KRAS G12D inhibitors

Abstract

The present disclosure relates to KRAS inhibitors and methods of using such compounds to treat cancer are provided.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 374,845, filed September 7, 2022, which is incorporated herein by reference in its entirety.

[0002] The present disclosure provides KRAS inhibitors, as well as methods of using the inhibitors to treat cancer. [Background technology]

[0003] The KRAS oncogene is a member of the Ras family of GTPases involved in many cell signaling processes. KRAS mutations are gain-of-function mutations present in up to 30% of all tumors, including approximately 90% of pancreatic cancers. KRAS G12D mutations are present 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 significance of this protein, numerous attempts have been made to develop Ras inhibitors, but such attempts have met with little success. This is primarily due to the difficulty of outcompeting GTP for the KRAS binding pocket within the cell and the lack of known allosteric regulatory sites. Therefore, agents that inhibit KRAS G12D are desirable. Summary of the Invention [Means for solving the problem]

[0004] In a first aspect, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof; W 1 is CR 2or N; R 1 is aryl or heteroaryl, wherein the aryl and heteroaryl are 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, halo, haloC1-C3 alkyl, hydroxy, and hydroxyC1-C3 alkyl; R 2 is hydrogen, C1-C3 alkoxy, C1-C3 alkyl, cyano, halo, haloC1-C3 alkyl, or hydroxy; R 3 is hydrogen, C1-C3 alkoxy, C1-C3 alkyl, cyano, halo, haloC1-C3 alkyl, or hydroxy; R 4 is hydrogen, C1-C3 alkyl, hydroxyC1-C6 alkyl, or haloC1-C6 alkyl; R 5 is -(C1-C3 alkyl)-R 6 or -(C1-C6 alkyl)NR c R d and R 6 teeth: In some cases, NR c R d C3-C6 cycloalkyl substituted with (C1-C3 alkyl)-; and A 5-10 membered monocyclic, bicyclic, or tricyclic fully or partially saturated or fully unsaturated ring system containing one nitrogen atom and optionally a second heteroatom selected from oxygen or nitrogen, wherein the ring contains 0-3 double bonds and the ring is optionally substituted with 1, 2, or 3 groups independently selected from C1-C3 alkoxy, C1-C3 alkoxyC1-C3 alkyl, C1-C3 alkyl, benzyl, halo, haloC1-C3 alkyl, hydroxy, hydroxyC1-C3 alkyl, and oxo. Selected from; R c and R dtogether with the nitrogen atom to which they are attached form a 5-10 membered monocyclic or bicyclic ring optionally containing one additional heteroatom selected from nitrogen, oxygen, and sulfur, the ring optionally being substituted with one, two, or three groups independently selected from C-C alkoxy, C-C alkoxyC-C alkyl, C-C alkyl, benzyl, halo, haloC-C alkyl, hydroxy, hydroxyC-C alkyl, and oxo; or R c and R d one of which 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; W 1 is CR 2 If R 4 is not hydrogen or C1-C3 alkyl (i.e., methyl, ethyl, or propyl).

[0005] In some embodiments, W 1 is CR 2 In some embodiments, R 2 is hydrogen or halo.

[0006] In some embodiments, W 1 is N.

[0007] In some embodiments, R 3 is a halo.

[0008] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is C1-C3 alkyl. In some embodiments, R 4 is hydroxy C1-C3 alkyl. In some embodiments, R 4 is haloC1-C3 alkyl.

[0009] In some embodiments, R 5 -(C1-C3 alkyl)-R 6In some embodiments, R 6 is a 5-10 membered fully or partially saturated or fully unsaturated ring system containing one nitrogen atom and optionally containing a second heteroatom selected from nitrogen and oxygen, the ring system being optionally substituted with one, two, or three groups independently selected from C-C alkoxy, C-C alkoxyC-C alkyl, C-C alkyl, benzyl, halo, haloC-C alkyl, hydroxy, hydroxyC-C alkyl, and oxo.

[0010] In some embodiments, R 5 teeth: [ka] wherein each ring is optionally substituted with 1, 2, or 3 groups independently selected from C1-C3 alkoxy, C1-C3 alkoxyC1-C3 alkyl, C1-C3 alkyl, benzyl, halo, haloC1-C3 alkyl, hydroxy, hydroxyC1-C3 alkyl, and oxo; [ka] indicates the point of attachment to the parent molecular moiety.

[0011] In some embodiments, R 5 teeth [ka] wherein z is 1, 2, or 3; 50 is independently selected from C-C alkyl, C-C alkoxy, C-C alkoxyC-C alkyl, halo, haloC-C alkyl, haloC-C alkoxy, hydroxy, hydroxyC-C alkyl, benzyl, and oxo. 5 teeth [ka] In some embodiments, z is 1 and R 50is a halo such as fluoro.

[0012] In some embodiments, R 5 teeth [ka] is.

[0013] In some embodiments, R 5 teeth [ka] wherein q and r are each independently 0, 1, or 2; R x and R y is independently selected from C1-C3 alkoxy, C1-C3 alkyl, halo, haloC1-C3 alkyl, and hydroxy.

[0014] In some embodiments, R 5 teeth [ka] wherein q, r, and d are each independently 0, 1, or 2; R x , R y , and R p is independently selected from C1-C3 alkoxy, C1-C3 alkyl, halo, haloC1-C3 alkyl, and hydroxy. 5 teeth [ka] is.

[0015] In some embodiments, R 5 teeth [ka] wherein q and r are each independently 0, 1, or 2; R x and R yis independently selected from C1-C3 alkoxy, C1-C3 alkyl, halo, haloC1-C3 alkyl, and hydroxy. 5 teeth [ka] is.

[0016] In some embodiments, R 5 teeth [ka] wherein q and r are each independently 0, 1, or 2; R x and R y is independently selected from C1-C3 alkoxy, C1-C3 alkyl, halo, haloC1-C3 alkyl, and hydroxy. 5 teeth [ka] is.

[0017] In some embodiments, R 5 teeth [ka] where R c and R d together with the nitrogen atom to which they are attached form a 5-10 membered monocyclic or bicyclic ring optionally containing one additional heteroatom selected from nitrogen, oxygen, and sulfur, the ring optionally being substituted with one, two, or three groups independently selected from C-C alkoxy, C-C alkoxyC-C alkyl, C-C alkyl, benzyl, halo, haloC-C alkyl, hydroxy, hydroxyC-C alkyl, and oxo, or R c and R d One of these 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.

[0018] In some embodiments, R 5 teeth [ka] wherein q is 0, 1, or 2; R x is selected from C1-C3 alkoxy, C1-C3 alkoxyC1-C3 alkyl, C1-C3 alkyl, benzyl, halo, haloC1-C3 alkyl, hydroxy, hydroxy1-C3 alkyl, and oxo. 5 teeth [ka] is.

[0019] In some embodiments, R 1 is substituted and R 1 One of the above substituents is haloC1-C3 alkyl.

[0020] In some embodiments, R 1 is naphthyl, which is optionally substituted with 1, 2, or 3 groups independently selected from C1-C3 alkyl, C2-C4 alkynyl, C3 cycloalkyl, halo, and hydroxy.

[0021] In some embodiments, R 1 teeth [ka] is.

[0022] In some embodiments, R 1 teeth [ka] is.

[0023] In some embodiments, W 1 is CR 2 and;R 2is hydrogen or chloro; R 3 is fluoro; R 1 teeth, [ka] Selected from;R 5 teeth, [ka] Selected from; [ka] indicates the point of attachment to the parent molecular moiety.

[0024] In some embodiments, W 1 is N;R 3 is fluoro; R 1 teeth, [ka] Selected from;R 5 teeth, [ka] Selected from; [ka] indicates the point of attachment to the parent molecular moiety.

[0025] In some embodiments, the compound of formula (I) is: [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0026] In some embodiments, the compound of formula (I) is: [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0027] In one embodiment, the compound of formula (I) is: 4-(4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-2-[(1-methyl-octahydro-1H-indol-3a-yl)methoxy]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol isomer 1; 4-(4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-2-[(1-methyl-octahydro-1H-indol-3a-yl)methoxy]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol isomer 2; 4-(4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-2-({1-methyl-1-azaspiro[4.4]nonan-6-yl}methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-[8-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[8-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-[8-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 5-ethynyl-6-fluoro-4-{8-fluoro-2-[(1-{[(3R)-3-fluoropyrrolidin-1-yl]methyl}cyclopropyl)methoxy]-4-[8-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]quinazolin-7-yl}naphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[8-(2,2,2-trifluoroethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 2-[3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]ethan-1-ol; 4-(2-{[(6'R,7'aR)-6'-fluoro-hexahydrospiro[cyclopropane-1,2'-pyrrolidin]-7'a-yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(1R,6'R,7'aR)-3,3,6'-trifluoro-hexahydrospiro[cyclopropane-1,2'-pyrrolidin]-7'a-yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; and 4-(2-{[(1S,6'R,7'aR)-3,3,6'-trifluoro-hexahydrospiro[cyclopropane-1,2'-pyrrolidin]-7'a-yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol, or a pharmaceutically acceptable salt thereof.

[0028] In a second aspect, the present disclosure provides: [ka] or a pharmaceutically acceptable salt thereof.

[0029] In some aspects, the present disclosure provides: 4-(2-{[(6'R,7'aR)-6'-fluoro-hexahydrospiro[cyclopropane-1,2'-pyrrolidin]-7'a-yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol 2TFA; 4-(2-{[(1R,6'R,7'aR)-3,3,6'-trifluoro-hexahydrospiro[cyclopropane-1,2'-pyrrolidin]-7'a-yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(1S,6'R,7'aR)-3,3,6'-trifluoro-hexahydrospiro[cyclopropane-1,2'-pyrrolidin]-7'a-yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; and 4-(2-{[(1R,6'R,7'aR)-3,3,6'-trifluoro-hexahydrospiro[cyclopropane-1,2'-pyrrolidine]-7'a-yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol or a pharmaceutically acceptable salt thereof.

[0030] In some aspects, the present disclosure provides an atropisomer of a compound of any of the preceding aspects. In certain embodiments, the compound is a stable atropisomer described herein.

[0031] In some aspects, the present disclosure provides pharmaceutical compositions comprising a compound described herein, including a compound of formula (I) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0032] In another aspect, the present disclosure provides a method for inhibiting KRAS Gl2D activity in a cell, comprising contacting the cell with a compound described herein, including a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. In one aspect, the contacting is in vitro. In one aspect, the contacting is in vivo.

[0033] In one aspect, the disclosure provides a method of inhibiting cell proliferation in vitro or in vivo, comprising contacting a cell with an effective amount of a compound described herein, including a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as defined herein.

[0034] In another aspect, the present disclosure provides a method for treating a cancer sensitive to KRAS G12D inhibition in a subject in need thereof, the method comprising administering to the subject a compound described herein, including a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0035] In another aspect, the disclosure provides a method of treating a cancer expressing a KRAS G12D mutation in a subject in need thereof, comprising administering to the subject a compound described herein, including a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0036] In another aspect, the disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a compound described herein, including a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from pancreatic cancer, colorectal cancer, lung cancer, gastric cancer, and combinations thereof.

[0037] In another aspect, the present disclosure provides a compound described herein, including a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in inhibiting KRAS G12D.

[0038] In another aspect, the disclosure provides the use of a compound described herein, including a compound of formula (I), as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer.

[0039] In another aspect, the present disclosure provides the use of a compound described herein, including a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting KRAS Gl2D activity.

[0040] In another aspect, the disclosure provides the use of a compound described herein, including a compound of formula (I), as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer, e.g., a cancer expressing a KRAS G12D mutation. DETAILED DESCRIPTION OF THE INVENTION

[0041] Unless otherwise specified, any atom with unsatisfied valences is assumed to have enough hydrogen atoms to satisfy the valences.

[0042] The singular forms "a," "an," and "the" include plural referents unless the context dictates otherwise.

[0043] As used herein, the term "or" refers to a logical or (i.e., and / or) and does not refer to an exclusive or unless expressly indicated by the terms "either," "unless," "alternatively," and words of similar effect.

[0044] As used herein, the phrase "or a pharmaceutically acceptable salt thereof" refers to at least one compound, or at least one salt of a compound, or a combination thereof. For example, "a compound of Formula (I) or a pharmaceutically acceptable salt thereof" includes, but is not limited to, a compound of Formula (I), two compounds of Formula (I), a pharmaceutically acceptable salt of a compound of Formula (I), one or more pharmaceutically acceptable salts of a compound of Formula (I) and a compound of Formula (I), and two or more pharmaceutically acceptable salts of a compound of Formula (I).

[0045] The term "C2-C4 alkenyl" as used herein refers to a group derived from a straight or branched chain hydrocarbon containing from 2 to 4 carbon atoms and one double bond.

[0046] The term "C1-C3 alkoxy," as used herein, refers to a C1-C3 alkyl group attached to the parent molecular moiety through an oxygen atom.

[0047] The term "C1-C3 alkoxy C1-C3 alkyl," as used herein, refers to a C1-C3 alkoxy group attached to the parent molecular moiety through a C1-C3 alkyl group.

[0048] The term "C1-C3 alkoxycarbonyl," as used herein, refers to a C1-C3 alkoxy group attached to the parent molecular moiety through a carbonyl group.

[0049] As used herein, the term "C1-C3 alkyl" refers to a group derived from a straight or branched chain saturated hydrocarbon containing from one to three (ie, 1, 2, or 3) carbon atoms.

[0050] As used herein, the term "C1-C6 alkyl" refers to a group derived from a straight or branched chain saturated hydrocarbon containing from 1 to 6 (ie, 1, 2, 3, 4, 5, or 6) carbon atoms.

[0051] The term "C1-C3 alkylcarbonyl," as used herein, refers to a C1-C3 alkyl group attached to the parent molecular moiety through a carbonyl group.

[0052] The term "C2-C4 alkynyl" as used herein refers to a group derived from a straight or branched chain hydrocarbon containing from 2 to 4 carbon atoms and one triple bond.

[0053] As used herein, the term "amino" refers to --NH.sub.2.

[0054] The term "amino C1-C3 alkyl," as used herein, refers to an amino group attached to the parent molecular moiety through a C1-C3 alkyl group.

[0055] The term "aryl," as used herein, refers to a phenyl group or a bicyclic fused ring system in which one or both rings are phenyl groups. Bicyclic fused ring systems consist of a phenyl group fused to a 4- to 6-membered aromatic or non-aromatic carbocyclic ring. The aryl groups of the present disclosure can be attached to the parent molecular moiety through any substitutable carbon atom in the group. Representative examples of aryl groups include, but are not limited to, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl.

[0056] As used herein, the term "cyano" refers to --CN.

[0057] The term "C3-C4 cycloalkyl" as used herein refers to a saturated monocyclic hydrocarbon ring system having 3 or 4 carbon atoms and 0 heteroatoms.

[0058] As used herein, the terms "halo" and "halogen" refer to F, Cl, Br, or I.

[0059] As used herein, the term "haloC1-C3 alkyl" refers to a C1-C3 alkyl group substituted with one, two, or three halogen atoms.

[0060] As used herein, the term "heteroaryl" refers to an aromatic 5- or 6-membered 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 systems in which a heteroaryl ring is fused to a 4- to 6-membered aromatic or non-aromatic ring containing 0, 1, or 2 additional heteroatoms selected from N, O, and S; and tricyclic systems in which a bicyclic system is fused to a 4- to 6-membered aromatic or non-aromatic ring containing 0, 1, or 2 additional heteroatoms selected from N, O, and S. A heteroaryl group is attached to the parent molecular moiety through any substitutable carbon or nitrogen atom in the group. Representative examples of fully saturated heteroaryl groups include, but are not limited to, alloxazine, benzo[1,2-d:4,5-d']bisthiazole, benzoxadiazolyl, benzoxazolyl, benzofuranyl, benzothienyl, furanyl, imidazolyl, indazolyl, indolyl, isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, purine, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, quinolinyl, thiazolyl, thienopyridinyl, thienyl, triazolyl, thiadiazolyl, and triazinyl.

[0061] The ring system may also be partially saturated, in which case at least one ring in the moiety contains one or two double bonds without providing an aromatic group. Suitable alicyclic moieties include, for example, cyclopropene, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, and cyclohexadiene. Partially saturated heterocyclic groups include, for example, 2,3-dihydroazetyl, 6H-1,2,5-thiadiazenyl, 2H,6H-1,5,2-diazinyl, 3,4,5,6-tetrahydro-2H-azepinyl, 1H-azepinyl, tetrahydropyridinyl, 1,2-dihydroazinyl, 1,4-dihydroazinyl, 2,3,4,5-tetrahydroazinyl, 2,3-dihydrooxolyl, 5H-1,2,3-oxathiazolyl, and 4H-oxynyl.

[0062] As used herein, the term "hydroxy" refers to --OH.

[0063] The terms "hydroxy C1-C3 alkyl" and "hydroxy C1-C6 alkyl," as used herein, refer to a hydroxy group attached to the parent molecular moiety through either a C1-C3 alkyl or a C1-C6 alkyl group, respectively.

[0064] The term "oxo" as used herein refers to =O.

[0065] An additional aspect of the subject matter described herein is the use of the disclosed compounds as radiolabeled ligands for the development of ligand binding assays or for monitoring in vivo adsorption, metabolism, distribution, receptor binding or occupancy, or compound disposition. For example, the compounds described herein can be prepared using radioisotopes, and the resulting radiolabeled compounds can be used to develop binding assays or for metabolic studies. Alternatively, and for the same purposes, the compounds described herein can be converted to radiolabeled forms by catalytic tritiation using methods known to those skilled in the art.

[0066] Certain compounds of the present disclosure exist as stereoisomers.When stereochemistry is not specified, it should be understood that the present disclosure encompasses all stereochemical isomeric forms or mixtures thereof that have the ability to inhibit KRAS G12D.Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials containing chiral centers, or by post-preparation separation of enantiomeric product mixtures, for example, by conversion to diastereomeric mixtures followed by separation or recrystallization, chromatographic techniques, or by direct separation of enantiomers using chiral chromatographic columns.Starting compounds of specific stereochemistry are commercially available, or can be prepared and resolved by techniques known in the art.

[0067] Certain compounds of the present disclosure can exist as tautomers, which are compounds produced by the phenomenon of a molecule's proton shifting to a different atom within the molecule. The term "tautomer" also refers to one of two or more structural isomers that exist in equilibrium and are easily converted from one isomer to another. All tautomers of the compounds described herein are included within the scope of the present disclosure.

[0068] Certain compounds of the present disclosure exist as atropisomers. The term "atropisomer" refers to a conformational stereoisomer that occurs when rotation around a single bond in a molecule is prevented or significantly retarded as a result of steric interactions with other parts of the molecule, and the substituents on both ends of the single bond are asymmetric (i.e., optical activity occurs without the need for an asymmetric carbon center or stereocenter). If the rotation barrier around a single bond is sufficiently high and the interconversion between conformations is sufficiently slow, separation and isolation of isomeric species may be possible. Atropisomers are enantiomers (or epimers) that lack a single asymmetric atom.

[0069] Atropisomers can be considered stable if the barrier to interconversion is high enough to allow the atropisomers to undergo little or no interconversion at room temperature for at least one week. In some embodiments, the atropisomers undergo little or no interconversion at room temperature for at least one year. In some embodiments, the atropisomer compounds of the present disclosure do not undergo more than about 5% interconversion to their respective atropisomers at room temperature for one week when the atropisomer compounds are in a substantially pure form, typically in the solid state. In some embodiments, the atropisomer compounds of the present disclosure do not undergo more than about 5% interconversion to their respective atropisomers at room temperature (approximately 25° C.) for one year. In some embodiments, the atropisomer compounds of the present disclosure are sufficiently stable to undergo only about 5% interconversion in aqueous pharmaceutical formulations held at 0° C. for at least one week. The present chemical compounds, pharmaceutical compositions, and methods are intended to include all such possible atropisomers, including racemic mixtures, diastereomeric mixtures, epimeric mixtures, optically pure forms of single atropisomers, and intermediate mixtures.

[0070] The energy barrier to thermal racemization of atropisomers can be determined by steric hindrance to free rotation of one or more bonds forming the chiral axis. Certain biaryl compounds exhibit atropisomerism in which rotation around an intercyclic bond lacking C2 symmetry is restricted. The free energy barrier to isomerization (enantiomerization) is a measure of the stability of the intercyclic bond with respect to rotation. Optical and thermal excitation can promote the racemization of such isomers, depending on electronic and steric factors.

[0071] Ortho-substituted biaryl compounds may exhibit this type of conformational rotational isomerism. Such biaryls have sp 2 -sp 2 The carbon-carbon interannular bond has a sufficiently high energy barrier to prevent free rotation, and the substituent W 1 ≠W 2 and W 3 ≠W4 are chiral atropisomers of enantiomers that make the molecule asymmetric. [ka]

[0072] W 1 :W 3 , W 1 :W 4 , and / or W 2 :W 4 , W 2 :W 3 The steric interactions between the two are large enough to make the planar conformation the energy maximum. Two non-planar, axially chiral enantiomers exist as atropisomers if their interconversion is slow enough that they can be isolated without each other. The bold and dashed lines in the diagrams shown above indicate moieties, or portions of molecules, that are sterically restricted due to rotational energy barriers. The bolded portions lie perpendicularly above the plane of the paper, and the dashed portions lie perpendicularly below the plane of the paper. The "flat" portions of the molecules (the left-hand rings in each of the two biaryls shown) lie within the plane of the paper.

[0073] The pharmaceutical compounds of the present disclosure may include one or more pharmaceutically acceptable salts. A "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the parent compound and does not impart any undesired toxicological effects (see, for example, Berge, SM et al., J. Pharm. Sci., 66:1-19 (1977)). Salts can be obtained during the final isolation and purification of the compounds described herein, or separately by reacting a free base functional group of the compound with a suitable acid, or by reacting an acidic group of the compound with a suitable base. Acid addition salts include those derived from non-toxic inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphoric acid, as well as non-toxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, aromatic acids, and aliphatic and aromatic sulfonic acids. Base addition salts include those derived from alkaline earth metals, such as sodium, potassium, magnesium, and calcium, and from non-toxic organic amines, such as N,N'-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, and procaine.

[0074] compound In a first aspect, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof: W 1 is CR 2 or N; R 1 is aryl or heteroaryl, wherein the aryl and heteroaryl are 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, halo, haloC1-C3 alkyl, hydroxy, and hydroxyC1-C3 alkyl; R 2is hydrogen, C1-C3 alkoxy, C1-C3 alkyl, cyano, halo, haloC1-C3 alkyl, or hydroxy; R 3 is hydrogen, C1-C3 alkoxy, C1-C3 alkyl, cyano, halo, haloC1-C3 alkyl, or hydroxy; R 4 is hydrogen, C1-C3 alkyl, hydroxyC1-C6 alkyl, or haloC1-C6 alkyl; R 5 is -(C1-C3 alkyl)-R 6 or -(C1-C6 alkyl)NR c R d and R 6 teeth: In some cases, NR c R d C3-C6 cycloalkyl substituted with (C1-C3 alkyl)-; and A 5-10 membered monocyclic, bicyclic, or tricyclic fully or partially saturated or fully unsaturated ring system containing one nitrogen atom and optionally a second heteroatom selected from oxygen or nitrogen, wherein the ring contains 0-3 double bonds and the ring is optionally substituted with 1, 2, or 3 groups independently selected from C1-C3 alkoxy, C1-C3 alkoxyC1-C3 alkyl, C1-C3 alkyl, benzyl, halo, haloC1-C3 alkyl, hydroxy, hydroxyC1-C3 alkyl, and oxo. Selected from; R c and R d together with the nitrogen atom to which they are attached form a 5-10 membered monocyclic or bicyclic ring optionally containing one additional heteroatom selected from nitrogen, oxygen, and sulfur, the ring optionally being substituted with one, two, or three groups independently selected from C-C alkoxy, C-C alkoxyC-C alkyl, C-C alkyl, benzyl, halo, haloC-C alkyl, hydroxy, hydroxyC-C alkyl, and oxo; or Rc and R d one of which 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; W 1 is CR 2 If R 4 is not hydrogen or C1-C3 alkyl (i.e., methyl, ethyl, or propyl).

[0075] In some embodiments, W 1 is CR 2 In some embodiments, R 2 is hydrogen or halo (eg, fluoro, chloro).

[0076] In some embodiments, W 1 is N.

[0077] In some embodiments, R 3 is halo (e.g., fluoro, chloro).

[0078] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is C1-C3 alkyl (e.g., methyl). In some embodiments, R 4 is hydroxy C1-C3 alkyl (e.g., hydroxyethyl). In some embodiments, R 4 is haloC1-C3 alkyl (e.g., trifluoroalkyl).

[0079] In some embodiments, R 5 -(C1-C3 alkyl)-R 6 In some embodiments, R 6 is a 5-10 membered, fully saturated or partially saturated ring system, or a fully unsaturated ring system that is monocyclic or bicyclic and contains one nitrogen atom and optionally a second heteroatom selected from nitrogen and oxygen. For example, R 6can be pyrrolidinyl, morpholinyl, pyrrolyl, pyrazolyl, 2-methylenepyrrolidinyl, cyclopenta[b]pyridinyl, cyclopenta[b]pyrrolyl, octahydropentalenyl, or 1-azaspiro[4.4]nonane. The ring system is optionally substituted with one, two, or three groups independently selected from C-C alkoxy, C-C alkoxyC-C alkyl, C-C alkyl, benzyl, halo, haloC-C alkyl, hydroxy, hydroxyC-C alkyl, and oxo.

[0080] In some embodiments, R 5 teeth: [ka] wherein each ring is optionally substituted with 1, 2, or 3 groups independently selected from C1-C3 alkoxy, C1-C3 alkoxyC1-C3 alkyl, C1-C3 alkyl, benzyl, halo, haloC1-C3 alkyl, hydroxy, hydroxyC1-C3 alkyl, and oxo; [ka] indicates the point of attachment to the parent molecular moiety. In some embodiments, the ring is substituted with halo (e.g., fluoro).

[0081] In some embodiments, R 5 teeth [ka] wherein z is 1, 2, or 3; 50 is independently selected from C-C alkyl, C-C alkoxy, C-C alkoxyC-C alkyl, halo, haloC-C alkyl, haloC-C alkoxy, hydroxy, hydroxyC-C alkyl, benzyl, and oxo. 5 teeth [ka] In some embodiments, z is 1 and R 50 is a halo such as fluoro.

[0082] In some embodiments, R 5 teeth [ka] is.

[0083] In some embodiments, R 5 teeth [ka] wherein q and r are each independently 0, 1, or 2; R x and R y is independently selected from C1-C3 alkoxy, C1-C3 alkyl, halo, haloC1-C3 alkyl, and hydroxy.

[0084] In some embodiments, R 5 teeth [ka] wherein q, r, and d are each independently 0, 1, or 2; R x , R y , and R p is independently selected from C1-C3 alkoxy, C1-C3 alkyl, halo, haloC1-C3 alkyl, and hydroxy. 5 teeth [ka] is.

[0085] In some embodiments, R 5 teeth [ka] wherein q and r are each independently 0, 1, or 2; R x and R yis independently selected from C1-C3 alkoxy, C1-C3 alkyl, halo, haloC1-C3 alkyl, and hydroxy. 5 teeth [ka] is.

[0086] In some embodiments, R 5 teeth [ka] wherein q and r are each independently 0, 1, or 2; R x and R y is independently selected from C1-C3 alkoxy, C1-C3 alkyl, halo, haloC1-C3 alkyl, and hydroxy. 5 teeth [ka] is.

[0087] In some embodiments, R 5 teeth [ka] where R c and R d together with the nitrogen atom to which they are attached form a 5-10 membered monocyclic or bicyclic ring optionally containing one additional heteroatom selected from nitrogen, oxygen, and sulfur, the ring optionally being substituted with one, two, or three groups independently selected from C-C alkoxy, C-C alkoxyC-C alkyl, C-C alkyl, benzyl, halo, haloC-C alkyl, hydroxy, hydroxyC-C alkyl, and oxo, or R c and R dis selected from hydrogen and C1-C3 alkyl, and the other is selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxycarbonyl, and C1-C3 alkylcarbonyl. For example, R c and R d can be taken together with the nitrogen atom to which they are attached to form pyrrolidinyl, morpholinyl, pyrrolyl, pyrazolyl, 2-methylenepyrrolidinyl, cyclopenta[b]pyridinyl, cyclopenta[b]pyrrolyl, octahydropentalenyl, or 1-azaspiro[4.4]nonane.

[0088] In some embodiments, R 5 teeth [ka] wherein q is 0, 1, or 2; R x is selected from C1-C3 alkoxy, C1-C3 alkoxyC1-C3 alkyl, C1-C3 alkyl, benzyl, halo, haloC1-C3 alkyl, hydroxy, hydroxy1-C3 alkyl, and oxo. 5 teeth [ka] is.

[0089] In some embodiments, R 1 is substituted and R 1 One of the above substituents is haloC1-C3 alkyl.

[0090] In some embodiments, R 1 is naphthyl, which is optionally substituted with 1, 2, or 3 groups independently selected from C1-C3 alkyl, C2-C4 alkynyl, C3 cycloalkyl, halo, and hydroxy.

[0091] In some embodiments, R 1 teeth [ka] is.

[0092] In some embodiments, R 1 teeth [ka] is.

[0093] In some embodiments, W 1 is CR 2 and;R 2 is hydrogen or chloro; R 3 is fluoro; R 1 teeth, [ka] Selected from;R 5 teeth, [ka] Selected from; [ka] indicates the point of attachment to the parent molecular moiety.

[0094] In some embodiments, W 1 is N;R 3 is fluoro; R 1 teeth, [ka] Selected from;R 5 teeth, [ka] Selected from; [ka] indicates the point of attachment to the parent molecular moiety.

[0095] In some aspects, the present disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein W1 is CR 2 and R 4 is hydroxyC1-C6 alkyl or haloC1-C6 alkyl.

[0096] In some aspects, the present disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein W 1 is N and R 4 is hydrogen.

[0097] In some embodiments, the compound of formula (I) is: [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0098] In some embodiments, the compound of formula (I) is: [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0099] In one embodiment, the compound of formula (I) is: 4-(4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-2-[(1-methyl-octahydro-1H-indol-3a-yl)methoxy]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol isomer 1; 4-(4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-2-[(1-methyl-octahydro-1H-indol-3a-yl)methoxy]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol isomer 2; 4-(4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-2-({1-methyl-1-azaspiro[4.4]nonan-6-yl}methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-[8-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[8-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-[8-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 5-ethynyl-6-fluoro-4-{8-fluoro-2-[(1-{[(3R)-3-fluoropyrrolidin-1-yl]methyl}cyclopropyl)methoxy]-4-[8-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]quinazolin-7-yl}naphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[8-(2,2,2-trifluoroethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 2-[3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]ethan-1-ol; 4-(2-{[(6'R,7'aR)-6'-fluoro-hexahydrospiro[cyclopropane-1,2'-pyrrolidin]-7'a-yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(1R,6'R,7'aR)-3,3,6'-trifluoro-hexahydrospiro[cyclopropane-1,2'-pyrrolidin]-7'a-yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; and 4-(2-{[(1S,6'R,7'aR)-3,3,6'-trifluoro-hexahydrospiro[cyclopropane-1,2'-pyrrolidin]-7'a-yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol, or a pharmaceutically acceptable salt thereof.

[0100] In a second aspect, the present disclosure provides: [ka] or a pharmaceutically acceptable salt thereof.

[0101] In one aspect, the present disclosure provides: 4-(2-{[(6'R,7'aR)-6'-fluoro-hexahydrospiro[cyclopropane-1,2'-pyrrolidin]-7'a-yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol 2TFA; 4-(2-{[(1R,6'R,7'aR)-3,3,6'-trifluoro-hexahydrospiro[cyclopropane-1,2'-pyrrolidin]-7'a-yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(1S,6'R,7'aR)-3,3,6'-trifluoro-hexahydrospiro[cyclopropane-1,2'-pyrrolidin]-7'a-yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; and 4-(2-{[(1R,6'R,7'aR)-3,3,6'-trifluoro-hexahydrospiro[cyclopropane-1,2'-pyrrolidin]-7'a-yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol, or a pharmaceutically acceptable salt thereof.

[0102] Pharmaceutical Composition In one aspect, the present disclosure provides compositions, e.g., pharmaceutical compositions, containing one or a combination of compounds described within this disclosure formulated with a pharmaceutically acceptable carrier. The pharmaceutical compositions of the present disclosure can also be administered in combination therapy, i.e., in combination with other agents described herein.

[0103] As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, as well as isotonic and absorption delaying agents, and the like that are physiologically compatible. In some embodiments, the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal, or epidermal administration (e.g., by injection or infusion). Depending on the route of administration, the active compound may be coated with a material to protect the compound from the action of acids and other natural conditions that may inactivate the compound.

[0104] The pharmaceutical compositions of the present disclosure can be administered via one or more administration routes using one or more of a variety of methods known in the art. As will be understood by those skilled in the art, the route and / or mode of administration will vary depending on the desired results. In some embodiments, the route of administration for the compounds of the present disclosure includes intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal, or other parenteral routes of administration, for example, by injection or infusion. As used herein, the phrase "parenteral administration" refers to a mode of administration other than enteral administration and topical administration, usually by injection, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and infusion.

[0105] Sterile injectable solution can be prepared by incorporating the required amount of active compound into a suitable solvent with one or a combination of the ingredients listed above as needed, and then sterilizing by microfiltration.Generally, dispersion is prepared by incorporating active compound into a sterile vehicle containing a basic dispersion medium and the other ingredients required from those listed above.For the preparation of sterile powder for sterile injectable solution, some preparation methods are vacuum drying and lyophilization (freeze-drying, lyophilization), which allows the powder of active ingredient plus any additional desired ingredients to be obtained from its previously sterile-filtered solution.

[0106] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils, and injectable organic esters. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0107] Pharmaceutically acceptable carriers include sterile aqueous solution or dispersion and sterile powder for the immediate preparation of sterile injectable solution or dispersion.The use of such media and agents for pharmaceutically effective substances is well known in the art.Except where any conventional media or agent is incompatible with active compound, it is contemplated to be used in the pharmaceutical composition of the present disclosure.In addition, auxiliary active compounds can also be incorporated into the composition.

[0108] Therapeutic compositions typically must be sterile and stable under the conditions of manufacture and storage. The compositions can be formulated as a solution or liquid whose ordered structure is suitable for high drug concentration. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. In many cases, it is desirable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin.

[0109] Alternatively, compounds of the present disclosure can be administered parenterally, for example, via topical, epidermal, or mucosal routes of administration, for example, intranasally, orally, intravaginally, rectally, sublingually, or topically.

[0110] Any pharmaceutical composition contemplated herein can be orally delivered, for example, via any acceptable and suitable oral formulation. Exemplary oral formulations include, but are not limited to, tablets, troches, lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups, and elixirs. Pharmaceutical compositions intended for oral administration can be prepared according to any method known in the art for preparing pharmaceutical compositions intended for oral administration. To provide a pharmaceutically acceptable formulation, pharmaceutical compositions according to the present disclosure may contain at least one agent selected from sweeteners, flavoring agents, coloring agents, demulcents, antioxidants, and preservatives.

[0111] Tablets can be prepared by mixing at least one compound described herein, including, for example, at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof, with at least one non-toxic pharmaceutically acceptable excipient that is suitable for the manufacture of tablets.

[0112] Aqueous suspensions are suspensions prepared by dissolving at least one compound described herein, including, for example, at least one compound of Formula (I) and / or at least one pharmaceutically acceptable salt thereof, in a solvent such as, for example, a suspending agent, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, alginic acid, polyvinylpyrrolidone, gum tragacanth, and gum acacia; a dispersing or wetting agent, for example, a naturally occurring phosphatide, such as lecithin; a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate; an ethylene oxide; The aqueous suspension may be prepared by mixing the aqueous suspension with at least one excipient suitable for the preparation of an aqueous suspension, such as, but not limited to, condensation products of ethylene oxide with long-chain aliphatic alcohols, such as heptadecathylene-oxycetanol; condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, such as polyoxyethylene sorbitol monooleate; and condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as polyethylene sorbitan monooleate. The aqueous suspension may also contain at least one preservative, such as ethyl p-hydroxybenzoate and n-propyl p-hydroxybenzoate; at least one coloring agent; at least one flavoring agent; and / or at least one sweetener, such as, but not limited to, sucrose, saccharin, and aspartame.

[0113] Oily suspensions can be prepared by suspending at least one compound described herein, including at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof, in vegetable oils such as peanut oil, sesame oil, and coconut oil; or mineral oils such as liquid paraffin. Oily suspensions can also contain at least one thickening agent, such as beeswax, hard paraffin, and cetyl alcohol. To make oily suspensions palatable, at least one sweetener and / or at least one flavoring agent described herein above can be added to the oily suspension. Oily suspensions can also contain at least one preservative, such as, but not limited to, an antioxidant, such as butylated hydroxyanisole and alpha-tocopherol.

[0114] Dispersible powders and granules can be prepared by mixing at least one compound described herein, including, for example, at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof, with at least one dispersing agent and / or wetting agent, at least one suspending agent, and / or at least one preservative. Suitable dispersing agents, wetting agents, and suspending agents have already been described above. Exemplary preservatives include, but are not limited to, antioxidants, such as ascorbic acid. In addition, dispersible powders and granules may also contain at least one excipient, including, but not limited to, sweeteners, flavoring agents, and coloring agents.

[0115] Active compound can be prepared with a carrier that protects compound from rapid release, for example, controlled release formulations, including implants, transdermal patches, and microencapsulated delivery systems.Biodegradable biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used.Many methods for preparing such formulations are patented or generally known to those skilled in the art.For example, see Robinson, JR, ed., Sustained and Controlled Release Drug Delivery Systems, Marcel Dekker, Inc., New York (1978).

[0116] Therapeutic compositions can be administered by medical devices known in the art. For example, in one embodiment, the therapeutic compositions of the present disclosure can be administered by needleless hypodermic injection devices, such as those disclosed in U.S. Patent No. 5,399,163, U.S. Patent No. 5,383,851, U.S. Patent No. 5,312,335, U.S. Patent No. 5,064,413, U.S. Patent No. 4,941,880, U.S. Patent No. 4,790,824, or U.S. Patent No. 4,596,556. Examples of well-known implants and modules useful in the present disclosure include U.S. Pat. No. 4,487,603, which discloses an implantable microinfusion pump for dispensing drugs at a controlled rate; U.S. Pat. No. 4,486,194, which discloses a therapeutic device for administering drugs through the skin; U.S. Pat. No. 4,447,233, which discloses a drug infusion pump for delivering drugs at a precise infusion rate; U.S. Pat. No. 4,447,224, which discloses a variable flow rate implantable infusion device for continuous drug delivery; U.S. Pat. No. 4,439,196, which discloses an osmotic drug delivery system with multi-chamber compartments; and U.S. Pat. No. 4,475,196, which discloses an osmotic drug delivery system. These patents are incorporated herein by reference. Many other such implants, delivery systems, and modules are known to those skilled in the art.

[0117] In certain embodiments, the compounds of the present disclosure can be administered parenterally, i.e., by injection, including but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, intrathecal, intraspinal, epidural, and intrasternal injection and / or infusion.

[0118] In some embodiments, the compounds of the present disclosure can be administered orally, i.e., via gelatin capsules, tablets, hard or soft capsules, or liquid capsules.

[0119] KRAS Inhibitor Uses / Treatment Methods The administration of a therapeutic agent described herein includes, but is not limited to, the administration of a therapeutically effective amount of the therapeutic agent. As used herein, the term "therapeutically effective amount" refers to, but is not limited to, the amount of a therapeutic agent for treating a condition treatable by administration of a composition comprising a KRAS inhibitor described herein. The amount is sufficient to exhibit a detectable therapeutic effect or an effect leading to improvement. The effect may include, but is not limited to, the treatment of the conditions listed herein. The exact effective amount for a given subject will depend on the subject's size and health, the nature and severity of the condition being treated, the recommendations of the treating physician, and the therapeutic agent or combination of therapeutic agents selected for administration.

[0120] For administration of the compounds described herein, the dosage ranges from about 0.0001 to 100 mg / kg, and more usually 0.01 to 40 mg / kg, of the host body weight. Exemplary treatment regimens entail administration once daily, twice weekly, three times weekly, once every week, 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.

[0121] The disclosed compounds potently inhibit anchorage-independent cell growth and therefore have the potential to inhibit tumor metastasis. Accordingly, in another aspect, the present disclosure provides a method of inhibiting tumor metastasis, comprising administering to a subject in need thereof a pharmaceutical composition comprising an effective amount of any of the compounds disclosed herein and a pharmaceutically acceptable carrier.

[0122] Ras mutations, including but not limited to KRAS mutations, have also been identified in hematological malignancies (e.g., cancers affecting the blood, bone marrow, and / or lymph nodes). Accordingly, certain embodiments relate to the administration of the disclosed compounds (e.g., in the form of a pharmaceutical composition) to patients in need of treatment for hematological malignancies. Such malignancies include, but are not limited to, leukemias and lymphomas. For example, the disclosed compounds can be used to treat diseases such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), and / or other leukemias. In other embodiments, the compounds are useful for treating lymphomas, such as all subtypes of Hodgkin's lymphoma or non-Hodgkin's lymphoma.

[0123] Determining whether a tumor or cancer contains a KRAS mutation can be done by evaluating the nucleotide sequence encoding the KRAS protein, by evaluating the amino acid sequence of the KRAS protein, or by evaluating the characteristics of a putative KRAS mutant protein. The sequence of the wild-type human KRAS protein is known in the art.

[0124] 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) assay, polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) assay, real-time PCR assay, PCR sequencing, mutant allele-specific PCR amplification (MASA) assay, direct sequencing, primer extension reaction, electrophoresis, oligonucleotide ligation assay, hybridization assay, TaqMan assay, SNP genotyping assay, high-resolution melting assay, and microarray analysis. In some embodiments, samples are evaluated for KRAS mutations, for example, by real-time PCR. In real-time PCR, a fluorescent probe specific to KRAS mutations is used. If a mutation is present, the probe binds and fluorescence is detected. In some embodiments, KRAS mutations are identified using, for example, direct sequencing of a specific region (e.g., exon 2 and / or exon 3) in the KRAS gene. This technique identifies all possible mutations within the sequenced region.

[0125] Methods for detecting mutations in KRAS proteins are known to those skilled in the art, including, but not limited to, detecting KRAS mutants using binding agents (e.g., antibodies) specific for mutant proteins, protein electrophoresis and Western blotting, and direct peptide sequencing.

[0126] The method of determining whether a tumor or cancer contains a KRAS mutation can use a variety of samples. In some embodiments, the sample is taken from a subject with a tumor or cancer. In some embodiments, the sample is taken from a subject with a cancer or tumor. In some embodiments, the sample is a fresh 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 DNA or RNA. The present disclosure also relates to a method of treating a hyperproliferative disorder in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof.In some embodiments, the methods include the treatment of acute myeloid leukemia, adolescent cancer, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor, atypical teratoma, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, pediatric cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative disorder, and / or pulmonary tuberculosis. Intestinal cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), germinal tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, nasal neuroblastoma, Ewing's sarcoma, extracranial germ cell tumors, extragonadal germ cell tumors, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, cardiac cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, pancreatic cell tumors, pancreatic neuroendocrine tumors, kidney Pancreatic cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, obstructive primary, metastatic squamous neck cancer with ductal carcinoma, oral cavity cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oral cavity cancer, lip and oral cavity cancer, oropharynx The present invention relates to the treatment of cancers such as ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, sinus and nasal 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, thymic carcinoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, childhood anomaly cancer, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancer. In some embodiments, the method relates to the treatment of non-cancerous hyperproliferative disorders such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or benign hyperplasia of the prostate (e.g., benign prostatic hyperplasia (BPH)).

[0127] In certain embodiments, the present disclosure relates to a method for treating lung cancer, comprising administering an effective amount of any of the above-mentioned compounds (or a pharmaceutical composition comprising the same) to a subject in need of lung cancer treatment. In certain embodiments, the lung cancer is non-small cell lung cancer (NSCLC), such as adenocarcinoma, squamous cell lung cancer, or large cell lung cancer. In other embodiments, the lung cancer is small cell lung cancer. Other lung cancers that can be treated by the disclosed compounds include, but are not limited to, ductal carcinoma, carcinoid tumor, and undifferentiated carcinoma.Subjects that may be treated with the compounds of the present disclosure, or pharmaceutically acceptable salts, esters, prodrugs, solvates, tautomers, hydrates, or derivatives of said compounds, according to the methods of the present disclosure, include, for example, acute myeloid leukemia, adolescent cancer, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor, atypical teratoma, embryonal 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, extrahepatic ductal carcinoma in situ (DCIS), germinal tumor, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, nasal neuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, cardiac cancer, liver cancer, Hodgkin's lymphoma melanoma, hypopharyngeal cancer, intraocular melanoma, pancreatic cell tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, obstructive primary, metastatic squamous neck cancer with neutral duct carcinoma, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oral The present invention also includes subjects diagnosed with cancer, including those diagnosed with cancer of the lip and oral cavity, oropharynx, ovary, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity, 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, thymus and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, childhood anomalies, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancer.In some embodiments, subjects treated with the compounds of the present disclosure include subjects diagnosed with a non-cancerous hyperproliferative disease, such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or benign hyperplasia of the prostate (e.g., benign prostatic hyperplasia (BPH)). The present disclosure further provides a method for modulating the activity of a mutant KRAS protein by contacting the protein with an effective amount of a compound of the present disclosure. Modulation can be inhibiting or activating protein activity. In some embodiments, the present disclosure provides a method for inhibiting protein activity by contacting a mutant KRAS protein in solution with an effective amount of a compound of the present disclosure. In some embodiments, the present disclosure provides a method for inhibiting the activity of a mutant KRAS protein by contacting a cell, tissue, or organ expressing the protein of interest. In some embodiments, the present disclosure provides a method for inhibiting the activity of a protein in a subject, including, but not limited to, a rodent and a mammal (e.g., a human), by administering to the subject an effective amount of a compound of the present disclosure. In some embodiments, the percentage of modulation is greater than 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the percentage of inhibition is greater than 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the disclosure provides methods of inhibiting KRAS activity in a cell by contacting the cell with a compound of the disclosure in an amount sufficient to inhibit the activity of mutant KRAS in the cell. In some embodiments, the disclosure provides methods of inhibiting mutant KRAS in a tissue by contacting the tissue with a compound of the disclosure in an amount sufficient to inhibit the activity of mutant KRAS in the tissue. In some embodiments, the disclosure provides methods of inhibiting KRAS in an organism by contacting the organism with a compound of the disclosure in an amount sufficient to inhibit the activity of KRAS in the organism. In some embodiments, the present disclosure provides methods of inhibiting KRAS activity in an animal by contacting the animal with a compound of the present disclosure in an amount sufficient to inhibit activity of KRAS in the animal.In some embodiments, the present disclosure provides a method for inhibiting KRAS in a mammal, comprising contacting the mammal with a compound of the present disclosure in an amount sufficient to inhibit KRAS activity in the mammal. In some embodiments, the present disclosure provides a method for inhibiting KRAS activity in a human by contacting the human with a compound of the present disclosure in an amount sufficient to inhibit KRAS activity in the human. The present disclosure also provides a method for treating a disease mediated by KRAS activity in a subject in need thereof. The present disclosure also provides a method of combination therapy in which a compound of the present disclosure or a pharmaceutically acceptable salt, ester, prodrug, solvate, tautomer, hydrate, or derivative thereof is used in combination with an agent known to regulate other pathways, or other components of the same pathway, or even an overlapping set of target enzymes. In one embodiment, such therapy includes, but is not limited to, the combination of one or more compounds of the present disclosure with chemotherapeutic agents, therapeutic antibodies, and radiation treatment.

[0128] Currently, many chemotherapeutic agents are known in the art and can be used in combination with the compounds of the present disclosure.In some embodiments, the chemotherapeutic agent is selected from the group consisting of antimitotic agents, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors, and antiandrogens.In some embodiments, the chemotherapeutic agent is an immuno-oncology (IO) agent that can enhance, stimulate, or upregulate the immune system.

[0129] The compounds described herein can be used in combination with the agents disclosed herein or other suitable agents, depending on the condition being treated. Thus, in some embodiments, one or more compounds of the present disclosure are co-administered with the other agents described above. When used in combination therapy, the compounds described herein are administered simultaneously with the second agent or separately. This co-administration can include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, the compounds described herein and any of the above agents can be formulated together in the same dosage form and administered simultaneously. Alternatively, the compounds of the present disclosure and any of the above agents (both in separate formulations) can be administered simultaneously. In another alternative, the compounds of the present disclosure can be administered followed by any of the above agents, or vice versa. In some embodiments of the separate administration protocol, the compounds of the present disclosure and any of the above agents are administered within minutes, hours, or days.

[0130] The compounds can be made by methods known in the art, including those described below, and including variations within the skill of one in the art. Some reagents and intermediates are known in the art. Other reagents and intermediates can be made by methods known in the art using readily available materials. Any variables used to describe the synthesis of the compounds (e.g., numbered "R" substituents) are intended only to illustrate how the compounds are made and should not be confused with variables used in the claims or other sections of this specification. The following methods are for illustrative purposes and are not intended to limit the scope of this disclosure.

[0131] synthesis General Scheme The compounds described herein can be prepared as shown in Scheme 1 and as described in Methods 1 and 2 below. [ka]

[0132] Method 1: In step 1, known compound A is reacted with an amine in a suitable solvent such as tetrahydrofuran (THF) along with a base such as diisopropylethylamine to provide compound B. In step 2, compound B is treated with potassium fluoride in a solvent such as dimethylacetamide to provide compound C. In step 3, compound C is coupled with an aryl boronic acid or ester under Suzuki conditions to provide compound D. In step 4, compound D is treated with an alcohol (ROH) in the presence of a base in a solvent such as THF to provide compound E.

[0133] Method 2: In step 5, compound C is treated with an alcohol (ROH) in the presence of a base to provide compound F. In step 6, compound F is coupled with an aryl boronic acid or ester under Suzuki conditions to provide compound E. Protecting groups such as tert-butyloxycarbonyl (Boc), p-methoxybenzyl (PMB), methoxymethyl (MOM), etc., can be introduced and removed as needed by those skilled in the art and as described in the Examples. Functionalization and elaboration of aryl, NRR', and OR groups to prepare compounds of general structure E are described in the Examples.

[0134] The compounds described herein can be prepared as shown in Scheme 2 below. [ka]

[0135] In step 1, known compound A is reacted with an amine in a suitable solvent such as THF, along with a base such as diisopropylethylamine, to provide compound B. In step 2, compound B is treated with an alcohol (ROH) in the presence of a base in a solvent such as THF to provide compound C. In step 3, compound C is coupled with an aryl boronic acid or ester under Suzuki conditions to provide compound D. Protecting groups such as tert-butyloxycarbonyl (Boc), p-methoxybenzyl (PMB), methoxymethyl (MOM), etc., can be introduced and removed as required by those skilled in the art and as described in the Examples. Functionalization and synthesis of aryl, NRR′, and OR groups to prepare compounds of general structure E are described in the Examples. [Example]

[0136] The present invention is further defined in the following examples. It should be understood that the examples are given by way of illustration only. From the above discussion and examples, those skilled in the art can ascertain the essential features of the present invention and can make various changes and modifications to adapt them to various uses and conditions without departing from the spirit and scope thereof. As a result, the present invention is not limited by the illustrative examples set forth herein below, but rather is defined by the claims appended hereto.

[0137] The following abbreviations are used in the Examples section below and elsewhere in the specification:

[0138] [Table 1]

[0139] The following chemical scheme illustrates the synthesis of 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[8-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Example 1-1). [ka]

[0140] Intermediate 2: Preparation of tert-butyl 3-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a stirred solution of commercially available 7-bromo-2,4-dichloro-8-fluoroquinazoline (15 g, 50.7 mmol) in 1,4-dioxane (150 mL) at 0° C., DIPEA (26.6 mL, 152 mmol) was added, followed by tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (12.9 g, 60.8 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to provide the crude product. The crude compound was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) using a 120 g silica gel column with 50-80% EtOAc / petroleum ether to give tert-butyl 3-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (17 g, 32.4 mmol, 64% yield) as a pale yellow solid. MS (ESI) m / z: 473.3 [M+2] + .

[0141] Intermediate 3: Preparation of tert-butyl 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-bromo-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of tert-butyl 3-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.95 g, 24.80 mmol) in THF (45 mL) at 0° C., NaH (0.194 g, 4.85 mmol, 60 w / w%) was added, and the reaction mixture was stirred for 1 hour. To this mixture, tert-butyl 3-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (9 g, 19.08 mmol) was added in portions (4 portions) at 0° C. The reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was quenched with ice-cold water and extracted with EtOAc (250 mL × 2). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to provide a crude residue, which was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (240 g column, 80-100% EtOAc in petroleum ether) to give tert-butyl 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-bromo-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (6.5 g, 10.93 mmol, 57% yield). MS (ESI) m / z: 594.5 (M+2). + .

[0142] Intermediate 4: Preparation of 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-bromo-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroquinazoline [ka] To a solution of tert-butyl 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-bromo-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (600 mg, 1.01 mmol) in acetonitrile (7 mL) was added 4 M HCl in dioxane (0.2 mL, 0.84 mmol) at 0° C., and the mixture was stirred for 1 h. The reaction mixture was diluted with DCM, neutralized with excess TEA, and washed with aqueous NaHCO. The organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure to provide 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-bromo-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroquinazoline (350 mg, 0.708 mmol, 70.1% yield) as an off-white solid, which was used in the next step without further purification. MS (ESI) m / z: 496.1 (M+2). + .

[0143] Preparation of Intermediate 5: 2-[3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-bromo-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]ethan-1-ol [ka] To a stirred solution of 2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-bromo-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroquinazoline (400 mg, 0.809 mmol) in ACN (2 mL) was added 2-bromoethan-1-ol (121 mg, 0.971 mmol) and potassium carbonate (224 mg, 1.618 mmol) at room temperature, and the mixture was then heated at 60° C. for 16 hours. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure, diluted with excess EtOAc, and filtered to provide a crude residue. The EtOAc layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated to provide a crude residue, which was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (24 g column, 80-100% EtOAc in petroleum ether, followed by 10% MeOH in DCM) to give 2-[3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-bromo-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]ethan-1-ol (400 mg, 0.743 mmol, 92% yield). MS (ESI) m / z: 540.3 (M+2). + 。

[0144] Intermediate 6: Preparation of 2-[3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]ethan-1-ol [ka] To a stirred solution of 2-[3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-bromo-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]ethan-1-ol (600 mg, 1.11 mmol) in 1,4-dioxane (15 mL) was added ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (628 mg, 1.23 mmol) and aqueous 2 M potassium phosphate tripotassium phosphate (1.7 mL, 3.34 mmol). The reaction mixture was degassed with argon for 5 minutes, then [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (72.6 mg, 0.11 mmol) was added and degassed again with argon for 3 minutes before heating for 16 hours at 50° C. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude residue that was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (80 g silica gel column using 50-100% EtOAc / petroleum ether) to give 2-[3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]ethan-1-ol (240 mg, 0.28 mmol, 26% yield) as a brown solid. MS(ESI)m / z:844.5[M+H] + .

[0145] Preparation of Intermediate 7: 2-[3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]ethan-1-ol [ka] To a stirred solution of 2-[3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]ethan-1-ol (240 mg, 0.284 mmol) in DMF (5 mL) was added CsF (432 mg, 2.84 mmol). The reaction mixture was heated at 50° C. for 1 h. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-[3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]ethan-1-ol (250 mg, 0.204 mmol, 72% yield) as a light brown liquid, which was used in the next step without purification. MS(ESI) m / z: 688.3 [M+H] + .

[0146] Example 1-1 This example describes the synthesis of 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[8-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. [ka]

[0147] To a solution of 2-[3-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]ethan-1-ol (Intermediate 30, 250 mg, 0.363 mmol) in acetonitrile (2 mL) was added 4 M HCl in dioxane (0.9 mL, 3.63 mmol) at 0° C. and the mixture was stirred for 2 hours. Volatiles were removed from the reaction mixture under reduced pressure and the crude residue was co-evaporated with 1,4-dioxane. The crude residue was then dissolved in 1,4-dioxane (2 mL), excess TEA (1 mL) was added, and evaporated under reduced pressure to provide an off-white solid. The crude compound was purified by Prep-HPLC [YMC-Triart C18 (250 mm × 21 mm, 5 μm particles); Mobile phase A: 5:95 acetonitrile (100%):water pH 9.5 with 10 mM ammonium bicarbonate; Mobile phase B: 95:5 acetonitrile (100%):water pH 9.5 with 10 mM ammonium bicarbonate; Gradient: 40% B, 2 min hold, 40-60% B over 15 min, then 100% B, 5 min hold; Flow rate: 20 mL / min; Temperature: 27 °C; Flow rate: 30.0 mL / min; Detection: 220 and Purification by UV at 254 nm gave 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[8-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (80 mg, 0.117 mmol, 32% yield) as an off-white solid. MS (ESI) m / z: 644.5 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ ppm=10.11(br s,1H),7.98-7.91(m,1H),7.76-7.69(m,1H),7.47-7.41(m,1H),7.34(d,J=2.5Hz,1H),7.14( dd,J=7.0,8.6Hz,1H),7.04(d,J=2.4Hz,1H),5.39-5.14(m,1H),4.43-4.37(m,1H),4.30-4.16 (m,2H),4.09-3.94(m,2H),3.82(s,1H),3.56-3.48(m,4H),3.41-3.34(m,3H),3.11-2.99(m, 3H),2.85-2.76(m,1H),2.43(s,2H),2.14-1.97(m,3H),1.85-1.72(m,4H),1.67-1.58(m,2H).

[0148] The examples in Table 1 were prepared from the appropriate starting materials according to the procedure described for Example 1-1.

[0149] [Table 2]

[0150] [Table 3]

[0151] The following chemical scheme illustrates the synthesis of 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Example 2-1). [ka]

[0152] Intermediate 8: Preparation of tert-butyl 3-{2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a stirred solution of commercially available 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (10 g, 39.6 mmol) in DCM (200 mL) at −40° C., DIPEA (20.8 mL, 119 mmol) was added, followed by tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (8.41 g, 39.6 mmol). The reaction mixture was stirred at −40° C. for 30 minutes. The reaction mixture was quenched with water and extracted with DCM. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to provide the crude product. The crude compound was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) using a 120 g silica gel column with 50-80% EtOAc / petroleum ether to give tert-butyl 3-{2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (13 g, 30.4 mmol, 77% yield) as a pale yellow solid. MS (ESI) m / z: 428.3 [M+H] + .

[0153] Intermediate 9: Preparation of (S)-ethyl 2-((1-phenylethyl)amino)cyclopent-1-ene-1-carboxylate [ka] To a stirred solution of ethyl 2-oxocyclopentane-1-carboxylate (140.5 g, 900 mmol) and 4 Å molecular sieves in DCM (500 mL) was added (S)-1-phenylethan-1-amine (109 g, 900 mmol) at room temperature. The reaction mixture was stirred under reflux for 1 day. The reaction mixture was cooled to room temperature and filtered through a CELITE™ pad (Sigma Alrich, St. Louis, MO). The filtrate was concentrated under reduced pressure to provide a crude residue, which was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) using 4–5% EtOAc / petroleum ether to give ethyl (S)-2-((1-phenylethyl)amino)cyclopent-1-ene-1-carboxylate (233 g, 898 mmol, 100% yield). MS (ESI) m / z: 259.8 [M+].

[0154] Intermediate 10: Preparation of ethyl (S,E)-1-(3-ethoxy-3-oxopropyl)-2-(((S)-1-phenylethyl)imino)cyclopentane-1-carboxylate [ka] To a mixture of zinc(II) chloride in 2-MeTHF (473 mL, 898 mmol) and ethyl acrylate (90 g, 898 mmol) at 0 °C, (S)-ethyl 2-((1-phenylethyl)amino)cyclopent-1-ene-1-carboxylate (233 g, 898 mmol) in THF (233 mL) was added dropwise and stirred at 0 °C for 16 h. The reaction mixture was neutralized with saturated NaOH solution and extracted with EtOAc (3 × 500 mL). The combined extracts were dried over anhydrous NaSO, filtered, and concentrated in vacuo to give ethyl (S,E)-1-(3-ethoxy-3-oxopropyl)-2-(((S)-1-phenylethyl)imino)cyclopentane-1-carboxylate (300 g, 835 mmol, 93% yield) as a colorless oil, which was used in the next step without further purification. MS(ESI)m / z:360.1[M+H] + .

[0155] Intermediate 11: Preparation of ethyl (4aS)-2-oxooctahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate [ka] A mixture of ethyl (S,E)-1-(3-ethoxy-3-oxopropyl)-2-(((S)-1-phenylethyl)imino)-cyclopentane-1-carboxylate (145 g, 403 mmol) and 10% palladium on carbon (35 g, 10 w / w%) in ethanol (336 mL) was hydrogenated under 50 psi (approximately 345 kPa) of hydrogen at room temperature for 18 hours. The reaction mixture was filtered through a CELITE™ pad (Sigma Alrich, St. Louis, MO), and the filtrate was concentrated under reduced pressure to provide a crude residue, which was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) using 4–5% EtOAc / petroleum ether to give ethyl (4aS)-2-oxooctahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate (36 g, 170 mmol, 42.2% yield) as a colorless oil. MS (ESI) m / z: 211.6 [M+].

[0156] Intermediate 12: Preparation of ((4aS,7aR)-octahydro-4aH-cyclopenta[b]pyridin-4a-yl)methanol [ka] A solution of ethyl (4aS)-2-oxooctahydro-4aH-cyclopenta[b]pyridine-4a-carboxylate (23.7 g, 112 mmol) in THF (415 mL) was added dropwise to an ice-cold solution of 1 M LAH (lithium aluminum hydride) (258 mL, 258 mmol) in THF. The reaction mixture was heated to 70° C. for 4 hours. The reaction mixture was cooled to 0° C. and quenched with water (9.8 mL), 10% NaOH (9 mL), and water (27 mL). The reaction mixture was then warmed to room temperature and stirred for 20 minutes. The reaction mixture was filtered through a CELITE™ pad (Sigma Alrich, St. Louis, MO) and washed with excess EtOAc. The filtrate was dried over NaSO, filtered, and concentrated under reduced pressure to give ((4aS,7aR)-octahydro-4aH-cyclopenta[b]pyridin-4a-yl)methanol (17.3 g, 111 mmol, 99% yield) as a white solid, which was used directly in the next step without further purification. MS (ESI) m / z: 156.0 [M+H] + .

[0157] Intermediate 13: Preparation of ((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methanol [ka] A solution of ((4aS,7aR)-octahydro-4aH-cyclopenta[b]pyridin-4a-yl)methanol (33.8 g, 218 mmol) in MeOH (335 mL) was cooled to 5 °C, and formaldehyde (51.0 mL, 653 mmol) was added over 5 min, followed by sodium triacetoxyborohydride (50.8 g, 239 mmol) in multiple portions, then stirred at room temperature for 4 h. After 4 h, the reaction mixture was concentrated, diluted with 300 mL 2-MeTHF, and then washed with saturated aqueous KCO. The aqueous phase was back-extracted with EtOAc (7x), and the organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to provide a crude residue. The compound was purified by chiral supercritical fluid chromatography (SFC) [(Column: BEH 2-ethylpyridine (5 × 25 cm, 5 μm); CO % 90%, cosolvent % 10%, 0.2% NH OH in MeOH; flow: 300 mL / min; back pressure: 100 bar (10,000 kPa); temperature 35 °C. Peak retention time = 2.53 min] to provide ((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methanol (28 g, 166 mmol, 76% yield). 1 H NMR(400MHz,CDCl3)δ ppm=3.82(br d,J=4.4Hz,1H),3.70-3.59(m,2H),2.86(t,J=7.7Hz,1H),2.55-2.46(m,1H),2.41-2.33(m,1H),2.33-2.24(m,3H),1.98-1.83(m,2H),1.83- 1.72(m,1H),1.68-1.51(m,4H),1.48-1.33(m,3H).

[0158] Intermediate 14: Preparation of tert-butyl 3a-(hydroxymethyl)octahydro-1H-indole-1-carboxylate [ka] To a stirred solution of commercially available (octahydro-3aH-indol-3a-yl)methanol (250 mg, 1.610 mmol), TEA (0.45 mL, 3.22 mmol) in acetonitrile (5 mL) was added Boc anhydride (0.75 mL, 3.22 mmol), and the mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with EtOAc (2×) and washed with 1 N hydrochloric acid (50 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (50 mL), water (50 mL), and brine solution (50 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to provide tert-butyl 3a-(hydroxymethyl)octahydro-1H-indole-1-carboxylate (250 mg, 0.979 mmol, 60.8% yield), which was used directly in the next step without further purification. MS(ESI)m / z:256.2[M+H] + .

[0159] Intermediate 15: Preparation of (1-methyloctahydro-3aH-indol-3a-yl)methanol [ka] To an ice-cold solution of tert-butyl 3a-(hydroxymethyl)octahydro-1H-indole-1-carboxylate (250 mg, 0.979 mmol) in THF (10 mL) was added dropwise 2.1 M LAH in THF (1.4 mL, 2.94 mmol). The reaction mixture was heated to 70° C. for 4 hours. The reaction mixture was cooled to 0° C. and quenched with water (0.1 mL), 10% NaOH (0.1 mL), and water (0.3 mL). The reaction mixture was then stirred for 10 minutes and filtered through a CELITE™ pad (Sigma Alrich, St. Louis, MO). The CELITE™ pad was washed with excess EtOAc. The filtrate was dried over NaSO, filtered, and concentrated under reduced pressure to give (1-methyloctahydro-3aH-indol-3a-yl)methanol (140 mg, 0.83 mmol, 84% yield) as a colorless liquid. m / z: 170.2 [M+H] + .

[0160] Intermediate 16: Preparation of (1-azaspiro[4.4]nonan-6-yl)methanol [ka] (1-Azaspiro[4.4]nonan-6-yl)methanol was synthesized according to the literature procedure shown in Saruengkhanphasit et al., J. Org. Chem., 2017, 82, 6489-6496.

[0161] Intermediate 17: 7-oxa-5-azatricyclo[7.3.0.0 1,5 Preparation of dodecane [ka] To a stirred solution of {1-azaspiro[4.4]nonan-6-yl}methanol (350 mg, 2.25 mmol) in dichloroethane (DCE) (5 mL) was added paraformaldehyde (135 mg, 4.51 mmol), p-toluenesulfonic acid monohydrate (86 mg, 0.451 mmol), and sodium triacetoxyborohydride (1433 mg, 6.76 mmol), and the mixture was stirred at room temperature for 16 h. The reaction mixture was then quenched with 10% aqueous NaHCO and extracted with DCM. The combined organics were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 7-oxa-5-azatricyclo[7.3.0.0]methanol. 1,5 ]dodecane (230 mg, 1.37 mmol, 61%) was obtained as a colorless liquid. LCMS (ESI) m / z: 168.15 [M+H] + .

[0162] Intermediate 18: Preparation of {1-methyl-1-azaspiro[4.4]nonan-6-yl}methanol [ka] 7-Oxa-5-azatricyclo[7.3.0.0 1,5To a stirred solution of 1-dodecane (480 mg, 2.87 mmol) in dry THF (10 mL) was added LiAlH (6.31 mL, 6.31 mmol, 1 M in THF) dropwise under nitrogen at 0 °C. The resulting mixture was warmed to room temperature and stirred for 16 h. Excess LiAlH was carefully quenched by the addition of saturated NaSO solution and diluted with EtOAc (100 mL). The resulting mixture was filtered through a CELITE™ pad (Sigma Alrich, St. Louis, MO) and washed with 10% MeOH in DCM (2 × 30 mL). The filtrate was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give {1-methyl-1-azaspiro[4.4]nonan-6-yl}methanol (260 mg, 1.54 mmol, 53% yield) as a viscous liquid. LCMS(ESI)m / z:170.2[M+H] + .

[0163] Preparation of Intermediate 19: tert-Butyl 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a stirred solution of tert-butyl 3-{2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5.0 g, 11.67 mmol) and ((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methanol (2.17 g, 12.84 mmol) in THF (60 mL) was added 1 M LiHMDS (lithium hexamethyldisilazide) in hexanes (35.0 mL, 35.0 mmol) under nitrogen at 0 °C. The reaction mixture was warmed to room temperature and stirred for 15 h. The reaction mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted with EtOAc (3x). The combined organic extracts were washed with water and brine solution, dried over Na2SO4, filtered, and evaporated under reduced pressure to provide a crude residue, which was purified by silica gel column chromatography using COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (120 g REDISEP™ column (Teledyne ISCO, Lincoln, NE), 80–100% EtOAc-petroleum ether) to afford tert-butyl 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3 g, 5.35 mmol, 46% yield) as a light brown solid. MS(ESI)m / z:562.3(M+H) + .

[0164] Preparation of Intermediate 20: tert-Butyl 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a stirred solution of tert-butyl 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.9 g, 1.60 mmol) in 1,4-dioxane (9 mL) and water (3 mL) was added tert-butyl 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2-fluoro-6-methyl-6-pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate) (0.9 g, 1.60 mmol) in 1,4-dioxane (9 mL) and water (3 mL) was added tert-butyl 3-(2-(2-fluoro-6-methyl-6-pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate) ( ... -(Methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (0.91 g, 1.76 mmol) and CsCO (1.57 g, 4.81 mmol), followed by PdCl(dppf) (dppf: 1,1'-bis(diphenylphosphino)ferrocene) (0.12 g, 0.16 mmol) were added. The reaction mixture was purged with N for 5 minutes and heated in a microwave reactor at 105 °C for 1 hour. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) using a 40 g silica gel column with 50-100% EtOAc / petroleum ether to give tert-butyl 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.8 g, 0.88 mmol, 55% yield) as a brown solid. MS(ESI)m / z:911.5[M+H] + .

[0165] Preparation of Intermediate 21: tert-Butyl 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a stirred solution of tert-butyl 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tris(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.9 g, 1.0 mmol) in DMF (10 mL) was added CsF (1.5 g, 9.88 mmol). The reaction mixture was heated at 50° C. for 1 hour. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.7 g, 0.93 mmol, 94% yield) as a brown oil, which was used in the next step without further purification. MS (ESI) m / z: 755.3 [M+H] + .

[0166] Example 2-1 This example describes the synthesis of 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. [ka]

[0167] To a solution of tert-butyl 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (700 mg, 0.93 mmol) in acetonitrile (7 mL) was added 4 M HCl in dioxane (0.5 mL, 1.85 mmol) at 0° C., and the mixture was stirred for 1 hour. The volatiles were removed under reduced pressure, and the crude residue was co-evaporated with 1,4-dioxane. The crude residue was then dissolved in 1,4-dioxane (2 mL), and excess TEA (1 mL) was added and evaporated under reduced pressure to provide an off-white solid. The crude compound was purified by preparative high performance liquid chromatography (HPLC) [column: Gemini NX C18 (250 mm × 21 mm ID, 5 u); mobile phase A = 10 mM ammonium bicarbonate in water pH 9.5; mobile phase B = acetonitrile; gradient = 0 (min) - 30%, 2 - 40%, 15 - 60%, 16 - 60%, 18 - 100%; temperature: 27 °C; flow rate: 19.0 mL / min; detection: UV at 220 and 254 nm] to give 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (140 mg, 0.22 mmol, 24% yield). MS(ESI)m / z:611.2[M+H]+ . 1 H NMR(400MHz,DMSO-d6)δ ppm=10.15(br s,1H),9.04(s,1H),7.98(dd,J=9.2,5.9Hz,1H),7.47(t,J=9.1Hz,1H),7.40(d,J=2.5Hz,1H),7.18(d,J=2.5Hz,1H),4.53-4.42(m,2H),4.32(br t,J=10.6Hz,1H),4.13(d,J=10.9Hz,1H),3.95(d,J=3.6Hz,1H),3.69-3.54(m,4H),2.73-2.69(m,1 H),2.28-2.16(m,4H),1.88-1.79(m,1H),1.76-1.67(m,5H),1.66-1.50(m,7H),1.45-1.36(m,1H).

[0168] Examples 2-2 to 2-4 Example 2-2 was prepared from the appropriate starting materials according to the procedure described for Example 2-1. [ka]

[0169] Crude compound (2-2) was purified by preparative HPLC [HPLC method: Preparative column: Kinetex EVO (250 x 21 mm x 5 μm); Mobile phase A: 10 mM ammonium bicarbonate in 9.5% water; Mobile phase B: acetonitrile:methanol; Gradient = 50-100% B over 17 min; Temperature: 27 °C; Flow rate: 19.0 mL / min; Detection: UV at 220 nm] to provide the racemate, which was further purified by chiral polar organic method (Column: Chiralpak-IE (250 x 4.6 mm, 5 μm); Mobile phase: 10 mM ammonium acetate in (ACN:MeOH): 50:50; Flow rate: 1.0 mL / min. Peak 1: Retention time = 8.17 min; Peak 2: Retention time = 9.63 min). Example 2-3 (Peak 1): MS (ESI) m / z: 611.2 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ ppm=10.16(s,1H),9.04(s,1H),7.98(dd,J=6.0,9.5Hz,1H),7.47(t,J=9.3Hz,1H),7.39(d,J=2.5Hz,1H ),7.18(d,J=2.5Hz,1H),4.53-4.38(m,2H),4.35-4.18(m,2H),3.94(s,1H),3.67-3.55(m,4H),3.05(br d,J=4.3Hz,1H),2.25-2.05(m,7H),1.91(s,2H),1.84-1.59(m,5H),1.53-1.28(m,7H).Example 2-4(Peak-2):MS(ESI)m / z:611.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ ppm=9.04(s,1H),7.98(dd,J=6.0,9.3Hz,1H),7.47(t,J=9.0Hz,1H),7.39(d,J=2.8H z,1H),7.18(d,J=2.5Hz,1H),4.52-4.38(m,2H),4.35-4.18(m,2H),3.94(s,1H),3.66 -3.61(m,1H),3.57-3.55(m,2H),3.04(td,J=4.6,8.9Hz,1H),2.23-2.10(m,4H),2.0 9-2.03(m,2H),1.91(s,2H),1.83-1.77(m,1H),1.72-1.57(m,5H),1.54-1.27(m,7H).

[0170] The examples in Table 2 were prepared from the appropriate starting materials according to the procedures described for Examples 2-1 to 2-4.

[0171] [Table 4]

[0172] The following chemical scheme illustrates the synthesis of 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[8-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. [ka]

[0173] Preparation of Intermediate 22: 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 commercially available 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (300 mg, 3.03 mmol) in dioxane (8 mL) was added DIPEA (0.476 mL, 2.72 mmol) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (193 mg, 0.908 mmol). The resulting mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to provide the crude product, which was diluted with EtOAc (50 mL) and washed with water (30 mL × 2) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (12 g, ISCO column, MeOH / DCM, 0-5%, 20 min) to give 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+2] + . 1H NMR(499MHz,DMSO-d6)δ ppm=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).

[0174] Preparation of Intermediate 23: 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) in DMA (80 mL) was added cesium fluoride (5.25 g, 34.6 mmol). The reaction mixture was degassed with nitrogen for 10 minutes and heated in a sealed tube at 88 °C for 5 hours. Water (200 mL) and EtOAc (150 mL) were added, and the reaction mixture was stirred for 15 minutes. The separated aqueous layer was extracted with EtOAc (2 × 100 mL), and the combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) using 15-25% EtOAc in petroleum ether as eluent to provide 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, 63.4% yield) as a pale yellow solid. MS (ESI) m / z 489.0 [M+1] + .

[0175] Preparation of Intermediate 24: tert-Butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-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-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.00 g, 4.08 mmol) in anhydrous 1,4-dioxane (20 mL) was added 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)pyridin-2-amine (5.8 g, 12.25 mmol), and PdCl(dppf) (149 mg, 0.204 mmol). The reaction mixture was degassed again and heated at 80 °C for 48 h. After completion of the reaction, the reaction mixture was cooled to ambient temperature, diluted with EtOAc (40 mL), filtered through a bed of CELITE™ (Sigma Alrich, St. Louis, MO), and concentrated under reduced pressure to give the crude product. The residue was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) using 30% EtOAc in petroleum ether to give tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.5 g, 1.74 mmol, 42% yield). 1 H NMR(400MHz,CDCl3):δ ppm=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,3H) ,4.39-4.21(m,4H),3.63(s,6H),2.29(s,3H),1.98-1.96(m,6H),1.76-1.63(m,2H),1.49(s,9H)LCMS(ESI)m / z:757.2 [M+H] + .

[0176] Preparation of Intermediate 25: tert-Butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-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-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.40 g, 1.849 mmol) in anhydrous ACN (15 mL) at 0° C. under nitrogen was added N-iodosuccinimide (0.42 g, 1.849 mmol) and trifluoroacetic acid (0.028 mL, 0.370 mmol). The reaction mixture was allowed to reach room temperature over 1 h. The reaction mixture was then quenched with saturated aqueous sodium thiosulfate (5 mL) and saturated aqueous sodium bicarbonate (4 mL). The mixture was extracted with EtOAc (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a crude residue. The crude residue was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) using 30% EtOAc in petroleum ether to afford tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.42 g, 1.560 mmol, 84% yield) as a pale yellow fluffy solid. LCMS (ESI) m / z: 883.3 [M+H] + .

[0177] Preparation of Intermediate 26: tert-Butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-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-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.40 g, 1.585 mmol) in anhydrous DMA (10 mL) in a sealed tube under nitrogen was added copper(I) iodide (0.60 g, 3.17 mmol). The reaction mixture was degassed for 10 minutes, then 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 (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude residue. The crude compound was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) using 30% EtOAc in petroleum ether to give tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.85 g, 0.630 mmol, 40% yield) as a pale yellow solid. 1 H NMR(400MHz,CDCl3):δ ppm=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).LCMS(ESI)m / z:825.2 [M+H] + .

[0178] Intermediates 27A and 27B: tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] Intermediate 26 (5.0 g, 6.06 mmol) was subjected to SFC separation (Method information: Column: CHIRALPAK™ IH (Daicel, Japan) (250 mm x 4.6 x 5 u), mobile phase 0.25% isopropanol) (wherein Peak-1 eluted at retention time = 5.85 min (2.4 g, 2.90 mmol, 40% yield), Peak-2 eluted at retention time = 9.53 min (2.4 g, 2.90 mmol, 40% yield). Peak-1 (27A): 1 H NMR(400MHz,CDCl3):δ ppm=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),4.59-4.5 5(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: (27B) 1 H NMR(400MHz,CDCl3):δ ppm=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),4.59-4.5 5(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.

[0179] Preparation of Intermediate 28: tert-Butyl 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(6-{bis[(4-methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of [(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methanol (0.205 g, 1.212 mmol, Intermediate 27B) in THF (5 mL) at 0° C., NaH (0.194 g, 4.85 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. To this mixture, tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1 g, 1.212 mmol) was added at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with ice and concentrated under reduced pressure. The crude material was partitioned between EtOAc and water. The organic layer was dried over sodium sulfate, filtered, and concentrated to give the crude material, which was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (24 g REDISEP™ column (Teledyne ISCO, Lincoln, NE), 0-10% MeOH-DCM) to give tert-butyl 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(6-{bis[(4-methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.70 g, 0.718 mmol, 59% yield). MS(ESI)m / z:974.4(M+H) + .

[0180] Preparation of Intermediate 29: 6-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-6-chloro-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroquinazolin-7-yl)-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine [ka] To a solution of tert-butyl 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(6-{bis[(4-methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (700 mg, 0.718 mmol) in acetonitrile (5 mL) was added 4 M HCl in dioxane (0.9 mL, 3.59 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred for 3 hours. The solvent was then removed under reduced pressure. The residue was diluted with MeOH, neutralized with excess TEA, and concentrated under reduced pressure again to provide 6-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-6-chloro-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroquinazolin-7-yl)-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine (410 mg, 0.47 mmol, 57% yield). MS (ESI) m / z: 874.3 (M+H). + .

[0181] Preparation of Intermediate 30: 6-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-6-chloro-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroquinazolin-7-yl)-N-[(4-methoxyphenyl)methyl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine [ka] To a solution of tert-butyl 3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(6-{bis[(4-methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.3 g, 0.31 mmol) in DCM (3 mL) was added TFA (0.12 mL, 1.54 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred for 1 hour. The solvent was then removed under reduced pressure, and the residue was diluted with DCM and neutralized with excess TEA. The organic layer was washed with aqueous NaHCO, dried over NaSO, filtered, and concentrated under reduced pressure to provide 6-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-6-chloro-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroquinazolin-7-yl)-N-[(4-methoxyphenyl)methyl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine (200 mg, 0.26 mmol, 86% yield). MS (ESI) m / z: 754.3 (M+H). + .

[0182] Preparation of Intermediate 31: 2-[3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-6-chloro-8-fluoro-7-(6-{[(4-methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromethyl)pyridin-2-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]ethan-1-ol [ka] To a stirred solution of 6-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-6-chloro-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroquinazolin-7-yl)-N-[(4-methoxyphenyl)methyl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine (25 mg, 0.033 mmol) in ACN (1 mL) was added 2-bromoethan-1-ol (5 mg, 0.04 mmol) and potassium carbonate (14 mg, 0.1 mmol) at room temperature, and the mixture was heated at 65° C. for 16 hours. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was diluted with EtOAc and filtered. The filtrate was washed with water and brine, then dried over sodium sulfate, filtered, and concentrated to provide 2-[3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-6-chloro-8-fluoro-7-(6-{[(4-methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromethyl)pyridin-2-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]ethan-1-ol (20 mg, 0.025 mmol, 76% yield), which was used in the next step without further purification. MS(ESI) m / z: 798.3 (M+H). + .

[0183] Example 3-1 This example describes the synthesis of 2-[3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]ethan-1-ol. [ka]

[0184] A 1-dram vial was charged with 2-[3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-6-chloro-8-fluoro-7-(6-{[(4-methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromethyl)pyridin-2-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]ethan-1-ol (Intermediate 44, 20 mg, 0.025 mmol)), triethylsilane (12 μL, 0.075 mmol), and TFA (39 μL, 0.50 mmol). The vial was then sealed and heated at 40° C. for 16 h. Volatiles were removed from the reaction mixture under reduced pressure, and the crude residue was co-evaporated with 1,4-dioxane. The crude residue was then dissolved in 1,4-dioxane (2 mL), excess TEA (1 mL) was added, and the mixture was evaporated under reduced pressure to provide a crude residue, which was purified by preparative HPLC [HPLC method: Preparative column: XBridge C18 (Waters, Milford, MA), 250 mm x 19 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 12% B at 0 min hold, 12-42% B over 25 min, then 100% B at 5 min hold; Flow rate: 20 mL / min; Detection: UV at 220 and 254 nm]. 2-[3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]ethan-1-ol (4.5 mg, 0.007 mmol, 26% yield). MS(ESI) m / z: 678.3 [M+H] + .

[0185] Intermediate 32: 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 (25 g, 101 mmol) in THF (25 mL) at 0° C., LiHMDS (131 mL, 131 mmol, 1 M in THF) was added, and the resulting mixture was stirred at the same temperature for 15 minutes. 3-Chloro-2-(chloromethyl)prop-1-ene (14.04 mL, 121 mmol) was added, and the resulting solution was stirred at room temperature for 4 hours. The reaction mixture was cooled to 0° C., saturated aqueous ammonium chloride (150 mL) was added, and the mixture was stirred for 15 minutes. Ethyl acetate (500 mL) was added, and the two layers were separated. The organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude residue was purified by silica gel chromatography eluting with 0-18% ethyl acetate in petroleum ether to give 1-(tert-butyl)2-methyl (2R,4R)-2-(2-(chloromethyl)allyl)-4-fluoropyrrolidine-1,2-dicarboxylate (24 g, 70.8 mmol, 70% yield). LCMS (ESI) m / z: 236.2 [(M-Boc)+H] + .

[0186] Intermediate 33: Preparation of (2R,4R)-2-(2-(chloromethyl)allyl)-4-fluoropyrrolidine-2-carboxylate methyl hydrochloride [ka] To a stirred solution of 1-(tert-butyl)-2-methyl (2R,4R)-2-(2-(chloromethyl)allyl)-4-fluoropyrrolidine-1,2-dicarboxylate (24.0 g, 71.5 mmol) in 1,4-dioxane (240 mL) at 0° C., HCl (179 mL, 715 mmol, 4 M in dioxane) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo to give methyl (2R,4R)-2-(2-(chloromethyl)allyl)-4-fluoropyrrolidine-2-carboxylate hydrochloride (19.2 g, 69.2 mmol, 97% yield) as an off-white solid. LCMS (ESI) m / z: 236.1 [M+H] + .

[0187] Intermediate 34: Preparation of methyl (2R,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolidine-7a(5H)-carboxylate [ka] To a stirred solution of (2R,4R)-2-(2-(chloromethyl)allyl)-4-fluoropyrrolidine-2-carboxylate hydrochloride (19.1 g, 70.2 mmol) in acetonitrile (190 mL) at 0° C., TEA (48.9 mL, 351 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. Water (150 mL) was added, and the reaction mixture was extracted with ethyl acetate (2×180 mL). The organic layer was washed with brine (120 mL), dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography eluting with 20% ethyl acetate and petroleum ether afforded methyl (2R,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (9.1 g, 42.0 mmol, 60% yield) as a yellow-orange oil. LCMS(ESI)m / z:200.2[M+H] + .

[0188] Intermediate 35: Preparation of methyl (6'R,7a'R)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-carboxylate [ka] To a solution of methyl (2R,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (10 g, 50.2 mmol) in toluene (10 mL) at −78° C., diiodomethane (16.20 mL, 201 mmol) and diethylzinc (100 mL, 100 mmol, 1 M in hexane) were added, and the resulting mixture was allowed to warm gradually to room temperature. After 3 hours, ice-cold water (100 mL) was added, and the mixture was extracted with ethyl acetate (3×100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography eluting with 20% ethyl acetate and petroleum ether gave methyl (6'R,7a'R)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-carboxylate (7 g, 32.8 mmol, 65% yield) as a colorless oil. LCMS (ESI) m / z: 214.2 [M+H] + .

[0189] Preparation of Intermediate 36: ((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 methyl (6'R,7a'R)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-carboxylate (7.0 g, 32.8 mmol) in THF (10 mL) at 0 °C, LAH (16.4 mL, 32.8 mmol, 2 M in THF) was added, and the resulting mixture was stirred at the same temperature for 2 h. Saturated aqueous NH4Cl (5 mL) was added dropwise until gas evolution ceased. Sodium sulfate was added, and the reaction mixture was diluted with DCM (20 mL). The reaction mixture was filtered through a CELITE™ pad (Sigma Alrich, St. Louis, MO) by washing with DCM (3 x 50 mL). All volatiles were evaporated under reduced pressure to give ((6'R,7a'R)-6'-fluorodihydro-1'H,3'H spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methanol (5.1 g, 27.3 mmol, 83% yield) as a pale yellow oil. LCMS (ESI) m / z: 186.3 [M+H] + .

[0190] Preparation of Intermediate 37: tert-Butyl 3-(2,8-difluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a stirred solution of tert-butyl 3-(7-bromo-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4.0 g, 8.79 mmol) in 9:1 v / v 1,4-dioxane and water (40 mL) was added ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (6.75 g, 13.18 mmol), CsCO (5.72 g, 17.57 mmol), and PdCl(dppf) (0.643 g, 0.879 mmol), and the reaction mixture was purged with nitrogen for 10 minutes and then stirred at 100 °C for 16 hours. The reaction mixture was cooled to room temperature, and water (80 mL) and ethyl acetate (150 mL) were added. The two layers were separated, and the organic layer was washed with brine (70 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by reverse-phase chromatography on a C18 column eluting with 0-100% acetonitrile and water gave tert-butyl 3-(2,8-difluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.5 g, 4.55 mmol, 52% yield). LCMS (ESI) m / z: 761.4 [M+H] + .

[0191] Preparation of Intermediate 38: tert-Butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-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 [ka] To a stirred solution of ((6'R,7a'R)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methanol (298 mg, 1.61 mmol) in THF (8 mL) at 0°C, 60% NaH (64.3 mg, 1.608 mmol) was added, and the resulting mixture was stirred at the same temperature for 30 minutes. A solution of tert-butyl 3-(2,8-difluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (680 mg, 0.894 mmol) in THF (5 mL) was added, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0° C., ice-cold water (40 mL) was added, and the mixture was extracted with ethyl acetate (2×80 mL). The organic layer was washed with brine (25 mL), dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography eluting with 25% ethyl acetate and petroleum ether afforded tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-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 (350 mg, 0.344 mmol, 39% yield). LCMS(ESI)m / z:926.2[M+H] + .

[0192] Preparation of Intermediate 39: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((6'R,7a'R)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)quinazolin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol [ka] To a stirred solution of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-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 (350 mg, 0.38 mmol) in DCM (3 mL) was added HCl (0.945 mL, 3.78 mmol, 4.0 M in dioxane) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (25 mL), washed with saturated sodium bicarbonate (1×8 mL), dried over sodium sulfate, filtered, and concentrated to give 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((6′R,7a′R)-6′-fluorodihydro-1′H,3′H-spiro[cyclopropane-1,2′-pyrrolidine]-7a′(5′H)-yl)methoxy)quinazolin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (290 mg, 94% yield). LCMS (ESI) m / z: 782.2 [M+H] + .

[0193] Example 4-1 This example describes the synthesis of 4-(2-{[(6'R,7'aR)-6'-fluoro-hexahydrospiro[cyclopropane-1,2'-pyrrolidin]-7'a-yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol 2TFA. [ka]

[0194] To a stirred solution of 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((6'R,7a'R)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)quinazolin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (290 mg, 0.371 mmol) in DCM (4 mL) was added tetra-n-butylammonium fluoride (TBAF) (1.85 mL, 1.85 mmol, 1.0 M in THF) and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (5 mL) and extracted with DCM (2 x 10 mL). The organic layer was washed with brine (1 x 5 mL), dried over sodium sulfate, filtered, and concentrated. Purification by preparative HPLC (eluent: THF:water:MeCN (50:20:30); column: KINETEX™ Biphenyl (Phenomenex, Torrance, CA) (250 x 21.2 mm, 5 micron; mobile phase A: 0.1% TFA in water; mobile phase B: acetonitrile; flow: 15 mL / min, gradient) gave 4-(2-{[(6'R,7'aR)-6'-fluoro-hexa(2-yl)-2-(4-( ... Hydrospiro[cyclopropane-1,2'-pyrrolidin]-7'a-yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol 2TFA (28 mg, 0.032 mmol, 9% yield) was obtained as an off-white solid. LCMS (ESI) m / z: 626.3 [M+H] + . 1H-NMR(400MHz,DMSO-d6):δ 11.20-11.36(br m,1H),10.21(br s,1H),9.25-9.36(m,1H),9.05(br s,1H),7.99(dd,J=9.2,6.0Hz,1H),7.84(d,J=8.51Hz,1H),7.48(dd,J=9.0,9.0Hz,1H),7.39(d,J=2.4Hz,1H),7 .32-7.36(m,1H),7.08(d,J=2.4Hz,1H),5.54-5.72(m,1H),4.70-4.60(m,2H),4.30-4.55(m,2H),4.18-4.25(br s,2H),3.90-4.05(m,1H),3.65-3.80(m,5H),3.15-3.25(m,1H),2.45-2.75(m,3H) ,1.95-2.05(m,4H),1.90(d,J=13.0Hz,1H),0.80-0.90(m,2H),0.60-0.75(m,2H).

[0195] Intermediate 40: Preparation of methyl (6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-carboxylate [ka] To a stirred solution of methyl (2R,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (2.0 g, 10.0 mmol) in THF (25 mL) were added sodium iodide (0.752 g, 5.02 mmol) and (trifluoromethyl)trimethylsilane (4.01 mL, 25.10 mmol), and the resulting mixture was stirred at 80 °C for 4 hours. The reaction mixture was cooled to room temperature, and water (80 mL) and ethyl acetate (2 × 200 mL) were added. The two layers were separated, and the organic layer was washed with aqueous sodium thiosulfate (1 × 100 mL, 0.1 M), brine (1 × 100 mL), dried over Na SO , filtered, and concentrated. Purification by silica gel chromatography eluting with 20% ethyl acetate and petroleum ether afforded methyl (6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-carboxylate (1.6 g, 6.34 mmol, 63.2% yield) as a mixture of diastereomers in a 63:37 ratio. LCMS (ESI) m / z: 250.2 [M+H] + .

[0196] Intermediate 41: Preparation of methyl (6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-carboxylate [ka] To a stirred solution of methyl (6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-carboxylate (1.6 g, 6.42 mmol) in THF (5 mL) was added LiAlH4 (19.26 mL, 19.26 mmol, 1 M in THF) dropwise at 0°C, and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0°C, saturated ammonium chloride (30 mL) was added, and the mixture was extracted with ethyl acetate (2 x 75 mL). The two layers were separated, and the organic layer was washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated to give ((6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methanol (1.3 g, 89%) as a mixture of diastereomers in a 63:37 ratio. LCMS (ESI) m / z: 222.1 [M+H] + .

[0197] Intermediate 42 and 43: tert-Butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((1R,6'R,7a'R)-2,2,6'-trifluorodihydro-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 (Intermediate 42) and preparation of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((1S,6'R,7a'R)-2,2,6'-trifluorodihydro-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 (intermediate 43) [ka] To a stirred solution of ((6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methanol (1.047 g, 4.73 mmol) in THF (20 mL) at 0°C, NaH (0.189 g, 4.73 mmol) was added, and the reaction mixture was stirred at the same temperature for 30 minutes. A solution of tert-butyl 3-(2,8-difluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.0 g, 2.63 mmol) in THF (5 mL) was added at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then cooled to 0° C., ice-cold water (50 mL) was added, and the mixture was stirred for 10 minutes before being extracted with ethyl acetate (2×80 mL). The organic layer was washed with brine (1×45 mL), dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography on neutral alumina eluting with 14% ethyl acetate in petroleum ether gave tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((1R,6'R,7a'R)-2,2,6'-trifluorodihydro-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 (Intermediate 42) (1.5 g, 1.543 mmol, 59% yield). LCMS (ESI) m / z: 962.4 [M+H] +Also isolated was a minor amount of the diastereomer tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((1S,6'R,7a'R)-2,2,6'-trifluorodihydro-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 (Intermediate 43) (450 mg, 0.463 mmol, 18% yield). LCMS (ESI) m / z: 962.4 [M+H] + The stereochemistry shown at the spiro ring center in intermediates 42 and 43 has been arbitrarily assigned.

[0198] Preparation of Intermediate 44: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((1R,6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)quinazolin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol [ka] To a stirred solution of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((1R,6'R,7a'R)-2,2,6'-trifluorodihydro-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 (1.5 g, 1.56 mmol) in DCM (15 mL) at 0° C. was added HCl (3.90 mL, 15.6 mmol, 4 M in dioxane) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (35 mL) and washed with saturated sodium bicarbonate solution (1×10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((1R,6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)quinazolin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (1.2 g). LCMS (ESI) m / z: 818.2 [M+H] + .

[0199] Example 5-1 This example describes the synthesis of 4-(2-{[(1R,6′R,7′aR)-3,3,6′-trifluoro-hexahydrospiro[cyclopropane-1,2′-pyrrolidin]-7′a-yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. [ka]

[0200] To a solution of 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((1R,6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)quinazolin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (1.2 g, 1.47 mmol) in DCM (10 mL) at 0°C, TBAF (7.33 mL, 7.33 mmol, 1 M in THF) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with DCM (2 x 15 mL). The organic layer was washed with brine (1 × 5 mL), dried over sodium sulfate, filtered, and concentrated to give a crude residue that was purified by preparative HPLC (eluent: THF:water:MeCN (50:20:30); column: X-bridge C18 (250 × 19) mm, 5 micron; mobile phase A: 0.1% TFA in water; mobile phase B: acetonitrile; flow: 20 mL / min; gradient) to give the desired product as the bis-TFA salt. Further purification by SFC (CHIRALPAK™ AD-H (Daicel Corporation, Japan) (250 × 4.6) mm, 5 microns; mobile phase—0.1% NH OH in 2-propanol) gave 4-(4-(3,8-4-(2-{[(1R,6′R,7′aR)-3,3,6′-trifluoro-hexahydrospiro[cyclopropane-1,2′-pyrrolidin]-7′a-yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (250 mg, 26%) as an off-white solid. LCMS (ESI) m / z: 662.2 [M+H] + . 1H-NMR(400MHz,DMSO-d6):δ 10.17(br s,1H),7.96(dd,J=9.2,6.0Hz,1H),7.40(d,J=8.40Hz,1H),7.46(dd,J=9.2,9.2Hz,1H),7.36(d,J=2.4Hz,1H),7.15-7.21(m,1H),7.07(d,J=2 .4Hz,1H),5.28-5.46(m,1H),4.17-4.36(m,4H),3.85(s,1H),3.17-3. 65(m,5H),2.70-2.88(m,3H),1.75-2.20(m,4H),1.45-1.80(m,7H)ppm.

[0201] Preparation of Intermediate 45: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((1S,6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)quinazolin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol [ka] To a stirred solution of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((1S,6'R,7a'R)-2,2,6'-trifluorodihydro-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 (450 mg, 0.468 mmol) in DCM (5 mL) at 0°C, HCl (1.17 mL, 4.68 mmol, 4 M in dioxane) was added and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with DCM (35 mL), washed with saturated aqueous sodium bicarbonate (1×10 mL), dried over sodium sulfate, filtered, and concentrated to give 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((1S,6′R,7a′R)-2,2,6′-trifluorodihydro-1′H,3′H-spiro[cyclopropane-1,2′-pyrrolidine]-7a′(5′H)-yl)methoxy)quinazolin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (370 mg, crude compound). LCMS (ESI) m / z: 818.2 [M+H] + .

[0202] Example 6-1 This example describes the synthesis of 4-(2-{[(1S,6′R,7′aR)-3,3,6′-trifluoro-hexahydrospiro[cyclopropane-1,2′-pyrrolidin]-7′a-yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. [ka]

[0203] To a stirred solution of 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((1S,6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)quinazolin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (370 mg, 0.45 mmol) in DCM (4 mL) at 0°C was added TBAF (2.26 mL, 2.26 mmol, 1 M in THF) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (1 mL) and extracted with DCM (2 x 8 mL). The organic layer was washed with brine (1 × 1 mL), dried over sodium sulfate, filtered, and concentrated. Purification by preparative HPLC (eluent: THF:water:MeCN (50:20:30); column: X-bridge C18 (150 × 19) mm, 5 micron; mobile phase A: 0.1% TFA in water; mobile phase B: acetonitrile; flow: 15 mL / min, gradient) afforded 4-(2-{[(1S,6'R,7'aR)-3,3,6'-trifluoro-hexahydrospiro[cyclopropane-1,2'-pyrrolidin]-7'a-yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (100 mg, 0.10 mmol, 22% yield) as an off-white solid. LCMS(ESI)m / z:662.2[M+H] + . 1 H-NMR(400MHz,DMSO-d6):δ 11.81(br s,1H),10.20(s,1H),9.25-9.40(m,1H),9.05-9.15(m,1H),7.99(dd,J=8.8 ,6.0Hz,1H),7.83(d,J=8.8Hz,1H),7.48(dd,J=9.2,9.2Hz,1H),7.39(d,J= 2.4Hz,1H),7.31-7.38(m,1H),7.08(d,J=2.4Hz,1H),5.53-5.70(m,1H),3. 45-4.70(m,14H),2.46-2.70(m,2H),2.33-2.40(m,1H),1.81-2.05(m,6H).

[0204] Preparation of Intermediate 46: tert-Butyl 3-(7-chloro-8-fluoro-2-(((6'R,7a'R)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a stirred solution of ((6'R,7a'R)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methanol (0.649 g, 3.50 mmol) in THF (15 mL) at 0°C, LiHMDS (4.67 mL, 4.67 mmol, 1 M in THF) was added, and the resulting mixture was stirred at the same temperature for 10 minutes. A solution of tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1 g, 2.335 mmol) in THF (10 mL) was added dropwise to the previous solution at 0°C, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0° C., ice-cold water (50 mL) was added, and the mixture was extracted with ethyl acetate (3×50 mL). The organic layer was washed with brine (1×50 mL), dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography eluting with 15% ethyl acetate and petroleum ether afforded tert-butyl 3-(7-chloro-8-fluoro-2-(((6′R,7a′R)-6′-fluorodihydro-1′H,3′H-spiro[cyclopropane-1,2′-pyrrolidine]-7a′(5′H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-azabicyclo[3.2.1]octane-8-carboxylate (400 mg, 0.624 mmol, 27% yield) as a pale yellow solid. LCMS (ESI) m / z: 577.2 [M+H] + .

[0205] Intermediate 47: tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((6'R,7a'R)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] tert-Butyl 3-(7-chloro-8-fluoro-2-(((6'R,7a'R)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.52 mmol) and ( To a mixture of (2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (666 mg, 1.30 mmol) in THF (10 mL) was added potassium phosphate tripotassium (1.04 mL, 1.56 mmol, 1.5 M aqueous solution) at room temperature and purged with nitrogen for 5 minutes. CATACXIUM™ A Pd G3 (Sigma Aldrich, St. Louis, MO) (76 mg, 0.104 mmol) was added, and the resulting mixture was stirred at 70° C. for 7 hours. The reaction mixture was cooled to room temperature, ice-cold water (50 mL) was added, and the mixture was extracted with ethyl acetate (3×50 mL). The organic layer was washed with brine (1×50 mL), dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography on neutral alumina eluting with 15% ethyl acetate in petroleum ether afforded tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((6'R,7a'R)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.32 mmol, 62% yield) as a pale yellow solid. LCMS (ESI) m / z: 927.5 [M+H] + .

[0206] Preparation of Intermediate 48: tert-Butyl 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((6'R,7a'R)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((6'R,7a'R)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-1)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.324 mmol) in THF (10 mL) at 0°C, TBAF (0.647 mL, 0.647 mmol, 1 M in THF) was added, and the resulting mixture was stirred at the same temperature for 30 minutes. The reaction mixture was diluted with ice-cold water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give tert-butyl 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((6'R,7a'R)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, crude compound). LCMS (ESI) m / z: 771.2 [M+H] + .

[0207] Example 7-1 This example describes the synthesis of 4-(2-{[(6'R,7'aR)-6'-fluoro-hexahydrospiro[cyclopropane-1,2'-pyrrolidin]-7'a-yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. [ka]

[0208] To tert-butyl 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((6'R,7a'R)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.259 mmol) in acetonitrile (5 mL) at 0°C, HCl (0.52 mL, 2.08 mmol, 4 M in dioxane) was added, and the resulting mixture was stirred at the same temperature for 2 hours. Triethylamine (0.1 mL) and ice-cold water (10 mL) were added, and the mixture was extracted with ethyl acetate (3 x 50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by preparative HPLC (eluent: THF:water:MeCN (50:20:30); column: Symmetry (300 × 19 mm) 7 μm, mobile phase A: 0.1% TFA in water; mobile phase B: MeCN; flow rate: 15 mL / min; gradient) gave the desired product as the bis-TFA salt. The bis-TFA salt was taken up in DCM (3 mL) and solid ammonium bicarbonate (50 mg) was added. After stirring the suspension at room temperature for 15 minutes, the suspension was filtered and the filtrate was concentrated. After lyophilization, 4-(2-{[(6'R,7'aR)-6'-fluoro-hexahydrospiro[cyclopropane-1,2'-pyrrolidin]-7'a-yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (20 mg, 0.030 mmol, 12% yield) was obtained as an off-white solid. LCMS (ESI) m / z: 627.3 [M+1] + . 1H-NMR(400MHz,DMSO-d6):δ 10.14(s,1H),9.04(s,1H),7.98(dd,J=9.2,6.00Hz,1H),7.47(t,J=9.20Hz,1H),7.40(d,J=2.80Hz,1H), 7.18(t,J=2.00Hz,1H),5.30-5.55(m,1H),4.44-4.55(m,1H),4.26-4.37(m,2H),4.12-4.18(m,1H),3.94- 3.97(m,1H),3.52-3.71(m,4H),2.88-3.04(m,1H),2.83(d,J=10Hz,1H),2.64(d,J=10Hz,1H),2.48-2.54( m,2H),2.30-2.42(m,1H),1.93-2.11(m,1H),1.78-1.89(m,2H),1.62-1.73(m,4H),0.45-0.57(m,4H)ppm.

[0209] Intermediates 49 and 50: tert-butyl 3-(7-chloro-8-fluoro-2-(((1R,6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate ( Preparation of 49) and tert-butyl 3-(7-chloro-8-fluoro-2-(((1S,6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50) [ka] To a stirred solution of ((6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methanol (1.30 g, 5.88 mmol) in THF (10 mL) at 0°C, LiHMDS (6.54 mL, 6.54 mmol, 1 M in THF) was added, and the reaction mixture was stirred at the same temperature for 20 minutes. A solution of tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.4 g, 3.27 mmol) in THF (10 mL) was added at 0°C, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then cooled to 0° C., ice-cold water (50 mL) was added, and the mixture was stirred for 10 minutes before being extracted with ethyl acetate (2×80 mL). The organic layer was washed with brine (1×45 mL), dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography on neutral alumina eluting with 32% ethyl acetate in petroleum ether afforded tert-butyl 3-(7-chloro-8-fluoro-2-(((1R,6′R,7a′R)-2,2,6′-trifluorodihydro-1′H,3′H-spiro[cyclopropane-1,2′-pyrrolidine]-7a′(5′H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 49) (760 mg, 1.20 mmol, 36.8% yield). LCMS(ESI)m / z:613.2[M+H] + Also isolated was a minor amount of the diastereomer tert-butyl 3-(7-chloro-8-fluoro-2-(((1S,6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 50) (310 mg, 0.50 mmol, 15% yield). LCMS (ESI) m / z: 613.2 [M+H] + The stereochemistry shown at the spiro ring center in intermediates 62 and 63 has been arbitrarily assigned.

[0210] Preparation of Intermediate 51: tert-Butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((1R,6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] tert-Butyl 3-(7-chloro-8-fluoro-2-(((1R,6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.49 mmol) To a mixture of ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (502 mg, 0.98 mmol) in THF (10 mL) was added potassium phosphate tripotassium (0.98 mL, 1.47 mmol, 1.5 M aqueous solution) at room temperature, and the mixture was purged with nitrogen for 5 minutes. CATACXIUM™ A Pd G3 (Sigma Aldrich, St. Louis, MO) (71.3 mg, 0.098 mmol) was added, and the resulting mixture was stirred at 70° C. for 7 hours. The reaction mixture was cooled to room temperature, ice-cold water (10 mL) was added, and extracted with ethyl acetate (3×20 mL). The organic layer was washed with brine (1×10 mL), dried over sodium sulfate, filtered, and concentrated. Purification by silica gel column chromatography eluting with 42% EtOAc in petroleum ether afforded tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((1R,6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (400 mg, 0.407 mmol, 83% yield) as a pale yellow solid. LCMS (ESI) m / z: 963.3 [M+H] + .

[0211] Preparation of Intermediate 52: tert-Butyl 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((1R,6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((1R,6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.311 mmol) in DMF (2.1 mL) was added cesium fluoride (95 mg, 0.623 mmol), and the resulting mixture was stirred at 50° C. for 3 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc (30 mL). The organic layer was washed with saturated aqueous NaHCO3 (1 x 10 mL), dried over sodium sulfate, filtered, and concentrated to give tert-butyl 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((1R,6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (240 mg). This material was used in the next step without further purification. LCMS (ESI) m / z: 807.2 [M+H] + .

[0212] Example 8-1 This example describes the synthesis of 4-(2-{[(1R,6′R,7′aR)-3,3,6′-trifluoro-hexahydrospiro[cyclopropane-1,2′-pyrrolidin]-7′a-yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. [ka]

[0213] To a solution of tert-butyl 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((1R,6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (240 mg, 0.297 mmol) in MeCN (2 mL) at 0°C, HCl (0.744 mL, 2.97 mmol, 4.0 M in dioxane) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and diluted with dichloromethane (20 mL). The organic layer was washed with saturated aqueous NaHCO3 (5 mL), dried over sodium sulfate, filtered and concentrated. Purification by preparative HPLC (eluent: THF:water:MeCN (50:20:30); column: Symmetry C8 (300 × 19) mm, 7 μm; mobile phase A: 5 mM aqueous ammonium formate, mobile phase B: MeCN; flow: 15 mL / min, gradient) gave 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((1R,6′R,7a′R)-2,2,6′-trifluorodihydro-1′H,3′H-spiro[cyclopropane-1,2′-pyrrolidine]-7a′(5′H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (45 mg, 0.064 mmol, 21.4% yield) as a pale yellow solid. LCMS(ESI)m / z:663.2[M+1]+ . 1 H-NMR(400MHz,DMSO-d6):δ 9.06(s,1H),7.98(dd,J=9.2,5.6Hz,1H),7.47(dd,J=8.8,8.8Hz,1H),7.40(d,J=2.4Hz,1H), 7.18(d,J=2.4Hz,1H),5.37(dt,J=53.6,3.75Hz,1H),4.52(d,J=12.4Hz,1H),4.22-4.38(m,3H) ),3.94(dd,J=2.4,0.8Hz,1H),3.58-3.73(m,4H),3.12-3.40(m,2H),2.70-2.89(m,2H),2.28 -2.40(m,1H),2.11-2.19(m,1H),1.88-2.06(m,2H),1.68-1.76(m,3H),1.48-1.64(m,2H)ppm.

[0214] Preparation of Intermediate 53: tert-Butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((1S,6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] tert-Butyl 3-(7-chloro-8-fluoro-2-(((1S,6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (290 mg, 0.47 mmol) To a mixture of ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (485 mg, 0.95 mmol) in THF (9 mL) was added tripotassium phosphate (0.95 mL, 1.42 mmol, 1.5 M aqueous solution) at room temperature, and the reaction was purged with nitrogen for 5 minutes. CATACXIUM™ A Pd G3 (Sigma Aldrich, St. Louis, MO) (68.9 mg, 0.095 mmol) was added, and the resulting mixture was stirred at 70° C. for 16 hours. The reaction mixture was cooled to room temperature, ice-cold water (10 mL) was added, and the mixture was extracted with ethyl acetate (3×20 mL). The organic layer was washed with brine (1×10 mL), dried over sodium sulfate, filtered, and concentrated. Purification by silica gel column chromatography eluting with 42% EtOAc in petroleum ether afforded tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((1S,6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (310 mg, 0.29 mmol, 61% yield) as a pale yellow solid. LCMS (ESI) m / z: 963.3 [M+H] + .

[0215] Preparation of Intermediate 54: tert-Butyl 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((1S,6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((1S,6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.311 mmol) in DMF (2.1 mL) was added cesium fluoride (95 mg, 0.623 mmol), and the resulting mixture was stirred at 50° C. for 3 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc (30 mL). The organic layer was washed with saturated aqueous NaHCO3 (1 x 10 mL), dried over sodium sulfate, filtered, and concentrated to give tert-butyl 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((1S,6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (230 mg). This material was used in the next step without further purification. LCMS (ESI) m / z: 807.2 [M+H] + .

[0216] Example 9-1 This example describes the synthesis of 4-(2-{[(1S,6'R,7'aR)-3,3,6'-trifluoro-hexahydrospiro[cyclopropane-1,2'-pyrrolidin]-7'a-yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. [ka]

[0217] To a solution of tert-butyl 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((1S,6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (230 mg, 0.285 mmol) in MeCN (2 mL) at 0° C., HCl (0.713 mL, 2.85 mmol, 4.0 M in dioxane) was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and diluted with dichloromethane (20 mL). The organic layer was washed with saturated aqueous NaHCO3 (5 mL), dried over sodium sulfate, filtered and concentrated. Purification by preparative HPLC (eluent: THF:water:MeCN (50:20:30); column: Symmetry C8 (300 × 19) mm, 7 μm; mobile phase A: 5 mM aqueous ammonium formate, mobile phase B: MeCN; flow: 15 mL / min, gradient) gave 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((1S,6′R,7a′R)-2,2,6′-trifluorodihydro-1′H,3′H-spiro[cyclopropane-1,2′-pyrrolidine]-7a′(5′H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (33 mg, 0.047 mmol, 17% yield) as a pale yellow solid. LCMS(ESI)m / z:663.2[M+1]+ . 1 H-NMR(400MHz,DMSO-d6):δ 10.2(br s,1H),9.05(s,1H),7.95-8.00(m,1H),7.47(dd,J=8.8,8.8Hz,1H),7.39(d,J=2.4Hz,1H),7.18(t,J=2.4 ,2.4Hz,1H),5.43(dt,J=56,3.6Hz,1H),4.47-4.58(m,1H),4.26-4.38(m,1H),4.16(d,J=10.8Hz,1H),3. 98-4.04(m,1H),3.93-3.96(m,1H),3.54-3.74(m,4H),3.23-3.44(m,1H),2.93-3.15(m,2H),2.77-2.83( m,1H),2.28-2.41(m,1H),2.05-2.24(m,2H),1.96-2.03(m,1H),1.66-1.74(m,3H),1.53-1.64(m,2H)ppm.

[0218] biological activity KRAS G12D RAF disruption assay Recombinant GMPPNP-loaded KRAS G12D (5 nM) was treated with compounds in assay buffer (50 mM Tris pH 7.5, 100 mM NaCl, 1 mM MgCl2, 1 mM DTT, 100 μg / ml BSA) for 20 min at room temperature. Recombinant GST-RAF1 RBD (9 nM) was added, followed by SA-Tb (0.25 nM), and the reaction mixture was incubated for 3 h. Homogeneous time-resolved fluorescence (HTRF) signals were measured (PerkinElmer Envision) to determine the signal ratio (λ em 520 / λ em 495) and calculate IC 50 Values ​​were calculated from dose-response curves.

[0219] KRAS G12D Nucleotide exchange assay Recombinant GDP-loaded KRAS G12D (20 nM) was treated with compounds in assay buffer (10 mM Hepes pH 7.4, 150 mM NaCl, 5 mM MgCl, 0.0025% Igepal-CA630, 0.05% BSA, 1 mM DTT, 0.5 nM SA-Tb) for 20 minutes at room temperature. BODIPY™-labeled GDP (ThermoFisher, Waltham, MA) (400 nM) and recombinant SOS (10 nM) were added, and the reaction was incubated for 30 minutes. HTRF signals were measured (PerkinElmer Envision) to determine the signal ratio (λ). em 520 / λ em 495) and calculate IC 50 Values ​​were calculated from dose-response curves.

[0220] KRAS G12D RAF destruction and KRAS G12D IC of the compounds described herein for the nucleotide exchange assay 50 The values ​​are shown in Table 3.

[0221] [Table 5]

[0222] It should be understood that the Detailed Description section, and not the Summary and Abstract sections, is intended to be used to interpret the claims. The Summary and Abstract sections are not intended to limit the scope of the disclosure and the appended claims in any way, as they may set forth one or more, but not all, exemplary aspects of the disclosure contemplated by the inventors.

[0223] This disclosure has been described above in terms of functional building blocks that illustrate the implementation of specified functions and relationships thereof. The boundaries of these functional building blocks have been arbitrarily defined herein for convenience of description. Alternate boundaries may be defined so long as the specified functions and relationships thereof are appropriately performed.

[0224] The foregoing description of the specified embodiments fully reveals the general nature of the present disclosure so that others can readily modify and / or adapt such specific embodiments for various uses by applying knowledge within the skill of the art without undue experimentation and without departing from the general concepts of the present disclosure. Such adaptations and modifications are therefore intended to be within the meaning and range of equivalents of the disclosed embodiments, based on the teaching and guidance provided herein. It is to be understood that the phraseology or terminology used herein is intended to be descriptive rather than limiting, as the terminology or terminology may be interpreted by one of ordinary skill in the art in light of the teaching and guidance.

[0225] The breadth and scope of the present disclosure should not be limited by any of the above-described exemplary aspects, but should be defined only in accordance with the following claims and their equivalents.

Claims

1. Formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt thereof; W １ is CR ２ or N; R １ is aryl or heteroaryl, and said aryl and said heteroaryl are optionally selected from the group consisting of C １ -C ３ Alkyl, C ２ -C ４ Alkenyl, C ２ -C ４ Alkynyl, Amino, Amino C １ -C ３ Alkyl, C ３ -C ４ Cycloalkyl, halo, haloC １ -C ３ Alkyl, hydroxy, and hydroxy C １ -C ３ substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkyl; R ２ is hydrogen, C １ -C ３ Alkoxy, C １ -C ３ Alkyl, cyano, halo, haloC １ -C ３ alkyl, or hydroxy; R ３ is hydrogen, C １ -C ３ Alkoxy, C １ -C ３ Alkyl, cyano, halo, haloC １ -C ３ alkyl, or hydroxy; R ４ is hydrogen, C １ -C ３ Alkyl, hydroxy C １ -C ６ Alkyl or haloC １ -C ６ is alkyl; R ５ is -(C １ -C ３ alkyl)-R ６ or -(C １ -C ６ alkyl)NR ｃ R ｄ and R ６ teeth: In some cases, NR ｃ R ｄ (C １ -C ３ C substituted with alkyl)- ３ -C ６ cycloalkyl; and A 5-10 membered monocyclic, bicyclic or tricyclic fully or partially saturated or fully unsaturated ring system containing one nitrogen atom and optionally a second heteroatom selected from oxygen or nitrogen, said ring containing 0-3 double bonds, said ring optionally being selected from C １ -C ３ Alkoxy, C １ -C ３ Alkoxy C １ -C ３ Alkyl, C １ -C ３ Alkyl, benzyl, halo, haloC １ -C ３ Alkyl, hydroxy, hydroxy C １ -C ３ a 5-10 membered monocyclic, bicyclic, or tricyclic fully or partially saturated or fully unsaturated ring system substituted with one, two, or three groups independently selected from alkyl and oxo; Selected from: R ｃ and R ｄ together with the nitrogen atom to which they are attached form a 5-10 membered monocyclic or bicyclic ring optionally containing one additional heteroatom selected from nitrogen, oxygen, and sulfur, said ring optionally containing C １ -C ３ Alkoxy, C １ -C ３ Alkoxy C １ -C ３ Alkyl, C １ -C ３ Alkyl, benzyl, halo, haloC １ -C ３ Alkyl, hydroxy, hydroxy C １ -C ３ substituted with one, two, or three groups independently selected from alkyl, and oxo; or R ｃ and R ｄ One of the groups is hydrogen and C １ -C ３ alkyl, and the other is selected from hydrogen, C １ -C ３ Alkyl, C １ -C ３ Alkoxycarbonyl, and C １ -C ３ alkylcarbonyl; However, W １ is CR ２ If R ４ is hydrogen or C １ -C ３ The compound, or a pharmaceutically acceptable salt thereof, provided that it is not alkyl.

2. W １ is CR ２ 2. The compound of claim 1, wherein:

3. R ２ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: is hydrogen or halo.

4. W １ is N; or a pharmaceutically acceptable salt thereof.

5. R ３ The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein: is halo.

6. R ４ 5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein: is hydrogen.

7. R ４ is C １ -C ３ 5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein: R is alkyl;

8. R ４ is hydroxy C １ -C ３ 6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein: R is 1 or 2;

9. R ４ Halo C １ -C ３ 6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein: R is 1 or 2;

10. R ５ Ha-(C １ -C ３ alkyl)-R ６ 10. The compound of any one of claims 1 to 9, wherein:

11. R ６ is a 5-10 membered fully or partially saturated or fully unsaturated ring system containing one nitrogen atom and optionally containing a second heteroatom selected from nitrogen and oxygen, said ring system optionally being selected from C １ -C ３ Alkoxy, C １ -C ３ Alkoxy C １ -C ３ Alkyl, C １ -C ３ Alkyl, benzyl, halo, haloC １ -C ３ Alkyl, hydroxy, hydroxy C １ -C ３ 11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, substituted with one, two, or three groups independently selected from alkyl and oxo.

12. R ５ teeth: 【Chemistry 2】 wherein each ring is optionally selected from C １ -C ３ Alkoxy, C １ -C ３ Alkoxy C １ -C ３ Alkyl, C １ -C ３ Alkyl, benzyl, halo, haloC １ -C ３ Alkyl, hydroxy, hydroxy C １ -C ３ substituted with 1, 2, or 3 groups independently selected from alkyl, and oxo; 【Chemistry 3】 12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein indicates the point of attachment to the parent molecular moiety.

13. R ５ teeth, 【Chemistry 4】 and During the ceremony: z is 1, 2, or 3; Each R ５０ is C １ -C ３ Alkyl, C １ -C ３ Alkoxy, C １ -C ３ Alkoxy C １ -C ３ Alkyl, halo, haloC １ -C ３ Alkyl, haloC １ -C ３ Alkoxy, hydroxy, hydroxy C １ -C ３ independently selected from alkyl, benzyl, and oxo; 【Chemistry 5】 13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein indicates the point of attachment to the parent molecular moiety.

14. R ５ teeth, 【Chemistry 6】 14. The compound of claim 13, wherein:

15. z is 1 and R ５０ 15. The compound of claim 13 or 14, or a pharmaceutically acceptable salt thereof, wherein: is halo.

16. R ５０ 16. The compound of any one of claims 13 to 15, or a pharmaceutically acceptable salt thereof, wherein is fluoro.

17. R ５ teeth, 【Chemistry 7】 and 【Chemistry 8】 17. The compound of any one of claims 13 to 16, or a pharmaceutically acceptable salt thereof, wherein indicates the point of attachment to the parent molecular moiety.

18. R ５ teeth, 【Chemistry 9】 and wherein q and r are each independently 0, 1, or 2; R ｘ and R ｙ is C １ -C ３ Alkoxy, C １ -C ３ Alkyl, halo, haloC １ -C ３ independently selected from alkyl, and hydroxy; 【Chemistry 10】 13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein indicates the point of attachment to the parent molecular moiety.

19. R ５ teeth, 【Chemistry 11】 and wherein q, r, and d are each independently 0, 1, or 2; R ｘ , R ｙ , and R ｐ is C １ -C ３ Alkoxy, C １ -C ３ Alkyl, halo, haloC １ -C ３ independently selected from alkyl, and hydroxy; 【Chemistry 12】 13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein indicates the point of attachment to the parent molecular moiety.

20. R ５ teeth, 【Chemistry 13】 and During the ceremony, 【Chemistry 14】 20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein indicates the point of attachment to the parent molecular moiety.

21. R ５ teeth, 【Chemistry 15】 and wherein q and r are each independently 0, 1, or 2; R ｘ and R ｙ is C １ -C ３ Alkoxy, C １ -C ３ Alkyl, halo, haloC １ -C ３ independently selected from alkyl, and hydroxy; 【Chemistry 16】 13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein indicates the point of attachment to the parent molecular moiety.

22. R ５ teeth, 【Chemistry 17】 and During the ceremony, 【Chemistry 18】 22. The compound of claim 21 , or a pharmaceutically acceptable salt thereof, wherein indicates the point of attachment to the parent molecular moiety.

23. R ５ teeth, 【Chemistry 19】 and wherein q and r are each independently 0, 1, or 2; R ｘ and R ｙ is C １ -C ３ Alkoxy, C １ -C ３ Alkyl, halo, haloC １ -C ３ independently selected from alkyl, and hydroxy; 【Chemistry 20】 13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein indicates the point of attachment to the parent molecular moiety.

24. R ５ teeth, 【Chemical 21】 and During the ceremony, 【Chemical 22】 24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein indicates the point of attachment to the parent molecular moiety.

25. R ５ teeth, 【Chemical 23】 13. The compound of claim 12, wherein:

26. R ５ teeth, 【Chemistry 24】 and wherein q is 0, 1, or 2; R ｘ is C １ -C ３ Alkoxy, C １ -C ３ Alkoxy C １ -C ３ Alkyl, C １ -C ３ Alkyl, benzyl, halo, haloC １ -C ３ Alkyl, hydroxy, hydroxy C １ -C ３ alkyl, and oxo; 【Chemistry 25】 26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein indicates the point of attachment to the parent molecular moiety.

27. R ５ teeth, 【Chemical 26】 and During the ceremony, 【Chemical 27】 27. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein indicates the point of attachment to the parent molecular moiety.

28. R １ is substituted, and R １ One of the above substituents is haloC １ -C ３ 28. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein:

29. R １ is naphthyl, and said naphthyl is optionally １ -C ３ Alkyl, C ２ -C ４ Alkynyl, C ３ 28. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, substituted with one, two, or three groups independently selected from cycloalkyl, halo, and hydroxy.

30. R １ teeth, 【Chemical 28】 and During the ceremony, 【Chemical 29】 30. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein indicates the point of attachment to the parent molecular moiety.

31. R １ teeth, 【Chemistry 30】 and During the ceremony, 【Chemical 31】 28. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein indicates the point of attachment to the parent molecular moiety.

32. W １ is CR ２ and R ２ is hydrogen or chloro; R ３ is fluoro; R １ teeth, 【Chemical 32】 is selected from R ５ teeth, 【Chemical 33】 Selected from: 【Chemical 34】 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein indicates the point of attachment to the parent molecular moiety.

33. W １ is N; R ３ is fluoro; R １ teeth, 【Chemistry 35】 Selected from: R ５ teeth, 【Chemical 36】 Selected from: 【Chemical 37】 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein indicates the point of attachment to the parent molecular moiety.

34.

38. 【Chemical 39】 1. A compound selected from the group consisting of: or a pharmaceutically acceptable salt of said compound.

35.

40. 【Chemistry 41】 1. A compound selected from the group consisting of: or a pharmaceutically acceptable salt of said compound.

36. 4-(4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-2-[(1-methyl-octahydro-1H-indol-3a-yl)methoxy]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol isomer 1; 4-(4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-2-[(1-methyl-octahydro-1H-indol-3a-yl)methoxy]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol isomer 2; 4-(4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-2-({1-methyl-1-azaspiro[4.4]nonan-6-yl}methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-[8-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[8-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-4-[8-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 5-ethynyl-6-fluoro-4-{8-fluoro-2-[(1-{[(3R)-3-fluoropyrrolidin-1-yl]methyl}cyclopropyl)methoxy]-4-[8-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]quinazolin-7-yl}naphthalen-2-ol; 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-1H-pyrrolidin-7a-yl]methoxy}-8-fluoro-4-[8-(2,2,2-trifluoroethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 2-[3-(2-{[(4aS,7aR)-1-methyl-octahydro-1H-cyclopenta[b]pyridin-4a-yl]methoxy}-7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]ethan-1-ol; 4-(2-{[(6'R,7'aR)-6'-fluoro-hexahydrospiro[cyclopropane-1,2'-pyrrolidin]-7'a-yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(1R,6'R,7'aR)-3,3,6'-trifluoro-hexahydrospiro[cyclopropane-1,2'-pyrrolidin]-7'a-yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; and 4-(2-{[(1S,6'R,7'aR)-3,3,6'-trifluoro-hexahydrospiro[cyclopropane-1,2'-pyrrolidin]-7'a-yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol 1. A compound selected from the group consisting of: or a pharmaceutically acceptable salt of said compound.

37.

42. 1. A compound selected from the group consisting of: or a pharmaceutically acceptable salt of said compound.

38. 4-(2-{[(6'R,7'aR)-6'-fluoro-hexahydrospiro[cyclopropane-1,2'-pyrrolidin]-7'a-yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol 2TFA; 4-(2-{[(1R,6'R,7'aR)-3,3,6'-trifluoro-hexahydrospiro[cyclopropane-1,2'-pyrrolidin]-7'a-yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(2-{[(1S,6'R,7'aR)-3,3,6'-trifluoro-hexahydrospiro[cyclopropane-1,2'-pyrrolidin]-7'a-yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; and 4-(2-{[(1R,6'R,7'aR)-3,3,6'-trifluoro-hexahydrospiro[cyclopropane-1,2'-pyrrolidin]-7'a-yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol, 1. A compound selected from the group consisting of: or a pharmaceutically acceptable salt of said compound.

39. 39. A pharmaceutical composition comprising a compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

40. 40. A method of treating a cancer sensitive to KRAS G12D inhibition in a subject in need thereof, comprising administering to said subject a compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt of said compound.

41. 40. A method of treating a cancer expressing a KRAS G12D mutation in a subject in need thereof, comprising administering to said subject a compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt of said compound.

42. 40. A method of treating cancer in a subject in need thereof, comprising administering to the subject a compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt of said compound, wherein the cancer is pancreatic, colorectal, lung, and / or gastric cancer.

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