxazolyl, purine, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, quinolinyl, thiazolyl, thienopyridinyl, thienyl, triazolyl, thiadiazolyl, and triazinyl.

[0102] In this specification, the term "hydroxy" refers to -OH.

[0103] As used herein, the term "hydroxy C1-C3 alkyl" refers to a hydroxyl group that is connected to the parent molecule via a C1-C3 alkyl group.

[0104] Another embodiment of the objects described herein is the use of the disclosed compounds as isotope-labeled ligands for the development of ligand binding assays or for monitoring adsorption, metabolism, distribution, receptor binding or receptor occupancy, or pharmacokinetics in vivo. For example, the compounds described herein may be prepared using radioisotopes, and the resulting isotope-labeled compounds may be used for the development of binding assays or metabolic studies. Alternatively, the compounds described herein may be converted to isotope-labeled compounds by catalytic tritiation using methods known to those skilled in the art for the same purposes.

[0105] Certain compounds in this disclosure exist as atropisomers. The term “atropisomer” refers to a stereoisomer that arises when steric interactions with other parts of the molecule hinder or greatly slow the rotation of an intramolecular single bond, resulting in asymmetric substituents at both ends of the single bond (i.e., optical activity arises without the need for an asymmetric carbon or stereocenter). If the rotational barrier of the single bond is sufficiently large and the interconversion between structures is sufficiently slow, separation and isolation of the isomers are possible. Atropisomers are enantiomers (or epimers) that do not have a single asymmetric atom.

[0106] Atropisomers are considered stable if the barriers to conversion are sufficiently high that the atropisomers are observed to remain largely or completely uninterconverted at room temperature for at least one week. In some embodiments, atropisomers remain largely or completely uninterconverted at room temperature for at least one year. In some embodiments, if the atropisomer compound is a common solid and in a substantially pure form, more than about 5% of the atropisomer compound of the Disclosure will remain largely or completely uninterconverted to the other atropisomer for one week at room temperature. In some embodiments, more than about 5% of the atropisomer compound of the Disclosure will remain largely or completely uninterconverted to the other atropisomer for one year at room temperature (approximately 25°C). In some embodiments, the atropisomer compound of the Disclosure in an aqueous pharmaceutical formulation stored at 0°C for at least one week is sufficiently stable that conversion of less than about 5% occurs. This chemical substance, pharmaceutical composition, and method are intended to include all possible atropisomers, such as racemic mixtures, diastereomer mixtures, epimer mixtures, a single optically pure atropisomer, and intermediate mixtures.

[0107] The energy barrier to thermal racemization of atropisomers can be determined by steric hindrance to the free rotation of one or more bonds forming a chiral axis. Certain biaryl compounds exhibit atropisomerism, where rotation around interring bonds lacking C2 symmetry is restricted. The free energy barrier to isomerization (enantiomerization) is a measure of the stability of the interring bonds associated with rotation. Depending on electronic and steric factors, racemization of such isomers is promoted by photoexcitation and thermal excitation.

[0108] Ortho-substituted biaryl compounds may exhibit the following types of stereostructures and rotational isomerisms. [ka] The substituent is W 1 ≠W 2 and W 3 ≠W 4 Therefore, biaryls, being asymmetric molecules, are enantiomers of chiral atropisomers, and sp between the aryl rings.2 carbon-sp 2 The carbon bond has a sufficiently high energy barrier to prevent free rotation.

[0109] W 1 :W 3 , W 1 :W 4 and / or W 2 :W 4 , W 2 :W 3 The steric interaction between them is sufficient to maximize the energy of the planar structure. Two non-planar axially asymmetric chiral enantiomers exist as atropisomers if their interconversion is slow enough to separate them freely from each other. The thick and dashed lines in the above structural formulas indicate parts or portions of the molecule that are sterically restricted due to rotational energy barriers. The thick-lined parts are perpendicular to the plane of the page, and the dashed parts are perpendicular to the plane of the page. The "planar" parts of the molecule (the left-hand rings of each of the two biaryls) are in the plane of the page.

[0110] The pharmaceutical compositions of this disclosure may contain one or more pharmaceutically acceptable salts. A “pharmaceutically acceptable salt” means a salt that maintains the intended biological activity of the parent compound and does not impose any undesirable toxic effects (see, for example, Berge, SM et al., J. Pharm. Sci., 66:1-19 (1977)). Such salts may be obtained during the final separation and purification of the compounds described herein, or individually by the reaction of the free base functional group of the compound with a suitable acid or the reaction of the acidic group of the compound with a suitable base. Acid addition salts include those obtained from non-toxic inorganic acids (e.g., hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, etc.) and non-toxic organic acids (e.g., aliphatic monocarboxylic acids and aliphatic dicarboxylic acids, phenyl-substituted alkanes, hydroxyalkanoates, aromatic acids, aliphatic sulfonic acids, and aromatic sulfonic acids, etc.). Base addition salts include those obtained from alkaline earth metals (e.g., sodium, potassium, magnesium, calcium, etc.) and non-toxic organic amines (e.g., N,N'-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine, etc.).

[0111] (Pharmaceutical composition) In another embodiment, the Disclosure provides pharmaceutical compositions comprising, for example, one of the compounds or a combination thereof described herein, formulated with a pharmaceutically acceptable carrier. The pharmaceutical compositions of the Disclosure may also be administered in combination therapy (i.e., administered in combination with another agent, as described herein).

[0112] As used herein, “pharmaceutically acceptable carriers” include any physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption retarders. In some embodiments, the carrier is suitable for intravenous administration by injection or infusion, intramuscular administration, subcutaneous administration, parenteral administration, intrathecal administration, or epithelial administration. Depending on the route of administration, the active compound may be coated with a substance that protects it from the action of acids and other natural conditions that may inactivate the compound.

[0113] The pharmaceutical compositions of this disclosure may be administered by one or more routes of administration using one or more different methods known to those skilled in the art. As will be understood to those skilled in the art, the route of administration and / or method of administration will vary depending on the desired result. In some embodiments, the routes of administration of the compounds of this disclosure include, for example, intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, intrathecal, or other parenteral administration by injection or infusion. As used herein, the phrase “parenteral administration” means a method of administration other than enteral and topical administration, and usually means administration by injection. This includes, but is not limited to, intravenous, intramuscular, intra-arterial, intrathecal, intra-articular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injections and infusions.

[0114] Sterile injectable solutions are prepared by adding the desired amount of the active compound to a suitable solvent along with one or a combination of the components listed above, and then sterilizing by microfiltration as necessary. Generally, dispersions are prepared by adding the active compound to a sterile vehicle containing a basic dispersion solvent and the desired other components from those listed above. In the preparation of sterile powders used for sterile injectable solutions, some preparation methods involve vacuum drying and freeze-drying to obtain powders of the active ingredient and any other desired components from a pre-sterilized filtered solution.

[0115] Examples of suitable water-soluble and water-insoluble carriers that may be used in the pharmaceutical compositions of this disclosure include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils, and injectable organic esters. Adequate fluidity can be maintained, for example, by the use of a coating substance (e.g., lecithin), by maintaining the desired particle size in the case of a dispersion, and by the use of a surfactant.

[0116] pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions, and sterile powders for the immediate preparation of sterile injectable solutions or dispersions. The use of such solvents and agents in pharmaceutically active substances is known to those skilled in the art. Unless any conventional solvent or agent is incompatible with the active compound, their use is expected in the pharmaceutical compositions of this disclosure. Additional active compounds may also be included in the compositions.

[0117] Therapeutic compositions are generally sterile and must be stable under manufacturing and storage conditions. The composition may be formulated as a solution or liquid with a structure suitable for high drug concentrations. The carrier may be a solvent or dispersion medium (e.g., water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol)), or a suitable mixture thereof. Adequate fluidity can be maintained, for example, by the use of a coating substance (e.g., lecithin), maintaining the desired particle size in the case of a dispersion, and the use of a surfactant. Often, it is desirable for the composition to contain an isotonic agent (e.g., sugars, polyalcohols (e.g., mannitol, sorbitol, or sodium chloride)). Sustained absorption of the injectable composition may be achieved by including an absorption retarder (e.g., monostearate and gelatin) in the composition.

[0118] Alternatively, the compounds of this disclosure may be administered by means other than parenteral administration (e.g., topical, epithelial, or mucosal administration (e.g., intranasal, oral, vaginal, rectal, sublingual, or topical administration)).

[0119] Any pharmaceutical composition discussed herein may be delivered orally by any suitable oral formulation, for example. Examples of oral formulations include, but are not limited to, tablets, lozenges, tablets, lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups, and elixirs. Pharmaceutical compositions for oral administration may be manufactured according to any method known in the art of manufacturing pharmaceutical compositions for oral administration. To provide a pharmaceutically acceptable formulation, the pharmaceutical compositions of this disclosure may contain at least one agent selected from sweeteners, flavoring agents, coloring agents, lubricants, antioxidants, and preservatives.

[0120] Tablets may be manufactured, for example, by mixing at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof, and at least one non-toxic, pharmaceutically acceptable excipient suitable for the manufacture of tablets.

[0121] Aqueous suspensions can be prepared, for example, by mixing at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof, and at least one additive suitable for the preparation of aqueous suspensions. Examples of additives suitable for the preparation of aqueous suspensions include, but are not limited to, suspending agents (e.g., sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, alginic acid, polyvinylpyrrolidone, tragacanth gum, and gum arabic), dispersants or wetting agents (e.g., naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide and long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), ethylene oxide and fatty acids and Examples include condensation products with partial esters derived from hexitol (e.g., polyoxyethylene sorbitol monooleate), and condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyethylene sorbitan monooleate). The aqueous suspension may also contain at least one preservative (e.g., ethyl p-hydroxybenzoate and n-propyl p-hydroxybenzoic acid), at least one coloring agent, at least one flavoring agent, and / or at least one sweetener (but not limited to, e.g., sucrose, saccharin, and aspartame).

[0122] An oily suspension may be prepared, for example, by suspending at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof in either a vegetable oil (e.g., peanut oil, sesame oil, and coconut oil) or a mineral oil (e.g., liquid paraffin). The oily suspension may also contain at least one thickening agent (e.g., beeswax, solid paraffin, and cetyl alcohol). To provide a drinkable oily suspension, at least one sweetener already described above and / or at least one flavoring agent may be added to the oily suspension. The oily suspension may further contain at least one preservative (but not limited to, for example, an antioxidant (e.g., butylhydroxyanisole, and α-tocopherol)).

[0123] Dispersible powders and granules may be produced, for example, by mixing at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof, at least one dispersant and / or wetting agent, at least one suspending agent, and / or at least one preservative. Suitable dispersants, wetting agents, and suspending agents have already been described above. Examples of preservatives, but not limited to, include antioxidants (e.g., ascorbic acid). Furthermore, dispersible powders and granules may also include at least one excipient (e.g., sweeteners, flavoring agents, and coloring agents, but not limited to)

[0124] The active compound may be manufactured together with a carrier that prevents rapid release (e.g., a controlled-release formulation such as an implant, transdermal patch, and microcapsule delivery system). Biodegradable, biocompatible polymers (e.g., ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoester, and polylactic acid) may be used. Many methods for manufacturing such formulations are patented or generally known to those skilled in the art. See, for example, Robinson, JR, ed., Sustained and Controlled Release Drug Delivery Systems, Marcel Dekker, Inc., New York (1978).

[0125] The therapeutic compositions may be administered by medical devices known to those skilled in the art. For example, in one embodiment, the therapeutic compositions of the present disclosure may be administered by needle-free subcutaneous injection devices (e.g., devices disclosed in U.S. Patents 5,399,163, 5,383,851, 5,312,335, 5,064,413, 4,941,880, 4,790,824, or 4,596,556). Examples of known implants and modules useful in this disclosure include the implantable microinfusion pump for constant-rate drug delivery disclosed in U.S. Patent No. 4,487,603; the therapeutic device for transcutaneous drug delivery disclosed in U.S. Patent No. 4,486,194; the drug infusion pump for precise-rate drug delivery disclosed in U.S. Patent No. 4,447,233; the implantable variable-rate infusion device for continuous drug delivery disclosed in U.S. Patent No. 4,447,224; the osmotic drug delivery system with a multi-chamber compartment disclosed in U.S. Patent No. 4,439,196; and the osmotic drug delivery system disclosed in U.S. Patent No. 4,475,196. These patents are incorporated herein by reference. Many other similar implants, delivery systems, and modules are known to those skilled in the art.

[0126] In one embodiment, the compounds of the present disclosure may be administered parenterally. That is, they may be administered by infusion including, but not limited to, intravenous, intramuscular, intra-arterial, intrathecal, intra-articular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injections and / or infusions.

[0127] In some embodiments, the compounds of the present disclosure may be administered orally. That is, they may be administered in the form of gelatin capsules, tablets, hard or soft capsules, or liquid capsules.

[0128] Use / treatment methods of KRAS inhibitors The administration of the therapeutic agents described herein may include the administration of a therapeutically effective dose. The term “therapeutic dose” as used herein refers to the amount of the therapeutic agent used to treat a condition treatable by the administration of a composition containing a KRAS inhibitor as described herein, but not limited to the following. This amount is sufficient to produce a therapeutic or remission effect. Such effect includes, for example, the treatment of the conditions listed herein, but not limited to the following. The exact effective dose for a subject depends on the subject’s size and health condition, the nature and severity of the condition being treated, the suggestion of the treating physician, and the therapeutic agent or combination of therapeutic agents administered.

[0129] In administering the compounds described herein, the dosage range is approximately 0.0001 to 100 mg / kg relative to the subject's body weight, and more generally, 0.01 to 40 mg / kg. Examples of treatment plans include administration once daily, once every two weeks, once every three weeks, once weekly, once every two weeks, once every three weeks, once every four weeks, once a month, once every three months, or once every three to six months.

[0130] The compounds disclosed herein strongly inhibit anchorage-independent cell proliferation and therefore have the potential to inhibit tumor metastasis. Accordingly, in another embodiment, the disclosure provides a method for inhibiting tumor metastasis, characterized by administering an effective amount of a pharmaceutical composition comprising any of the compounds disclosed herein and a pharmaceutically acceptable carrier to a target subject.

[0131] Ras mutations, not just KRAS mutations, are also found in hematological malignancies (e.g., cancers affecting the blood, bone marrow, and / or lymph nodes). Therefore, one embodiment relates to the administration of the disclosed compounds (e.g., in the form of pharmaceutical compositions) to patients requiring treatment for hematological malignancies. Such malignancies include, but are not limited to, leukemias and lymphomas. For example, the compounds of this disclosure may be used to treat diseases such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myeloid leukemia (CML), acute monocytic leukemia (AMoL), and / or other leukemias. In another embodiment, the compounds are useful in treating any subtype of lymphoma, such as Hodgkin lymphoma or non-Hodgkin lymphoma.

[0132] The determination of whether a tumor or cancer contains a KRAS mutation can be made by evaluating the nucleotide sequence encoding the KRAS protein, the amino acid sequence of the KRAS protein, or the characteristics expected of a KRAS mutant protein. The sequence of the wild-type human KRAS protein is known to those skilled in the art.

[0133] Methods for detecting KRAS mutations are known to those skilled in the art. These methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays, polymerase chain reaction-single-strand structural polymorphism (PCR-SSCP) assays, real-time PCR assays, PCR sequencing, allele-specific PCR amplification (MASA) assays, direct sequencing, primer extension, electrophoresis, oligonucleotide ligation assays, hybrid assays, TaqMan assays, SNP genotyping assays, high-resolution melting curve analysis, and microarrays. In some embodiments, samples containing KRAS mutations were evaluated by real-time PCR. Real-time PCR uses a KRAS mutation-specific fluorescent probe. If a mutation is present, the probe binds and fluorescence is detected. In some embodiments, KRAS mutations are identified in specific regions of the KRAS gene (e.g., exon 2 and / or exon 3) using direct sequencing. This method identifies all possible mutations in the sequenced region.

[0134] Methods for detecting KRAS mutations are known to those skilled in the art. These methods include, but are not limited to, detection of KRAS mutations using mutant protein-specific binders (e.g., antibodies), protein electrophoresis and Western blotting, and direct peptide sequencing.

[0135] A variety of samples may be used to determine whether a tumor or cancer contains a KRAS mutation. In some embodiments, the sample is taken from a subject having a tumor or cancer. In some embodiments, the sample is a freshly taken tumor / cancer sample. In some embodiments, the sample is a frozen tumor / cancer sample. In some embodiments, the sample is a formalin-fixed paraffin-embedded sample. In some embodiments, the sample is processed into a cell lysate. In some embodiments, the sample is processed into a DNA or RNA. The disclosure also relates to a method for treating a hyperproliferative disorder in a mammal, characterized by administering a therapeutically effective amount of the disclosed compound, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof, to the mammal.In some embodiments, the method is used for acute myeloid leukemia, adolescent cancers, pediatric adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendiceal cancer, astrocytoma, atypical teratoma, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, atypical teratoma, embryonic tumor, germ cell tumor, primary lymphoma, cervical cancer, pediatric cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), and chronic myeloproliferative disease. Colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma in situ (DCIS), embryonic tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, neuroblastoma disseminated, Ewing's sarcoma, extracranial germ cell tumors, extramandibular germ cell tumors, eye cancer, fibrous histiocytoma, gallbladder cancer, stomach cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, gestational trophoblastic tumors, pilocytic cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, pancreatic islet cell tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, Lip and oral cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous cell carcinoma of unknown primary origin, midline cancer, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasmacytic neoplasm, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), lip and oral cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, This relates to the treatment of cancers such as papillomatosis, paraganglioma, sinus cancer and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, gastric cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, pharyngeal cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, chorioblastoma, rare childhood cancers, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or viral cancers.In some embodiments, the method relates to the treatment of noncancerous hyperproliferative disorders such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or the prostate (e.g., benign prostatic hyperplasia (BPH)).

[0136] In one aspect, the Disclosure relates to a method for treating lung cancer, characterized by administering an effective amount of any of the above compounds (or pharmaceutical compositions thereof) to a subject of interest. In one aspect, the lung cancer is non-small cell lung cancer (NSCLC) (e.g., adenocarcinoma, squamous cell lung cancer, or large cell lung cancer). In another aspect, the lung cancer is small cell lung cancer. Other lung cancers treatable with the disclosed compounds include, but are not limited to, adenomas, carcinoid tumors, and undifferentiated carcinomas. Subjects that can be treated with the disclosed compounds, or their pharmaceutically acceptable salts, esters, prodrugs, solvates, tautomers, hydrates, or derivatives thereof, according to the method of the Disclosure, are, for example, subjects diagnosed with: acute myeloid leukemia, adolescent cancer, pediatric adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendiceal cancer, astrocytoma, atypical teratoma, basal cell carcinoma, cholangiocarcinoma, bladder cancer, Bone cancer, brainstem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, atypical teratoma, embryonic tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative disorder, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma in situ (DCIS), embryonic tumor, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, Neuroblastoma disseminated, Ewing's sarcoma, extracranial germ cell tumor, extramandibular germ cell tumor, eye cancer, fibrous bone histiocytoma, gallbladder cancer, stomach cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, pilocytic cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, pancreatic islet cell tumor, pancreatic neuroendocrine tumor, kidney cancer, laryngeal cancer, lip and oral cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer Lymphoma, metastatic squamous cell carcinoma of unknown primary origin, midline cancer, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasmacytic neoplasm, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip cancer and oral cancer, oropharyngeal cancer,Ovarian cancer, pancreatic cancer, papilloma, paraganglioma, sinus cancer and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, gastric cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, pharyngeal cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, chorioblastoma, rare childhood cancers, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or viral cancers. In some embodiments, subjects treated with the compounds of this disclosure are subjects diagnosed with noncancerous hyperproliferative disorders such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate cancer (e.g., benign prostatic hyperplasia (BPH)). The Disclosure further provides methods for modulating the activity of a mutant KRAS protein by contacting the protein with an effective amount of the compound of the Disclosure. Such modification may be inhibition or activation of the protein. In some embodiments, the Disclosure provides a method for inhibiting the activity of a protein by contacting the mutant KRAS protein with an effective amount of the compound of the Disclosure in solution. In some embodiments, the Disclosure provides a method for inhibiting the activity of a mutant KRAS protein by contacting it with cells, tissues, or organs expressing the protein of interest. In some embodiments, the Disclosure provides a method for inhibiting the activity of a target protein, such as in rodents and mammals (e.g., humans), by administering an effective amount of the compound of the Disclosure. In some embodiments, the modulated percentage exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the inhibited percentage exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the Disclosure provides a method for inhibiting cellular KRAS activity by contacting cells with an amount of the Disclosure compound sufficient to inhibit cellular KRAS mutagenesis. In some embodiments, the Disclosure provides a method for inhibiting mutant KRAS in tissue by contacting tissue with an amount of the Disclosure compound sufficient to inhibit tissue mutant KRAS activity. In some embodiments, the Disclosure provides a method for inhibiting KRAS activity in an organism by contacting the organism with an amount of the Disclosure compound sufficient to inhibit the organism's KRAS mutagenesis. In some embodiments, the Disclosure provides a method for inhibiting KRAS activity in an organism by contacting the animal with an amount of the Disclosure compound sufficient to inhibit animal KRAS mutagenesis. In some embodiments, the Disclosure provides a method for inhibiting KRAS activity in an organism by contacting a mammal with an amount of the Disclosure compound sufficient to inhibit mammalian KRAS mutagenesis. In some embodiments, the Disclosure provides a method for inhibiting KRAS activity in an organism by contacting a human with an amount of the Disclosure compound sufficient to inhibit human KRAS mutagenesis. The Disclosure provides a method for treating KRAS activity-mediated diseases in subjects requiring treatment.The disclosure also provides combination therapeutic methods using the compounds of the disclosure, or their pharmaceutically acceptable salts, esters, prodrugs, solvates, tautomers, hydrates, or derivatives, in combination with agents known to modulate other pathways, or agents known to modulate other components of those pathways, or agents with overlapping sets of target enzymes. In some embodiments, such therapies include, but are not limited to, combinations of one or more compounds of the disclosure with chemotherapeutic agents, therapeutic antibodies, and radiotherapy.

[0137] Many chemotherapies are now known to those skilled in the art and may be used in combination with the compounds of this disclosure. In some embodiments, the chemotherapies are selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating agents, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, bioresponse modifiers, antihormone agents, angiogenesis inhibitors, and antiandrogens. In some embodiments, the chemotherapeutic agents are immunoneoplastic (IO) agents that enhance, stimulate, or upregulate the immune system.

[0138] The compounds described herein may be used in combination with the agents disclosed herein or other appropriate agents, depending on the condition being treated. Therefore, in some embodiments, one or more of the compounds disclosed herein are administered together with the other agents described above. When combination therapy is performed, the compounds described herein are administered simultaneously with or separately from the second agent. This combination administration may include simultaneous administration of two agents of the same dosage form, simultaneous administration of different dosage forms, and separate administration. In other words, the compounds described herein and any of the above-mentioned agents may be formulated together in the same dosage form and administered simultaneously. Alternatively, the compounds of this disclosure and any of the above-mentioned agents may be administered simultaneously in different dosage forms. Furthermore, the compounds of this disclosure may be administered, followed by any of the above-mentioned agents, or vice versa. In some embodiments of individual administration, the compounds of this disclosure and any of the above-mentioned agents may be administered after several minutes, several hours, or several days.

[0139] The compounds can be prepared by methods known in the art, including those described below, and can be modified within the scope of those skilled in the art. Some reagents and intermediates are known to those skilled in the art. Other reagents and intermediates can be prepared by methods known in the art using readily available chemicals. Any variables (such as numbered "R" substituents) are intended solely to illustrate methods for preparing the compounds and should not be confused with variables used in the claims or other sections of this specification. The methods described below are illustrative and do not limit the scope of this disclosure.

[0140] synthesis General Scheme The compounds described herein can be prepared as described below and in methods 1 to 4. [ka]

[0141] Method 1: In Step 1, known compound A (CAS 1698028-11-3) was reacted with an amine in a suitable solvent (e.g., THF) along with a base (e.g., diisopropylethylamine) to obtain compound B. In Step 2, compound B was treated with potassium fluoride in a solvent (e.g., dimethylacetamide) to obtain compound C. In Step 3, compound C was coupled with an arylboronic acid or ester under Suzuki coupling conditions to obtain compound D. In Step 4, compound D was treated with ROH in a solvent (e.g., THF) in the presence of a base to obtain compound E.

[0142] Method 2: The amino group of compound E may be converted to another amino group according to the following procedure. In step 5, compound F was obtained by base hydrolysis. In step 6, an amine substituent was introduced using a coupling agent (e.g., BOP) in the presence of a base in a solvent (e.g., dichloromethane) to obtain compound E.

[0143] Method 3: In step 7, compound H was treated with POCl3 in the presence of a base to obtain compound G. Compound G was treated with a suitable amine in a solvent (e.g., dimethylacetamide) in the presence of a base to obtain compound E.

[0144] Method 4: In step 9, compound B was treated with an alcohol of formula R-OH in the presence of a base to obtain compound H. In step 10, compound H was coupled with an arylboronic acid or ester under Suzuki coupling conditions to obtain compound E. Those skilled in the art may introduce and remove desired protecting groups (e.g., Boc, PMB, MOM, etc.), which are described in the examples. Functionalization and synthesis of aryl, NRR', and OR groups for the compound of general structure E are described in the examples.

[0145] Examples The present invention is further defined in the following embodiments, which should be understood to be given solely by description. From the above discussion and embodiments, those skilled in the art can elucidate the essential features of the invention and make changes and modifications to adapt it to a wide range of conditions and applications without departing from the essence and scope of the invention. As a result, the present invention is not limited by the embodiments described below, but rather is defined by the claims appended herein.

[0146] Abbreviation The following abbreviations are used in the following examples and elsewhere in this specification. [Table 1] [Table 2]

[0147] Example 1-1 4-(6-chloro-4-{3,9-diazabicyclo[4.2.1]nonan-9-yl}-8-fluoro-2-{[(2S)-1-methylpyrrolidine-2-yl]methoxy}quinazoline-7-yl)naphthalene-2-ol [ka] Intermediate 1A: Preparation of tert-butyl 4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate [ka] To a solution of 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (1 g, 3.03 mmol) and DIPEA (1.32 mL, 7.57 mmol) / THF (15 mL), tert-butylpiperazine-1-carboxylate (0.56 g, 3.03 mmol) was added under a nitrogen atmosphere and stirred at 25°C for 2 hours. This mixture was then concentrated. The resulting residue was diluted with ethyl acetate (60 mL) and washed with water (30 mL x 2) and saline solution (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (silica gel, petroleum ether:ethyl acetate = 10:1-4:1) to obtain tert-butyl 4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate (1.33 g, 2.77 mmol, yield 91.5%) as a yellow solid. MS(ESI)m / z 481.0 [M+1] + ; 1 H NMR(400MHz, CDCl3) δ 7.77(d, J=1.6Hz, 1H), 3.93-3.84(m, 4H), 3.72-3.61(m, 4H), 1.50(s, 9H)

[0148] Intermediate 1B: Preparation of tert-butyl(S)-4-(7-bromo-6-chloro-8-fluoro-2-((1-methylpyrrolidine-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate [ka] To a solution of tert-butyl 4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate (540 mg, 1.125 mmol) / DMSO (6 mL), cesium fluoride (342 mg, 2.249 mmol) and (S)-(1-methylpyrrolidine-2-yl)methanol (324 mg, 2.81 mmol) were added, and the mixture was heated at 100°C for 2 hours. After the mixture cooled to room temperature, saturated NaHCO3 (50 mL) was added. The inorganic layer was extracted with DCM (50 mL x 2). The extracted DCM layers were washed together with saline solution, dried with (Na2SO4), filtered, and then concentrated. The obtained residue was purified by silica column chromatography (40 g, elution: 0-10% MeOH / DCM (containing 0.5% TEA)) to obtain tert-butyl(S)-4-(7-bromo-6-chloro-8-fluoro-2-((1-methylpyrrolidine-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate (0.43 g, 0.769 mmol, yield 68.4%) as a yellow solid. MS(ESI) m / z 558.2 / 560.2 [M+1] +

[0149] Intermediate 1C: Preparation of tert-butyl 4-(6-chloro-8-fluoro-7-(3-hydroxynaphthalene-1-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)piperazine-1-carboxylate [ka] A suspension of tert-butyl(S)-4-(7-bromo-6-chloro-8-fluoro-2-((1-methylpyrrolidine-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate (430 mg, 0.769 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (249 mg, 0.923 mmol), Na2CO3 (245 mg, 2.308 mmol) / 1,4-dioxane (10 mL), and water (2 mL) was degassed with N2 for 5 minutes, and then tetrakis(triphenylphosphine)palladium(0) (178 mg, 0.154 mmol) was added all at once. The resulting mixture was degassed with N2 and then heated by microwave at 95°C for 1 hour. The reaction was cooled to RT, filtered, and the filtered cake was washed with dioxane (2 mL x 3). The filtrate and washings were combined and concentrated. The resulting residue was purified with silica (24 g, elution: 0-10% MeOH / DCM (containing 0.5% TEA)) to obtain tert-butyl 4-(6-chloro-8-fluoro-7-(3-hydroxynaphthalene-1-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)piperazine-1-carboxylate (174 mg, 0.280 mmol, yield 36.4%) as a yellow solid. MS(ESI) m / z 622.4 [M+1] +

[0150] Intermediate 1D: Preparation of 6-chloro-8-fluoro-7-(3-hydroxynaphthalene-1-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4(3H)-one [ka] A solution of tert-butyl 4-(6-chloro-8-fluoro-7-(3-hydroxynaphthalene-1-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)piperazine-1-carboxylate (400 mg, 0.643 mmol) / EtOH (5 mL) and water (0.5 mL) was treated with sodium hydroxide (1.286 mL, 1.286 mmol), and the reaction was stirred at 50°C for 16 hours. This mixture was concentrated under vacuum. The resulting residue was purified by flash silica gel chromatography (elution: 0-10% MeOH / DCM (containing 0.5% TEA)) to obtain the desired compound (174 mg, 0.383 mmol, yield 59.6%) as a white solid. MS(ESI) m / z: 454.1 [M+H] +

[0151] Intermediate 1E: Preparation of tert-butyl9-(6-chloro-8-fluoro-7-(3-hydroxynaphthalene-1-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)-3,9-diazabicyclo[4.2.1]nonane-3-carboxylate [ka] 6-Chloro-8-fluoro-7-(3-hydroxynaphthalene-1-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazolin-4-ol (10 mg, 0.022 mmol), tert-butyl 3,9-diazabicyclo[4.2.1]nonane-3-carboxylate (5.98 mg, 0.026 mmol), and a mixture of DIEA (11.54 μL, 0.066 mmol) / DCM (2 mL) were mixed with BOP (12.18 mg, 0.028 mmol), and the reaction was stirred at room temperature for 16 hours. The reaction was quenched with aqueous NaHCO3 solution (4 mL) and extracted with DCM (5 mL x 3). The organic layers were washed together with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue was dissolved in THF (2 mL) and TBAF (88 μL, 0.088 mmol) was added. This mixture was stirred at room temperature for 15 minutes, and the reaction mixture was concentrated. The resulting residue was purified with silica (4 g, elution: 0-10% MeOH / DCM (containing 0.5% TEA)) to obtain 1E (12 mg, 0.018 mmol, yield 82%). MS(ESI) m / z: 662.7 [M+H] +

[0152] Example 1-1: Preparation of 4-(4-(3,9-diazabicyclo[4.2.1]nonan-9-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol [ka] tert-butyl9-(6-chloro-8-fluoro-7-(3-hydroxynaphthalene-1-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)-3,9-diazabicyclo[4.2.1]nonane-3-carboxylate (12 mg, 0.018 mmol) was treated with 30% TFA / DCM (1 mL) at room temperature for 30 minutes. Next, the reaction mixture was concentrated, and the crude product was purified by preparative HPLC (conditions: column: XBridge C18, 200mm x 19mm, particle size: 5μm; mobile phase A: 5:95 acetonitrile:water (containing ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing ammonium acetate); gradient: elute at 14% B for 0 minutes, then elute at 14-54% B for 20 minutes, then elute at 100% B for 0 minutes; flow rate: 20 mL / min; column temperature: 25°C). The fractions containing the desired product were combined and dried using a centrifugal evaporator. The obtained substance was further purified by preparative HPLC (conditions: column: XBridge C18, 200mm x 19mm, particle size: 5μm; mobile phase A: 5:95 acetonitrile:water (containing 0.05% trifluoroacetic acid); mobile phase B: 95:5 acetonitrile:water (containing 0.05% trifluoroacetic acid); gradient: elution with 2% B for 0 minutes, then elution with 2-42% B for 20 minutes, followed by elution with 100% B for 0 minutes; flow rate: 20 mL / min; column temperature: 25°C). The fractions containing the desired product were combined and dried using a centrifugal evaporator to obtain Example 1-1 (1.3 mg, 1.6 μmol, yield 9.1%). MS(ESI) m / z 562.2 [M+1] + ; 1H NMR (500MHz, DMSO-d6) δ 8.28-7.93(m, 1H), 7.83-7.61(m, 1H), 7.54-7.35(m, 1H), 7.27-7.18(m, 2H), 7.11-6.93(m, 2H), 5.49-5.11(m, 1H), 4.79-4.47(m, 2H), 4.29-4.06(m, 1H), 3.23-3.09(m, 1H), 2.98-2.76(m, 2H), 2.72(s, 3H), 2.65-2.56(m, 1H), 2.33-2.08(m, 2H), 2.01-0.67(m, 11H)

[0153] The examples in Table 1 were prepared from suitable starting materials according to the procedure described in Example 1-1. [Table 3]

[0154] Example 2-1 6-(6-chloro-4-{3,9-diazabicyclo[4.2.1]nonan-3-yl}-8-fluoro-2-{[(2S)-1-methylpyrrolidine-2-yl]methoxy}quinazoline-7-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine [ka] Intermediate 2A: Preparation of 6-bromo-N,N-bis(4-methoxybenzyl)-4-methylpyridine-2-amine [ka] To a solution of 6-bromo-4-methylpyridine-2-amine (1 g, 5.35 mmol) / DMF (20 mL), NaH (0.64 g, 16 mmol, 60%) was added at 0°C and the mixture was stirred at 0°C for 0.5 hours. Then, 1-(chloromethyl)-4-methoxybenzene (2.1 g, 13.4 mmol) was added, and the mixture was stirred at 0°C for 1.5 hours. The reaction was quenched with saturated NH4Cl (20 mL), extracted with ethyl acetate (20 mL x 3), and the organic layers were washed together with brine (50 mL) and dried over anhydrous Na2SO4. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 5:1) to obtain 6-bromo-N,N-bis(4-methoxybenzyl)-4-methylpyridine-2-amine (2 g, 4.68 mmol, yield 87.5%) as a colorless oil. 1 H NMR(400MHz, CDCl3) δ 7.16(d, J=8.8Hz, 4H), 6.88-6.84(m, 4H), 6.60(s, 1H), 6.16(s, 1H), 4.64(s, 4H), 3.80(s, 6H), 2.13(s, 3H)

[0155] Intermediate 2B: Preparation of (6-(bis(4-methoxybenzyl)amino)-4-methylpyridine-2-yl)boronic acid [ka] KOAc (459.32 mg, 4.68 mmol) was added to a solution of 6-bromo-N,N-bis(4-methoxybenzyl)-4-methylpyridine-2-amine (1000 mg, 2.34 mmol), bis(pinacolato)diborone (832.5 mg, 3.28 mmol), and (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (171 mg, 0.23 mmol) / 1,4-dioxane (20 mL). Under a nitrogen atmosphere, this mixture was stirred at 90°C for 5 hours, and the reaction mixture was filtered. The resulting crude product: (6-(bis(4-methoxybenzyl)amino)-4-methylpyridine-2-yl)boronic acid (918 mg, 2.34 mmol, crude) / 1,4-dioxane (20 mL) was used in the next step without purification. MS(ESI)m / z 393.3 [M+1] +

[0156] Preparation of intermediate 2C: tert-butyl 4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate [ka] To a solution of 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (1 g, 3.03 mmol) and DIPEA (1.32 mL, 7.57 mmol) / THF (15 mL), tert-butylpiperazine-1-carboxylate (0.56 g, 3.03 mmol) was added under a nitrogen atmosphere. The reaction mixture was stirred at 25°C for 2 hours, and the mixture was then concentrated. The resulting residue was diluted with ethyl acetate (60 mL) and washed with water (30 mL x 2) and saline solution (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (silica gel, petroleum ether:ethyl acetate = 10:1~4:1) to obtain tert-butyl 4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate (1.33 g, 2.77 mmol, yield 91.5%) as a yellow solid. MS(ESI)m / z 481.0 [M+3] + ; 1H NMR(400MHz, CDCl3) δ 7.77(d, J=1.6Hz, 1H), 3.93-3.84(m, 4H), 3.72-3.61(m, 4H), 1.50(s, 9H)

[0157] Intermediate 2D: Preparation of tert-butyl 4-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)piperazine-1-carboxylate [ka] A solution of tert-butyl 4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate (1000 mg, 2.08 mmol) and potassium fluoride (2420 mg, 41.65 mmol) / DMA (10 mL) was stirred at 110°C for 12 hours under a nitrogen atmosphere. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic layers were washed together with saline solution (30 mL x 3) and dried over anhydrous sodium 2SO4. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (silica gel, petroleum ether:ethyl acetate = 20:1~3:1) to obtain tert-butyl 4-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)piperazine-1-carboxylate (730 mg, 1.57 mmol, yield 75.6%) as a yellow solid. MS(ESI)m / z 463.1 [M+1] +

[0158] Intermediate 2E: Preparation of tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridine-2-yl)-6-chloro-2,8-difluoroquinazoline-4-yl)piperazine-1-carboxylate [ka] A solution of tert-butyl 4-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)piperazine-1-carboxylate (600 mg, 1.29 mmol), (6-(bis(4-methoxybenzyl)amino)-4-methylpyridine-2-yl)boronic acid (756 mg, 1.93 mmol), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (104 mg, 0.14 mmol), and potassium phosphate (548 mg, 2.59 mmol) / 1,4-dioxane (20 mL) and water (2 mL) was stirred at 60°C for 12 hours under a nitrogen atmosphere, and the mixture was filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (silica gel, petroleum ether:ethyl acetate = 10:1-3:1) to obtain tert-butyl 4-(7-(4-(bis(4-methoxybenzyl)amino)-6-methylpyridine-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperazine-1-carboxylate (600 mg, 0.82 mmol, yield 63.4%) as a yellow oil. MS(ESI)m / z 731.4 [M+1] + ; 1 H NMR(400MHz, CDCl3) δ 7.76(d, J=1.2Hz, 1 H), 7.18(d, J=8.8Hz, 4 H), 6.85(d, J=8.8Hz, 4H), 6.59(s, 1H), 6.37(s, 1H), 4.69(s, 4H), 3.98-3.87(m, 4H), 3.80(s, 6H), 3.69-3.65(m, 4H), 2.27(s, 3H), 1.51(s, 9H)

[0159] Intermediate 2F: Preparation of tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridine-2-yl)-6-chloro-2,8-difluoroquinazoline-4-yl)piperazine-1-carboxylate [ka] A solution of tert-butyl 4-(7-(4-(bis(4-methoxybenzyl)amino)-6-methylpyridine-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperazine-1-carboxylate (800 mg, 1.09 mmol), TosOH (5 mg, 0.05 mmol), and NIS (1200 mg, 5.33 mmol) / DMF (10 mL) was stirred at 25°C for 12 hours. The reaction mixture was diluted with water (15 mL) and ethyl acetate (15 mL), and the mixture was extracted with ethyl acetate (30 mL x 3). The organic layers were washed together with saline solution (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 10:1~3:1) to obtain tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridine-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperazine-1-carboxylate (400 mg, 0.467 mmol, yield 42.7%) as a yellow solid. MS(ESI)m / z 857.2 [M+1] + ; 1 H NMR(400MHz, CDCl3) δ 7.82(d, J=1.2Hz, 1H), 7.17(d, J=8.4Hz, 4H), 6.86(d, J=8.4Hz, 4H), 6.48(s, 1H), 4.76-4.65(m, 2H), 4.62-4.50(m, 2H), 4.01-3.92(m, 4H), 3.82(s, 6H), 3.72-3.63(m, 4H), 2.38(s, 3H), 1.52(s, 9H)

[0160] Intermediate 2G: Preparation of tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-2,8-difluoroquinazoline-4-yl)piperazine-1-carboxylate [ka] A mixture of tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridine-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperazine-1-carboxylate (400 mg, 0.4700 mmol), methyl 2,2-difluoro-2-fluorosulfonylacetate (1345 mg, 7 mmol), and CuI (267 mg, 1.4 mmol) / DMA (10 mL) was stirred at 80°C for 5 hours under a nitrogen atmosphere. The reaction mixture was then cooled to room temperature, CuI (267 mg, 1.4 mmol) was added, and methyl 2,2-difluoro-2-fluorosulfonylacetate (1345 mg, 7 mmol) was added to the mixture. The reaction mixture was stirred at 80°C for a further 12 hours under a nitrogen atmosphere. The mixture was diluted with ELISA (50 mL) and filtered. The filtrate was washed with saline solution (30 mL x 3), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 10:1~3:1) to obtain tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperazine-1-carboxylate (270 mg, 0.34 mmol, yield 72.4%) as a yellow solid. MS(ESI)m / z 799.0 [M+1] +

[0161] Preparation of intermediate 2H: tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-2,8-difluoroquinazoline-4-yl)piperazine-1-carboxylate [ka] To a solution of (2S)-1-methylpyrrolidine-2-ylmethanol (97.6 mg, 0.85 mmol) / THF (10 mL), NaH (81 mg, 2.03 mmol, 60%) was added at 0°C and the mixture was stirred at 0°C for 0.5 hours. tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperazine-1-carboxylate (270 mg, 0.34 mmol) / THF (5 mL) was added, and the mixture was stirred at 0°C for 1 hour. The reaction mixture was then quenched with saturated NH4Cl (20 mL) and extracted with siRNA (20 mL x 3). The organic layers were washed together with brine (30 mL) and dried over anhydrous Na2SO4. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, DCM:MeOH = 10:1) to obtain tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperazine-1-carboxylate (250 mg, 0.28 mmol, yield 82.7%) as a white solid. MS(ESI)m / z 894.5 [M+1] +

[0162] Intermediate 2I: Preparation of 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4(3H)-one [ka] A mixture of tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperazine-1-carboxylate (250 mg, 0.28 mmol) and NaOH (224 mg, 5.59 mmol) / ethanol (30 mL) and water (10 mL) was stirred at 45°C for 3 days. The mixture was quenched with 2N HCl to pH=6-7. This mixture was concentrated under reduced pressure to remove EtOH. The resulting residue was extracted with DCM (20 mL x 3). The organic layers were washed together with saline solution (30 mL) and dried over anhydrous Na2SO4. This mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4(3H)-one (200 mg, 0.28 mmol, yield 98.5%) as a pale yellow solid. MS(ESI)m / z 726.3 [M+1] + ; 1 H NMR(400MHz, CDCl3) δ 8.07(s, 1H), 7.14(d, J=8.4Hz, 4H), 6.85(d, J=8.4Hz, 4H), 6.41(s, 1H), 4.98-4.65(m, 4H), 4.59-4.49(m, 2H), 3.80(s, 6H), 3.55-3.38(m, 1H), 2.90(d, J=8.0Hz, 3H), 2.41(s, 3H), 2.31-2.21(m, 2H), 2.14-2.03(m, 2H), 1.37-1.19(m, 2H)

[0163] Intermediate 2J: Preparation of tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate [ka] To a solution of 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4(3H)-one (50 mg, 0.0700 mmol) and tert-butyl 3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (75 mg, 0.3300 mmol) / DCM (1 mL), DIEA (0.07 mL, 0.7800 mmol) and BOP (105 mg, 0.4100 mmol) were added, and the mixture was stirred at 25°C for 12 hours. The reaction mixture was diluted with water (20 mL) and then extracted with dichloromethane (15 mL x 3). The organic layers were washed together with saline solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to preparative HPLC (additive: TFA, instrument: ACSWH-GX-N; column: Phenomenex Synergi C18 150x25mmx10um; mobile phase A: H2O (0.1% TFA) and mobile phase B: acetonitrile; gradient: linear elution over 10 minutes from 56% to 86% of B; flow rate: 25 mL / min; column temperature: RT; wavelength: The solution was purified at 220 nm and 254 nm to obtain the desired product: tert-butyl3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazolin-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (40 mg, 0.043 mmol) as a yellow solid. MS(ESI)m / z: 934.7 [M+H] +

[0164] Example 2-1 6-(6-chloro-4-{3,9-diazabicyclo[4.2.1]nonan-3-yl}-8-fluoro-2-{[(2S)-1-methylpyrrolidine-2-yl]methoxy}quinazoline-7-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine [ka] A solution of tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazolin-4-yl)-3,6-diazabicyclo[3.2.2]nonane-6-carboxylate (45 mg, 0.05 mmol) / TFA (4 mL, 52.24 mmol) was stirred at 50°C for 4 hours, and the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by preparative HPLC (additive: formic acid; instrument: GX-c; column: Phenomenex luna C18 150x25mm, 10um; mobile phase A: H2O (0.225% FA) and mobile phase B: acetonitrile; gradient: linear elution over 10 minutes from 3% to 33% B; flow rate: 25 mL / min; column temperature: RT; wavelength: 220 nm, 254 nm) to obtain the desired product: 6-(4-(3,6-diazabicyclo[3.2.2]nonan-3-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (17.98 mg, 0.028 mmol) as a yellow solid. MS(ESI)m / z: 594.2 [M+H] +1 H NMR (400MHz, CD3OD) δ 8.51(s, 2H), 7.93(s, 1H), 6.62(s, 1H), 4.76-4.69(m, 1H), 4.66-4.58(m, 1H), 4.54-4.42(m, 1H), 4.13-3.98(m, 2H), 3.97-3.88(m, 1H), 3.65-3.50(m, 4H), 3.49-3.43(m, 1H), 3.05-2.97(m, 1H), 2.92(s, 3H), 2.55-2.48(m, 1H), 2.45(s, 3H), 2.36-2.27(m, 1H), 2.13-2.05(m, 3H), 2.04-1.97(m, 2H), 1.94-1.81(m, 2H)

[0165] The examples in Table 2 were prepared from suitable starting materials according to the procedure described in Example 2-1. [Table 4]

[0166] Example 3 6-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine [ka] Intermediate 3A: Preparation of octahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate ethyl [ka] Intermediate 3A was prepared according to the method for compound 25a described in Molecules 2017, 22, 827.

[0167] Intermediate 3B: Preparation of 1-benzyl 4a-ethyl(4aS,7aR)-hexahydro-1H-cyclopenta[b]pyridine-1,4a(2H)-dicarboxylate [ka] To a solution of octahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate ethyl (1.7 g, 8.62 mmol) and TEA (2.40 mL, 17.23 mmol) / THF (10 mL), N-(benzyloxycarbonyl)succinimide (1.718 g, 6.89 mmol) was added, and the mixture was stirred at room temperature for 18 hours. This mixture was then diluted with toluene (15 mL) and washed with saturated sodium bicarbonate aqueous solution (2 x 15 mL). The ethyl acetate layer was dried over sodium sulfate, filtered, and concentrated. The resulting crude product was subjected to ISCO flash chromatography (silica gel, gradient = DCM:20% MeOH / DCM 100:0~50:50) to obtain 1-benzyl 4a-ethylhexahydro-1H-cyclopenta[b]pyridine-1,4a(2H)-dicarboxylate (2.20 g, 6.64 mmol, yield 77%). 1-benzyl 4α-ethylhexahydro-1H-cyclopenta[b]pyridine-1,4α(2H)-dicarboxylate (2.20 g) was subjected to SFC chiral separation [column: Cellulose-4 (5*25cm, 5μm), method = CO2 / IPA:heptane (1:3, containing 0.1% aqueous ammonia), 320 mL / min] to obtain 1-benzyl 4α-ethyl(4aS,7aR)-hexahydro-1H-cyclopenta[b]pyridine-1,4α(2H)-dicarboxylate (640 mg, 1.835 mmol, yield 21.29%). LCMS(ESI) m / z: 332.3 [M+H] + LC retention time: 1.05 min (Waters Acquity UPLC BEH C18, 2.1 x 50 mm, particle size: 1.7 μm; Mobile phase A: Water (containing 0.05% TFA); Mobile phase B: ACN (containing 0.05% TFA); Gradient: Elute over 1 minute from 2% to 98% B, then elute over 0.5 minutes at 98% B; Flow rate: 0.8 mL / min; Detection: MS and UV (220 nm)). 1H NMR (499MHz, chloroform-d) δ 7.41-7.28(m, 5H), 5.17 (br s, 2H), 4.13 (br d, J=6.4Hz, 2H), 2.86 (br s, 1H), 2.15 (br d, J=10.8Hz, 1H), 2.03-1.90(m, 1H), 1.90-1.74(m, 4H), 1.73-1.63(m, 1H), 1.58-1.42(m, 3H), 1.27-1.14(m, 4H), 0.98-0.68(m, 1H)

[0168] Preparation of intermediate 8C: (4aS,7aR)-octahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate ethyl [ka] A mixture of 1-benzyl 4α-ethyl (4aS,7aR)-hexahydro-1H-cyclopenta[b]pyridine-1,4a(2H)-dicarboxylate (640 mg, 1.931 mmol) and 10% Pd-C (103 mg, 0.097 mmol) / MeOH (10 mL) was subjected to hydrogen at a hydrogen atmosphere (1 atm) for 18 hours. The Pd / C was filtered, and the filtrate was concentrated to obtain crude (4aS,7aR)-octahydro-4aH-cyclopenta[b]pyridine-4α-carboxylate ethyl (385 mg, 1.854 mmol, yield 96%) as a clear oil. 1 H NMR(499MHz, CDCl3) δ 4.17(dtt, J=10.6, 7.1, 3.6Hz, 2H), 3.57(t, J=6.1Hz, 1H), 2.90(ddd, J=13.0, 7.7, 3.7Hz, 1H), 2.71(ddd, J=13.0, 7.0, 3.6Hz, 1H), 2.01-1.92(m, 2H), 1.84-1.62(m, 7H), 1.60-1.40(m, 2H), 1.28(t, J=7.1Hz, 3H)

[0169] Intermediate 3D: Preparation of (4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate ethyl [ka] (4aS,7aR)-octahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate ethyl (385 mg, 1.952 mmol) and a solution of formaldehyde (37 wt%, H2O (176 mg, 5.85 mmol) / MeOH (5.0 mL)) were mixed with sodium borohydride (123 mg, 1.952 mmol), and the mixture was stirred at room temperature for 18 hours. The mixture was then concentrated. The resulting residue was diluted with toluene (5 mL) and washed with saturated sodium carbonate aqueous solution (2 x 5 mL). The ethyl acetate layer was dried over sodium sulfate, filtered, and concentrated to obtain crude (4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate ethyl (380 mg, 1.798 mmol, yield 92%). 1 H NMR(499MHz, CDCl3) δ 4.24-4.12(m, 2H), 3.29(t, J=6.4Hz, 1H), 2.60-2.51(m, 1H), 2.36-2.28(m, 3H), 2.00-1.88(m, 2H), 1.83-1.60(m, 8H), 1.56-1.40(m, 1H), 1.32-1.26(m, 3H)

[0170] Intermediate 3E: Preparation of ((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridine-4a-yl)methanol [ka] To a solution of (4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridine-4a-ethyl carboxylate (380 mg, 1.798 mmol) / anhydrous THF (2.0 mL), lithium aluminum hydride (1.0 M, THF solution, 4496 μL, 4.50 mmol) was added, and the mixture was stirred at room temperature for 18 hours. 0.3 mL of saline solution was added dropwise to this mixture. 5.0 mL of toluene (5.0 mL) was then added to the mixture. The reaction mixture was filtered, and the filtrate was concentrated to obtain crude ((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridine-4a-yl)methanol (327 mg, 1.739 mmol, 97% yield). 1 ¹H NMR (499MHz, chloroform-d) δ 3.69-3.62 (m, 2H), 2.87 (t, J=7.6Hz, 1H), 2.51 (td, J=11.1, 3.4Hz, 1H), 2.43-2.35 (m, 1H), 2.30 (s, 3H), 2.01-1.85 (m, 2H), 1.82-1.74 (m, 1H), 1.68-1.52 (m, 6H), 1.47-1.42 (m, 1H), 1.39-1.33 (m, 1H)

[0171] Intermediate 3F: Preparation of tert-butyl 3-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (300 mg, 3.03 mmol) / dioxane (8 mL), DIPEA (0.476 mL, 2.72 mmol) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (193 mg, 0.908 mmol) were added. The resulting mixture was stirred at 25°C for 2 hours and then concentrated. The resulting residue was diluted with ethyl acetate (50 mL) and washed with water (30 mL x 2) and saline solution (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (12 g, ISCO column, MeOH / DCM, 0-5%, 20 min) to obtain tert-butyl 3-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (415 mg, 0.82 mmol, 90% yield) as a white solid. MS(ESI)m / z 507.0 [M+1] + ; 1 H NMR (499MHz, DMSO-d6) δ 8.10(d, J=1.9Hz, 1H), 4.38 (br d, J=10.6Hz, 2H), 4.25 (br s, 2H), 3.66(m, 2H) 1.79(m, 2H), 1.62(m, 2H), 1.47(s, 9H)

[0172] Intermediate 3G: Preparation of tert-butyl 3-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a degassed solution of tert-butyl 3-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1 g, 3.03 mmol) / DMA (80 mL), cesium fluoride (5.25 g, 34.6 mmol) was added. This mixture was degassed under nitrogen for 10 minutes and heated in a sealed tube at 88°C for 5 hours. Water (200 mL) and ethyl acetate (150 mL) were added, and the mixture was stirred for 15 minutes. The separated aqueous layer was extracted with ethyl acetate (2 x 100 mL), the organic layers were dried together over anhydrous Na2SO4, filtered, and concentrated. The obtained residue was purified by flash column chromatography (eluent: 15-25% ethyl acetate / petroleum ether) to obtain tert-butyl 3-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4.7 g, 8.77 mmol, yield 63.4%) as a pale yellow solid. MS(ESI)m / z 489.0 [M+1] +

[0173] Preparation of intermediate 3H: tert-butyl3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridine-2-yl)-6-chloro-2,8-difluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] In Example 3, potassium phosphate (1.73 g, 8.17 mmol), N,N-bis(4-methoxybenzyl)-4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-amine (5.8 g, 12.25 mmol), and PdCl2 (dppf) (149 mg, 0.204 mmol) were added to a degassed solution of G (2.00 g, 4.08 mmol) / anhydrous 1,4-dioxane (20 mL). The mixture was degassed again and heated at 80°C for 48 hours. The reaction vessel was then cooled to ambient temperature and diluted with ethyl acetate (40 mL) and Celite. (登録商標)The mixture was filtered and concentrated under reduced pressure to obtain the crude product. The resulting residue was purified by silica gel column chromatography (30% ethyl acetate / petroleum ether) to obtain tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridine-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.5 g, 1.74 mmol, yield 42%). 1 H NMR (400MHz, CDCl3): δ 7.76(d, J=1.6Hz, 1H), 7.20-7.18(d, J=8.8Hz, 4H), 6.86(dt, J=9.6Hz, 4H), 6.60(s, 1H), 6.38(s, 1H), 4.60(s, LCMS(ESI)m / z: 757.2 [M+H] +

[0174] Intermediate 3I: Preparation of tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridine-2-yl)-6-chloro-2,8-difluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a stirred solution of tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridine-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.40 g, 1.849 mmol) / anhydrous acetonitrile (15 mL), N-iodosuccinimide (0.42 g, 1.849 mmol) and trifluoroacetic acid (0.028 mL, 0.370 mmol) were added under nitrogen at 0°C. The reaction mixture was allowed to return to room temperature over 1 hour. The reaction mixture was then quenched with saturated sodium thiosulfate aqueous solution (5 mL) and saturated sodium bicarbonate aqueous solution (4 mL). The mixture was extracted with ethyl acetate (3 x 20 mL). The organic layers were dried together over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude residue. The obtained crude residue was purified by silica gel column chromatography (30% ethyl acetate / petroleum ether) to obtain tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridine-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.42 g, 1.560 mmol, yield 84%) as a pale yellow solid. LCMS(ESI)m / z: 883.3 [M+H] +

[0175] Intermediate 3J: Preparation of tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-2,8-difluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a stirred solution of tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridine-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.40 g, 1.585 mmol) / anhydrous DMA (10 mL), copper(I) iodide (0.60 g, 3.17 mmol) was added in a sealed tube under a nitrogen atmosphere. After degassing the reaction mixture for 10 minutes, methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.91 g, 4.76 mmol) was added, and the reaction mixture was heated at 90°C for 12 hours. The reaction mixture was diluted with diethyl ether (20 mL) and water (10 mL). The layers were separated, and the aqueous layer was extracted with diethyl ether (3 x 20 mL). The organic layers were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude residue. The crude material was purified by silica gel column chromatography (30% ethyl acetate / petroleum ether) to obtain tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.85 g, 0.630 mmol, yield 40%) as a pale yellow solid. 1 H NMR (400MHz, CDCl3): δ 7.77(s, 1H), 7.16(d, J=8.8Hz, 4H), 6.87(dt, J=9.6 and 2.8Hz, 4H), 6.43(s, 1H), 4.76-4.72(m, 2H), 4.59-4.55(m, 2H), 3.81(s, 6H), 2.43(s, 3H), 1.97-1.82(m, 4H), 1.97-1.82(m, 4H), 1.53(s, 9H)ppm; LCMS(ESI)m / z: 825.2 [M+H] +

[0176] Intermediate 3K and 3L: tert-butyl3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-2,8-difluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] Example 3J (5.0g, 6.06 mmol) was separated into a single atropisomer using SFC (column: Chiralpak IH (250mm x 4.6 x 5u), mobile phase: 0.25% isopropanol). Peak 1 eluted with a retention time of 5.85 minutes (2.4g, 2.90 mmol, 40% yield), and Peak 2 eluted with a retention time of 9.53 minutes (2.4g, 2.90 mmol, 40% yield). Peak 1 (3K): 1 H NMR (400MHz, CDCl3): δ 7.78(s, 1H), 7.16(d, J=8.8Hz, 4H), 6.87(dt, J=9.6 and 2.8Hz, 4H), 6.43(s, 1H), 4.76-4.72(m, 2H), 4.59-4.55(m, 2H), 3.81(s, 6H), 2.43(s, 3H), 1.97-1.82(m, 4H), 1.97-1.82(m, 4H), 1.53(s, 9H)ppm; LCMS(ESI)m / z: 825.2 [M+H] + LCMS(ESI)m / z: 825.2 [M+H] + ; [α] 23.5 (MeOH=0.10)=+96.00 Peak 2 (3L): 1H NMR (400MHz, CDCl3): δ 7.78(s, 1H), 7.16(d, J=8.8Hz, 4H), 6.87(dt, J=9.6 and 2.8Hz, 4H), 6.43(s, 1H), 4.76-4.72(m, 2H), 4.59-4.55(m, 2H), 3.81(s, 6H), 2.43(s, 3H), 1.97-1.82(m, 4H), 1.97-1.82(m, 4H), 1.53(s, 9H)ppm; LCMS(ESI)m / z: 825.2 [M+H] + ; [α] 23.3 (MeOH=0.10)=-110.00

[0177] Intermediate 3M: Preparation of tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridine-4a-yl)methoxy)quinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of 3 L of the intermediate and ((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridine-4a-yl)methanol (41.0 mg, 0.242 mmol) / anhydrous THF (1.0 mL), LiHMDS (1.0 M, THF solution, 364 μL, 0.364 mmol) was added under nitrogen at room temperature, and the mixture was stirred at room temperature for 18 hours. The mixture was diluted with DMF (1 mL), and the resulting crude product was preparatively HPLC (Phenomenex, Luna The sample was eluted over 30 minutes using a 5μm, 30x250mm container, at a flow rate of 30mL / min, with a gradient of 20%A to 100%B; A = H2O / ACN / TFA (90:10:0.1), B = H2O / ACN / TFA (10:90:0.1)) to obtain tert-butyl3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridine-4a-yl)methoxy)quinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (267 mg, 0.233 mmol, yield 96%). LCMS(ESI)m / z: 974.5 [M+H] + LC retention time: 1.13 min (Waters Acquity UPLC BEH C18, 2.1 x 50 mm, particle size: 1.7 μm; Mobile phase A: Water (containing 0.05% TFA); Mobile phase B: ACN (containing 0.05% TFA); Gradient: Elute over 1 minute from 2% to 98% B, then elute over 0.5 minutes at 98% B; Flow rate: 0.8 mL / min; Detection: MS and UV (220 nm))

[0178] Preparation of intermediate 3N: 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridine-4a-yl)methoxy)quinazolin-4-ol [ka] A mixture of 1.0 M sodium hydroxide (2453 μL, 2.453 mmol) and tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridine-4a-yl)methoxy)quinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (267 mg, 0.245 mmol) / EtOH (20 mL) was stirred at 65°C for 3 days. The mixture was then concentrated to remove the EtOH. The mixture was extracted with ELISA (2 x 15 mL), the ethyl acetate layer was dried over sodium sulfate, filtered, and concentrated. The obtained crude product was purified by preparative HPLC (Phenomenex, Luna 5 μm 30x250 mm, flow rate = 30 mL / min, gradient = elution of 20% A to 100% B over 30 minutes; A = H2O / ACN / TFA (90:10:0.1), B = H2O / ACN / TFA (10:90:0.1)). The pure fractions were combined and concentrated. The pure product was then diluted with Depositphotos (15 mL) and washed with saturated sodium carbonate aqueous solution (2 x 15 mL). The ethyl acetate layer was dried over sodium sulfate, filtered, and concentrated to obtain 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridine-4a-yl)methoxy)quinazolin-4-ol (60 mg, 0.077 mmol, yield 31.4%) as a yellowish-brown solid. LCMS(ESI)m / z: 780.3 [M+H] + LC retention time: 1.04 min (Waters Acquity UPLC BEH C18, 2.1 x 50 mm, particle size: 1.7 μm; Mobile phase A: Water (containing 0.05% TFA); Mobile phase B: ACN (containing 0.05% TFA); Gradient: Elute over 1 minute from 2% to 98% B, then elute over 0.5 minutes at 98% B; Flow rate: 0.8 mL / min; Detection: MS and UV (220 nm))

[0179] Example 3: Preparation of 6-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine [ka] 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridine-4a-yl)methoxy)quinazolin-4-ol (25 mg, 0.032 mmol), tert-butyl(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (10.88 mg, 0.048 mmol), and BOP (21.26 mg, 0.048 mmol) / DCM (1.0 mL) were mixed with DIEA (16.79 μL, 0.096 mmol), and the mixture was stirred at room temperature for 18 hours. The mixture was then concentrated. The crude product obtained was purified by preparative HPLC (Phenomenex, Luna 5μ, 30x250mm, flow rate = 30 mL / min, gradient = elution of 20% A to 100% B over 30 minutes; A = H2O / ACN / TFA (90:10:0.1), B = H2O / ACN / TFA (10:90:0.1)) to obtain tert-butyl(1S,6R)-3-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridine-4a-yl)methoxy)quinazoline-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate. A mixture of tert-butyl(1S,6R)-3-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridine-4a-yl)methoxy)quinazoline-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate / water (1 drop), triethylsilane (1 drop), and TFA (1.5 mL) was stirred at 40°C for 18 hours. The mixture was then concentrated. The obtained crude product was purified by preparative HPLC (Phenomenex, Luna 5μ, 30x250mm, flow rate = 30 mL / min, gradient = elution of 20% A to 100% B over 30 minutes, A = H2O / ACN / TFA (90:10:0.1), B = H2O / ACN / TFA (10:90:0.1)).The pure fraction was loaded into an Oasis MCX cation-mixed polymer cartridge (150 mg), the cartridge was washed with methanol (30 mL), and the product was eluted with 0.1 N ammonia / methanol (5.0 mL). The ammonia eluent was concentrated, and the resulting product was lyophilized in ACN / H2O (1:1, 5 mL) to obtain 4 6-(4-((1S,6R)-3,9-diazabicyclo[4.2.1]nonan-3-yl)-6-chloro-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridine-4a-yl)methoxy)quinazoline-7-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (10.96 mg, 0.016 mmol, yield 50.1%) as a white powder. LCMS(ESI)m / z: 648.2 [M+H]. + LC retention time: 1.27 min (Waters Acquity UPLC BEH C18, 2.1 x 50 mm, particle size: 1.7 μm; Mobile phase A: Water (containing 0.05% TFA); Mobile phase B: ACN (containing 0.05% TFA); Gradient: Elute over 1 minute from 2% to 98% B, then elute over 0.5 minutes at 98% B; Flow rate: 0.8 mL / min; Detection: MS and UV (220 nm)). 1 H NMR (499MHz, methanol-d4) δ 7.96(d, J=1.5Hz, 1H), 6.62(s, 1H), 4.55-4.47(m, 2H), 4.27(d, J=10.7Hz, 1H), 4.05-3.91(m, 2H), 3.84-3.77(m, 2H), 3.68(dd, J=13.5, 3.9Hz, 1H), 2.87 (br s, 1H), 2.73-2.64(m, 1H), 2.47(d, J=1.2Hz, 3H), 2.44-2.35(m, 1H), 2.33(s, 3H), 2.29-2.18(m, 1H), 2.13-1.92(m, 4H), 1.91-1.82(m, 2H), 1.81-1.64(m, 8H), 1.63-1.54(m, 1H)

[0180] Example 4-1 6-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine [ka] Intermediate 4A: Preparation of tert-butyl-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol and HCl (81 mg, 0.509 mmol) / DCM were stirred together, and sodium carbonate (231 mg, 2.181 mmol) was added. The reaction mixture was sonicated for 10 minutes and then stirred at room temperature for 30 minutes. The solvent was decanted, and the mixture was concentrated under reduced pressure to obtain ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol as the free base. The resulting crude residue was dissolved in anhydrous THF (5 mL) and cooled to 0°C. Then sodium hydride (60%, dispersed in mineral oil, 12.21 mg, 0.509 mmol) was added. The reaction mixture was stirred at the same temperature for 30 minutes, and then 3 L of the intermediate (280 mg, 0.339 mmol) / THF (1 mL) was added dropwise. The reaction mixture was stirred overnight at room temperature. The reaction mixture was then cooled with ice, quenched with saturated ammonium chloride aqueous solution (10 mL), and extracted with ethyl acetate (2 x 20 mL). The organic layers were washed together with water, then with saline solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was subjected to column chromatography (Grace REVELERIS). (登録商標)The solution was purified using a 50g snap, dry-packed, neutral alumina (50-100% ethyl acetate / petroleum ether). The desired fractions were collected and concentrated under reduced pressure to obtain tert-butyl-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (240 mg, 0.241 mmol, yield 71%). LCMS(ESI) m / z: 965.8 [M+H] +

[0181] Intermediate 4B: Preparation of 7-(5-(bis(4-methoxybenzyl)amino)-3-methyl-2-(trifluoromethyl)phenyl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazolin-4-ol [ka] To a stirred solution of tert-butyl-3-(7-(5-(bis(4-methoxybenzyl)amino)-3-methyl-2-(trifluoromethyl)phenyl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (240 mg, 0.249 mmol) / ethanol (5 mL), NaOH (1 M aqueous solution, 199 mg, 0.498 mmol) was added, and the mixture was heated at 70°C for 48 hours. The reaction mixture was then concentrated under reduced pressure to obtain the crude residue. This was purified by column chromatography (Biotage, neutral alumina, 30-40% ethyl acetate / petroleum ether) to obtain 7-(5-(bis(4-methoxybenzyl)amino)-3-methyl-2-(trifluoromethyl)phenyl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazolin-4-ol (60 mg, 0.077 mmol, yield 31%) as a grayish-white solid. LCMS(ESI) m / z: 771.2 [M+H] +

[0182] Preparation of intermediate 4C: tert-butyl(1S,6R)-3-(4-methoxybenzyl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate [ka] To a stirred solution of tert-butyl 3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (4.5 g, 19.88 mmol) and 4-methoxybenzaldehyde (3.25 g, 23.86 mmol) / DCE (50 mL), DIPEA (17.36 mL, 99 mmol) was added. The reaction mixture was stirred at 25°C for 15 minutes, and then cooled to 0°C. After 15 minutes, sodium triacetoxybora hydride (12.64 g, 59.7 mmol) was gradually added to the reaction mixture while maintaining the temperature below 5°C. After the addition, the reaction mixture was gradually warmed to 25°C and stirred overnight. The reaction mixture was then quenched with saturated ammonium chloride aqueous solution (10 mL) and extracted with dichloromethane (3 x 20 mL). The organic layers were washed together with water and saturated brine, then dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude compound obtained was purified by silica gel chromatography (60-120 mesh, elution: 10-15% ethyl acetate / petroleum ether) to obtain tert-butyl-3-(4-methoxybenzyl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate. Chiral SFC separation was performed on the pure fraction [column: Chiralpak ADH (250 x 4.6) mm, 5 μm, method = 0.5% isopropylamine / MeOH_10, retention time = 5.00 min], yielding tert-butyl(1R,6S)-3-(4-methoxybenzyl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (1.9 g, 5.48 mmol, yield 28%) as a light brown oil, and tert-butyl(1S,6R)-3-(4-methoxybenzyl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (2 g, 5.77 mmol, yield 29%) as a light brown oil. LCMS(ESI) m / z: 347.2 [M+H] + ; 1H NMR (400MHz, DMSO-d6, 298K) δ 7.31-7.19(m, 2H), 6.88(d, J=8.6Hz, 2H), 5.78-5.71(m, 1H), 4.15-3.89(m, 2H), 3.73(s, 3H), 3.49(s, 2H), 2.78-2.60(m, 1H), 2.48-2.42(m, 1H), 2.40(d, J=2.8Hz, 1H), 2.20-1.99(m, 2H), 1.96-1.55(m, 4H), 1.40(d, J=1.6Hz, 9H)ppm

[0183] Preparation of intermediate 4D: tert-butyl(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate [ka] To a stirred solution of tert-butyl(1S,6R)-3-(4-methoxybenzyl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (1500 mg, 4.33 mmol) / EtOH (20 mL), Pd / C (921 mg, 8.66 mmol) was added at 25°C. The resulting mixture was stirred under a hydrogen atmosphere (1 atm) at 25°C for 3 hours. The reaction mixture was then filtered through Celite, washed with ethanol, and the filtrate was concentrated under reduced pressure to obtain the crude compound. The obtained crude residue was purified by column chromatography (Biotage, neutral alumina, MeOH / dichloromethane (10%)) to obtain tert-butyl(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (700 mg, 71%). LCMS(ESI) m / z: 227.1 [M+H] +

[0184] Intermediate 4E: Preparation of tert-butyl(1S,6R)-3-(7-(5-(bis(4-methoxybenzyl)amino)-3-methyl-2-(trifluoromethyl)phenyl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazoline-5-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate [ka] To a stirred solution of 7-(5-(bis(4-methoxybenzyl)amino)-3-methyl-2-(trifluoromethyl)phenyl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazolin-4-ol (55 mg, 0.072 mmol) / acetonitrile (2 mL), BOP (47.4 mg, 0.107 mmol) and TEA (0.015 mL, 0.107 mmol) were added. After stirring for 5 minutes, tert-butyl(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (20.23 mg, 0.089 mmol) was added, and the mixture was stirred at 40°C for 16 hours. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 x 15 mL). The organic layers were washed together with saline solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. This was purified by column chromatography (Biotage, neutral alumina, 30-40% ethyl acetate / petroleum ether) to obtain tert-butyl(1S,6R)-3-(7-(5-(bis(4-methoxybenzyl)amino)-3-methyl-2-(trifluoromethyl)phenyl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazoline-5-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (55 mg, 0.052 mmol, yield 73%). LCMS(ESI) m / z: 979.51 [M+H] +

[0185] Example 4-1 6-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine [ka] To a stirred solution of tert-butyl(1S,6R)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (55 mg, 0.056 mmol) / TFA (1 mL), water (0.01 mL) and triethylsilane (0.898 μL, 5.62 μmol) were added, and the mixture was stirred at 40°C for 16 hours. The reaction mixture was then concentrated under reduced pressure to obtain the crude residue. This was purified by silica gel column chromatography (5-7% methanol / DCM) to obtain 6-(4-((1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazoline-7-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (16 mg, 0.023 mmol, yield 41%). LCMS(ESI)m / z: 638.3 [M+H] + ; 1H-NMR (400MHz, MeOD): δ 7.97(s, 1H), 6.62(s, 1H), 5.33(d, J=54.00Hz, 2H), 4.50(d, J=13.20Hz, 1H), 4.22-4.48(m, 2H), 4.01-4.03(m, 1H), 3.72-3.94(m, 4H), 3.24-3.33(m, 2H), 3.04-3.06(m, 1H), 2.47(s, 3H), 2.14-2.29(m, 9H), 1.98-2.02(m, 1H), 1.70-1.72(m, 2H)ppm

[0186] The examples in Table 3 were prepared from suitable starting materials according to the procedure described in Example 4-1. [Table 5]

[0187] Example 5 6-(2-{[(2S,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine [ka] Intermediate 5A (isomer 1) and 5B (isomer 2): Preparation of tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-2,8-difluoroquinazoline-4-yl)piperazine-1-carboxylate [ka] In a sealed tube, a stirred solution of tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridine-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperazine-1-carboxylate (21 g, 24.50 mmol) / anhydrous DMA (210 mL) was added to a nitrogen atmosphere, and copper(I) iodide (21 g, 24.50 mmol) was added. After degassing the reaction mixture for 10 minutes, methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (21 g, 24.50 mmol) was added, and the reaction mixture was heated at 90°C for 12 hours. After cooling to room temperature, the reaction mixture was diluted with diethyl ether (200 mL) and water (50 mL). The layers were separated, and the aqueous layer was extracted with diethyl ether (3 x 50 mL). The organic layers were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude residue. This was purified by silica gel column chromatography (30% ethyl acetate / petroleum ether) to obtain tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperazine-1-carboxylate (15.1 g, 16.44 mmol, yield 67%) as a pale yellow solid. The atrop isomers were separated using SFC (column: Chiralpak IH (250 mm x 4.6 x 5 μm), mobile phase: 25% isopropanol). Peak 1 (intermediate 5A) eluted at a retention time of 6.00 minutes (0.73 g, 0.98 mmol, yield 37%). LC-MS (ESI) m / z: 825.2 [M+H] + Peak 2 (intermediate 5B) eluted at a retention time of 9.262 minutes (0.77 g, 0.97 mmol, 38%). LC-MS (ESI) m / z: 825.2 [M+H] +

[0188] Preparation of intermediate 5C: tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((2S,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazoline-4-yl)piperazine-1-carboxylate [ka] To a stirred solution of ((2S,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (100 mg, 0.626 mmol) / THF (5 mL), sodium hydride (60%, dispersed in mineral oil, 25.02 mg, 0.626 mmol) was added at 0°C and the mixture was stirred for 30 minutes. Intermediate 5B (250 mg, 0.313 mmol) / THF (5 mL) was added dropwise to the reaction mixture at 0°C and the mixture was then stirred at ambient temperature for 2 hours. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (10 mL) and extracted with ethyl acetate (2 x 20 mL). The organic layers were washed together with water and brine, then dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The product, tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((2S,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazoline-4-yl)piperazine-1-carboxylate (398 mg, 0.246 mmol, yield 79%), was used in the next reaction without further purification. LC-MS (ESI) m / z: 938.3 [M+H] +

[0189] Intermediate 5D: Preparation of 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((2S,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazolin-4-ol [ka] To a stirred solution of tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((2S,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazoline-4-yl)piperazine-1-carboxylate (398 mg, 0.424 mmol) / EtOH (5 mL) and THF (1 mL), NaOH (1 M aqueous solution, 1696 mg, 4.98 mmol) was added. After stirring at 70°C for 48 hours, the reaction mixture was concentrated under reduced pressure to obtain the crude residue. This was purified by column chromatography (Biotage, neutral alumina, 30-40% ethyl acetate / petroleum ether) to obtain 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((2S,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazolin-4-ol (150 mg, 0.175 mmol, yield 41%) as a pale yellow oily substance. LCMS(ESI)m / z: 770.2 [M+H] +

[0190] Intermediate 5E: Preparation of tert-butyl(1S,6R)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((2S,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazoline-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate [ka] To a stirred solution of 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((2S,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazolin-4-ol (30 mg, 0.039 mmol) / acetonitrile (1 mL), TEA (8.14 μL, 0.058 mmol) and BOP (25.8 mg, 0.058 mmol) were added. After stirring for 5 minutes, tert-butyl(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (11.02 mg, 0.049 mmol) was added to the reaction mixture, and the mixture was heated at 40°C for 24 hours. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 x 15 mL). The organic layers were washed together with saline solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude compound. The obtained crude residue was purified by column chromatography (Biotage, neutral alumina, 45% ethyl acetate / petroleum ether) to obtain tert-butyl(1S,6R)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((2S,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazoline-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (28 mg, 0.027 mmol, yield 69%). LCMS(ESI)m / z: 979.5 [M+H] +

[0191] Example 5 6-(2-{[(2S,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine [ka] To a stirred solution of tert-butyl(1S,6R)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((2S,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (28 mg, 0.029 mmol) / TFA (1 mL), triethylsilane (0.457 μL, 2.86 μmol) and water (0.05 mL, 2.78 mmol) were added. The reaction was stirred at 40°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (Biotage, Sfar KP-Amino, elution: 50-100% ethyl acetate / petroleum ether) to obtain 6-(4-((1S,6R)-3,9-diazabicyclo[4.2.1]nonan-3-yl)-6-chloro-8-fluoro-2-(((2S,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazoline-7-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (11.4 mg, 0.018 mmol, yield 62%). LCMS(ESI) m / z: 638.08 [M+H] + ; 1 H-NMR (400MHz, MeOD) δ 7.97(d, J=1.60Hz, 1H), 6.63(s, 1H), 5.37(d, J=52.80Hz, 1H), 4.41-4.89(m, 3H), 4.02-4.13(m, 1H), 3.88-3.94(m, 4H), 3.49-3.50(m, 2H), 2.88-3.28(m, 3H), 2.50-2.16(m, 1H), 0.47(s, 3H), 2.19-2.47(m, 1H), 2.12-2.18(m, 4H), 1.91-2.02(m, 3H), 1.79-1.88(m, 2H) ppm

[0192] Example 6 4-{6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonan-3-yl]-8-fluoro-2-{[(2S)-1-methylpyrrolidine-2-yl]methoxy}quinazoline-7-yl}naphthalene-2-ol [ka] Intermediate 6A (isomer 1) and 6B (isomer 2): Preparation of tert-butyl-3-(6-chloro-2,8-difluoro-7-(3-(methoxymethoxy)naphthalene-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] A degassed solution of tert-butyl(1R,5S)-3-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.0g, 2.042mmol)) / 1,4-dioxane (60mL) is mixed with 2-(3-(methoxymethoxy)naphthalene-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.28g, 4.08mmol), Cs2CO3 (1.3g, 4.08mmol), Pd2(dba)3 (93mg, 0.102mmol), and pentaphenyl(di-tert-butylphosphino)ferrocene (0.073g, 0.102mmol, QPhos, Cas No: (312959-24-3) was added. The mixture was degassed again in a pressure-resistant vial and heated at 70°C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude residue. This was purified by silica gel column chromatography (30% ethyl acetate / petroleum ether) to obtain tert-butyl-3-(6-chloro-2,8-difluoro-7-(3-(methoxymethoxy)naphthalene-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.0 g, 1.591 mmol, 78%) as a light brown solid. LCMS(ESI) m / z: 597.2 [M+H] + SFC was performed on the purified compound to separate the atrop isomers (column: Chiralpak ADH (250mm x 4.6 x 5μ), mobile phase: 30% isopropanol). Peak 1 (intermediate 6A) eluted at a retention time of 2.72 minutes (230 mg, 46%). LC-MS (ESI) m / z: 597.2 [M+H] + Peak 2 (intermediate 6B) eluted at a retention time of 5.47 minutes (205 mg, 41%). LC-MS (ESI) m / z: 597.2 [M+H] +

[0193] Preparation of intermediate 6C: tert-butyl 3-(6-chloro-8-fluoro-7-(3-(methoxymethoxy)naphthalene-1-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a stirred solution of (S)-(1-methylpyrrolidine-2-yl)methanol (38.6 mg, 0.335 mmol) / THF (5 mL), NaH (60%, dispersed in mineral oil, 12.06 mg, 0.301 mmol) was added at 0°C, and the reaction mixture was stirred for 30 minutes. Intermediate 6A (100 mg, 0.167 mmol) / THF (1 mL) was then added dropwise. The reaction mixture was stirred at ambient temperature for 2 hours, then quenched with saturated ammonium chloride aqueous solution (10 mL), followed by extraction with ethyl acetate (2 x 20 mL). The organic layers were washed together with water and brine, then dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. This was purified by column chromatography (Grace REVELERIS®, 50 g snap, dry packed, neutral alumina, 50-100% ethyl acetate / petroleum ether). The desired fractions were collected and concentrated under reduced pressure to obtain tert-butyl3-(6-chloro-8-fluoro-7-(3-(methoxymethoxy)naphthalene-1-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (90 mg, 0.118 mmol, yield 71%) as a pale yellow oil. LCMS(ESI)m / z: 691.8 [M+H] +

[0194] Intermediate 6D: Preparation of 6-chloro-8-fluoro-7-(3-(methoxymethoxy)naphthalene-1-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazolin-4-ol [ka] To a stirred solution of tert-butyl 3-(6-chloro-8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 0.173 mmol) / ethanol (5 mL), NaOH (1 M aqueous solution, 199 mg, 0.498 mmol) was added and the mixture was stirred at 70°C for 48 hours. The reaction mixture was then concentrated under reduced pressure to obtain the crude residue. This was purified by column chromatography (Biotage, neutral alumina, 30-40% ethyl acetate / petroleum ether) to obtain 6-chloro-8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazolin-4-ol (35 mg, 0.069 mmol, yield 40%) as a grayish-white solid. LCMS(ESI) m / z: 500.1 [M+H] +

[0195] Intermediate 6E: Preparation of tert-butyl(1S,6R)-3-(6-chloro-8-fluoro-7-(3-(methoxymethoxy)naphthalene-1-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazoline-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate [ka] To a stirred solution of 6-chloro-8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazolin-4-ol (35 mg, 0.070 mmol) / acetonitrile (1 mL), TEA (0.015 mL, 0.105 mmol) and BOP (46.6 mg, 0.105 mmol) were added. After stirring for 5 minutes, tert-butyl(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (19.88 mg, 0.088 mmol) was added, followed by heating at 40°C for 24 hours. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 x 15 mL). The organic layers were washed together with saline solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude compound. The resulting residue was purified by column chromatography (Biotage, neutral alumina, 40% ethyl acetate / petroleum ether) to obtain tert-butyl(1S,6R)-3-(6-chloro-8-fluoro-7-(3-(methoxymethoxy)naphthalene-1-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazolin-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (30 mg, 0.039 mmol, yield 56%). LCMS(ESI)m / z: 707.2 [M+H] +

[0196] Example 6 4-{6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonan-3-yl]-8-fluoro-2-{[(2S)-1-methylpyrrolidine-2-yl]methoxy}quinazoline-7-yl}naphthalene-2-ol [ka] To a stirred solution of tert-butyl(1S,6R)-3-(6-chloro-8-fluoro-7-(3-(methoxymethoxy)naphthalene-1-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazolin-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (30 mg, 0.042 mmol) / methanol (1 mL), HCl (4.0 M, dioxane solution, 0.159 mL, 0.637 mmol) was added at ice-cold temperature. The reaction was allowed to return to room temperature and then stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude residue. This was purified by preparative HPLC [column: Xselect C18 (150x19) mm, 5 μm, mobile phase A: 10 mM ammonium acetate aqueous solution, mobile phase B: acetonitrile] to obtain 4-(4-((1S,6R)-3,9-diazabicyclo[4.2.1]nonan-3-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol (4 mg, 6.67 μmol, yield 16%). LCMS(ESI) m / z: 707.2 [M+H] + ; 1 H-NMR (400MHz, MeOD): δ 8.11(d, J=1.60Hz, 1H), 7.78(d, J=8.40Hz, 1H), 7.42-7.46(m, 1H), 7.21-7.29(m, 4H), 7.05(s, 1H), 4.52-4.67(m, 3H), 3.93-4.00(m, 5H), 3.33-3.34(m, 1H), 2.83(s, 4H), 2.18-2.28(m, 4H), 2.00-2.04(m, 3H), 1.85-1.96(m, 2H)ppm

[0197] Example 7 4-(2-{[(2R,7aR)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)naphthalene-2-ol [ka] Intermediate 7A: Preparation of tert-butyl-3-(6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalene-1-yl)quinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a stirred solution of ((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (53.3 mg, 0.335 mmol) / THF (5 mL), NaH (60%, dispersed in mineral oil, 12.06 mg, 0.301 mmol) was added at 0°C, and the reaction mixture was stirred for 30 minutes. Intermediate 6A (100 mg, 0.167 mmol) / THF (1 mL) was then added dropwise. The reaction mixture was stirred at ambient temperature for 2 hours, then quenched with saturated ammonium chloride aqueous solution (10 mL), followed by extraction with ethyl acetate (2 x 20 mL). The organic layers were washed together with water and brine, then dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. This was analyzed by column chromatography (Grace REVELERIS). (登録商標) The solution was purified using a 50g snap, dry-packed, neutral alumina (50-100% ethyl acetate / petroleum ether). The desired fractions were collected and concentrated under reduced pressure to obtain tert-butyl-3-(6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalene-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 0.150 mmol, yield 90%) as a pale yellow oil. LCMS(ESI)m / z: 735.8 [M+H] +

[0198] Intermediate 7B: Preparation of 6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalene-1-yl)quinazolin-4-ol [ka] To a stirred solution of tert-butyl-3-(6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalene-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (230 mg, 0.312 mmol) / ethanol (5 mL), NaOH (1 M aqueous solution, 1249 mg, 3.12 mmol) was added and the mixture was stirred at 70°C for 48 hours. The reaction mixture was then concentrated under reduced pressure to obtain the crude residue. This was purified by column chromatography (Biotage, neutral alumina, 30-40% ethyl acetate / petroleum ether) to obtain 6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)quinazolin-4-ol (35 mg, 0.061 mmol, yield 19%) as a grayish-white solid. LCMS(ESI) m / z: 542.2 [M+H] +

[0199] Preparation of intermediate 7C: tert-butyl(1S,6R)-3-(6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalene-1-yl)quinazoline-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate [ka] To a stirred solution of 6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalene-1-yl)quinazolin-4-ol (35 mg, 0.065 mmol) / acetonitrile (1 mL), TEA (0.014 mL, 0.097 mmol) and BOP (42.8 mg, 0.097 mmol) were added. After stirring for 5 minutes, tert-butyl(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (18.27 mg, 0.081 mmol) was added, and the mixture was heated at 40°C for 24 hours. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 x 15 mL). The organic layer was washed with saline solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude compound. The resulting residue was purified by column chromatography (Biotage, neutral alumina, 30-40% ethyl acetate / petroleum ether) to obtain tert-butyl(1S,6R)-3-(6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalene-1-yl)quinazolin-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (38 mg, 0.048 mmol, yield 75%). LCMS(ESI) m / z: 751.2 [M+H] + Example 7 4-(2-{[(2R,7aR)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)naphthalene-2-ol [ka] To a stirred solution of tert-butyl(1S,6R)-3-(6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalene-1-yl)quinazolin-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (30 mg, 0.042 mmol) / methanol (1 mL), HCl (4.0 M dioxane, 0.159 mL, 0.637 mmol) was added at ice-cold temperature. The reaction was allowed to return to room temperature and then stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude residue. This was purified by preparative HPLC [column: Xselect C18 (150x19) mm, 5 μm, mobile phase A: 10 mM ammonium acetate aqueous solution, mobile phase B: acetonitrile] to obtain 4-(4-((1S,6R)-3,9-diazabicyclo[4.2.1]nonan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazoline-7-yl)naphthalen-2-ol (7 mg, 0.01 μmol, yield 35%) as a grayish-white solid. LCMS(ESI) m / z: 562.3 [M+H] +1 H-NMR (400MHz, MeOD): δ 8.11(d, J=1.60Hz, 1H), 7.78(d, J=8.40Hz, 1H), 7.42-7.46(m, 1H), 7.21-7.29(m, 4H), 7.05(s, 1H), 4.52-4.67(m, 3H), 3.93-4.00(m, 5H), 3.33-3.34(m, 1H), 2.83(s, 4H), 2.18-2.28(m, 4H), 2.00-2.04(m, 3H), 1.85-1.96(m, 2H)ppm

[0200] Examples 8-1 and 8-2 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-5-ethylnaphthalene-2-ol [ka] Intermediate 8A: Preparation of tert-butyl-3-(7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (195 mg, 1.225 mmol) / THF (8 mL) was stirred, then NaH (61.3 mg, 1.531 mmol) was added at 0°C and the mixture was stirred for a further 30 minutes. Next, a solution of tert-butyl-3-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 1.021 mmol) / THF (2 mL) was added, and the mixture was gradually allowed to return to room temperature over 1 hour. The reaction mixture was quenched with saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic layers were washed together with water and brine, then dried over Na2SO4 and concentrated to obtain the crude residue. This was then subjected to silica gel column chromatography (instrument: CombiFlash, 40 g RediSep). (登録商標) The compound was purified by column chromatography (70-80% siRNA / petroleum ether) to obtain tert-butyl-3-(7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (400 mg, 0.636 mmol, yield 62.3%). MS(ESI)m / z: 628.2 [M+H] +

[0201] Intermediate 8B: Preparation of tert-butyl 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-6-chloro-7-[8-ethyl-3-(methoxymethoxy)naphthalene-1-yl]-8-fluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a stirred solution of tert-butyl-3-(7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (700 mg, 1.113 mmol) / 1,4-dioxane (5 mL), 2-(8-ethyl-3-(methoxymethoxy)naphthalene-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (457 mg, 1.336 mmol) and tripotassium phosphate (1.5 M aqueous solution, 1.484 mL, 2.226 mmol) were added at room temperature. The reaction mixture was purged with nitrogen for 5 minutes, and then Pd(Ph3P)4 (129 mg, 0.111 mmol) was added. The reaction mixture was purged again with nitrogen for 3 minutes and heated at 85°C for 16 hours. The reaction mixture was cooled, filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the crude compound. This was then subjected to silica gel column chromatography (instrument: CombiFlash, 24g RediSep). (登録商標) The solution was purified using a column (eluent: petroleum ether / ethyl acetate). The desired product was eluted with 60-70% ethyl acetate / petroleum ether. The pure fractions were combined and concentrated, then dried under reduced pressure to obtain tert-butyl 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-6-chloro-7-[8-ethyl-3-(methoxymethoxy)naphthalene-1-yl]-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (350 mg, 0.458 mmol, yield 41.1%) as a brown solid. MS(ESI)m / z: 764.3 [M+H]+

[0202] Intermediate 8C: Preparation of 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-6-chloro-7-[8-ethyl-3-(methoxymethoxy)naphthalene-1-yl]-8-fluoro-3,4-dihydroquinazoline-4-one [ka] A suspension of tert-butyl 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-6-chloro-7-[8-ethyl-3-(methoxymethoxy)naphthalene-1-yl]-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.262 mmol) / EtOH (2 mL) was treated with NaOH (1 M aqueous solution, 2.62 mL, 2.62 mmol). The reaction mixture was stirred at 70°C for 16 hours. The reaction mixture was then concentrated under reduced pressure, the resulting residue was diluted with ethyl acetate, washed with saline solution, dried over Na2SO4, filtered, and concentrated to obtain the crude compound: 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-6-chloro-7-[8-ethyl-3-(methoxymethoxy)naphthalene-1-yl]-8-fluoro-3,4-dihydroquinazolin-4-one (160 mg) as a white solid. MS(ESI)m / z: 570.2 [M+H] +

[0203] Intermediate 8D: Preparation of tert-butyl(1S,6R)-3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-6-chloro-7-[8-ethyl-3-(methoxymethoxy)naphthalene-1-yl]-8-fluoroquinazoline-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate [ka] A solution of 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-6-chloro-7-[8-ethyl-3-(methoxymethoxy)naphthalene-1-yl]-8-fluoro-3,4-dihydroquinazolin-4-one (160 mg, 0.281 mmol), tert-butyl(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (76 mg, 0.337 mmol), and BOP (186 mg, 0.421 mmol) / acetonitrile (2 mL) was treated with TEA (0.078 mL, 0.561 mmol), and the reaction mixture was stirred at 80°C for 8 hours. The reaction mixture was then concentrated under reduced pressure to obtain the crude residue. The obtained crude compound was purified by silica gel column chromatography (instrument: CombiFlash, 0-10% MeOH / DCM (containing 0.5% TEA)) to obtain the desired compound: tert-butyl(1S,6R)-3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-6-chloro-7-[8-ethyl-3-(methoxymethoxy)naphthalene-1-yl]-8-fluoroquinazolin-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (80 mg, 0.103 mmol, yield 36.6%). MS(ESI)m / z: 778.3 [M+H] +

[0204] Examples 8-1 and 8-2 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-5-ethylnaphthalene-2-ol [ka] To a solution of tert-butyl(1S,6R)-3-(2-{[(2R,7aS)-2-fluorohexahydro-1H-pyrrolidine-7a-yl]methoxy}-6-chloro-7-[8-ethyl-3-(methoxymethoxy)naphthalene-1-yl]-8-fluoroquinazolin-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (80 mg, 0.103 mmol) / MeOH (2 mL), HCl (4 M, 1,4-dioxane, 2 mL, 65.8 mmol) was added dropwise at 0°C, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure, azeotropically mixed with toluene (twice), neutralized with DIPEA, and concentrated again under reduced pressure to obtain the crude residue. The obtained crude compound was purified by preparative HPLC, followed by chiral separation using chiral HPLC to obtain atropisomers 1 and 2: 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-5-ethylnaphthalene-2-ol. Preparative HPLC conditions (Column: YMC-EXRS (250 x 21.2 mm), 5 μm; Mobile phase A = 10 mM ammonium bicarbonate aqueous solution (pH 9.5), Mobile phase B = acetonitrile:MeOH (1:1), Flow rate: 20 mL / min; Retention time = 12.6 min) Preparative chiral conditions (Column: Cellulose-C5 (250x21), 5μ; Mobile phase: 0.1% DEA / MeOH; Flow rate: 20 mL / min; Retention time for peak 1 = 5.3 min, Retention time for peak 2 = 6.3 min) Example 8-1: MS(ESI)m / z: 634.3[M+H] + ; 1H NMR (400MHz, DMSO-d6) δ=11.0 (bs, 1H), 7.97(s, 1H), 7.68-7.66(m, 1H), 7.40-7.33(m, 1H), 7.28(d, J=2.6Hz, 1H), 7.13-7.11(m, 1H), 6.86(d, J=2.6Hz, 1H), 5.39-5.17(m, 1H), 4.38-4.34(m, 1H), 4.13-4.09(m, 1H), 4.00(d, J=10.4Hz, 1H), 3.95-3.79(m, 3H), 3.72-3.64(m, 3H), 3.12-3.06(m, 4H), 3.04-2.98(m, 2H), 2.88-2.78(m, 2H), 2.36- 2.26(m, 2H), 2.16-2.10(m, 1H), 2.01-1.95(m, 1H), 1.90-1.84(m, 3H), 1.56-1.30(m, 3H), 0.87(t, J=7.4Hz, 3H) Example 8-2: MS(ESI)m / z: 634.3[M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ=7.97(s, 1H), 7.68-7.66(m, 1H), 7.38-7.34(m, 1H), 7.28(d, J=2.6Hz, 1H), 7.12-7.11(m, 1H), 6.87(d, J=2.6Hz, 1H), 5.38-5.18(m, 1H), 4.47-4.43(m, 1H), 4.11(d, J=10.4Hz, 1H), 3.99(d, J=10.4Hz, 1H), 3.93-3.82(m, 3H), 3.70-3.64(m, 3H), 3.11-3.05(m, 4H), 3.09-2.99(m, 2H), 2.88-2.77(m, 2H), 2.36 -2.30(m, 2H), 2.15-2.07(m, 1H), 2.08-2.00(m, 1H), 1.91-1.81(m, 3H), 1.47-1.26(m, 3H), 0.86(t, J=7.4Hz, 3H)

[0205] The examples in Table 4 were prepared from suitable starting materials according to the procedure described in Example 8. [Table 6] [Table 7] [Table 8]

[0206] Example 9-1 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)naphthalene-2-ol [ka] Intermediate 9A: Preparation of tert-butyl(1S,6R)-3-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate [ka] To a solution of 7-bromo-2,4-dichloro-8-fluoroquinazoline (250 mg, 0.845 mmol) and DIEA (148 μL, 0.845 mmol) / THF (30 mL), tert-butyl(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (191 mg, 0.845 mmol) was added under nitrogen at 0°C, and the mixture was stirred at 0°C for 1 hour and at room temperature for 18 hours. This mixture was then concentrated. This mixture was then diluted with toluene (35 mL) and washed with saturated sodium bicarbonate aqueous solution (2 x 35 mL). The ethyl acetate layer was dried over sodium sulfate, filtered, and concentrated. The crude product obtained was subjected to ISCO flash chromatography (silica gel, gradient: hexane / siRNA 100:0~60:40) to obtain tert-butyl(1S,6R)-3-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (362 mg, 0.708 mmol, yield 84%) as a white foam. LCMS(ESI) m / z: 486 [M+H] + LC retention time: 1.14 min (Waters Acquity UPLC BEH C18, 2.1 x 50 mm, particle size: 1.7 μm; Mobile phase A: Water (containing 0.05% TFA); Mobile phase B: ACN (containing 0.05% TFA); Gradient: Elute over 1 minute from 2% to 98% B, then elute over 0.5 minutes at 98% B; Flow rate: 0.8 mL / min; Detection: MS and UV (220 nm))

[0207] Intermediate 9B: Preparation of tert-butyl(1S,6R)-3-(7-bromo-2,8-difluoroquinazolin-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate [ka] A mixture of tert-butyl(1S,6R)-3-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (362 mg, 0.745 mmol) and potassium fluoride (87 mg, 1.490 mmol) / DMSO (5.0 mL) was stirred at 100°C for 2 days. This mixture was then diluted with ethyl acetate (25 mL) and washed with saturated sodium bicarbonate aqueous solution (2 x 25 mL). The ethyl acetate layer was dried over sodium sulfate, filtered, and concentrated. The crude product obtained was subjected to ISCO flash chromatography (silica gel, gradient: hexane / siRNA 100:0~40:60) to obtain tert-butyl(1S,6R)-3-(7-bromo-2,8-difluoroquinazolin-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (270 mg, 0.547 mmol, yield 73.3%) as a white foam. LCMS(ESI) m / z: 470 [M+H] + LC retention time: 1.09 min (Waters Acquity UPLC BEH C18, 2.1 x 50 mm, particle size: 1.7 μm; Mobile phase A: Water (containing 0.05% TFA); Mobile phase B: ACN (containing 0.05% TFA); Gradient: Elute over 1 minute from 2% to 98% B, then elute over 0.5 minutes at 98% B; Flow rate: 0.8 mL / min; Detection: MS and UV (220 nm))

[0208] Preparation of intermediate 9C: tert-butyl(1S,6R)-3-(7-bromo-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridine-4a-yl)methoxy)quinazoline-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate [ka] To a solution of ((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridine-4a-yl)methanol (72.9 mg, 0.430 mmol) and tert-butyl(1S,6R)-3-(7-bromo-2,8-difluoroquinazolin-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (202 mg, 0.430 mmol) / THF (30 mL), lithium bis(trimethylsilyl)amide (THF solution, 646 μL, 0.646 mmol) was added under nitrogen at 0°C. The mixture was stirred at 0°C for 1 hour, and then stirred at room temperature for 18 hours. The mixture was then concentrated. The crude product obtained was purified by chromatography (ISCO C18 100g column, flow rate = 60 mL / min, gradient = elution of 20% A to 100% B over 20 minutes; A = H2O / ACN / TFA (90:10:0.1), B = H2O / ACN / TFA (10:90:0.1)). The pure fractions were combined and concentrated to obtain tert-butyl(1S,6R)-3-(7-bromo-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridine-4a-yl)methoxy)quinazoline-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate as a white solid. LCMS(ESI) m / z: 619 [M+H] + Retention time: 0.88 min (Waters Acquity UPLC BEH C18, 2.1 x 50 mm, particle size: 1.7 μm; Mobile phase A: Water (containing 0.05% TFA); Mobile phase B: ACN (containing 0.05% TFA); Gradient: Elute over 1 minute from 2% to 98% B, then elute over 0.5 minutes at 98% B; Flow rate: 0.8 mL / min; Detection: MS and UV (220 nm))

[0209] Example 9-1 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridine-4a-yl]methoxy}-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)naphthalene-2-ol [ka] tert-butyl(1S,6R)-3-(7-bromo-8-fluoro-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridine-4a-yl)methoxy)quinazoline-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (20 mg, 0.032 mmol), 2-(3-(methoxymethoxy)naphthalene-1-yl)-4,4 A mixture of ,5,5-tetramethyl-1,3,2-dioxaborolane (10.67 mg, 0.034 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (1.054 mg, 1.617 μmol), and 2.0 M tripotassium phosphate (48.5 μL, 0.097 mmol) / 1,4-dioxane (1 mL) was stirred under nitrogen at 50°C for 18 hours. Then, HCl (5 mL) was added to this mixture, the ethyl acetate layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude product. A solution of this crude product / DCM (0.6 mL), TES (1 drop), and TFA (0.4 mL) was stirred at room temperature for 30 minutes. This mixture was then concentrated. The obtained crude product was purified by preparative HPLC (Phenomenex, Luna 5μ, 30x250mm, flow rate = 30 mL / min, gradient = elution of 20% A to 100% B over 12 minutes, A = H2O / ACN / TFA (90:10:0.1), B = H2O / ACN / TFA (10:90:0.1)). The pure fractions were combined and loaded into an Oasis MCX cation mixed-mode polymer cartridge (150 mg). The cartridge was washed with methanol (30 mL), and the product was eluted with 0.1N ammonia / methanol (5.0 mL). The ammonia eluent was evaporated, and the pure product was then freeze-dried with ACN / H2O (1:1, 5 mL) to obtain the desired product (9.15 mg, 0.015 mmol, yield 47.2%) as a white powder. LCMS(ESI)m / z: 582 [M+H] +LC retention time: 0.69 min (Waters Acquity UPLC BEH C18, 2.1 x 50 mm, particle size: 1.7 μm; Mobile phase A: Water (containing 0.05% TFA); Mobile phase B: ACN (containing 0.05% TFA); Gradient: Elute over 1 minute from 2% to 98% B, then elute over 0.5 minutes at 98% B; Flow rate: 0.8 mL / min; Detection: MS and UV (220 nm)). 1 H NMR (499MHz, methanol-d4) δ 7.99(d, J=8.7Hz, 1H), 7.75(d, J=8.3Hz, 1H), 7.51-7.40(m, 2H), 7.30-7.21(m, 3H), 7.12(d, J=2.3Hz, 1H), 4.77-4.61(m, 1H), 4.50 (br d, J=11.2Hz, 1H), 4.30(d, J=10.7Hz, 1H), 4.13-3.94(m, 2H), 3.86-3.78(m, 2H), 3.72-3.58(m, 1H), 2.90 (br t, J=5.7Hz, 1H), 2.69(ddd, J=11.6, 7.4, 4.2Hz, 1H), 2.41-2.32(m, 4H), 2.26-2.08(m, 3H), 2.07-1.93(m, 2H), 1.90-1.69(m, 10H), 1.67 (br s, 1H), 1.64-1.55(m, 1H)

[0210] The examples in Table 5 were prepared from suitable starting materials according to the procedure described in Example 9-1. [Table 9] [Table 10]

[0211] Example 10-1 6-{6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonan-3-yl]-2-({1-[(dimethylamino)methyl]cyclopropyl}methoxy)-8-fluoroquinazoline-7-yl}-4-methyl-5-(trifluoromethyl)pyridine-2-amine [ka] Intermediate 10A: Preparation of {1-[(dimethylamino)methyl]cyclopropyl}methanol [ka] To a solution of methyl 1-(dimethylcarbamoyl)cyclopropane-1-carboxylate (8 g, 46.7 mmol) / THF (150 mL), LiAlH4 (2.4 M, THF solution, 38.9 mL, 93 mmol) was slowly added at 0°C, and the reaction mixture was stirred at room temperature for 4 hours. The reaction was cooled, quenched with water (20 mL), 10% NaOH solution (40 mL), and water (40 mL), and extracted with ethyl acetate. The organic layers were washed together with water and brine, and dried over anhydrous Na2SO4. 、 The solution was filtered and concentrated under reduced pressure to obtain {1-[(dimethylamino)methyl]cyclopropyl}methanol (3.7 g, 28.6 mmol, yield 61.3%) as a yellow liquid. 1 H NMR (300MHz, CDCl3) δ ppm 5.30-4.15(m, 1H), 3.55(s, 2H), 2.41(s, 2H), 2.31(s, 6H), 0.54-0.47(m, 2H), 0.39-0.32(m, 2H)

[0212] Intermediate 10B: Preparation of tert-butyl 3-[7-(6-{bis[(4-methoxyphenyl)-methyl]amino}-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-2-({1-[(dimethylamino)methyl]cyclopropyl}-methoxy)-8-fluoroquinazoline-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of {1-[(dimethylamino)methyl]cyclopropyl}methanol / THF (2 mL), NaH (29.1 mg, 0.727 mmol) was added at 0°C, and the mixture was stirred at the same temperature for 30 minutes. Then, the intermediate 3K was added, and the mixture was gradually allowed to return to room temperature over 2 hours. The reaction mixture was then quenched with saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic layers were washed together with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude residue. This was purified by silica gel column chromatography (CombiFlash, 40g RediSep® column, 50-60% siRNA / petroleum ether) to obtain tert-butyl 3-[7-(6-{bis[(4-methoxyphenyl)-methyl]amino}-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-2-({1-[(dimethylamino)methyl]cyclopropyl}-methoxy)-8-fluoroquinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (250 mg, 0.268 mmol, yield 73.6%) as a pale yellow solid. MS(ESI)m / z: 934.3(M+H) +

[0213] Intermediate 10C: Preparation of 7-(6-{bis[(4-methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-2-({1-[(dimethylamino)methyl]cyclopropyl}methoxy)-8-fluoroquinazolin-4-ol [ka] To a solution of tert-butyl 3-[7-(6-{bis[(4-methoxyphenyl)-methyl]amino}-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-2-({1-[(dimethylamino)methyl]cyclopropyl}-methoxy)-8-fluoroquinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 0.161 mmol) / ethanol (2 mL) and THF (2 mL), NaOH (1 M aqueous solution, 1.605 mL, 1.605 mmol) was added, and the reaction mixture was stirred at 70°C for 16 hours. The reaction mixture was then concentrated, the resulting crude residue was dissolved in ethyl acetate, washed with saline solution, and concentrated under reduced pressure to obtain the crude residue of 7-(6-{bis[(4-methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-2-({1-[(dimethylamino)methyl]cyclopropyl}methoxy)-8-fluoroquinazolin-4-ol (70 mg, 0.095 mmol, yield 58.9%). MS(ESI)m / z: 740.2(M+H) +

[0214] Intermediate 10D: Preparation of tert-butyl(1S,6R)-3-[7-(6-{bis[(4-methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-2-({1-[(dimethylamino)methyl]cyclopropyl}methoxy)-8-fluoroquinazoline-4-yl]-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate [ka] 7-(6-{bis[(4-methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-2-({1-[(dimethylamino)methyl]cyclopropyl}methoxy)-8-fluoroquinazolin-4-ol (70 mg, 0.095 mmol), tert-butyl(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (25.7 mg, 0.113 mmol), and BOP (62.7 mg, 0.142 mmol) / ACN (3 mL) were mixed with TEA (0.026 mL, 0.189 mmol), and the mixture was stirred at 80°C for 8 hours. The reaction mixture was then concentrated under reduced pressure. The obtained crude compound was purified by silica gel column chromatography to obtain tert-butyl(1S,6R)-3-[7-(6-{bis[(4-methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-2-({1-[(dimethylamino)methyl]cyclopropyl}methoxy)-8-fluoroquinazolin-4-yl]-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (70 mg, 0.074 mmol, yield 78%). MS(ESI)m / z: 948.2(M+H) +

[0215] Example 10-1 6-{6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonan-3-yl]-2-({1-[(dimethylamino)methyl]cyclopropyl}methoxy)-8-fluoroquinazoline-7-yl}-4-methyl-5-(trifluoromethyl)pyridine-2-amine [ka] A stirred solution of TFA (1.5 mL, 19.47 mmol) and triethylsilane (0.5 mL, 3.13 mmol) was added at room temperature to tert-butyl(1S,6R)-3-[7-(6-{bis[(4-methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-2-({1-[(dimethylamino)methyl]cyclopropyl}methoxy)-8-fluoroquinazolin-4-yl]-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (70 mg, 0.074 mmol), and the resulting mixture was heated at 40°C for 24 hours. The reaction mixture was then concentrated under reduced pressure, azeotropically mixed with toluene (twice), neutralized with DIPEA, concentrated under reduced pressure, and the crude residue was obtained. This was purified by preparative HPLC (column / dimensions: Waters XBridge C18 (150mm x 19mm ID, 5μ); mobile phase A = 10mM ammonium acetate, mobile phase B = acetonitrile; flow rate: 20 mL / min; retention time = 1.748 min) to obtain 6-{6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonan-3-yl]-2-({1-[(dimethylamino)methyl]cyclopropyl}methoxy)-8-fluoroquinazolin-7-yl}-4-methyl-5-(trifluoromethyl)pyridine-2-amine (2.4 mg, 3.68 μmol, yield 4.98%). LCMS(ESI) m / z: 608.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ ppm 7.87(s, 1H), 6.85(s, 2H), 6.50(s, 1H), 5.36-5.01(m, 1H), 4.40-4.32(m, 1H), 4.28-4.17(m, 2H), 4.13-4.06(m, 1H), 4.03-3.84(m, 2H), 3.79-3.62(m, 2H), 2.38(m, 4H), 2.32-2.27(m, 2H), 2.21(m, 7H), 1.91(m, 3H), 1.72-1.60(m, 1H), 0.64(m, 2H), 0.46-0.38 (m, 2H)

[0216] The examples in Table 6 were prepared from suitable starting materials according to the procedure described in Example 10-1. [Table 11] [Table 12] [Table 13] [Table 14] [Table 15]

[0217] Example 11-1 4-{4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonan-3-yl]-2-({1-[(dimethylamino)methyl]cyclopropyl}methoxy)-8-fluoroquinazoline-7-yl}-5-ethynyl-6-fluoronaphthalene-2-ol [ka] Intermediate 11A: Preparation of tert-butyl(1S,6R)-3-[7-bromo-2-({1-[(dimethylamino)methyl]cyclopropyl}methoxy)-8-fluoroquinazoline-4-yl]-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate [ka] To a solution of (1-((dimethylamino)methyl)cyclopropyl)methanol (186 mg, 1.441 mmol) / THF (2 mL), NaH (57.6 mg, 1.441 mmol) was slowly added at 0°C, and the mixture was stirred at the same temperature for 30 minutes. Then, tert-butyl(1S,6R)-3-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (350 mg, 0.720 mmol) was added, and the mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was then quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layers were washed together with water and saline solution, dried over Na2SO4, filtered, and concentrated to obtain the crude product: tert-butyl(1S,6R)-3-(7-bromo-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoroquinazolin-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (350 mg, 0.605 mmol, yield 84%). MS(ESI)m / z: 580.1(M+H+2)

[0218] Intermediate 11B: Preparation of tert-butyl(1S,6R)-3-[2-({1-[(dimethylamino)methyl]cyclopropyl}methoxy)-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]quinazoline-4-yl]-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate [ka] To a degassed solution of tert-butyl(1S,6R)-3-(7-bromo-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoroquinazolin-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (300 mg, 0.519 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (319 mg, 0.622 mmol), and Na2CO3 (0.778 mL, 1.556 mmol) / 1,4-dioxane (5 mL), bis(triphenylphosphine)dichloropalladium(II) (36.4 mg, 0.052 mmol) was added, and the mixture was heated at 100°C for 2 hours. The reaction was then diluted with water and extracted with ethyl acetate. The organic layers were washed together with water and brine, dried over Na2SO4, filtered, and concentrated to obtain the crude residue. This was purified by silica gel column chromatography to obtain tert-butyl(1S,6R)-3-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (130 mg, 0.147 mmol, yield 28.4%). MS(ESI)m / z: 884.5(M+1)

[0219] Example 11-1 4-{4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonan-3-yl]-2-({1-[(dimethylamino)methyl]cyclopropyl}methoxy)-8-fluoroquinazoline-7-yl}-5-ethynyl-6-fluoronaphthalene-2-ol [ka] To a solution of 4-(4-((1S,6R)-3,9-diazabicyclo[4.2.1]nonan-3-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoroquinazolin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (120 mg, 0.162 mmol) / DMF (3 mL), CsF (123 mg, 0.811 mmol) was added at room temperature, and the mixture was stirred at 55 °C for 24 hours. The reaction mixture was then concentrated to obtain the crude residue. The crude material was separated by preparative HPLC (conditions: column: Waters XBridge C18 (19x150mm, particle size: 5μm); mobile phase A: 10mM ammonium acetate; mobile phase B: acetonitrile; gradient: elution with 10-35% B for 20 minutes, then elution with 100% B for 5 minutes; flow rate: 20mL / min), followed by purification by SFC to obtain 4-(4-((1S,6R)-3,9-diazabicyclo[4.2.1]nonan-3-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol (0.9 mg, 1.388 μmol, yield 0.856%). MS(ESI) m / z: 584.3 [M+H] +

[0220] The examples in Table 7 were prepared from intermediate 9A and a suitable starting material according to the procedure described in Example 11-1. [Table 16] [Table 17] [Table 18] [Table 19]

[0221] Example 12-1 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-5-fluoronaphthalene-2-ol [ka] Preparation of intermediate 12A-1: tert-butyl(1S,6R)-3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-7-bromo-8-fluoroquinazoline-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate [ka] To a stirred solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (246 mg, 1.544 mmol) / THF (20 mL), sodium hydride (49.4 mg, 2.059 mmol) was added, and the mixture was stirred at 0°C for 1 hour. To this reaction mixture, tert-butyl(1S,6R)-3-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (500 mg, 1.029 mmol) was added, and the mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched with water, extracted with ethyl acetate (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain tert-butyl(1S,6R)-3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-7-bromo-8-fluoroquinazolin-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate as a yellow solid. MS(ESI)m / z: 608.2 [M+H] +

[0222] Intermediate 12A: Preparation of tert-butyl(1S,6R)-3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-8-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate [ka] To a degassed solution of tert-butyl(1S,6R)-3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-7-bromo-8-fluoroquinazolin-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (120 mg, 0.197 mmol), bis(pinacolato)diborone (75 mg, 0.296 mmol), and potassium acetate (38.7 mg, 0.394 mmol) / 1,4-dioxane (3 mL), PdCl2(dppf) (14.43 mg, 0.020 mmol) was added, and the mixture was heated at 120°C for 1.5 hours. The reaction mixture was then filtered through Celite, and the filtrate was used in the next step without further workup or purification.

[0223] Intermediate 12B: Preparation of tert-butyl(1S,6R)-3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-7-(6-{bis[(4-methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-8-fluoroquinazoline-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate [ka] tert-butyl(1S,6R)-3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-8-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (crude product, 100 mg, 0.153 mmol) / 1,4-dioxane (2 mL), 6-chloro-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (CAS: To a degassed solution of 2411793-22-9 (83 mg, 0.183 mmol) and 1.5 M tripotassium phosphate aqueous solution (0.305 mL, 0.458 mmol), PdCl2 (dppf) (11.16 mg, 0.015 mmol) was added, and the mixture was stirred at 100°C for 6 hours. The reaction mixture was then diluted with water and extracted with ethyl acetate. The organic layers were washed together with water and brine, dried over Na2SO4, filtered, and concentrated to obtain the crude residue. The obtained crude residue was purified by silica gel column chromatography (24 g RediSep® column, elution: HCl / petroleum ether gradient of 60-100%). The fraction containing the desired product was concentrated to obtain tert-butyl(1S,6R)-3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-7-(6-{bis[(4-methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-8-fluoroquinazoline-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (70 mg, 0.074 mmol, yield 48.6%). LCMS(ESI)m / z: 944.3 [M+H] +

[0224] Example 12-1 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-5-fluoronaphthalene-2-ol [ka] A stirred solution of TFA (1.5 mL, 19.47 mmol) and triethylsilane (0.5 mL, 3.13 mmol) was added to tert-butyl(1S,6R)-3-(2-{[(2R,7aS)-2-fluorohexahydro-1H-pyrrolidine-7a-yl]methoxy}-7-(6-{bis[(4-methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-8-fluoroquinazolin-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (70 mg, 0.074 mmol) at room temperature, and the mixture was heated at 40°C for 24 hours. The reaction mixture was then concentrated under reduced pressure, azeotropically mixed with toluene (twice), neutralized with DIPEA, concentrated under reduced pressure, and the crude residue was obtained. This was purified by preparative HPLC [HPLC conditions: column / dimensions: column: Kinetex EVO (250mm x 21mm ID, 5μ); mobile phase A = 10mM ammonium bicarbonate aqueous solution (pH 9.5), mobile phase B = acetonitrile:MeOH (1:1), flow rate: 19mL / min; retention time = 11.72 min] to obtain 6-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidine-7a-yl]methoxy}-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (18mg, 0.030 mmol, yield 40.2%). LCMS(ESI) m / z: 604.5 [M+H] +1H NMR (400MHz, DMSO-d6) δ ppm 7.86-7.79(m, 1H), 7.18-7.07(m, 1H), 6.82-6.71(m, 2H), 6.47-6.44(m, 1H), 5.39-5.15(m, 1H), 4.53-4.40(m, 1H), 4.13-4.05(m, 1H), 4.02-3.92(m, 1H), 3.88-3.77(m, 2H), 3.70-3.60(m, 2H), 3.46-3.38(m, 2H), 3.12-3.05(m, 2H), 3.04-2.98(m, 1H), 2.86-2.77(m, 1H), 2.37-2.35(m, 3H), 2.16-2.09(m, 1H), 2.01-1.92(m, 3H), 1.84-1.80(s, 3H), 1.79-1.68(m, 3H), 1.50-1.36(m, 2H)

[0225] The examples in Table 8 were prepared from suitable starting materials according to the procedure described in Example 12-1. [Table 20] [Table 21]

[0226] Example 13-1 6-(2-{[(6'R,7'aR)-6'-fluoro-hexahydrospiro[cyclopropane-1,2'-pyrrolidine]-7'a-yl]methoxy}-6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine [ka] Intermediate 13A: Preparation of 1-(tert-butyl)2-methyl(2R,4R)-2-(2-(chloromethyl)allyl)-4-fluoropyrrolidine-1,2-dicarboxylate [ka] To a stirred solution of 1-(tert-butyl)2-methyl(2S,4R)-4-fluoropyrrolidine-1,2-dicarboxylate (50 g, 202 mmol), LiHMDS (1MTHF solution, 303 mL, 303 mmol) was added dropwise over 30 minutes under a nitrogen atmosphere and while maintaining the temperature at -45°C. After stirring at the same temperature for 1 hour, a solution of 3-chloro-2-(chloromethyl)propa-1-ene (30.3 g, 243 mmol) / anhydrous THF (300.0 mL) was added dropwise. The reaction mixture was slowly brought to room temperature over 2 hours and stirred for 16 hours. The reaction mixture was carefully quenched with saturated ammonium chloride solution (40 mL) and extracted with ethyl acetate (2 x 200 mL). The organic layers were washed together with water and saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The obtained crude residue was purified by column chromatography (Grace, 350 g snap, dry packed, silica gel (230-400 mesh, elution: 10-30% ethyl acetate / petroleum ether)). The desired fractions were collected and concentrated under reduced pressure to obtain 1-(tert-butyl)2-methyl(2R,4R)-2-(2-(chloromethyl)allyl)-4-fluoropyrrolidine-1,2-dicarboxylate (64 g, 91 mmol, yield 45%) as a colorless liquid. LCMS(ESI) m / z: 336.1 [M+H] +

[0227] Intermediate 13B: Preparation of (2R,4R)-2-(2-(chloromethyl)allyl)-4-fluoropyrrolidine-2-carboxylate methyl [ka] To a stirred solution of 1-(tert-butyl)2-methyl(2R,4R)-2-(2-(chloromethyl)allyl)-4-fluoropyrrolidine-1,2-dicarboxylate (64 g, 191 mmol) in anhydrous DCM (600 mL), HCl (4.0 M, dioxane solution, 119 mL, 476 mmol) was added under a nitrogen atmosphere at 0°C. The reaction mixture was stirred at ambient temperature for 6 hours, followed by concentration under reduced pressure to obtain (2R,4R)-2-(2-(chloromethyl)allyl)-4-fluoropyrrolidine-2-carboxylate methyl·HCl (50 g, 180 mmol, yield 94%) as a light brown solid. LCMS(ESI) m / z: 236.2 [M+H] +

[0228] Intermediate 13C: Preparation of (2R,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolidine-7a(5H)-methyl carboxylate [ka] (2R,4R)-2-(2-(chloromethyl)allyl)-4-fluoropyrrolidine-2-carboxylate methyl (50 g, 212 mmol) / anhydrous acetonitrile (500 mL) was stirred, to which TEA (44.4 mL, 318 mmol) was added, and the mixture was stirred at ambient temperature for 16 hours. The reaction mixture was then diluted with water (50 mL) and treated with aqueous bicarbonate solution (70 mL). The resulting solution was extracted with DCM (2 x 300 mL), the organic layers were washed together with saturated brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain (2R,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolidine-7a(5H)-carboxylate methyl (35 g, 176 mmol, yield 83%) as a brown liquid. LCMS(ESI) m / z: 200.1 [M+H] +

[0229] Intermediate 13D: Preparation of (6'R,7a'R)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-methyl carboxylate [ka] To a stirred solution of (2R,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolidine-7a(5H)-methyl carboxylate (2.0 g, 10.04 mmol) / anhydrous toluene (20 mL), diiodomethane (3.64 mL, 45.2 mmol) was added at 0°C under a nitrogen atmosphere. After stirring the reaction mixture at 0°C for 30 minutes, diethylzinc (50.2 mL, 50.2 mmol, 1 M hexane solution) was added dropwise. The reaction mixture was heated to room temperature and stirred for 16 hours, then quenched with saturated NH4Cl aqueous solution (5 mL). The suspension was extracted with ethyl acetate (2 x 20 mL). The organic layers were dried together over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude residue. This was purified by column chromatography (neutral alumina, 40-50% ethyl acetate / petroleum ether) to obtain (6'R,7a'R)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-methyl carboxylate (2.0 g, 8.05 mmol, yield 80%) as a colorless liquid. LCMS-ELSD(ESI)m / z: 204.1 [M+H] +

[0230] Intermediate 13E: Preparation of ((6'R,7a'R)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methanol [ka] To a stirred solution of (6'R,7a'R)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-methyl carboxylate (2.0 g, 9.38 mmol) / THF (20 mL), LiAlH4 (4.69 mL, 9.38 mmol, 2 M, THF solution) was added at 0°C. The reaction mixture was stirred at ambient temperature for 3 hours, and then quenched by adding saturated ammonium chloride aqueous solution at 0°C. After the foaming subsided, anhydrous sodium sulfate was added to the reaction mixture, followed by DCM (20 mL). The reaction mixture was stirred for 20 minutes and then filtered. The filtrate was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain ((6'R,7a'R)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methanol (110 mg, 0.592 mmol, yield 6%) as a colorless liquid. LCMS-ELSD(ESI)m / z: 186.2 [M+H] +

[0231] Intermediate 13F: Preparation of tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((6'R,7a'R)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)quinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] ((6'R,7a'R)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methanol (0.090 g, 0.485 mmol) / anhydrous THF (5.0 mL) was stirred, and sodium hydride (60%, dispersed in mineral oil, 0.019 g, 0.485 mmol) was added at 0°C. The reaction mixture was stirred at the same temperature for 30 minutes. While maintaining the temperature at 0°C, a solution of intermediate 3K (0.2 g, 0.242 mmol) / THF (2 mL) was added dropwise. The mixture was allowed to return to room temperature over 2 hours, the reaction was quenched with saturated ammonium chloride aqueous solution (1 mL), and extracted with ethyl acetate (3 x 5 mL). The organic layers were combined and dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain the crude product. The crude product obtained was purified by column chromatography (Grace, 50g snap, dry-packed, neutral alumina, 50-100% ethyl acetate / petroleum ether). The desired fraction was collected and concentrated under reduced pressure to obtain tert-butyl3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((6'R,7a'R)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)quinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.21g, 0.199 mmol, yield 82%) as a pale yellow solid. LCMS(ESI)m / z: 990.4 [M+H] +

[0232] Intermediate 13G: Preparation of 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((6'R,7a'R)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)quinazolin-4-ol [ka] To a stirred solution of tert-butyl3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((6'R,7a'R)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (240 mg, 0.242 mmol) / ethanol (5 mL), a 10% NaOH solution (2.42 mL, 2.423 mmol) was added, and the reaction was heated at 70°C for 48 hours. The reaction mixture was then concentrated under reduced pressure to obtain the crude residue. This was purified by column chromatography (Biotage, neutral Al2O3, 30-40% ethyl acetate / petroleum ether) to obtain 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((6'R,7a'R)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)quinazolin-4-ol (172 mg, 0.110 mmol, yield 46%) as a viscous liquid. LCMS(ESI)m / z: 796.2 [M+H] +

[0233] Preparation of intermediate 13H: tert-butyl(1S,6R)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((6'R,7a'R)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)quinazoline-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate [ka] To a stirred solution of 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((6'R,7a'R)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)quinazolin-4-ol (0.17 g, 0.214 mmol) / acetonitrile (2 mL), BOP (0.142 g, 0.320 mmol) and TEA (0.045 mL, 0.320 mmol) were added. After stirring for 5 minutes, tert-butyl(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (0.097 g, 0.427 mmol) was added, and the mixture was stirred at 40°C for 16 hours. The reaction mixture was then quenched with water (10 mL) and extracted with ethyl acetate (2 x 15 mL). The organic layer was washed with saline solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product (70 mg). The resulting residue was purified by column chromatography (Biotage, neutral alumina, 30-40% ethyl acetate / petroleum ether) to obtain tert-butyl(1S,6R)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((6'R,7a'R)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)quinazoline-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (150 mg, 0.103 mmol, 48% yield). LCMS(ESI) m / z: 1004.4 [M+H] +

[0234] Example 13-1 6-(2-{[(6'R,7'aR)-6'-fluoro-hexahydrospiro[cyclopropane-1,2'-pyrrolidine]-7'a-yl]methoxy}-6-chloro-4-[(1S,6R)-3,9-diazabicyclo[4.2.1]nonane-3-yl]-8-fluoroquinazoline-7-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine [ka] To a stirred solution of tert-butyl(1S,6R)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((6'R,7a'R)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)quinazolin-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (0.15 g, 0.149 mmol) / TFA (1 mL), water (0.01 mL) and triethylsilane (0.024 mL, 0.149 mmol) were added. The reaction was stirred at 40°C for 16 hours, and the reaction mixture was then concentrated under reduced pressure to obtain the crude residue. This was purified by preparative HPLC [column: Xbridge C18 (250x19) mm, 5 μm; mobile phase A: 0.1% aqueous ammonium formate; mobile phase B: acetonitrile; flow rate: 15 mL / min; gradient: elution of 30-70% B over 15 minutes], and the desired compound (10 mg, 0.012 mmol, yield 8%) was obtained as a grayish-white solid. LC-MS (ESI) m / z: 664.4 [M+H] + ; 1 H NMR (400MHz, CD3SOCD3, 298K) δ: 8.27-8.16(m, 1H), 7.96-7.78(m, 1H), 6.92-6.76(m, 1H), 6.50(s, 1H), 5.54-5.24(m, 1H), 4.43-4.24(m, 1H), 4.19-4.03(m, 1H), 3.95-3.83(m, 1H), 3.82-3.75(m, 2H), 3.74-3.62(m, 2H), 3.34-3.23(m, 3H), 3.08-2.88(m, 1H), 2.86-2.77(m, 5H), 2.68 (td, J=1.8, 3.5Hz, 2H), 2.63(d, J=10.0Hz, 1H), 2.41-2.29(m, 3H), 2.13-1.71(m, 5H), 1.46 (br s, 1H), 0.63-0.36(m, 2H)ppm

[0235] Intermediate 14-1: Preparation of N-(5-bromonaphthalene-1-yl)-1,1,1-trimethyl-N-(trimethylsilyl)silaneamine [ka] To a stirred solution of 5-bromonaphthalene-1-amine (40 g, 180 mmol) / anhydrous THF (650 mL), LiHMDS (1 M, THF solution, 396 mL, 396 mmol) was added dropwise over 30 minutes at -78°C under a nitrogen atmosphere. The reaction mixture was slowly heated to 20°C over 30 minutes and then cooled again to -78°C. To this reaction mixture, a solution of TMSCl (48.3 mL, 378 mmol) / anhydrous THF was added dropwise at -78°C and the mixture was slowly heated to 20°C over 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the crude residue. The obtained crude residue was dissolved in hexane (100 mL), filtered by Celite, and the filtrate was concentrated under reduced pressure to obtain the crude product as a red oil. This was purified by flash column chromatography (silica gel (100-200), eluent: petroleum ether). The pure fraction was concentrated under reduced pressure to obtain N-(5-bromonaphthalene-1-yl)-1,1,1-trimethyl-N-(trimethylsilyl)silanamine (61 g, 166 mmol, 92% yield) as a brown liquid. LCMS(ESI) m / z: 366.45 [M+H] +

[0236] Intermediate 14-2: Preparation of 5-fluoronaphthalene-1-amine [ka] To a stirred solution of N-(5-bromonaphthalene-1-yl)-1,1,1-trimethyl-N-(trimethylsilyl)silanamine (100 g, 273 mmol) / anhydrous THF (1400 mL), n-butyllithium (164 mL, 409 mmol) was added dropwise over 30 minutes at -78°C under an N2 atmosphere. After the addition was complete, the reaction mixture was stirred for 10 minutes, and then a solution of N-fluorobenzenesulfonimide (138 g, 437 mmol) / anhydrous THF (400 mL) was added dropwise over 20 minutes at -78°C. The resulting reaction mixture was slowly heated at 20°C for 1 hour, diluted with ice-cold water (1000 mL), and extracted with ethyl acetate (3 x 800 mL). The extracted organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude residue. The obtained residue was purified by flash column chromatography (silica gel (100-200), eluent: 10-20% ethyl acetate / petroleum ether). The pure fraction was concentrated under reduced pressure to obtain the crude compound. This was further purified by reverse-phase column chromatography (80% acetonitrile / 0.01% aqueous ammonium formate). The pure fraction was concentrated under reduced pressure to obtain 5-fluoronaphthalene-1-amine (20 g, 115 mmol, yield 42.3%) as a brown solid. LCMS(ESI) m / z: 162.19 [M+H] +

[0237] Intermediate 14-3: Preparation of 2,4-dibromo-5-fluoronaphthalene-1-amine [ka] To a stirred solution of 5-fluoronaphthalene-1-amine (40 g, 228 mmol) / acetic acid (800 mL), bromine (25.9 mL, 502 mmol) was carefully added over 30 minutes at 0°C, and the resulting mixture was stirred at 70°C for 1 hour. The reaction mixture was filtered, and the filter cake was washed with acetic acid (2 x 200 mL). The resulting residue was suspended in 10% NaOH solution (600 mL) and filtered. The filter cake was washed with water (200 mL), dried under reduced pressure, and crude 2,4-dibromo-5-fluoronaphthalene-1-amine (66 g, 170 mmol, yield 74.3%) was obtained as a pale yellow solid. The obtained crude compound was used in the next step without further purification. LCMS(ESI)m / z: 319.98 [M+H] +

[0238] Intermediate 14-4: Preparation of 5-bromo-6-fluoronaphtho[1,2-d][1,2,3]oxadiazole [ka] To a stirred solution of 2,4-dibromo-5-fluoronaphthalene-1-amine (66 g, 170 mmol) / acetic acid (1000 mL), propionic acid (136 mL, 1815 mmol) was added at 0°C. After 10 minutes, sodium nitrite (17.56 g, 255 mmol) was gradually added to the reaction mixture at 0°C. The reaction mixture was stirred at 0°C for 30 minutes and then heated to 25°C over 1 hour. The reaction mixture was diluted with cold water (2000 mL), stirred for 10 minutes, and filtered. The resulting solid was washed with water (2 x 500 mL), dried under reduced pressure, and crude 5-bromo-6-fluoronaphtho[1,2-d][1,2,3]oxadiazole (40 g, 118 mmol, yield 69%) was obtained as a brown solid. This was used in the next step without further purification. LCMS(ESI)m / z: 265.9 [M+H] +

[0239] Intermediate 14-5: Preparation of 4-bromo-5-fluoronaphthalene-2-ol [ka] 5-Bromo-6-fluoronaphtho[1,2-d][1,2,3]oxadiazole (40 g, 118 mmol) / ethanol (500 mL) and tetrahydrofuran (250 mL) were stirred together. NaBH4 (8.91 g, 235 mmol) was added gradually over 30 minutes under nitrogen at 0°C. The reaction was stirred at the same temperature for 30 minutes, then warmed to 25°C. The reaction mixture was carefully quenched with aqueous ammonium chloride (20 mL), concentrated under reduced pressure, and EtOH was removed. The suspension was extracted with ethyl acetate (3 x 500 mL), the organic layers were dried together over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 4-bromo-5-fluoronaphthalene-2-ol (30 g, 86 mmol, 73% yield). This was used in the next step without further purification. LCMS(ESI) m / z: 241.08 [M+H] +

[0240] Intermediate 14-6: Preparation of 1-bromo-8-fluoro-3-(methoxymethoxy)naphthalene [ka] To a stirred solution of 4-bromo-5-fluoronaphthalene-2-ol (30 g, 86 mmol) and DIPEA (22.50 mL, 129 mmol) / anhydrous dichloromethane (300 mL), MOM-Cl (7.83 mL, 103 mmol) was added dropwise over 10 minutes at 0°C under a nitrogen atmosphere. The mixture was allowed to return to room temperature and stirred for 1 hour. The reaction mixture was diluted with cold water (500 mL) and extracted with DCM (2 x 500 mL). The organic layers were washed together with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude residue. The obtained crude compound was purified by flash column chromatography (silica gel (100-200), eluent: 5-10% ethyl acetate / petroleum ether). The pure fraction was concentrated under reduced pressure to obtain 1-bromo-8-fluoro-3-(methoxymethoxy)naphthalene (20.5 g, 68.3 mmol, 80% yield) as a brown solid. LC-MS (ESI) m / z: 285.01 [M+H] +

[0241] Intermediate 14-7: Preparation of 2-(8-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] To a degassed solution of 1-bromo-8-fluoro-3-(methoxymethoxy)naphthalene (15 g, 50.0 mmol), bis(pinacolato)diborone (25.4 g, 100 mmol), and potassium acetate (14.72 g, 150 mmol) in anhydrous toluene (300 mL), PdCl2 (dppf) (3.66 g, 5.00 mmol) was added under an inert atmosphere at room temperature. This mixture was stirred at 110 °C for 3 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 250 mL). The organic layers were washed together with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude residue. The crude substance was purified by flash column chromatography (silica (100-200 mesh), eluent: 2-4% ethyl acetate / petroleum ether). The pure fraction was concentrated under reduced pressure to obtain a brown, viscous substance. This was further purified by reverse-phase column chromatography (eluent: 80% acetonitrile / 0.01% aqueous ammonium formate). The pure fraction was concentrated under reduced pressure to obtain 2-(8-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9 g, 26.6 mmol, yield 53.2%) as a grayish-white solid. LCMS(ESI) m / z: 332.1 [M+H] + 1H-NMR (400MHz, DMSO-d6): δ 7.52(d, J=0.80Hz, 1H), 7.42-7.44(m, 1H), 7.36-7.38(m, 1H), 7.33-7.35(m, 1H), 7.03(dd, J=1.20, 7.60Hz, 1H), 5.31(s, 2H), 3.52(s, 3H), 1.46(s, 12H)ppm

[0242] Intermediate 15-1: Preparation of 8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol [ka] To a stirred solution of naphthalene-1,3-diol (20 g, 125 mmol), (bromoethinyl)triisopropylsilane (34.3 g, 131 mmol), and potassium acetate (24.51 g, 250 mmol) / anhydrous dioxane (200 mL), dichloro(p-cymene)ruthenium(II) (dimer) (7.65 g, 12.49 mmol) was added under a nitrogen atmosphere, and the mixture was stirred at 110°C for 12 hours. The reaction mixture was cooled to ambient temperature and filtered through Celite. The Celite was washed with ELISA (2 x 100 mL), and the filtrates were combined and concentrated under reduced pressure to obtain the crude residue. The obtained crude product was purified by flash column chromatography (silica: 100-200 mesh, eluent: 12-15% ethyl acetate / petroleum ether). The pure fraction was concentrated under reduced pressure to obtain 8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (30 g, 85 mmol, yield 67.7%). LC-MS(ESI) m / z: 341.55 [M+H] +

[0243] Intermediate 15-2: Preparation of 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-ol [ka] 8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (25 g, 73.4 mmol) / anhydrous DCM (300 mL) was stirred, and DIPEA (38.5 mL, 220 mmol) was added under nitrogen at -10°C. After 10 minutes, MOM-Cl (6.13 mL, 81 mmol) was added dropwise to the reaction mixture under a nitrogen atmosphere over 20 minutes, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was diluted with DCM (100 mL) and washed with saline solution (200 mL). The organic layers were dried together over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude residue. The crude material was purified by flash column chromatography (silica: 100-200 mesh, eluent: 5-10% ethyl acetate / petroleum ether). The pure fraction was concentrated under reduced pressure to obtain 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol (21 g, 53.5 mmol, yield 72.9%) as a pale yellow oil. LCMS(ESI)m / z: 385.60 [M+H] +

[0244] Intermediate 15-3: Preparation of 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl pyruvate [ka] 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol (20 g, 52.0 mmol), TEA (21.75 mL, 156 mmol), DMAP (1.271 g, 10.40 mmol) / anhydrous DCM (200 mL) were stirred together, and pivaloyl chloride (12.80 mL, 104 mmol) was added dropwise over 10 minutes at -10°C under a nitrogen atmosphere. The resulting mixture was stirred under nitrogen at room temperature for 2 hours. The reaction mixture was then diluted with DCM (200 mL) and washed with saline solution (200 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude residue. The obtained crude product was purified by flash column chromatography (silica: 100-200 mesh, eluent: 10-15% ethyl acetate / petroleum ether). The pure fraction was concentrated under reduced pressure to obtain 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl pyruvate (23 g, 49.1 mmol, 94% yield) as a pale yellow oil. LCMS(ESI)m / z: 469.2 [M+H] +

[0245] Intermediate 15-4: Preparation of 8-ethynyl-3-(methoxymethoxy)naphthalene-1-yl pyruvate [ka] To a stirred solution of 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl pyruvate (12 g, 25.6 mmol) / anhydrous DMF (130 mL), anhydrous CsF (27.2 g, 179 mmol) was added at room temperature under a nitrogen atmosphere, and the mixture was stirred for 2 hours. The reaction mixture was diluted with DCM (200 mL) and washed with saline solution (200 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude residue. The obtained crude product was purified by flash column chromatography (silica: 100-200 mesh, eluent: 5-8% ethyl acetate / petroleum ether). The pure fraction was concentrated under reduced pressure to obtain 8-ethynyl-3-(methoxymethoxy)naphthalen-1-yl pyruvate (7 g, 20.62 mmol, 81% yield). LCMS(ESI)m / z: 313.3 [M+H] +

[0246] Intermediate 15-5: Preparation of 8-ethyl-3-(methoxymethoxy)naphthalen-1-yl pyruvate [ka] To a stirred solution of 8-ethynyl-3-(methoxymethoxy)naphthalen-1-yl pyruvate (7 g, 22.41 mmol) / anhydrous methanol (70 mL), Pd / C (1.4 g, 13.16 mmol) was added at 25°C. The suspension was degassed under reduced pressure and purged several times with H2. This mixture was stirred under an H2 atmosphere (1 atm) at 25°C for 5 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain the crude residue. The crude material was purified by flash column chromatography (silica: 100-200 mesh, eluent: 15-20% ethyl acetate / petroleum ether). The pure fraction was concentrated under reduced pressure to obtain 8-ethyl-3-(methoxymethoxy)naphthalen-1-yl pyruvate (6.56 g, 17.83 mmol, yield 80%) as a pale yellow oil. LCMS(ESI) m / z: 316.1 [M+H] +

[0247] Intermediate 15-6: Preparation of 8-ethyl-3-(methoxymethoxy)naphthalene-1-ol [ka] To a stirred solution of 8-ethyl-3-(methoxymethoxy)naphthalen-1-yl pyruvate (10 g, 31.6 mmol) / THF:water:MeOH (5:1:5), anhydrous LiOH (1.135 g, 47.4 mmol) was added under nitrogen at room temperature, and the mixture was stirred at the same temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to remove the MeOH. The reaction mixture was diluted with toluene (150 mL) and washed with brine (200 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude residue. The crude material was purified by flash column chromatography (silica: 100-200 mesh, eluent: 25-30% ethyl acetate / petroleum ether). The pure fraction was concentrated under reduced pressure to obtain 8-ethyl-3-(methoxymethoxy)naphthalen-1-ol (6 g, 25.8 mmol, yield 82%). LCMS(ESI)m / z: 233.2 [M+H] +

[0248] Intermediate 15-7: Preparation of 8-ethyl-3-(methoxymethoxy)naphthalene-1-yltrifluoromethanesulfonate [ka] 8-ethyl-3-(methoxymethoxy)naphthalen-1-ol (3 g, 12.92 mmol) and DIPEA (22.50 mL, 129 mmol) / anhydrous dichloromethane (50 mL) were stirred together, and Tf2O (2.182 mL, 12.92 mmol) was added dropwise under nitrogen at -40°C. The resulting reaction mixture was allowed to return to room temperature and stirred for 1 hour. This reaction mixture was diluted with cold water (500 mL) and extracted with DCM (2 x 500 mL). The organic layers were washed together with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude residue. The obtained crude compound was purified by flash column chromatography (silica gel: 100-200, eluent: 5-10% ethyl acetate / petroleum ether). The pure fraction was concentrated under reduced pressure to obtain 8-ethyl-3-(methoxymethoxy)naphthalene-1-yltrifluoromethanesulfonate (3.5 g, 9.03 mmol, yield 69.9%) as a pale yellow oil. LCMS(ESI) m / z: 365.3 [M+H] +

[0249] Intermediate 15-8: Preparation of 2-(8-ethyl-3-(methoxymethoxy)naphthalene-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] To a stirred solution of 8-ethyl-3-(methoxymethoxy)naphthalene-1-yltrifluoromethanesulfonate (7.4 g, 20.31 mmol) / 1,4-dioxane (80 mL), bis(pinacolato)diborone (12.89 g, 50.8 mmol) and potassium acetate (5.98 g, 60.9 mmol) were added. This mixture was degassed, purged with nitrogen for 5 minutes, and PdCl2 (dppf) (1.659 g, 2.031 mmol) was added. The resulting mixture was stirred under nitrogen at 100°C for 3 hours. This reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (250 mL). The organic layers were washed together with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude residue. The obtained crude product was purified by flash column chromatography (silica (100-200 mesh), 2-4% ethyl acetate / petroleum ether). The pure fraction was concentrated under reduced pressure to obtain a brown, viscous substance. This was purified again by reverse-phase column chromatography (eluent: 80% acetonitrile / 0.01% aqueous ammonium formate). The pure fraction was concentrated under reduced pressure to obtain 2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.5 g, 13.10 mmol, yield 64.5%). LCMS(ESI) m / z: 344.2 [M+H] +1 H-NMR (400MHz, CDCl3): δ 7.62(dd, J=0.80, 8.00Hz, 1H), 7.36-7.44(m, 3H), 7.27(t, J=0.40Hz, 1H), 5.31(s, 2H), 3.53(s, 3H), 3.21 (q, J=7.20Hz, 2H), 1.46(s, 12H), 1.38(t, J=7.60Hz, 3H)ppm

[0250] Intermediate 16-1: Preparation of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol [ka] To a stirred solution of 7-fluoronaphthalene-1,3-diol (20 g, 112 mol), (bromoethinyl)triisopropylsilane (30.8 g, 118 mmol), and potassium acetate (22.03 g, 225 mmol) / anhydrous dioxane (200 mL), dichloro(p-cymene)ruthenium(II) (dimer) (6.87 g, 11.23 mmol) was added under a nitrogen atmosphere at room temperature, and the mixture was stirred under a nitrogen atmosphere at 110 °C for 12 hours. The resulting reaction mixture was filtered through Celite, and the Celite was washed with ELISA (2 x 50 mL). The filtrate was collected and concentrated under reduced pressure to obtain the crude residue. The crude material was purified by flash column chromatography (silica: 100-200 mesh, eluent: 5-10% ethyl acetate / petroleum ether). The pure fraction was concentrated under reduced pressure to obtain 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (32 g, 88 mmol, 79% yield) as a pale yellow oil. LCMS(ESI) m / z: 359.1 [M+H] +

[0251] Intermediate 16-2: Preparation of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol [ka] To a stirred solution of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (10 g, 27.9 mmol) / anhydrous DCM (100 mL), DIEA (14.61 mL, 84 mmol) was added under nitrogen at 0°C. After stirring the reaction mixture at the same temperature for 10 minutes, MOM-Cl (2.54 mL, 33.5 mmol) was added dropwise to the reaction mixture. The resulting mixture was stirred under nitrogen at room temperature for 1 hour, the reaction mixture was diluted with cold water (50 mL), and extracted with DCM (2 x 100 mL). The organic layers were washed together with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude residue. The crude material was purified by flash column chromatography (silica: 100-200 mesh, eluent: 5-10% ethyl acetate / petroleum ether). The pure fraction was concentrated under reduced pressure to obtain 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol (10 g, 24.84 mmol, 89% yield). LCMS(ESI) m / z: 403.1 [M+H] +

[0252] Intermediate 16-3: Preparation of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl pyruvate [ka] To a stirred solution of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol (17 g, 42.2 mmol) / anhydrous DCM (170 mL), TEA (17.66 mL, 127 mmol) and DMAP (1.032 g, 8.45 mmol) were added under a nitrogen atmosphere at 0°C. After stirring the reaction mixture at the same temperature for 10 minutes, pivaloyl chloride (6.23 mL, 50.7 mmol) was added dropwise. The resulting reaction mixture was stirred at room temperature for 2 hours, diluted with cold water (50 mL), and extracted with DCM (2 x 100 mL). The organic layers were washed together with saline solution (200 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain the crude residue. The crude material was purified by flash column chromatography (silica: 100-200 mesh, eluent: 20-25% ethyl acetate / petroleum ether). The pure fraction was concentrated under reduced pressure to obtain 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl pyruvate (19 g, 35.1 mmol, yield 83%). LCMS(ESI) m / z: 487.2 [M+H] +

[0253] Intermediate 16-4: Preparation of 8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl pyruvate [ka] 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ylpyruvic acid (20 g, 41.1 mmol) / anhydrous DMF (150 mL) was stirred, and CsF (43.7 g, 288 mmol) was added to the mixture at room temperature under a nitrogen atmosphere, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with DCM (200 mL) and washed with saline solution (200 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude residue. The crude material was purified by flash column chromatography (silica: 100-200 mesh, eluent: 5-8% ethyl acetate / petroleum ether). The pure fraction was concentrated under reduced pressure to obtain 8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl pyruvate (12 g, 32.7 mmol, yield 80%) as a pale yellow oil. LCMS(ESI)m / z: 331.2 [M+H] +

[0254] Intermediate 16-5: Preparation of 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl pyruvate [ka] 10% Pd / C (3g, 28.2 mmol) was added at 25°C to a stirred solution of 8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl pyruvate (15g, 45.4 mmol) / ethanol (150 mL). The suspension was degassed under reduced pressure and purged several times with H2. The mixture was stirred at 25°C for 5 hours under an H2 atmosphere (1 atm). The reaction mixture was filtered and concentrated under reduced pressure to obtain the crude residue. The obtained crude product was purified by flash column chromatography (silica: 100-200 mesh, eluent: 15-20% ethyl acetate / petroleum ether). The pure fraction was concentrated under reduced pressure to obtain 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl pyruvate (14g, 34.3 mmol, yield 76%) as a pale yellow oil. LCMS(ESI)m / z: 335.1 [M+H] +

[0255] Intermediate 16-6: Preparation of 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-ol [ka] To a stirred solution of 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl pyruvate (5 g, 14.95 mmol) / MeOH (50 mL), anhydrous LiOH (0.537 g, 22.43 mmol) was added under nitrogen at room temperature. The resulting mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the MeOH. The reaction mixture was diluted with Depositphotos (150 mL) and washed with saline solution (200 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude residue. The crude material was purified by flash column chromatography (silica: 100-200 mesh, eluent: 25-30% ethyl acetate / petroleum ether). The pure fraction was concentrated under reduced pressure to obtain 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-ol (3.5 g, 12.59 mmol, yield 84%). LCMS(ESI)m / z: 251.2 [M+H] +

[0256] Intermediate 16-7: Preparation of 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yltrifluoromethanesulfonate [ka] 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-ol (1.5 g, 5.99 mmol) and DIEA (3.66 mL, 20.98 mmol) / anhydrous dichloromethane (50 mL) were stirred together, and Tf2O (1.215 mL, 7.19 mmol) was added dropwise at -10°C. The resulting reaction mixture was allowed to return to room temperature and stirred for 1 hour. This reaction mixture was diluted with cold water (500 mL) and then extracted with DCM (2 x 500 mL). The organic layers were washed together with saline solution (50 mL) and dried over anhydrous Na2SO4. 、The mixture was filtered and concentrated under reduced pressure to obtain a crude residue. The obtained crude compound was purified by flash column chromatography (silica gel: 100-200, eluent: 5-10% ethyl acetate / petroleum ether). The pure fraction was concentrated under reduced pressure to obtain 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yltrifluoromethanesulfonate (1.8 g, 4.66 mmol, yield 78%) as a pale yellow oil. LCMS(ESI) m / z: 383.0 [M+H] +

[0257] Intermediate 16-8: Preparation of 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] To a stirred solution of 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yltrifluoromethanesulfonate (2.5 g, 6.54 mmol) / anhydrous 1,4-dioxane (80 mL), bis(pinacolato)diborone (4.15 g, 16.35 mmol) and potassium acetate (1.925 g, 19.62 mmol) were added. The resulting mixture was degassed and purged with nitrogen for 5 minutes. Then, PdCl2 (dppf) (0.534 g, 0.654 mmol) was added to this reaction mixture. The resulting mixture was stirred under a nitrogen atmosphere at 100°C for 2 hours. The reaction mixture was then diluted with water (50 mL) and extracted with ethyl acetate (250 mL). The organic layers were washed together with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude residue. The obtained crude material was purified by flash column chromatography (silica: 100-200 mesh, eluent: 2-4% ethyl acetate / petroleum ether). The pure fraction was concentrated under reduced pressure to obtain a brown, viscous substance. This was purified again by reverse-phase column chromatography (80% acetonitrile / 0.01% aqueous ammonium formate). The pure fraction was concentrated under reduced pressure to obtain 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.8 g, 4.99 mmol, yield 76%). LCMS(ESI)m / z: 329 [M-OCH3] + ; 1 H-NMR (400MHz, CDCl3): δ 7.77(t, J=8.40Hz, 1H), 7.54(s, 1H), 7.37(t, J=9.60Hz, 1H), 7.28(s, 1H), 5.31(s, 2H), 3.42(s, 3H), 3.03(d, J=6.80Hz, 2H), 1.39(s, 12H), 1.19(t, J=7.20Hz, 3H)ppm

[0258] Intermediate 17-1: Preparation of 1-(tert-butyl)2-methyl-(S)-4,4-difluoropyrrolidine-1,2-dicarboxylate [ka] To a stirred solution of 1-(tert-butyl)2-methyl(S)-4-oxopyrrolidine-1,2-dicarboxylate (30.0 g, 123 mmol) / DCM (20.0 mL), DAST (81 mL, 617 mmol) was added dropwise at 0°C, and the mixture was stirred at ambient temperature for 16 hours. The reaction mixture was quenched with water and extracted with dichloromethane. The organic layers were washed together with water and saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The obtained crude product was purified by column chromatography (Grace, 340 g snap, dry packed, silica (230-400 mesh), elution: 20-50% ethyl acetate / petroleum ether). The desired fraction was collected and concentrated under reduced pressure to obtain 1-(tert-butyl)2-methyl-(S)-4,4-difluoropyrrolidine-1,2-dicarboxylate (28 g, 90 mmol, yield 73.4%) as a light brown liquid. LCMS-ELSD(ESI)m / z: 166.2 [M+H-Boc] +

[0259] Intermediate 17-2: Preparation of 1-(tert-butyl)2-methyl-2-(3-((tert-butyldimethylsilyl)oxy)propyl)-4,4-difluoropyrrolidine-1,2-dicarboxylate [ka] To a stirred solution of 1-(tert-butyl)2-methyl-(S)-4,4-difluoropyrrolidine-1,2-dicarboxylate (28 g, 106 mmol) / THF (300.0 mL), LiHMDS (158 mL, 158 mmol) was added dropwise at -45°C. The reaction mixture was stirred at the same temperature for 30 minutes, after which (3-bromopropoxy)(tert-butyl)dimethylsilane (40.1 g, 158 mmol) was added dropwise. The reaction mixture was stirred at the same temperature for 30 minutes, then slowly allowed to return to room temperature. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (15 mL), then diluted with water (50 mL). The mixture was extracted with ethyl acetate (3 x 100 mL), the organic layers were dried together over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (20-30% ethyl acetate / petroleum ether) to obtain 1-(tert-butyl)2-methyl-2-(3-((tert-butyldimethylsilyl)oxy)propyl)-4,4-difluoropyrrolidine-1,2-dicarboxylate (35 g, 80 mmol, yield 76%) as a light brown liquid. LCMS-ELSD(ESI)m / z: 388.2 [M+H-Boc] +

[0260] Intermediate 17-3: Preparation of 1-(tert-butyl)2-methyl-4,4-difluoro-2-(3-hydroxypropyl)pyrrolidine-1,2-dicarboxylate [ka] To a stirred solution of 1-(tert-butyl)2-methyl-2-(3-((tert-butyldimethylsilyl)oxy)propyl)-4,4-difluoropyrrolidine-1,2-dicarboxylate (35.0 g, 80 mmol) / THF (50 mL), TBAF (1 M, THF solution, 80 mL, 80 mmol) was added dropwise at 25°C, and the mixture was stirred at the same temperature for 4 hours. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (90 mL) and diluted with ethyl acetate (100 mL). The mixture was extracted with ethyl acetate (3 x 150 mL), the organic layers were dried together over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude residue was obtained as a colorless oil. The obtained crude product was purified by silica gel column chromatography (50% ethyl acetate / petroleum ether) to obtain 1-(tert-butyl)2-methyl-4,4-difluoro-2-(3-hydroxypropyl)pyrrolidine-1,2-dicarboxylate (20 g, 57.9 mmol, yield 72.4%) as a light brown liquid. LCMS-ELSD(ESI)m / z: 224.2 [M+H-Boc] +

[0261] Intermediate 17-4: Preparation of 1-(tert-butyl)2-methyl-4,4-difluoro-2-(3-iodopropyl)pyrrolidine-1,2-dicarboxylate [ka] To a stirred solution of 1-(tert-butyl)2-methyl-4,4-difluoro-2-(3-hydroxypropyl)pyrrolidine-1,2-dicarboxylate (20 g, 61.9 mmol) / DCM (100 mL), triphenylphosphine (48.7 g, 186 mmol) and imidazole (8.42 g, 124 mmol) were added at 0°C. The reaction mixture was stirred for 10 minutes, after which iodine (62.8 g, 247 mmol) was added. This reaction mixture was stirred at room temperature for 12 hours, and then quenched with saturated sodium thiosulfate aqueous solution (30 mL). The suspension was extracted with dichloromethane (2 x 200 mL), the organic layers were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude residue. This crude product was purified by silica gel column chromatography (10-20% ethyl acetate / petroleum ether) to obtain 1-(tert-butyl)2-methyl-4,4-difluoro-2-(3-iodopropyl)pyrrolidine-1,2-dicarboxylate (20 g, 46.1 mmol, yield 75%) as a colorless oil. LCMS-ELSD(ESI)m / z: 333.0 [M+H-Boc] +

[0262] Intermediate 17-5: Preparation of methyl 4,4-difluoro-2-(3-iodopropyl)pyrrolidine-2-carboxylate [ka] To a stirred solution of 1-(tert-butyl)2-methyl-4,4-difluoro-2-(3-iodopropyl)pyrrolidine-1,2-dicarboxylate (15 g, 34.6 mmol) / DCM (100 mL), HCl / 1,4-dioxane (4 M, 8.66 mL, 34.6 mmol) was added at 0°C, and the mixture was stirred at ambient temperature for 16 hours. This reaction mixture was then concentrated under reduced pressure to obtain the crude residue of (S)-4,4-difluoro-2-(3-iodopropyl)pyrrolidine-2-carboxylate methylHCl (11.5 g, 31.1 mmol, 90% yield) at room temperature. This was used in the next step without further purification. LCMS-ELSD(ESI)m / z: 334.1 [M+H] +

[0263] Intermediate 17-6: Preparation of 2,2-difluorotetrahydro-1H-pyrrolidine-7a(5H)-methyl carboxylate [ka] To a stirred solution of methyl 4,4-difluoro-2-(3-hydroxypropyl)pyrrolidine-2-carboxylate·HCl (11.5 g, 51.5 mmol) / THF (120.0 mL), TEA (35.9 mL, 258 mmol) was added at 0°C, followed by heating at 45°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude residue. This was purified by column chromatography (neutral alumina, 40-50% ethyl acetate / petroleum ether) to obtain methyl 2,2-difluorotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (6 g, 43.5 mmol, yield 81%) as a brown liquid.

[0264] Intermediate 17-7: Preparation of (2,2-difluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol [ka] To a stirred solution of methyl 2,2-difluorotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (12.0 g, 58.5 mmol) / anhydrous THF (20.0 mL), LiAlH4 (117 mL, 117 mmol) was added dropwise over 10 minutes under nitrogen at 0°C. The mixture was stirred at the same temperature for 1 hour, then saturated ammonium chloride aqueous solution (5 mL) was added and the mixture was quenched at 0°C. After the foaming subsided, anhydrous sodium sulfate was added to the reaction mixture, followed by dichloromethane (20 mL). The reaction mixture was stirred for 20 minutes and filtered. The filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude residue of (2,2-difluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (4.1 g, 23.02 mmol, yield 39.4%) as a pale yellow liquid. LCMS-ELSD(ESI)m / z: 178.1 [M+H] +

[0265] Intermediate 18-1: Preparation of 7-fluoro-3-(methoxymethoxy)-8-{2-[tris(propan-2-yl)silyl]ethynyl}naphthalene-1-yltrifluoromethanesulfonate [ka] To a solution of 7-fluoro-3-(methoxymethoxy)-8-{2-[tris(propan-2-yl)silyl]ethynyl}naphthalen-1-ol (intermediate 16-2, 8.6 g, 22.25 mmol) and DIPEA (11.66 mL, 66.7 mmol) / DCM (35 mL), trifluoromethanesulfonic acid anhydride (5.64 mL, 33.4 mmol) was added dropwise at -40°C, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was diluted with water and extracted with DCM. The organic layers were washed together with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude residue. This was purified by silica gel column chromatography (instrument: CombiFlash, 80g RediSep® column, 5-10% siRNA / petroleum ether) to obtain 7-fluoro-3-(methoxymethoxy)-8-{2-[tris(propan-2-yl)silyl]ethynyl}naphthalene-1-yltrifluoromethanesulfonate (8.5g, 16.39 mmol, yield 73.7%) as a yellow oily substance. 1 H NMR (400MHz, DMSO-d6) δ ppm 8.12(dd, J=9.3, 5.8Hz, 1H), 7.78(d, J=2.5Hz, 1H), 7.65(t, J=9.0Hz, 1H), 7.51(d, J=2.0Hz, 1H), 5.37(s, 2H), 3.43(s, 3H), 1.31-1.08(m, 21H)

[0266] Intermediate 18-2: Preparation of {2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl]ethynyl}tris(propan-2-yl)silane [ka] To a degassed solution of 7-fluoro-3-(methoxymethoxy)-8-{2-[tris(propan-2-yl)silyl]ethynyl}naphthalene-1-yltrifluoromethanesulfonate (4.0 g, 7.48 mmol), potassium acetate (2.203 g, 22.45 mmol), and bis(pinacolato)diborone (3.80 g, 14.96 mmol) / toluene (40 mL), 1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.547 g, 0.748 mmol) was added, and the mixture was heated at 120 °C for 3 hours. The reaction mixture was cooled, filtered through Celite, and washed with ethyl acetate. The filtrate was washed with water and saline solution, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude residue. This was purified by silica gel column chromatography (instrument: CombiFlash, 40g RediSep® column, 10% siRNA / petroleum ether) to obtain {2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl]ethynyl}tris(propan-2-yl)silane (2.4g, 4.68 mmol, yield 62.6%) as a pale yellow solid. MS(ESI)m / z 513.4 [M+1] +

[0267] (biological activity) KRAS G12D RAF disruption assay Recombinant GMPPNP-conjugated KRAS G12D (5nM) was treated with assay buffer (50mM Tris pH 7.5, 100mM NaCl, 1mM MgCl2, 1mM DTT, 100ug / mL BSA) at room temperature for 20 minutes. Recombinant GST-RAF1 RBD (9nm) was added, followed by SA-Tb (0.25nm), and the reaction mixture was incubated for 3 hours. The HTRF signal was measured (PerkinElmer Envision), and the signal ratio (λ) was measured. em 520 / λ em Calculate 495) and take IC from the dose-response curve. 50 The value was calculated.

[0268] KRASG12D nucleotide exchange assay Recombinant GDP-bound KRAS G12D (20 nm) was treated with the compound in assay buffer (10 mM Hepes pH 7.4, 150 mM NaCl, 5 mM MgCl2, 0.0025% Igepal-CA630, 0.05% BSA, 1 mM DTT, 0.5 nM SA-Tb) at room temperature for 20 minutes. BIODIPY-labeled GDP (400 nm) and recombinant SOS (10 nm) were added, and the reaction was incubated for 30 minutes. The HTRF signal was measured (PerkinElmer Envision), and the signal ratio (λ) was measured. em 520 / λ em Calculate 495) and take IC from the dose-response curve. 50 The value was calculated.

[0269] Compound IC described herein 50 The values ​​are shown in Table 9. [Table 22] [Table 23] [Table 24]

[0270] It is understood that the detailed description section, rather than the summary and abstract section, is intended to be used to interpret the claims. The summary and abstract section may provide one or more examples of embodiments of the present disclosure as considered by the inventors, but may not provide all examples, and is therefore not intended to limit the present disclosure and the claims.

[0271] This disclosure uses the components of functional groups to illustrate the function of specific functional groups and their relationships, as described above. The boundaries of these functional group components are arbitrarily defined herein for the sake of explanation. Different boundaries may be defined as long as the specific functional groups and their relationships function appropriately.

[0272] The general nature of this disclosure will be fully revealed by the description of the specific embodiments described above, so that persons other than the inventors can easily modify and / or adapt the above-described embodiments to various applications by applying the knowledge of those skilled in the art, without excessive experimentation and without deviating from the fundamental concepts of this disclosure. Therefore, such applications and modifications are intended to be within the same meaning as the embodiments of this disclosure, based on the content and guidance presented herein. The expressions and terminology used herein are for illustrative purposes only and should be understood not to be limited to the expressions or terminology used herein as interpreted by those skilled in the art in light of the content and guidance.

[0273] The scope of this disclosure should not be limited to any exemplary embodiments described above, but should be defined solely by the following claims and their equivalents.

Claims

1. Equation (I): 【Chemistry 1】 [In the formula, R 1 is aryl or heteroaryl, wherein said aryl and heteroaryl are C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, amino, aminoC 1 -C 3 alkyl, C 3 -C 4 cycloalkyl, halogen, haloC 1 -C 3 alkoxy, haloC 1 -C 3 alkyl, hydroxy, and hydroxyC 1 -C 3 alkyl, and may be optionally substituted with 1, 2, 3, 4, or 5 independently selected substituents; R 2 and R 3 is hydrogen, C 1 -C 3 Alkoxy, C 1 -C 3 Alkyl, cyano, halogen, halo C 1 -C 3 Selected independently from alkyl and hydroxyl; R 4 teeth, 【Chemistry 2】 Selected from; here R a is hydrogen or C 1 -C 3 It is alkyl; n is 0, 1, 2, 3, or 4; Each R b C 1 -C 3 Alkyl, C 3 -C 6 Either independently selected from cycloalkyl, halogen, and hydroxyl; or two R b The groups may also form a 3- to 6-membered cycloalkyl ring together with the carbon atoms to which they are bonded; and 【Transformation 3】 This represents a point connected to a part of the parent molecule; R 5 teeth, 【Chemistry 4】 Selected from the group consisting of; here q, r, and d are each independently either 0 or 1; R x, R y, and R p are independently selected from C1-C3 alkoxy, C1-C3 alkyl, halogen, halo-C1-C3 alkyl, and hydroxy; and R c and R d These, together with the nitrogen atom to which they are bonded, form a 5- to 10-membered mono-ring or di-ring that further includes one heteroatom appropriately selected from nitrogen, oxygen, and sulfur, where the ring is C 1 -C 3 Alkoxy, C 1 -C 3 Alkoxy C 1 -C 3 Alkyl, C 1 -C 3 Alkyl, benzyl, halogen, halo C 1 -C 3 Alkyl, hydroxy, hydroxy C 1 -C 3 They may be appropriately substituted with one, two, or three groups independently selected from alkyl and oxo groups; or R c and R d One of them is hydrogen and C 1 -C 3 Selected from alkyl, the other is hydrogen, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxycarbonyl, and C 1 -C 3 Selected from alkylcarbonyls] Compounds of or pharmaceutically acceptable salts thereof.

2. In the formula, R 4 but, 【Transformation 5】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the above.

3. In the formula, R 2 and R 3 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein each of the compounds is a halogen.

4. In the formula, R 5 but, 【Transformation 6】 A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.

5. In the formula, R 5 but, 【Transformation 7】 A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.

6. In the formula, R 1 is naphthyl, and the naphthyl is substituted with a hydroxyl group, and C as appropriate. 1 -C 3 Alkyl, C 2 -C 4 A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, which may be further substituted with one or two groups selected from alkynyls and halogens.

7. In the formula, R 1 but, 【Transformation 8】 A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.

8. In the formula, R 1 but, 【Chemistry 9】 A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.

9. In the formula, R 1 but, 【Chemistry 10】 A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.

10. In the formula, R 1 but, 【Chemistry 11】 A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.

11. In the formula, R 2 is hydrogen; R 3 is fluoro; R 1 but, 【Chemistry 12】 Selected from; and R 5 but, 【Chemistry 13】 Selected from; here 【Chemistry 14】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein represents a point of connection to a portion of the parent molecule.

12. In the formula, R 2 is Chlorophyll; R 3 is fluoro; R 1 but, 【Chemistry 15】 Selected from; and R 5 but, 【Chemistry 16】 Selected from; here 【Chemistry 17】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein represents a point of connection to a portion of the parent molecule.

13. Formula (II): [Chemistry 18] [In the formula, R 1 but, 【Chemistry 19】 Selected from; here 【Chemistry 20】 This represents a point connected to a part of the parent molecule; R 4 but, 【Chemistry 21】 Selected from; here R a However, hydrogen or C 1 -C 3 It is alkyl; and 【Chemistry 22】 represents a point connected to a part of the parent molecule; and R 5 but, 【Chemistry 23】 Selected from; here 【Chemistry 24】 [This represents a point that connects to a part of the parent molecule.] Compounds of or pharmaceutically acceptable salts thereof.

14. below: 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】 A compound selected from or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, for treating cancers susceptible to KRAS G12D inhibition.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, for treating cancer expressing the KRAS G12D mutation.

18. A pharmaceutical composition for treating cancer, comprising a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein the cancer is pancreatic cancer, colorectal cancer, lung cancer, and / or gastric cancer.

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