KRAS G12D INHIBITORS

CROSS-REFERENCE TO RELATED APPLICATIONS

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

FIELD

[0002] The present disclosure provides KRAS inhibitors. Methods of treating cancers using the inhibitors are also provided.

BACKGROUND

[0003] The KRAS oncogene is a member of the Ras family of GTPases that are involved in numerous cellular signaling processes. KRAS mutations are gain-of-function mutations that are present in up to 30% of all tumors, including as many as 90% of pancreatic cancers. KRAS G12D mutation is present in 28% of all pancreatic ductal adenocarcinoma patients, 13% of all colorectal carcinoma patients, 4% of all non-small cell lung carcinoma patients and 3% of all gastric carcinoma patients (e g., see https://www.mycancergenome.org/content/alteration/kras- gl2d/). Due to the clinical significance of this protein, many attempts have been made to develop Ras inhibitors, but such attempts have been mostly unsuccessful. This is largely due to the difficulty in outcompeting GTP for the KRAS binding pocket in cells, and the lack of known allosteric regulatory sites. Accordingly, agents that inhibit KRAS G12D are desired.

SUMMARY

[0004] In a first aspect, the present disclosure provides a compound of formula (I):

or a pharmaceutically acceptable salt thereof; wherein:

W ¹ is CR ² orN;

R ¹ is aryl or heteroaryl, wherein the aryl and the heteroaryl are optionally substituted with one, two, three, four, or five substituents independently selected from C ₁ -C ₃ alkyl, C2-C4alkenyl, C2-Cralkynyl, amino, aminoC ₁ -C ₃ alkyl, C ₃ -C ₄ cycloalkyl, halo, haloC ₁ -C ₃ alkyl, hydroxy, and hydroxyC ₁ -C ₃ 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, hydroxyC ₁ -C ₆ alkyl, or haloC ₁ -C ₆ alkyl; and

R ⁵ is -(Ci-C3alkyl)-R ⁶ or -(C ₁ -C ₆ alkyl)NR ^c R ^d , wherein R ⁶ is selected from: a C3-C6cycloalkyl optionally substituted with NR ^c R ^d (C1-C3alkyl)-; and a five- to ten-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 zero to three double bonds and wherein the ring is optionally substituted with one, two, or three groups independently selected from Ci- C3alkoxy, C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl, C ₁ -C ₃ alkyl, benzyl, halo, haloC ₁ -C ₃ alkyl, hydroxy, hydroxyCi- C3alkyl, and oxo; wherein

R ^c and R ^d , together with the nitrogen atom to which they are attached, form a fi veto ten-membered ring monocyclic or bicyclic ring optionally containing one additional heteroatom selected from nitrogen, oxygen, and sulfur, wherein the ring is optionally substituted with one, two, or three groups independently selected from C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl, C ₁ -C ₃ alkyl, benzyl, halo, haloC ₁ -C ₃ alkyl, hydroxy, hydroxyC ₁ -C ₃ alkyl, and oxo; or one of R ^c and R ^d is selected from 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; provided that when W ¹ is CR ² , then R ⁴ is not hydrogen or C ₁ -C ₃ alkyl (i.e., methyl, ethyl, or propyl).

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

[0006] In some aspects, W ¹ is N.

[0007] In some aspects, R ³ is halo.

[0008] In some aspects, R ⁴ is hydrogen. In some aspects, R ⁴ is C ₁ -C ₃ alkyl. In some aspects,

R ⁴ is hydroxyC ₁ -C ₃ alkyl. In some aspects, R ⁴ is haloC ₁ -C ₃ alkyl.

[0009] In some aspects, R ⁵ is -(Ci-C3alkyl)-R ⁶ . In some aspects, R ⁶ is a five- to tenmembered fully or partially saturated or fully unsaturated ring system containing one nitrogen atom and optionally containing a second heteroatom selected from nitrogen and oxygen wherein the ring system is optionally substituted with one, two, or three groups independently selected from Ci- Csalkoxy, C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl, C ₁ -C ₃ alkyl, benzyl, halo, haloC ₁ -C ₃ alkyl, hydroxy, hydroxyCi- C ₃ alkyl, and oxo.

[0010] In some aspects, wherein R ⁵ is selected from: wherein each ring is optionally substituted with one, two, or three groups independently selected from C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl, Ci-C3alkyl, benzyl, halo, haloC ₁ -C ₃ alkyl, hydroxy, hydroxyCi-C -alkyl, and oxo, and denotes the point of attachment to the parent molecular moiety. [0011] In some aspects, independently selected from C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl, halo, haloCi- C ₃ alkyl, haloC ₁ -C ₃ alkoxy, hydroxy, hydroxyC ₁ -C ₃ alkyl, benzyl, and oxo. In some aspects, R ⁵ is . In some aspects, z is 1 and R ⁵⁰ is halo, such as fluoro.

[0012]

[0013] In some aspects, R ⁵ is wherein q and r are each independently 0, 1, or 2; and R ^x and R ^y are independently selected from C ₁ -C ₃ alkoxy, Ci-Caalkyl, halo, haloC ₁ -C ₃ alkyl, and hydroxy.

[0014] wherein q, r, and d are each independently 0, 1, or 2; and R ^x , R ^y , and R ^p are independently selected from C ₁ -C ₃ alkoxy, Ci- C ₃ alkyl, halo, haloC ₁ -C ₃ alkyl, and hydroxy. In some aspects, R ⁵ is

[0015] In some aspects, wherein wherein q and r are each independently 0, 1, or 2; and R ^x and R ^y are independently selected from C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkyl, halo, haloC ₁ -C ₃ alkyl, and hydroxy. In some aspects

[0016] In some aspects, wherein q and r are each independently 0, 1, or 2; and R ^x and R ^y are independently selected from C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkyl, halo, haloC ₁ -C ₃ alkyl, and hydroxy. In some aspects

[0017] In some aspects, , wherein R ^c and R ^d , together with the nitrogen atom to which they are attached, form a five- to ten-membered ring monocyclic or bicyclic ring optionally containing one additional heteroatom selected from nitrogen, oxygen, and sulfur, wherein the ring is optionally substituted with one, two, or three groups independently selected from C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl, C ₁ -C ₃ alkyl, benzyl, halo, haloC ₁ -C ₃ alkyl, hydroxy, hydroxyC ₁ -C ₃ alkyl, and oxo; or one of R ^c and R ^d is selected from hydrogen and Ci- 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.

[0018] In some aspects, R ⁵ is wherein q is 0, 1, or 2; and R ^x is selected from C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl, C ₁ -C ₃ alkyl, benzyl, halo, haloCi- C ₃ alkyl, hydroxy, hydroxyC ₁ -C ₃ alkyl, and oxo. In some aspects, R ⁵ is

[0019] In some aspects, R ¹ is substituted, and wherein one of the substituents on R ¹ is haloC ₁ -C ₃ alkyl.

[0020] In some aspects, R ¹ is naphthyl, wherein the naphthyl is optionally substituted with one, two, or three groups independently selected from C ₁ -C ₃ alkyl, C2-C4alkynyl, Cscycloalkyl, halo, and hydroxy.

[0021] In some aspects, R ¹ is

[0022] In some aspects, R ¹ is [0023] In some aspects, W ¹ is CR ² ; R ² is hydrogen or chloro; R ³ is fluoro; R ¹ is selected the point of attachment to the parent molecular moiety.

[0024] In some aspects, W ¹ is N; R ³ is fluoro; R ¹ is selected from denotes the point of attachment to the parent molecular moiety. In some aspects, the compound of formula (I) is selected from the group consisting

[0026] In some aspects, the compound of formula (I) is selected from the group consisting of:

[0027] In an aspect, the compound of formula (I) is selected from the group consisting of: 4-(4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-2-[(l-meth yl-octahydro-lH-indol-3a- yl)methoxy]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluorona phthalen-2-ol isomer 1;

4-(4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-2-[(l-m ethyl-octahydro-lH-indol-3a- yl)methoxy]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluorona phthalen-2-ol isomer 2;

4-(4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-2-({l-m ethyl-l-azaspiro[4.4]nonan-6- yl}methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluorona phthalen-2-ol;

4-(2-{[(4aS,7aR)-l-methyl-octahydro-lH-cyclopenta[b]pyrid in-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- fluoronaphthal en-2-ol ;

4-(2-{[(2R,7aS)-2-fluoro-hexahydro-lH-pyrrolizin-7a-yl]me thoxy}-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)-l-methyl-octahydro-lH-cyclopenta[b]pyrid in-4a-yl]methoxy}-8-fluoro-4-[8- (2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]quinazoli n-7-yl)-5-ethynyl-6- fluoronaphthal en-2-ol ; 5-ethynyl-6-fluoro-4- { 8-fluoro-2-[(l - { [(3R)-3 -fluoropyrrolidin- 1 - yl]methyl }cyclopropyl)methoxy]-4-[8-(2 -hydroxy ethyl)-3,8-diazabicyclo[3.2.1 ]octan-3- yl] quinazolin-7 -yl } naphthal en-2-ol ;

4-(2-{[(2R,7aS)-2-fluoro-hexahydro-lH-pyrrolizin-7a-yl]me thoxy}-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)-l-methyl-octahydro-lH-cyclopenta[b]py ridin-4a-yl]methoxy}-7-[6-amino- 4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-8-fluoroq uinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octan-8-yl]ethan-l-ol;

4-(2-{[(6'R,7'aR)-6'-fluoro-hexahydrospiro[cyclopropane-l ,2'-pyrrolizine]-7'a-yl]methoxy}-4- {3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoropyrido[4,3-d]pyr imidin-7-yl)-5-ethynyl-6- fluoronaphthal en-2-ol ;

4-(2-{[(lR,6'R,7'aR)-3,3,6'-trifluoro-hexahydrospiro[cycl opropane-l,2'-pyrrolizine]-7'a- yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoropy rido[4,3-d]pyrimidin-7-yl)-5- ethynyl-6-fluoronaphthalen-2-ol; and

4-(2-{[(lS,6'R,7'aR)-3,3,6'-trifluoro-hexahydrospiro[cycl opropane-l,2'-pyrrolizine]-7'a- yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoropy rido[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 a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof

[0029] In some aspects, the present disclosure provides a compound selected from the group consisting of

4-(2-{[(6'R,7'aR)-6'-fluoro-hexahydrospiro[cyclopropane-l ,2'-pyrrolizine]-7'a- yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroqu inazolin-7-yl)-5-ethynyl-6- fluoronaphthalen-2-ol 2TFA;

4-(2-{[(lR,6'R,7'aR)-3,3,6'-trifluoro-hexahydrospiro[cycl opropane-l,2'-pyrrolizine]-7'a- yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroqu inazolin-7-yl)-5-ethynyl-6- fluoronaphthal en-2-ol ;

4-(2-{[(lS,6'R,7'aR)-3,3,6'-trifluoro-hexahydrospiro[cycl opropane-l,2'-pyrrolizine]-7'a- yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroqu inazolin-7-yl)-5-ethynyl-6- fluoronaphthalen-2-ol; and

4-(2-{[(lR,6'R,7'aR)-3,3,6'-trifluoro-hexahydrospiro[cycl opropane-l,2'-pyrrolizine]-7'a- yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoropy rido[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 prior aspects. In certain embodiments, the compound is a stable atropisomer as described herein.

[0031] In some aspects, the present disclosure provides a pharmaceutical composition 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 G12D activity in a 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 another aspect, the present disclosure provides a method of inhibiting cell proliferation, in vitro or in vivo, the method 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 susceptible 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 present disclosure provides a method for treating cancer expressing KRAS G12D mutation 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.

[0036] In another aspect, the present disclosure provides a method for treating cancer 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, 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 the inhibition of KRAS G12D. [0038] In another aspect, the present disclosure provides a use of a compound described herein, including a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the treatment of cancer.

[0039] In another aspect, the present disclosure provides the use of a compound described herein, including a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the inhibition of KRAS G12D activity.

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

DETAILED DESCRIPTION

[0041] Unless otherwise indicated, any atom with unsatisfied valences is assumed to have hydrogen atoms sufficient 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” is a logical disjunction (i.e., and/or) and does not indicate an exclusive disjunction unless expressly indicated such as with 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 the 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), a compound of formula (I) and one or more pharmaceutically acceptable salts of the compound of formula (I), and two or more pharmaceutically acceptable salts of a compound of formula (I).

[0045] The term “C2-C4alkenyl,” as used herein, refers to a group derived from a straight or branched chain hydrocarbon containing from two to four carbon atoms and one double bond.

[0046] The term “C ₁ -C ₃ alkoxy,” as used herein, refers to a C ₁ -C ₃ alkyl group attached to the parent molecular moiety through an oxygen atom.

[0047] The term “C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl,” as used herein, refers to a C ₁ -C ₃ alkoxy group attached to the parent molecular moiety through a Ci-C -alkyl group. [0048] The term “C ₁ -C ₃ alkoxycarbonyl,” as used herein, refers to a C ₁ -C ₃ alkoxy group attached to the parent molecular moiety through a carbonyl group.

[0049] The term “C ₁ -C ₃ alkyl,” as used herein, refers to a group derived from a straight or branched chain saturated hydrocarbon containing from one to three (i.e., 1, 2, or 3) carbon atoms.

[0050] The term “C ₁ -C ₆ alkyl,” as used herein, refers to a group derived from a straight or branched chain saturated hydrocarbon containing from one to six (i.e., 1, 2, 3, 4, 5, or 6) carbon atoms.

[0051] The term “C ₁ -C ₃ alkylcarbonyl,” as used herein, refers to a C ₁ -C ₃ alkyl group attached to the parent molecular moiety through a carbonyl group.

[0052] The term “C ₂ -C ₄ alkynyl,” as used herein, refers to a group derived from a straight or branched chain hydrocarbon containing from two to four carbon atoms and one triple bond.

[0053] The term “amino,” as used herein, refers to -NHz.

[0054] The term “aminoC ₁ -C ₃ alkyl,” as used herein, refers to an amino group attached to the parent molecular moiety through a C ₁ -C ₃ alkyl group.

[0055] The term “aryl,” as used herein, refers to a phenyl group, or a bicyclic fused ring system wherein one or both of the rings is a phenyl group. Bicyclic fused ring systems consist of a phenyl group fused to a four- to six-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] The term “cyano,” as used herein, refers to -CN.

[0057] The term “C ₃ -C ₄ cycloalkyl,” as used herein, refers to a saturated monocyclic hydrocarbon ring system having three or four carbon atoms and zero heteroatoms.

[0058] The terms “halo” and “halogen,” as used herein, refer to F, Cl, Br, and I.

[0059] The term “haloC ₁ -C ₃ alkyl,” as used herein, refers to a C ₁ -C ₃ alkyl group substituted with one, two, or three halogen atoms.

[0060] The term “heteroaryl,” as used herein, refers to an aromatic five- or six-membered ring where at least one atom is selected from N, O, and S, and the remaining atoms are carbon. The term “heteroaryl” also includes bicyclic systems where a heteroaryl ring is fused to a four- to six-membered aromatic or non-aromatic ring containing zero, one, or two additional heteroatoms selected from N, O, and S; and tricyclic systems where a bicyclic system is fused to a four- to sixmembered aromatic or non-aromatic ring containing zero, one, or two additional heteroatoms selected from N, O, and S. The heteroaryl groups are 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[l,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] A ring system can also be partially saturated, in which at least one ring in the moiety contains one or two double bonds without providing an aromatic group. Suitable alicyclic moieties include, e g., cyclopropene, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, and cylcohexadiene. Partially saturated heterocycle groups include, e.g., 2,3-dihdyroazetyl, 6H-1,2,5- thiadiazenyl, 2H,6H-l,5,2-dithaizinyl, 3,4,5,6-tetrahydro-2H-azepinyl, IH-azepinyl, tetrahydropyridinyl, 1 ,2-dihydroazinyl, 1,4-dihydroazinyl, 2,3,4,5-tetrahydroazinyl, 2,3- dihydrooxolyl, 5H- 1,2, 3 -oxathiazolyl, and 4H-oxinyl.

[0062] The term “hydroxy,” as used herein, refers to -OH.

[0063] The terms “hydroxyC ₁ -C ₃ alkyl” and “hydroxyC ₁ -C ₆ alkyl,” as used herein, refers to a hydroxy group attached to the parent molecular moiety through either a C ₁ -C ₃ alkyl or C ₁ -C ₆ alkyl group, respectively.

[0064] The term “oxo,” as used herein, refers to =0.

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

[0066] Certain compounds of the present disclosure exist as stereoisomers. It should be understood that when stereochemistry is not specified, the present disclosure encompasses all stereochemical isomeric forms, or mixtures thereof, which possess the ability inhibit KRAS G12D. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, or direct separation of enantiomers on chiral chromatographic columns. Starting compounds of particular stereochemistry are either commercially available or can be made 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 where a proton of a molecule shifts to a different atom within that molecule. The term “tautomer” also refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomer to another. All tautomers of the compounds described herein are included within the present disclosure.

[0068] Certain compounds of the present disclosure exist as atropisomers. The term “atropisomers” refers to conformational stereoisomers which occur when rotation about a single bond in the molecule is prevented, or greatly slowed, as a result of steric interactions with other parts of the molecule and the substituents at both ends of the single bond are asymmetrical (i.e., optical activity arises without requiring an asymmetric carbon center or stereocenter). Where the rotational barrier about the single bond is high enough, and interconversion between conformations is slow enough, separation and isolation of the isomeric species may be permitted. Atropisomers are enantiomers (or epimers) without a single asymmetric atom.

[0069] The atropisomers can be considered stable if the barrier to interconversion is high enough to permit the atropisomers to undergo little or no interconversion at room temperature for at least a week. In some aspects the atropisomers undergo little or no interconversion at room temperature for at least a year. In some aspects, an atropisomeric compound of the disclosure does not undergo more than about 5% interconversion to its opposite atropisomer at room temperature during one week when the atropisomeric compound is in substantially pure form, which is generally a solid state. In some aspects, an atropisomeric compound of the disclosure does not undergo more than about 5% interconversion to its opposite atropisomer at room temperature (approximately 25 °C) during one year. In some aspects, the atropisomeric compounds of the disclosure are stable enough to undergo no more than about 5% interconversion in an aqueous pharmaceutical formulation held at 0 °C for at least one week. The present chemical entities, pharmaceutical compositions and methods are meant 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 may be determined by the steric hindrance to free rotation of one or more bonds forming a chiral axis. Certain biaryl compounds exhibit atropisomerism where rotation around an interannular bond lacking C2 symmetry is restricted. The free energy barrier for isomerization (enantiomerization) is a measure of the stability of the interannular bond with respect to rotation. Optical and thermal excitation can promote racemization of such isomers, dependent on electronic and steric factors.

[0071] Ortho-substituted biaryl compounds may exhibit this type of conformational, rotational isomerism. Such biaryls are enantiomeric, chiral atropisomers where the sp ² -sp ² carboncarbon, interannular bond between the aryl rings has a sufficiently high energy barrier to prevent free rotation, and where substituents W ¹ # W ² and W ³ W ⁴ render the molecule asymmetric.

[0072] The steric interaction between W ^X :W ³ , W ^X :W ⁴ , and/or W ² :W ⁴ , W ² :W ³ is large enough to make the planar conformation an energy maximum. Two non-planar, axially chiral enantiomers then exist as atropisomers when their interconversion is slow enough such that they can be isolated free of each other. Bold lines and dashed lines in the figures shown above indicate those moieties, or portions of the molecule, which are sterically restricted due to a rotational energy barrier. Balded moieties exist orthogonally above the plane of the page, and dashed moieties exist orthogonally below the plane of the page. The 'flat' part of the molecule (the left ring in each of the two depicted biaryls) is in the plane of the page.

[0073] The pharmaceutical compositions of the disclosure can 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 e.g., Berge, S.M. et al., J. Pharm. Sci., 66:1-19 (1977)). The salts can be obtained during the final isolation and purification of the compounds described herein, or separately be reacting a free base function 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 nontoxic inorganic acids, such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous and the like, as well as from nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like. Base addition salts include those derived from alkaline earth metals, such as sodium, potassium, magnesium, calcium and the like, as well as from nontoxic organic amines, such as N,N'-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine and the like.

Compounds

[0074] In a first aspect, the present disclosure provides a compound of formula (I): or a pharmaceutically acceptable salt thereof; wherein:

W ¹ is CR ² orN;

R ¹ is aryl or heteroaryl, wherein the aryl and the heteroaryl are optionally substituted with one, two, three, four, or five substituents independently selected from C ₁ -C ₃ alkyl, C2-C4alkenyl, C2-C4alkynyl, amino, aminoC ₁ -C ₃ alkyl, C ₃ -C ₄ cycloalkyl, halo, haloC ₁ -C ₃ alkyl, hydroxy, and hydroxyC ₁ -C ₃ 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, hydroxyC ₁ -C ₆ alkyl, or haloC ₁ -C ₆ alkyl; and

R ⁵ is -(Ci-C3alkyl)-R ⁶ or -(C ₁ -C ₆ alkyl)NR ^c R ^d , wherein R ⁶ is selected from: a C ₃ -C ₆ cycloalkyl optionally substituted with NR ^c R ^d (Ci-C3alkyl)-; and a five- to ten-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 zero to three double bonds and wherein the ring is optionally substituted with one, two, or three groups independently selected from Ci- Csalkoxy, C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl, C ₁ -C ₃ alkyl, benzyl, halo, haloC ₁ -C ₃ alkyl, hydroxy, hydroxyCi- C ₃ alkyl, and oxo; wherein

R ^c and R ^d , together with the nitrogen atom to which they are attached, form a fi veto ten-membered ring monocyclic or bicyclic ring optionally containing one additional heteroatom selected from nitrogen, oxygen, and sulfur, wherein the ring is optionally substituted with one, two, or three groups independently selected from C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl, C ₁ -C ₃ alkyl, benzyl, halo, haloC ₁ -C ₃ alkyl, hydroxy, hydroxyC ₁ -C ₃ alkyl, and oxo; or one of R ^c and R ^d is selected from 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; provided that when W ¹ is CR ² , then R ⁴ is not hydrogen or C ₁ -C ₃ alkyl (i.e., methyl, ethyl, or propyl).

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

[0076] In some aspects, W ¹ is N.

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

[0078] In some aspects, R ⁴ is hydrogen. In some aspects, R ⁴ is C ₁ -C ₃ alkyl (e.g., methyl). In some aspects, R ⁴ is hydroxyC ₁ -C ₃ alkyl (e.g., hydroxyethyl). In some aspects, R ⁴ is haloCi- C ₃ alkyl (e.g., trifluoroalkyl).

[0079] In some aspects, R ⁵ is -(Ci-C3alkyl)-R ⁶ . In some aspects, R ⁶ is a five- to tenmembered fully or partially saturated or fully unsaturated ring system that is monocyclic or bicyclic and contains one nitrogen atom and optionally containing a second heteroatom selected from nitrogen and oxygen. For example, R ⁶ can be pyrrolidinyl, morpholinyl, pyrrolyl, pyrazolyl, 2- methylenepyrrolidinyl, cyclopenta[b]pyridinyl, cyclopenta[b]pyrrolyl, octahydropental enyl, or 1- azaspiro[4.4]nonane. The ring system is optionally substituted with one, two, or three groups independently selected from C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl, C ₁ -C ₃ alkyl, benzyl, halo, haloC ₁ -C ₃ alkyl, hydroxy, hydroxyC ₁ -C ₃ alkyl, and oxo.

[0080] In some aspects, wherein R ⁵ is selected from:

with one, two, or three groups independently selected from C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl, C ₁ -C ₃ alkyl, benzyl, halo, haloC ₁ -C ₃ alkyl, hydroxy, hydroxyC ₁ -C ₃ alkyl, and oxo, and denotes the point of attachment to the parent molecular moiety. In some aspect, the ring is substituted with halo (e.g., fluoro).

[0081] In some aspects, independently selected from C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl, halo, haloCi- C ₃ alkyl, haloCi-Cralkoxy, hydroxy, hydroxyCi-Caalkyl, benzyl, and oxo. In some aspects, R ⁵ is halo, such as fluoro. wherein q and r are each independently 0, 1, or 2; and R ^x and R ^y are independently selected from C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkyl, halo, haloC ₁ -C ₃ alkyl, and hydroxy. [0084] wherein q, r, and d are each independently 0, 1, or 2; and R ^x , R ^y , and R ^p are independently selected from C ₁ -C ₃ alkoxy, Ci- C ₃ alkyl, halo, haloC ₁ -C ₃ alkyl, and hydroxy. In some aspects, R ⁵ is

[0085] In some aspects, wherein wherein q and r are each independently 0, 1, or 2; and R ^x and R ^y are independently selected from C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkyl, halo, haloC ₁ -C ₃ alkyl, and hydroxy. In some aspects,

[0086] In some aspects, R ⁵ is wherein q and r are each independently 0, 1, or 2; and R ^x and R ^y are independently selected from C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkyl, halo, haloC ₁ -C ₃ alkyl, and hydroxy. In some aspects, R ⁵ is

[0087] In some aspects, R ⁵ is wherein R ^c and R ^d , together with the nitrogen atom to which they are attached, form a five- to ten-membered ring monocyclic or bicyclic ring optionally containing one additional heteroatom selected from nitrogen, oxygen, and sulfur, wherein the ring is optionally substituted with one, two, or three groups independently selected from C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl, C ₁ -C ₃ alkyl, benzyl, halo, haloCi-Cialkyl, hydroxy, hydroxyC ₁ -C ₃ alkyl, and oxo; or one of R ^c and R ^d is selected from hydrogen and Ci-Cialkyl and the other is selected from hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxycarbonyl, and Ci-Cialkylcarbonyl. For example, R ^c and R ^d , together with the nitrogen atom to which they are attached, can form pyrrolidinyl, morpholinyl, pyrrolyl, pyrazolyl, 2-methylenepyrrolidinyl, cyclopenta[b]pyridinyl, cyclopenta[b]pyrrolyl, octahydropental enyl, or l-azaspiro[4.4]nonane.

[0088] In some aspects, R ⁵ is wherein q is 0, 1, or 2; and R ^x is selected from C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl, C ₁ -C ₃ alkyl, benzyl, halo, haloCi- C ₃ alkyl, hydroxy, hydroxyC ₁ -C ₃ alkyl, and oxo. In some aspects, R ⁵ is

[0089] In some aspects, R ¹ is substituted, and wherein one of the substituents on R ¹ is haloC ₁ -C ₃ alkyl.

[0090] In some aspects, R ¹ is naphthyl, wherein the naphthyl is optionally substituted with one, two, or three groups independently selected from C ₁ -C ₃ alkyl, C2-C4alkynyl, C3cycloalkyl, halo, and hydroxy.

[0091] In some aspects, R ¹ is

[0092] In some aspects, R ¹ is ₃

[0093] In some aspects, W ¹ is CR ² ; R ² is hydrogen or chloro; R ³ is fluoro; R ¹ is selected from denotes the point of attachment to the parent molecular moiety.

[0094] In some aspects, W ¹ is N; R ³ is fluoro; R ¹ is selected from

; and denotes the point of attachment to the parent molecular moiety.

[0095] In some aspects, the present disclosure provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein W ¹ is CR ² and R ⁴ is hydroxyC ₁ -C ₆ alkyl, or haloC ₁ -C ₆ alkyl.

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

[0097] In some aspects, the compound of formula (I) is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof

[0098] In some aspects, the compound of formula (I) is selected from the group consisting

4-(4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-2-[(l-m ethyl-octahydro-lH-indol-3a- yl)methoxy]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluorona phthalen-2-ol isomer 1; 4-(4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-2-[(l-meth yl-octahydro-lH-indol-3a- yl)methoxy]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluorona phthalen-2-ol isomer 2;

4-(4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-2-({l-m ethyl-l-azaspiro[4.4]nonan-6- yl}methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluorona phthalen-2-ol;

4-(2-{[(4aS,7aR)-l-methyl-octahydro-lH-cyclopenta[b]pyrid in-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- fluoronaphthal en-2-ol ;

4-(2-{[(2R,7aS)-2-fluoro-hexahydro-lH-pyrrolizin-7a-yl]me thoxy}-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)-l-methyl-octahydro-lH-cyclopenta[b]pyrid in-4a-yl]methoxy}-8-fluoro-4-[8- (2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]quinazoli n-7-yl)-5-ethynyl-6- fluoronaphthal en-2-ol ;

5-ethynyl-6-fluoro-4- { 8-fluoro-2-[(l - { [(3R)-3 -fluoropyrrolidin- 1 - yl]methyl }cyclopropyl)methoxy]-4-[8-(2 -hydroxy ethyl)-3,8-diazabicyclo[3.2. l]octan-3- yl] quinazolin-7 -yl } naphthal en-2-ol ;

4-(2-{[(2R,7aS)-2-fluoro-hexahydro-lH-pyrrolizin-7a-yl]me thoxy}-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)-l-methyl-octahydro-lH-cyclopenta[b]py ridin-4a-yl]methoxy}-7-[6-amino- 4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-8-fluoroq uinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octan-8-yl]ethan-l-ol;

4-(2-{[(6'R,7'aR)-6'-fluoro-hexahydrospiro[cyclopropane-l ,2'-pyrrolizine]-7'a-yl]methoxy}-4- {3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoropyrido[4,3-d]pyr imidin-7-yl)-5-ethynyl-6- fluoronaphthal en-2-ol ;

4-(2-{[(lR,6'R,7'aR)-3,3,6'-trifluoro-hexahydrospiro[cycl opropane-l,2'-pyrrolizine]-7'a- yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoropy rido[4,3-d]pyrimidin-7-yl)-5- ethynyl-6-fluoronaphthalen-2-ol; and

4-(2-{[(lS,6'R,7'aR)-3,3,6'-trifluoro-hexahydrospiro[cycl opropane-l,2'-pyrrolizine]-7'a- yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoropy rido[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 a compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

[0101] In an aspect, the present disclosure provides a compound selected from the group consisting of

4-(2-{[(6'R,7'aR)-6'-fluoro-hexahydrospiro[cyclopropane-l ,2'-pyrrolizine]-7'a- yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroqu inazolin-7-yl)-5-ethynyl-6- fluoronaphthalen-2-ol 2TFA;

4-(2-{[(lR,6'R,7'aR)-3,3,6'-trifluoro-hexahydrospiro[cycl opropane-l,2 ^, -pyrrolizine]-7'a- yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroqu inazolin-7-yl)-5-ethynyl-6- fluoronaphthal en-2-ol ;

4-(2-{[(lS,6'R,7'aR)-3,3,6'-trifluoro-hexahydrospiro[cycl opropane-l,2'-pyrrolizine]-7'a- yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroqu inazolin-7-yl)-5-ethynyl-6- fluoronaphthalen-2-ol; and

4-(2-{[(lR,6'R,7'aR)-3,3,6'-trifluoro-hexahydrospiro[cycl opropane-l,2'-pyrrolizine]-7'a- yl]methoxy}-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoropy rido[4,3-d]pyrimidin-7-yl)-5- ethynyl-6-fluoronaphthalen-2-ol, or a pharmaceutically acceptable salt thereof. Pharmaceutical Compositions

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

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

[0104] The pharmaceutical compositions of the present disclosure can be administered via one or more routes of administration using one or more of a variety of methods known in the art. As will be appreciated by the skilled artisan, the route and/or mode of administration will vary depending upon the desired results. In some aspects, the routes of administration for compounds of the disclosure include intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal or other parenteral routes of administration, for example by injection or infusion. The phrase “parenteral administration” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, 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 solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by sterilization microfiltration. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, some methods of preparation are vacuum drying and freeze-drying (lyophilization) that yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. [0106] Examples of suitable aqueous and non-aqueous carriers that can be employed in the pharmaceutical compositions of the disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), 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 solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the pharmaceutical compositions of the disclosure is contemplated. Supplementary active compounds can also be incorporated into the compositions.

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

[0109] Alternatively, the compounds of the disclosure can be administered via a non- parenteral route, such as a topical, epidermal or mucosal route of administration, for example, intranasally, orally, vaginally, rectally, sublingually or topically.

[0110] Any pharmaceutical composition contemplated herein can, for example, be delivered orally via any acceptable and suitable oral preparation. Exemplary oral preparations include, but are not limited to, for example, 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 methods known in the art for manufacturing pharmaceutical compositions intended for oral administration. In order to provide pharmaceutically palatable preparations, a pharmaceutical composition in accordance with the disclosure can contain at least one agent selected from sweetening agents, flavoring agents, coloring agents, demulcents, antioxidants, and preserving agents.

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

[0112] An aqueous suspension can be prepared, for example, by admixing at least one compound described herein, including at leat one compound of formula (I), and/or at least one pharmaceutically acceptable salt thereof with at least one excipient suitable for the manufacture of an aqueous suspension, including, but are not limited to, for example, suspending agents, such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, alginic acid, polyvinyl-pyrrolidone, gum tragacanth, and gum acacia; dispersing or wetting agents, such as, for example, a naturally-occurring phosphatide, e.g., lecithin; condensation products of alkylene oxide with fatty acids, such as, for example, polyoxyethylene stearate; condensation products of ethylene oxide with long chain aliphatic alcohols, such as, for example, heptadecathylene-oxycetanol; condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as, for example, polyoxyethylene sorbitol monooleate; and condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as, for example, polyethylene sorbitan monooleate. An aqueous suspension can also contain at least one preservative, such as, for example, ethyl and n-propyl p-hydroxybenzoate; at least one coloring agent; at least one flavoring agent; and/or at least one sweetening agent, including but not limited to, for example, sucrose, saccharin, and aspartame.

[0113] Oily suspensions can, for example, be prepared by suspending at least one compound described herein, including at least one compound described herein, including at leat one compound of formula (I), and/or at least one pharmaceutically acceptable salt thereof in either a vegetable oil, such as, for example, arachis oil, sesame oil, and coconut oil; or in mineral oil, such as, for example, liquid paraffin. An oily suspension can also contain at least one thickening agent, such as, for example, beeswax, hard paraffin, and cetyl alcohol. In order to provide a palatable oily suspension, at least one of the sweetening agents already described herein above, and/or at least one flavoring agent can be added to the oily suspension. An oily suspension can further contain at least one preservative, including, but not limited to, for example, an anti-oxidant, such as, for example, butylated hydroxyanisol, and alpha-tocopherol. [0114] Dispersible powders and granules can, for example, be prepared by admixing at least one compound described herein, including at least one compound of formula (I), and/or at least one pharmaceutically acceptable salt thereof with at least one dispersing and/or wetting agent, at least one suspending agent, and/or at least one preservative. Suitable dispersing agents, wetting agents, and suspending agents are already described above. Exemplary preservatives include, but are not limited to, for example, anti-oxidants, e.g., ascorbic acid. In addition, dispersible powders and granules can also contain at least one excipient, including, but not limited to, for example, sweetening agents, flavoring agents, and coloring agents.

[0115] The active compounds can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are patented or generally known to those skilled in the art. See, e.g., Robinson, J.R., ed., Sustained and Controlled Release Drug Delivery Systems, Marcel Dekker, Inc., New York (1978).

[0116] Therapeutic compositions can be administered with medical devices known in the art. For example, in one aspect, a therapeutic composition of the disclosure can be administered with a needleless hypodermic injection device, such as the devices disclosed in U.S. Patent Nos. 5,399,163, 5,383,851, 5,312,335, 5,064,413, 4,941,880, 4,790,824, or 4,596,556. Examples of well-known implants and modules useful in the present disclosure include: U.S. Patent No. 4,487,603, which discloses an implantable micro-infusion pump for dispensing medication at a controlled rate; U.S. Patent No. 4,486,194, which discloses a therapeutic device for administering medication through the skin; U.S. Patent No. 4,447,233, which discloses a medication infusion pump for delivering medication at a precise infusion rate; U.S. Patent No. 4,447,224, which discloses a variable flow implantable infusion apparatus for continuous drug delivery; U.S. Patent No. 4,439,196, which discloses an osmotic drug delivery system having multi-chamber compartments; and U.S. Patent 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 aspects, the compounds of the present disclosure can be administered parenterally, i.e., by injection, including, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and/or infusion.

[0118] In some aspects, the compounds of the present disclosure can be administered orally, i.e, via a gelatin capsule, tablet, hard or soft capsule, or a liquid capsule.

Use of KRAS Inhibitors/Methods of Treating

[0119] Administration of a therapeutic agent described herein includes, without limitation, administration of a therapeutically effective amount of therapeutic agent. The term “therapeutically effective amount” as used herein refers, without limitation, to an amount of a therapeutic agent to treat a condition treatable by administration of a composition comprising the KRAS inhibitors described herein. That amount is the amount sufficient to exhibit a detectable therapeutic or ameliorative effect. The effect can include, for example and without limitation, treatment of the conditions listed herein. The precise effective amount for a subject will depend upon the subject's size and health, the nature and extent of the condition being treated, recommendations of the treating physician, and therapeutics or combination of therapeutics 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. An exemplary treatment regime entails administration once per day, bi-weekly, tri-weekly, weekly, once every two weeks, once every three weeks, once every four weeks, once a month, once every 3 months, or once every 3 to 6 months.

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

[0122] Ras mutations including but not limited to KRAS mutations have also been identified in hematological malignancies (e.g., cancers that affect blood, bone marrow and/or lymph nodes). Accordingly, certain aspects are directed to administration of a disclosed compounds (e g., in the form of a pharmaceutical composition) to a patient in need of treatment of a hematological malignancy. Such malignancies include, but are not limited to leukemias and lymphomas. For example, the presently disclosed compounds can be used for treatment of diseases such as Acute lymphoblastic leukemia (ALL), Acute myelogenous leukemia (AML), Chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Chronic myelogenous leukemia (CML), Acute monocytic leukemia (AMoL) and/ or other leukemias. In other aspects, the compounds are useful for treatment of lymphomas such as all subtypes of Hodgkins lymphoma or non-Hodgkins lymphoma.

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

[0124] Methods for detecting a KRAS mutation are known by those of skill in the art. These methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) assays, real-time PCR assays, PCR sequencing, mutant allele-specific PCR amplification (MASA) assays, direct sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high resolution melting assays and microarray analyses. In some aspects, samples are evaluated for KRAS mutations including by real-time PCR. In real-time PCR, fluorescent probes specific for the KRAS mutation are used. When a mutation is present, the probe binds and fluorescence is detected. In some aspects, the KRAS mutation is identified using a direct sequencing method of specific regions (e.g., exon 2 and/or exon 3) in the KRAS gene, for example. This technique will identify all possible mutations in the region sequenced.

[0125] Methods for detecting a mutation in a KRAS protein are known by those of skill in the art. These methods include, but are not limited to, detection of a KRAS mutant using a binding agent (e.g., an antibody) specific for the mutant protein, protein electrophoresis and Western blotting, and direct peptide sequencing.

[0126] Methods for determining whether a tumor or cancer comprises a KRAS mutation can use a variety of samples. In some aspects, the sample is taken from a subject having a tumor or cancer. In some aspects, the sample is taken from a subject having a cancer or tumor. In some aspects, the sample is a fresh tumor/cancer sample. In some aspects, the sample is a frozen tumor/cancer sample. In some aspects, the sample is a formalin-fixed paraffin-embedded sample. In some aspects, the sample is processed to a cell lysate. In some aspects, the sample is processed to DNA or RNA. he disclosure also relates to a method of treating a hyperproliferative disorder in a mammal that comprises administering to said 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 aspects, said method relates to the treatmentof cancer such as acute myeloid leukemia, cancer in adolescents, adrenocortical carcinoma childhood, AIDS- related cancers (e.g. Lymphoma and Kaposi's Sarcoma), anal cancer, appendix cancer, astrocytomas, atypical teratoid, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumors, burkitt lymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germ cell tumor, primary lymphoma, cervical cancer, childhood cancers, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myleoproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gall bladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, isletcell tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary, midline tract carcinoma, mouth cancer, multiple endocrine neoplasia syndromes, multiple myeloma/plasma cell neoplasm, mycosis fungoides, myelodysplastic syndromes, myelodysplastic/myeloproliferative neoplasms, multiple myeloma, merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach (gastric) cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-Cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, trophoblastic tumor, unusual cancers of childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or Viral-Induced cancer. In some aspects, said method relates to the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e. g., benign prostatic hypertrophy (BPH)). [0127] In certain aspects, the disclosure relates to methods for treatment of lung cancers, the methods comprise administering an effective amount of any of the above described compound (or a pharmaceutical composition comprising the same) to a subject in need thereof. In certain aspects the lung cancer is a non-small cell lung carcinoma (NSCLC), for example adenocarcinoma, squamous-cell lung carcinoma or large-cell lung carcinoma. In other aspects, the lung cancer is a small cell lung carcinoma. Other lung cancers treatable with the disclosed compounds include, but are not limited to, glandular tumors, carcinoid tumors and undifferentiated carcinomas. Subjects that can be treated with compounds of the disclosure, or pharmaceutically acceptable salt, ester, prodrug, solvate, tautomer, hydrate or derivative of said compounds, according to the methods of this disclosure include, for example, subjects that have been diagnosed as having acute myeloid leukemia, acute myeloid leukemia, cancer in adolescents, adrenocortical carcinoma childhood, AIDS-related cancers (e.g. Lymphoma and Kaposi's Sarcoma), anal cancer, appendix cancer, astrocytomas, atypical teratoid, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumors, burkitt lymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germcell tumor, primary lymphoma, cervical cancer, childhood cancers, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myleoproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gall bladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary, midline tract carcinoma, mouth cancer, multiple endocrine neoplasia syndromes, multiple myeloma/plasma cell neoplasm, mycosis fungoides, myelodysplastic syndromes, myelodysplastic/myeloproliferative neoplasms, multiple myeloma, merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasalcavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach (gastric) cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-Cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, trophoblastic tumor, unusual cancers of childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or Viral- Induced cancer. In some aspects subjects that are treated with the compounds of the disclosure include subjects that have been diagnosed as having a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e. g., psoriasis), restenosis, or prostate (e. g., benign prostatic hypertrophy (BPH)). The disclosure further provides methods of modulating a mutant KRAS protein activity by contacting the protein with an effective amount of a compound of the disclosure. Modulation can be inhibiting or activating protein activity. In some aspects, the disclosure provides methods of inhibiting protein activity by contacting the mutant KRAS protein with an effective amount of a compound of the disclosure in solution. In some aspects, the disclosure provides methods of inhibiting the mutant KRAS protein activity by contacting a cell, tissue, organ that express the protein of interest. In some aspects, the disclosure provides methods of inhibiting protein activity in a subject including but not limited to rodents and mammal (e g., human) by administering into the subject an effective amount of a compound of the disclosure. In some aspects, the percentage modulation exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some aspects, the percentage of inhibiting exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some aspects, the disclosure provides methods of inhibiting KRAS activity in a cell by contacting said cell with an amount of a compound of the disclosure sufficient to inhibit the activity of a KRAS mutant in said cell. In some aspects, the disclosure provides methods of inhibiting mutant KRAS in a tissue by contacting said tissue with an amount of a compound of the disclosure sufficient to inhibit the activity of mutant KRAS in said tissue. In some aspects, the disclosure provides methods of inhibiting KRAS in an organism by contacting said organism with an amount of a compound of the disclosure sufficient to inhibit the activity of KRAS in said organism. In some aspects, the disclosure provides methods of inhibiting KRAS activity in an animal by contacting said animal with an amount of a compound of the disclosure sufficient to inhibit the activity of KRAS in said animal. In some aspects, the disclosure provides methods of inhibiting KRAS including in a mammal by contacting said mammal with an amount of a compound of the disclosure sufficient to inhibit the activity of KRAS in said mammal. In some aspects, the disclosure provides methods of inhibiting KRAS activity in a human by contacting said human with an amount of a compond of the disclosure sufficient to inhibit the activity of KRAS in said human. The present disclosure provides methods of treating a disease mediated by KRAS activity in a subject in need of such treatment, he present disclosure also provides methods for combination therapies in which an agent known to modulate other pathways, or other components of the same pathway, or even overlapping sets of target enzymes are used in combination with a compound of the present disclosure, or a pharmaceutically acceptable salt, ester, prodrug, solvate, tautomer, hydrate or derivative thereof. In one aspect, such therapy includes but is not limited to the combination of one or more compounds of the disclosure with chemotherapeutic agents, therapeutic antibodies, and radiation treatment.

[0128] Many chemotherapeutics are presently known in the art and can be used in combination with the compounds of the disclosure. In some aspects, the chemotherapeutic is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and antiandrogens. In some aspects, the chemotherapeutic agent is an immunooncology (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. Hence, in some aspects the one or more compounds of the disclosure will be co-administered with other agents as described above. When used in combination therapy, the compounds described herein are administered with the second agent simultaneously or separately. This administration in combination can include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, a compound described herein and any of the agents described above can be formulated together in the same dosage form and administered simultaneously. Alternatively, a compound of the disclosure and any of the agents described above can be simultaneously administered, wherein both the agents are present in separate formulations. In another alternative, a compound of the present disclosure can be administered just followed by and any of the agents described above, or vice versa. In some aspects of the separate administration protocol, a compound of the disclosure and any of the agents described above are administered a few minutes apart, or a few hours apart, or a few days apart. [0130] The compounds can be made by methods known in the art including those described below and including variations within the skill of 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 (e.g. numbered “R” substituents) used to describe the synthesis of the compounds are intended only to illustrate how to make the compounds and are not to be confused with variables used in the claims or in other sections of the specification. The following methods are for illustrative purposes and are not intended to limit the scope of the disclosure.

Synthesis

General Schemes

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

Scheme 1 [0132] Method 1: In Step 1, known compound A is reacted with an amine in a suitable solvent, such as tetrahydrofuran (THF), with a base, such as diisopropylethylamine, to provide compound B. In Step 2, treatment of compound B with potassium fluoride in a solvent, such as dimethylacetamide, provides compound C. In Step 3, compound C is coupled with an arylboronic 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, treatment of compound C with an alcohol (ROH) in the presence of base provides compound F. In Step 6, compound F is coupled with an arylboronic acid or ester under Suzuki conditions to provide compound E. Protecting groups, such as tertbutyl oxy carbonyl (Boc), p-methoxybenzyl (PMB), methoxymethyl (MOM), etc. can be introduced and removed as required by one skilled in the art and as described in the examples.

Functionalization and elaboration of the 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 below in Scheme 2.

Scheme 2

[0135] In Step 1, known compound A is reacted with an amine in a suitable solvent, such as THF, 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 arylboronic 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 one skilled in the art and as described in the examples. Functionalization and elaboration of the aryl, NRR', and OR groups to prepare compounds of general structure E are described in the examples.

EXAMPLES

[0136] The 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 the Examples, one skilled in the art can ascertain the essential characteristics of the invention, and without departing from the spirit and scope thereof, can make various changes and modifications to adapt the invention to various uses and conditions. As a result, the 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 example section below and elsewhere herein:

[0138] The following chemical scheme illustrates a synthesis of 4-(2-{[(2R,7aS)-2-fluoro- hexahydro- lH-pyrrolizin-7a-yl]methoxy }-8-fluoro-4-[8-(2 -hydroxy ethyl)-3, 8- diazabicyclo[3 2.1]octan-3-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen -2-ol (Example 1-1).

[0139] Preparation of Intermediate 2: tert-butyl 3-(7-bromo-2-chloro-8-fluoroquinazolin-

4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Boc [0140] 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 was added DIPEA (26.6 mL, 152 mmol) 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 h. 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) (120 g silica gel column, using 50 to 80% EtOAc/pet ether) to afford 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] Preparation of Intermediate 3: tert-butyl 3-(2-{[(2R,7aS)-2-fluoro-hexahydro- lH-pyrrolizin-7a-yl]methoxy}-7-bromo-8-fluoroquinazolin-4-yl )-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate

[0142] 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 was added NaH (0.194 g, 4.85 mmol, 60% w/w) and the reaction mixture was stirred for 1 h. To this mixture was added 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) portion wise (4 portions) at 0 °C. The reaction mixture was allowed to warm to room temperature and was stirred for 16 h. The reaction mixture was quenched with ice cold water and extracted with EtOAc (250 mL X 2). The organic layers were washed with brine, dried over NazSOi, 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 pet. ether) to afford tert-butyl 3- (2- { [(2R, 7aS)-2-fluoro-hexahydro- 1 H-pyrrolizin-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) ⁺ .

[0143] Preparation of Intermediate 4: 2-{[(2R,7aS)-2-fluoro-hexahydro-lH-pyrrolizin-7a- yl]methoxy}-7-bromo-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8- fluoroquinazoline

[0144] To a solution of tert-butyl 3-(2-{[(2R,7aS)-2-fluoro-hexahydro-lH-pyrrolizin-7a- yl]methoxy}-7-bromo-8-fluoroquinazolin-4-yl)-3,8-diazabicycl o[3.2.1]octane-8-carboxylate (600 mg, 1.01 mmol) in acetonitrile (7 mL), was added 4M HC1 in dioxane (0.2 mL, 0.84 mmol) at 0 °C and the mixture was stirred for Ih. The reaction mixture was diluted with DCM, neutralized with excess TEA, and washed with aqueous NaHCOi solution. The organic layer was washed with water, dried over NarSOr, filtered, and concentrated under reduced pressure to provide 2- {[(2R,7aS)-2-fluoro-hexahydro-lH-pyrrolizin-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 taken for the next step without further purification. MS(ESI) m/z: 496.1 (M+2) ⁺ .

[0145] Preparation of Intermediate 5: 2-[3-(2-{[(2R,7aS)-2-fluoro-hexahydro-lH- pyrrolizin-7a-yl]methoxy}-7-bromo-8-fluoroquinazolin-4-yl)-3 ,8-diazabicyclo[3.2.1]octan-8- yl]ethan-l-ol

5. [0146] To a stirred solution of 2-{[(2R,7aS)-2-fluoro-hexahydro-lH-pyrrolizin-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-l-ol (121 mg, 0.971 mmol) and potassium carbonate (224 mg, 1.618 mmol) at room temperature and then the mixture was heated at 60 °C for 16 h. The reaction mixture was cooled to room temperature, 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 the crude residue which was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (24 g column, 80 - 100% EtOAc in pet.ether followed by 10% MeOH in DCM) to afford 2-[3-(2-{[(2R,7aS)-2-fluoro-hexahydro-lH-pyrrolizin-7a-yl]me thoxy}-7-bromo-8- fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]eth an-l-ol (400 mg, 0.743 mmol, 92% yield). MS(ESI) m/z: 540.3 (M+2) ⁺ .

[0147] Preparation of Intermediate 6: 2-[3-(2-{[(2R,7aS)-2-fluoro-hexahydro-lH- pyrrolizin-7a-yl]methoxy}-8-fluoro-7-[7-fluoro-3-(methoxymet hoxy)-8-{2-[tris(propan-2- yl)silyl]ethynyl}naphthalen-l-yl]quinazolin-4-yl)-3,8-diazab icyclo[3.2.1]octan-8-yl]ethan-l-ol

6.

[0148] To a stirred solution of 2-[3-(2-{[(2R,7aS)-2-fluoro-hexahydro-lH-pyrrolizin-7a- yl]methoxy}-7-bromo-8-fluoroquinazolin-4-yl)-3,8-diazabicycl o[3.2.1]octan-8-yl]ethan-l-ol

(600 mg, 1.11 mmol) in 1,4-dioxane (15 mL), was added ((2-fluoro-6-(methoxymethoxy)-8- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-l-yl )ethynyl)triisopropylsilane (628 mg, 1.23 mmol) and aqueous 2M potassium phosphate, tribasic (1.7 mL, 3.34 mmol). The reaction mixture was degassed with argon for 5 minutes, and then [l,l'-bis(di- tertbutylphosphino)ferrocene]dichloropalladium(II) (72.6 mg, 0.11 mmol) was added and again degassed with argon for 3 minutes and then heated at 50 °C for 16 h. 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 afford a crude residue, which was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (80 g silica gel column, using 50 to 100% EtOAc/Pet ether) to afford 2-[3-(2-{[(2R,7aS)-2-fluoro-hexahydro-lH-pyrrolizin-7a- yl]methoxy}-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tr is(propan-2- yl)silyl]ethynyl}naphthalen-l-yl]quinazolin-4-yl)-3,8-diazab icyclo[3.2.1]octan-8-yl]ethan-l-ol (240 mg, 0.28 mmol, 26% yield) as a brown solid. MS(ESI) m/z: 844.5 [M+H] ⁺ .

[0149] Preparation of Intermediate 7: 2-[3-(2-{[(2R,7aS)-2-fluoro-hexahydro-lH- pyrrolizin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxyme thoxy)naphthalen-l-yl]-8- fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]eth an-l-ol

7.

[0150] To a stirred solution of 2-[3-(2-{[(2R,7aS)-2-fluoro-hexahydro-lH-pyrrolizin-7a- yl]methoxy}-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{2-[tr is(propan-2- yl)silyl]ethynyl}naphthalen-l-yl]quinazolin-4-yl)-3,8-diazab icyclo[3.2.1]octan-8-yl]ethan-l-ol (240 mg, 0.284 mmol) in DMF (5 mb) 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 afford 2-[3-(2-{[(2R,7aS)-2-fluoro- hexahydro-lH-pyrrolizin-7a-yl]methoxy}-7-[8-ethynyl-7-fluoro -3- (methoxymethoxy)naphthalen-l-yl]-8-fluoroquinazolin-4-yl)-3, 8-diazabicyclo[3.2.1]octan-8- yl]ethan-l-ol (250 mg, 0.204 mmol, 72% yield) as a pale brown liquid, which was taken for the next step without purification. MS(ESI) m/z: 688.3 [M+H] ⁺ . EXAMPLE 1-1

[0151] This example describes a synthesis of 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-lH- pyrrolizin-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

[0152] To a solution of 2-[3-(2-{[(2R,7aS)-2-fluoro-hexahydro-lH-pyrrolizin-7a- yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthal en-l-yl]-8-fluoroquinazolin-4- yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]ethan-l-ol (Intermediate 30, 250 mg, 0.363 mmol) in acetonitrile (2 mL), was added 4M HC1 in dioxane (0.9 mL, 3.63 mmol) at 0 °C and the mixture was stirred for 2 h. The volatiles from the reaction mixture were removed under reduced pressure and the crude residue was co-evaporated with 1,4-di oxane. Then, the crude residue was dissolved in 1,4-di oxane (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 Prep-HPLC [YMC-Triart Cl 8 (250 mm x 21 mm, 5-pm particles); Mobile Phase A: 5:95 acetonitrile (100%): water with 10 mM ammonium bicarbonate pH 9.5; Mobile Phase B: 95:5 acetonitrile (100%): water with 10 mM ammonium bicarbonate pH 9.5; Gradient: a 2-minute hold at 40% B, 40-60% B over 15 minutes, then a 5-minute hold at 100% B; Flow Rate: 20 mL/min Temperature: 27 °C; Flow rate: 30.0 mL/min; Detection: UV at 220 &254 nm] to afford 4-(2-{[(2R,7aS)-2-fluoro-hexahydro-lH- pyrrolizin-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] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) S 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 = 2.5 Hz, 1H), 7.14 (dd, J = 7.0, 8.6 Hz, 1H), 7.04 (d, J = 2.4 Hz, 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).

[0153] Examples in Table 1 were prepared according to procedures described for Example 1-1 from appropriate starting materials.

Table 1

[0154] The following chemical scheme illustrates a synthesis of 4-(2-{[(4aS,7aR)-l- methyl-octahydro-lH-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-fluoron aphthalen-2-ol (Example 2-1).

[0155] Preparation of Intermediate 8: tert-butyl 3-{2,7-dichloro-8-fluoropyrido[4,3- d]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylat e

[0156] 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 was added DIPEA (20.8 mL, 119 mmol) 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, fdtered and evaporated under reduced pressure to provide the crude product. The crude compound was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (120 g silica gel column, using 50 to 80% EtOAc/petroleum (pet) ether) to afford tert-butyl 3-{2,7- dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl}-3,8-diazabicyc lo[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] ⁺ .

[0157] Preparation of Intermediate 9: ethyl (S)-2-(( 1 -phenylethyl)amino)cy cl opent- 1-ene- 1 -carboxylate

9.

[0158] To a stirred solution of ethyl 2-oxocyclopentane-l -carboxylate (140.5 g, 900 mmol) and 4 A molecular sieves in DCM (500 mL)) was added (S)-l-phenylethan-l -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, 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/pet ether) to afford ethyl (S)-2-((l-phenylethyl)amino)cy cl opent- 1-ene-l -carboxylate (233 g, 898 mmol, 100% yield). MS(ESI) m/z: 259.8 [M+],

[0159] Preparation of Intermediate 10: ethyl (S,E)-l-(3-ethoxy-3-oxopropyl)-2-(((S)-l- phenylethyl)imino)cyclopentane-l -carboxylate

10.

[0160] To a mixture of zinc(II) chloride in 2-MeTHF (473 mL, 898 mmol) and ethyl acrylate (90 g, 898 mmol) at 0 °C was added ethyl (S)-2-((l-phenylethyl)amino)cyclopent-l-ene- 1-carboxylate (233 g, 898 mmol) in THF (233 mL) dropwise and stirred at 0 °C for 16 h. The reaction mixture was neutralized with saturated NaOH solution and extracted with EtOAc (3X500 mL). The combined extracts were dried over anhydrous Na2S€)4, filtered, and concentrated in vacuo to afford ethyl (S,E)-l-(3-ethoxy-3-oxopropyl)-2-(((S)-l-phenylethyl)imino)c yclopentane- 1-carboxylate (300 g, 835 mmol, 93% yield)) as a colorless oil which was taken for the next step without further purification. MS(ESI) m/z: 360.1 [M+H] ⁺ .

[0161] Preparation of Intermediate 11: ethyl (4aS)-2-oxooctahydro-4aH- cyclopenta[b]pyridine-4a-carboxylate

11.

[0162] A mixture of ethyl (S,E)-l-(3-ethoxy-3-oxopropyl)-2-(((S)-l-phenylethyl)imino)- cyclopentane-l-carboxylate (145 g, 403 mmol) and 10% palladium on carbon (35 g, 10% w/w ) in ethanol (336 mL) was hydrogenated under 50 psi (about 345 kPa) of hydrogen for 18 h at room temperature. 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/pet ether) to afford ethyl (4aS)-2-oxooctahydro-4aH-cyclopenta[b]pyridine-4a-carboxylat e (36 g, 170 mmol, 42.2% yield) as a colorless oil. MS(ESI) m/z: 211.6 [M+],

[0163] Preparation of Intermediate 12: ((4aS,7aR)-octahydro-4aH-cyclopenta[b]pyridin- 4a-yl)methanol

12.

[0164] A solution of ethyl (4aS)-2-oxooctahydro-4aH-cyclopenta[b]pyridine-4a- carboxylate (23.7 g, 112 mmol) in THF (415 mL) was added drop wise to an ice-cold solution of IM 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, quenched with water (9.8 mL), 10% NaOH (9 mL) and water (27 mL). Then, the reaction mixture was allowed to warm 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 Na2SO4, filtered, and concentrated under reduced pressure to afford ((4aS,7aR)- octahydro-4aH-cyclopenta[b]pyridin-4a-yl)methanol (17.3 g, 111 mmol, 99% yield) as a white solid which was taken as such for the next step without further purification. MS(ESI) m/z: 156.0 [M+H] ⁺ .

[0165] Preparation of Intermediate 13: ((4aS,7aR)-l-methyloctahydro-4aH- cyclopenta[b]pyridin-4a-yl)methanol

13.

[0166] 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 added formaldehyde (51.0 mL, 653 mmol) over 5 min, followed by sodium triacetoxyhydroborate (50.8 g, 239 mmol) in many portions and then stirred at room temperature for 4 h. After 4h, the reaction mixture was concentrated and then diluted with 300 mL 2-MeTHF, then washed with saturated aqueous K2CO3 solution. The aqueous phase was back-extracted with EtOAc (7x), and the organic layer was dried over Na2SOr, 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><25cm, 5pm); % CO2 90%, % of co-solvent 10%, 0.2% NH4OH in MeOH; Flow: 300 mL/min; Back pressure: 100 bar (10,000 kPa); temp. 35 °C. Peak retention time = 2.53 min] to provide ((4aS,7aR)-l-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl) methanol (28 g, 166 mmol, 76% yield). ‘H NMR (400 MHz, CDCh) 5 ppm = 3.82 (br d, J = 4.4 Hz, 1H), 3.70 - 3.59 (m, 2H), 2.86 (t, J = 7.7 Hz, 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).

[0167] Preparation of Intermediate 14: tert-butyl 3a-(hydroxymethyl)octahydro-lH- indole- 1 -carboxylate Boc

14.

[0168] 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 (2X) and washed with IN hydrochloric acid (50 mL). The combined organic extracts were washed with a saturated aqueous sodium bicarbonate solution (50 mL), water (50 mL), and brine solution (50 mL). The organic layer was dried over NazSCU, filtered, and concentrated under reduced pressure to provide tert-butyl 3a- (hydroxymethyl)octahydro-lH-indole-l -carboxylate (250 mg, 0.979 mmol, 60.8% yield), which was taken as such in the next step without further purification. MS(ESI) m/z: 256.2 [M+H] ⁺ .

[0169] Preparation of Intermediate 15: (l-methyloctahydro-3aH-indol-3a-yl)methanol

15.

[0170] To an ice cold solution of tert-butyl 3a-(hydroxymethyl)octahydro-lH-indole-l- carboxylate (250 mg, 0.979 mmol) in THF (10 mL) was added 2.1 M LAH (1.4 mL, 2.94 mmol) in THF, dropwise. The reaction mixture was heated to 70 °C for 4 hours. The reaction mixture was cooled to 0 °C, quenched with water (0.1 mL), 10% NaOH (0.1 mL) and water (0.3 mL). Then, the reaction mixture was stirred for 10 min and filtered through a CELITE™ pad (Sigma Alrich, St. Louis, MO). The CELITE™ pad was washed with excess EtOAc. The filtrate was dried over NazSOi, filtered, and concentrated under reduced pressure to afford (l-methyloctahydro-3aH- indol-3a-yl) methanol (140 mg, 0.83 mmol, 84% yield) as a colorless liquid, m/z: 170.2 [M+H] ⁺ .

[0171] Preparation of Intermediate 16: (l-azaspiro[4.4]nonan-6-yl)methanol

16.

[0172] (l-Azaspiro[4.4]nonan-6-yl)methanol was synthesized according to the literature procedure set forth in Saruengkhanphasit et al., J. Org. Chem., 2017, 82, 6489-6496.

[0173] Preparation of Intermediate 17: 7-oxa-5-azatricyclo[7.3.0.0 ¹ ’ ⁵ ]dodecane

17.

[0174] To a stirred solution of { l-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. Then, the reaction mixture was quenched with 10% aqueous NaHCO3 solution and extracted with DCM. The combined organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to provide 7-oxa-5-azatricyclo[7.3.0.0 ¹ ’ ⁵ ]dodecane (230 mg, 1.37 mmol, 61%) as colorless liquid. LCMS (ESI) m/z: 168.15 [M+H] ⁺ .

[0175] Preparation of Intermediate 18: {l-methyl-l-azaspiro[4.4]nonan-6-yl}methanol

18.

[0176] To a stirred solution of 7-oxa-5-azatricyclo[7.3.0.0 ^1,5 ]dodecane (480 mg, 2.87 mmol) in dry THF (10 mL) was added LiAlH4 (6.31 mL, 6.31 mmol, IM in THF) dropwise at 0 °C under nitrogen. The resulting mixture was allowed to warm to room temperature and stirred for 16 h. The excess LiAIHr was carefully quenched by addition of saturated Na2SO4 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 x 30 mL). The filtrate was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford {1-methyl-l- 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] ⁺ .

[0177] Preparation of Intermediate 19: tert-butyl 3-(2-{[(4aS,7aR)-l-methyl-octahydro- lH-cyclopenta[b]pyridin-4a-yl]methoxy}-7-chloro-8-fluoropyri do[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1 ]octane-8-carboxylate

[0178] To a stirred solution 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)-l- methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methanol (2.17 g, 12.84 mmol) in THF (60 mL) was added IM LiHMDS (lithium hexamethyldisilazide) in hexanes (35.0 mL, 35.0 mmol) at 0 °C under nitrogen. The reaction mixture was allowed to warm to room temperature and stirred for 15 h. The reaction mixture was quenched with saturated ammonium chloride solution (20 rnL) and extracted with EtOAc (3X). The combined organic extracts were washed with water and brine solution, dried over NazSCh, 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 to 100% EtOAc - pet ether) to afford tert-butyl 3-(2-{[(4aS,7aR)-l-methyl- octahydro-lH-cyclopenta[b]pyridin-4a-yl]methoxy}-7-chloro-8- fluoropyrido[4,3-d]pyrimi din-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3 g, 5.35 mmol, 46% yield) as a pale brown solid. MS(ESI) m/z: 562.3 (M+H) ⁺ .

[0179] Preparation of Intermediate 20: tert-butyl 3-(2-{[(4aS,7aR)-l-methyl-octahydro- lH-cyclopenta[b]pyridin-4a-yl]methoxy(-8-fluoro-7-[7-fluoro- 3-(methoxymethoxy)-8-{2- [tris(propan-2-yl)silyl]ethynyl (naphthal en-l-yl]pyrido[4,3-d]pyrimidin-4-yl)-3, 8- diazabicyclo[3.2.1 ]octane-8-carboxylate

20.

[0180] To a stirred solution of tert-butyl-3-(2-{[(4aS,7aR)-l-methyl-octahydro-lH- 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 ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-d ioxaborolan-2- yl)naphthalen-l-yl)ethynyl)triisopropylsilane (0.91 g, 1.76 mmol), and CS2CO3 (1.57 g, 4.81 mmol) followed by PdCh(dppf) (dppf: l,l'-bis(diphenylphosphino)ferrocene) (0.12 g, 0.16 mmol). The reaction mixture was purged with N2 for 5 min and heated at 105 °C for 1 h in a microwave reactor. 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 afford the crude product, which was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (using 40 g silica gel column, using 50 to 100% EtOAc/Pet ether) to afford tert-butyl 3-(2-{[(4aS,7aR)-l-methyl- octahydro-lH-cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-7- [7-fluoro-3-(methoxymethoxy)- 8-{2-[tris(propan-2-yl)silyl]ethynyl}naphthalen-l-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] ⁺ .

[0181] Preparation of Intermediate 21: tert-butyl 3-(2-{[(4aS,7aR)-l-methyl-octahydro- lH-cyclopenta[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro -3- (methoxymethoxy)naphthalen-l-yl]-8-fluoropyrido[4,3-d]pyrimi din-4-yl)-3,8- diazabicyclo[3.2.1 ]octane-8-carboxylate

21.

[0182] To a stirred solution of tert-butyl 3-(2-{[(4aS,7aR)-l-methyl-octahydro-lH- cyclopenta[b]pyridin-4a-yl]methoxy}-8-fluoro-7-[7-fluoro-3-( methoxymethoxy)-8-{2- [tris(propan-2-yl)silyl]ethynyl}naphthalen-l-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 h. 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 afford tert-butyl 3-(2-{[(4aS,7aR)-l-methyl-octahydro-lH-cyclopenta[b]pyridin- 4a- yl]methoxy}-7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthal en-l-yl]-8-fluoropyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylat e (0.7 g , 0.93 mmol, 94% yield) as a brown oil, which was taken for the next step without further purification. MS(ESI) m/z: 755.3 [M+H] ⁺ .

EXAMPLE 2-1

[0183] This examples describes a synthesis of 4-(2-{[(4aS,7aR)-l-methyl-octahydro-lH- 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.

[0184] To a solution of tert-butyl 3-(2-{[(4aS,7aR)-l-methyl-octahydro-lH- cyclopenta[b]pyridin-4a-yl]methoxy}-7-[8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-l- 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 4M HC1 in dioxane (0.5 mL, 1.85 mmol) at 0 °C and the mixture was stirred for 1 h. The volatiles were removed under reduced pressure and the crude residue was co-evaporated with 1,4-dioxane. Then the crude residue was dissolved in 1,4-dioxane (2 mL) and excess TEA (1 mL) was added and then evaporated under reduced pressure to provide an off-white solid. The crude compound was purified by Prep-high performance liquid chromatography (HPLC) [Column: Gemini NX C18 (250 mm x 21 mm ID, 5u); 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 & 254 nm] to afford 4-(2-{[(4aS,7aR)-l-methyl-octahydro-lH- 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 (400 MHz, DMSO-ds) 5 ppm = 10.15 (br s, 1H), 9.04 (s, 1H), 7.98 (dd, J = 9.2, 5.9 Hz, 1H), 7.47 (t, J = 9.1 Hz, 1H), 7.40 (d, J = 2.5 Hz, 1H), 7.18 (d, J = 2.5 Hz, 1H), 4.53 - 4.42 (m, 2H), 4.32 (br t, J = 10.6 Hz, 1H), 4.13 (d, J = 10.9 Hz, 1H), 3.95 (d, J = 3.6 Hz, 1H), 3.69 - 3.54 (m, 4H), 2.73 - 2.69 (m, 1H), 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).

EXAMPLES 2-2 to 2-4

[0185] Example 2-2 was prepared according to procedures described for Example 2-1 from appropriate starting materials.

2-2 (racemic) 2-3 (Isomer 1) 2-4 Isomer 2)

[0186] The crude compound (2-2) was purified by Prep-HPLC [HPLC Method: Preparative column: Kinetex EVO (250 x 21mm x 5p), Mobile phase A: 10mM ammonium bicarbonate in water-9.5; Mobile phase B: acetonitrile : methanol; Gradient = 50-100 % B over 17 minutes; 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 4.6mm, 5u); Mobile phase: lOmM ammonium acetate in (ACN:MeOH):50:50

FLOW:1.0ml\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] ⁺ ; ¹ H NMR (400 MHz, DMSO-de) 5 ppm = 10.16 (s, 1H), 9.04 (s, 1H), 7.98 (dd, J = 6.0, 9.5 Hz, 1H), 7.47 (t, J = 9.3 Hz, 1H), 7.39 (d, J = 2.5 Hz, 1H), 7.18 (d, J = 2.5 Hz, 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 = 4.3 Hz, 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 (400 MHz, DMSO-d6) 5 ppm = 9.04 (s, 1H), 7.98 (dd, J = 6.0, 9.3 Hz, 1H), 7.47 (t, J = 9.0 Hz, 1H), 7.39 (d, J = 2.8 Hz, 1H), 7.18 (d, J = 2.5 Hz, 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, 8.9 Hz, 1H), 2.23 - 2.10 (m, 4H), 2.09 - 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).

[0187] Examples in Table 2 were prepared according to procedures described for Examples 2-1 to 2-4 from appropriate starting materials. Table 2

[0302] The following chemical scheme illustrates a synthesis of 4-(2-{[(2R,7aS)-2-fluoro- hexahydro- lH-pyrrolizin-7a-yl]methoxy }-8-fluoro-4-[8-(2 -hydroxy ethyl)-3, 8- diazabicyclo[3 2.1]octan-3-yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen -2-ol.

[0188] Preparation of Intermediate 22: tert-butyl 3-(7-bromo-2,6-di chi oro-8- fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbo xylate

Boc i

[0189] 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 mLx2) and brine (50 mL). The organic phase was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure. The residue was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (12g, ISCO column, MeOH/DCM, 0-5%, 20 min.) to afford 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] ⁺ . ¹ H NMR (499 MHz, DMSO-de) 8 ppm = 8.10 (d, J = 1.9 Hz, 1H), 4.38 (br d, J = 10.6 Hz, 2H), 4.25 (br s, 2H), 3.66 (m, 2H) 1.79 (m, 2H), 1.62 (m, 2H), 1.47 s, 9H). [0190] Preparation of Intermediate 23: tert-butyl 3-(7-bromo-6-chloro-2,8- difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-car boxylate

23.

[0191] 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 was heated at 88 °C for 5 h in a sealed tube. 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 X 100 mL) and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) with 15-25% EtOAc in petroleum ether as an 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+l] ⁺ .

[0192] 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

24.

[0193] 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-l,3,2-dioxaborolan-2-yl)pyridin-2-ami ne (5.8 g, 12.25 mmol) and PdCh(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 allowed to cool to ambient temperature, diluted with EtOAc (40 mL), filtered through a bed of a CELITE™ pad (Sigma Alrich, St. Louis, MO) and concentrated under reduced pressure to afford crude product. The residue was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) using 30% EtOAc in petroleum ether to obtain 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). ’H NMR (400 MHz, CDCl ₃ ) 5 ppm = 7.76 (d, J = 1.6 Hz, 1H), 7.20 - 7.18 (d, J = 8.8 Hz, 4H), 6.86 (dt, J = 9.6 Hz, 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] ⁺ .

[0194] Preparation of Intermediate 25: tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-3- iodo-4-methylpyri din-2 -yl)-6-chl oro-2, 8-difluoroquinazolin-4-yl)-3, 8 diazabicyclo[3.2.1]octane- 8-carboxylate

25.

[0195] 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) under nitrogen at 0 °C were 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 one hour. The reaction mixture was then quenched with saturated aqueous sodium thiosulphate (5 mL) and saturated aqueous sodium bicarbonate (4 mL). The mixture was extracted with EtOAc (3x20 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered, and concentrated under vacuum to obtain the crude residue. The crude residue was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) using 30% EtOAc in petroleum ether to obtain tert-butyl 3-(7-(6- (bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-6-c hloro-2,8-difluoroquinazolin-4- yl)-3,8 diazabicyclo[3.2.1]octane-8-carboxylate (1.42 g, 1.560 mmol, 84% yield) as pale yellow fluffy solid. LCMS (ESI) m/z: 883.3 [M+H] ⁺ .

[0196] Preparation of Intermediate 26: tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4- methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluor oquinazolin-4-yl)-3,8- diazabicyclo[3.2.1 ]octane-8-carboxylate

26.

[0197] 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 10 minutes before the addition of methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.91 g, 4.76 mmol) and the reaction mixture was heated at 90 °C for 12 h.. 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 (3x20 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to obtain the crude residue. The crude compound was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) using 30% EtOAc in petroleum ether to obtain tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3- (trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazol in-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, CDCl ₃ ): 5 ppm = 7.77 (s, 1H), 7.16 (d, J = 8.8 Hz, 4H), 6.87 (dt, J = 9.6 and 2.8 Hz, 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] ⁺ .

[0198] Intermediates 27A and 27B: tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4- methyl-3- (trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazol in-4-yl)-3,8- diazabicyclo[3.2.1 ]octane-8-carboxylate

Intermediate 27A (Isomer 1)

Intermediate 27B (Isomer 2).

[0199] Intermediate 26 (5.0 g, 6.06 mmol) was subjected to SFC separation (Method Information: Column: CHIRALPAK™ IH (Daicel, Japan) (250mm x 4.6 x 5u), mobile phasefl.25% Isopropanol), where Peak- 1 eluted at retention time=5.85 min (2.4 g, 2.90 mmol, 40% yield) and Peak-2 at retention time=9.53 min (2.4 g, 2.90 mmol, 40% yield). Peak-1 (27A): ¹ H NMR (400MHz, CDCl ₃ ): 5 ppm = 7.78 (s, IH), 7.16 (d, J = 8.8 Hz, 4H), 6.87 (dt, J = 9.6 and 2.8 Hz, 4H), 6.43 (s, IH), 4.76-4.72 (m, 2H), 4.59-4.55 (m, 2H), 3.81 (s, 6H), 2.43 (s, 3H), 1.97-1.82 (m, 4H), 1.97-1.82 (m, 4H), 1.53 (s, 9H) ppm. LCMS (ESI) m/z: 825.2 [M+H] ⁺ . LCMS (ESI) m/z: 825.2 [M+H] ⁺ . [a] ^{23 5} (MeOH = 0.10) = +96.00; Peak-2: (27B) 'H NMR (400MHz, CDCl ₃ ): 5 ppm = 7.78 (s, IH), 7.16 (d, J = 8.8 Hz, 4H), 6.87 (dt, J = 9.6 and 2.8 Hz, 4H), 6.43 (s, IH), 4.76-4.72 (m, 2H), 4.59-4.55 (m, 2H), 3.81 (s, 6H), 2.43 (s, 3H), 1.97-1.82 (m, 4H), 1.97-1.82 (m, 4H), 1.53 (s, 9H) ppm. LCMS (ESI) m/z: 825.2 [M+H] ⁺ . [a] ^{23 3} (MeOH = 0.10) = -110.00.

[0200] Preparation of Intermediate 28: tert-butyl 3-(2-{[(4aS,7aR)-l-methyl-octahydro- lH-cyclopenta[b]pyridin-4a-yl]methoxy}-7-(6-{bis[(4-methoxyp henyl)methyl]amino}-4-methyl- 3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoroquinazolin -4-yl)-3,8- diazabicyclo[3.2.1 ]octane-8-carboxylate

28.

[0201] To a solution of [(4aS,7aR)-l-methyl-octahydro-lH-cyclopenta[b]pyridin-4a- yl]methanol (0.205 g, 1.212 mmol, Intermediate 27B) in THF (5 mL) at 0°C was addedNaH (0.194 g, 4.85 mmol) and the mixture was stirred at room temperature for 30 minutes. To this mixture was added tert-butyl (lR,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) at 0 °C, and the mixture was stirred at room temperature for 1 h. 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 sulphate, filtered, and concentrated to afford the crude material, which was purified by COMBIFLASH™ chromatography (Teledyne ISO, Lincoln, NE) (24 g REDISEP™ column (Teledyne ISCO, Lincoln, NE), 0 to 10% MeOH - DCM) to afford tert-butyl 3-(2- {[(4aS,7aR)-l-methyl-octahydro-lH-cyclopenta[b]pyridin-4a-yl ]methoxy}-7-(6-{bis[(4- methoxyphenyl)methyl]amino}-4-methyl-3-(tri fluoromethyl)pyri din-2 -yl)-6-chloro-8- fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbo xylate (0.70 g, 0.718 mmol, 59% yield). MS(ESI) m/z: 974.4 (M+H) ⁺ .

[0202] Preparation of Intermediate 29: 6-(2-{[(4aS,7aR)-l-methyl-octahydro-lH- cyclopenta[b]pyridin-4a-yl]methoxy}-6-chloro-4-{3,8-diazabic yclo[3.2.1]octan-3-yl}-8- fluoroquinazolin-7-yl)-N,N-bis[(4-methoxyphenyl)methyl]-4-me thyl-5-(trifluoromethyl)pyridin- 2-amine

29.

[0203] To a solution of tert-butyl 3-(2-{[(4aS,7aR)-l-methyl-octahydro-lH- cyclopenta[b]pyridin-4a-yl]methoxy}-7-(6-{bis[(4-methoxyphen yl)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 4M HC1 in dioxane (0.9 mL, 3.59 mmol) at 0 °C. The reaction mixture was allowed to warm to room temperature and was stirred for 3 h. Then, the solvent was removed under reduced pressure. The residue was diluted with MeOH, neutralized with excess TEA and again concentrated under reduced pressure to provide 6-(2-{[(4aS,7aR)-l-methyl-octahydro-lH-cyclopenta[b]pyridin- 4a-yl]methoxy}-6- chloro-4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fhioroquinazo lin-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) ⁺ .

[0204] Preparation of Intermediate 30: 6-(2-{[(4aS,7aR)-l-methyl-octahydro-lH- cyclopenta[b]pyridin-4a-yl]methoxy}-6-chloro-4-{3,8-diazabic yclo[3.2.1]octan-3-yl}-8- fluoroquinazolin-7-yl)-N-[(4-methoxyphenyl)methyl]-4-methyl- 5-(trifluoromethyl)pyri din-2- amine

30.

[0205] To a solution of tert-butyl 3-(2-{[(4aS,7aR)-l-methyl-octahydro-lH- cyclopenta[b]pyridin-4a-yl]methoxy}-7-(6-{bis[(4-methoxyphen yl)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 allowed to warm to room temperature and stirred for 1 h. Then, the solvent was removed under reduced pressure, and the residue was diluted with DCM and neutralized with excess TEA. The organic layer was washed with aq.NaHCCh solution, dried over NazSCU, filtered, and concentrated under reduced pressure to provide 6-(2-{[(4aS,7aR)-l-methyl- octahydro-lH-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-m ethyl-5-(trifluoromethyl)pyridin- 2-amine (200 mg, 0.26 mmol, 86% yield). MS(ESI) m/z: 754.3 (M+H) ⁺ .

[0206] Preparation of Intermediate 31 : 2-[3-(2-{[(4aS,7aR)-l-methyl-octahydro-lH- 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-l-ol

[0207] To a stirred solution of 6-(2-{[(4aS,7aR)-l-methyl-octahydro-lH- cyclopenta[b]pyridin-4a-yl]methoxy}-6-chloro-4-{3,8-diazabic yclo[3.2.1]octan-3-yl}-8- fluoroquinazolin-7-yl)-N-[(4-methoxyphenyl)methyl]-4-methyl- 5-(trifluoromethyl)pyri din-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 h. 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 and then dried over sodium sulfate, filtered, and concentrated to provide 2-[3-(2- {[(4aS,7aR)-l-methyl-octahydro-lH-cyclopenta[b]pyridin-4a-yl ]methoxy}-6-chloro-8-fluoro-7- (6-{[(4-methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromet hyl)pyridin-2-yl)quinazolin-4- yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]ethan-l-ol (20 mg, 0.025 mmol, 76% yield) which was taken for the next step without further purification. MS(ESI) m/z: 798.3 (M+H) ⁺ .

EXAMPLE 3-1

[0208] This examples describes a synthesis of 2-[3-(2-{[(4aS,7aR)-l-methyl-octahydro- lH-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]oct an-8-yl]ethan-l-ol.

3-1

[0209] A one dram vial was charged with 2-[3-(2-{[(4aS,7aR)-l-methyl-octahydro-lH- cyclopenta[b]pyridin-4a-yl]methoxy}-6-chloro-8-fluoro-7-(6-{ [(4- methoxyphenyl)methyl]amino}-4-methyl-3-(trifluoromethyl)pyri din-2-yl)quinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octan-8-yl]ethan-l-ol (Intermediate 44, 20 mg, 0.025 mmol)), triethylsilane (12 pL, 0.075 mmol) and TFA (39 pL, 0.50 mmol). Then the vial was sealed and heated at 40 °C degrees for 16 h. The volatiles from the reaction mixture were removed under reduced pressure and the crude residue was co-evaporated with 1,4-dioxane. Then the crude residue was dissolved in 1,4-dioxane (2 mL) and excess TEA (1 mL) was added and the mixture was evaporated under reduced pressure to provide a crude residue which was purified by Prep-HPLC [HPLC Method: Preparative column: XBridge C18 (Waters, Milford, MA), 250 mm x 19 mm, 5-pm 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: a 0-minute hold at 12% B, 12-42% B over 25 minutes, then a 5-minute hold at 100% B; Flow Rate: 20 mL/min; Detection: UV at 220 &254 nm] to afford 2-[3-(2-{[(4aS,7aR)-l-methyl-octahydro-lH-cyclopenta[b]pyrid in-4a- yl]methoxy }-7-[6-amino-4-methyl-3-(tri fluoromethyl)pyri din-2 -yl]-6-chl oro-8-fluoroquinazolin- 4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]ethan-l-ol (4.5 mg, 0.007 mmol, 26% yield). MS(ESI) m/z: 678.3 [M+H] ⁺ .

[0210] Preparation of intermediate 32: 1 -(tert-butyl) 2-methyl (2R,4R)-2-(2-

(chloromethyl)allyl)-4-fluoropyrrolidine- 1 ,2-dicarboxylate [0211] To a stirred solution of 1 -(tert-butyl) 2-methyl (2S,4R)-4-fluoropyrrolidine-l,2- dicarboxylate (25 g, 101 mmol) in THF (25 mL) at 0 °C was added LiHMDS (131 mL, 131 mmol, 1 M in THF) and the resulting mixture was stirred at the same temperature for 15 min. 3-Chloro- 2-(chloromethyl)prop-l-ene (14.04 mL, 121 mmol) was added and the resulting solution was stirred at room temperature for 4 h. The reaction mixture was cooled to 0 °C and saturated aqueous ammonium chloride (150 mL) was added, and the mixture was stirred for 15 min. 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 afford 1 -(tert-butyl) 2-methyl (2R,4R)-2-(2-(chloromethyl)allyl)-4-fluoropyrrolidine-l,2-di carboxylate (24 g, 70.8 mmol, 70% yield). LCMS (ESI) m/z: 236.2 [(M-Boc)+H] ⁺ .

[0212] Preparation of intermediate 33: methyl (2R,4R)-2-(2-(chloromethyl)allyl)-4- fluoropyrrolidine-2-carboxylate hydrochloride

33.

[0213] To a stirred solution of 1 -(tert-butyl) 2-methyl (2R,4R)-2-(2-(chloromethyl)allyl)- 4-fluoropyrrolidine-l,2-dicarboxylate (24.0 g, 71.5 mmol) in 1,4-dioxane (240 mL) at 0 °C was added HCI (179 mL, 715 mmol, 4 M in dioxane) and the reaction mixture was allowed to stir at room temperature for 16 h. The reaction mixture was concentrated under vacuum to afford methyl (2R,4R)-2-(2-(chloromethyl)allyl)-4-fluoropyrrolidine-2-carb oxylate hydrochloride (19.2 g, 69.2 mmol, 97% yield) as an off-white solid. LCMS (ESI) m/z: 236.1 [M+H] ⁺ .

[0214] Preparation of intermediate 34: methyl (2R,7aR)-2-fluoro-6-methylenetetrahydro- lH-pyrrolizine-7a(5H)-carboxylate

34.

[0215] To a stirred solution of methyl (2R,4R)-2-(2-(chloromethyl)allyl)-4- fluoropyrrolidine-2-carboxylate hydrochloride (19.1 g, 70.2 mmol) in acetonitrile (190 mL) at 0 °C was added TEA (48.9 mL, 351 mmol) and the reaction mixture was allowed to stir at room temperature for 16 h. Water (150 mL) was added, and the reaction mixture was extracted with ethyl acetate (2x180 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-lH-pyrrolizine- 7a(5H)-carboxylate (9.1 g, 42.0 mmol, 60% yield) as an yellow-orange oil. LCMS (ESI) m/z: 200.2 [M+H] ⁺ .

[0216] Preparation of intermediate 35: methyl (6'R,7a'R)-6'-fluorodihydro-rH,3'H- spiro[cyclopropane-l,2'-pyrrolizine]-7a'(5'H)-carboxylate

35.

[0217] To a solution of methyl (2R,7aR)-2-fluoro-6-methylenetetrahydro-lH-pyrrolizine- 7a(5H)-carboxylate (10 g, 50.2 mmol) in toluene (10 mL) at -78 °C was added diiodomethane (16.20 mL, 201 mmol) and diethylzinc (100 mL, 100 mmol, 1 M in hexanes), and the resulting mixture was gradually warmed to room temperature. After 3 h, ice-cold water (100 mL) was added, and the mixture was extracted with ethyl acetate (3x100 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 afforded methyl (6'R,7a'R)-6'-fluorodihydro-TH,3'H- spiro[cyclopropane-l,2'-pyrrolizine]-7a'(5'H)-carboxylate (7 g, 32.8 mmol, 65% yield) as a colorless oil. LCMS (ESI) m/z: 214.2 [M+H] ⁺ .

[0218] Preparation of intermediate 36: ((6'R,7a'R)-6'-fluorodihydro-rH,3'H- spiro[cyclopropane-l,2'-pyrrolizin]-7a'(5'H)-yl) methanol

36.

[0219] To a stirred solution of methyl (6'R,7a'R)-6'-fhiorodihydro-TH,3'H- spiro[cyclopropane-l,2'-pyrrolizine]-7a'(5'H)-carboxylate (7.0 g, 32.8 mmol) in THF (10 mL) at 0 °C was added LAH (16.4 mL, 32.8 mmol, 2 M in THF), and the resulting mixture was stirred at the same temperature for 2 h. Saturated aqueous NH4Q (5 mL) was added dropwise until the 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 (3x50 mL). All the volatiles were evaporated under reduced pressure to afford ((6'R,7a'R)-6'-fluorodihydro-rH,3'Hspiro[cyclopropane-l,2'-p yrrolizin]-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] ⁺ .

[0220] Preparation of intermediate 37: tert-butyl 3-(2,8-difluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl) naphthalen-l-yl)quinazolin-4-yl)-3,8- diazabicyclo[3.2.1 ]octane-8-carboxylate

37.

[0221] 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-l,3,2-d ioxaborolan-2- yl)naphthalen-l-yl)ethynyl)triisopropylsilane (6.75 g, 13.18 mmol), CS2CO3 (5.72 g, 17.57 mmol) and PdC12(dppf) (0.643 g, 0.879 mmol) and the reaction mixture was purged with nitrogen for 10 min, and then stirred at 100 °C for 16 h. 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 Cl 8 column eluting with 0-100% acetonitrile and water afforded tert-butyl 3-(2,8-difluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-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] ⁺ .

[0222] Preparation of intermediate 38: tert-butyl 3-(8-fluoro-7-(7-fluoro-3-

(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen -l-yl)-2-(((6R,7a'R)-6'- fluorodihydro-rH,3'H-spiro[cyclopropane-l,2'-pyrrolizin]-7a' (5'H)-yl)methoxy)quinazolin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0223] To a stirred solution of ((6'R,7a'R)-6'-fluorodihydro-TH,3'H-spiro[cyclopropane- l,2'-pyrrolizin]-7a'(5'H)-yl)methanol (298 mg, 1.61 mmol) in THF (8 mL) at 0 °C was added 60% NaH (64.3 mg, 1.608 mmol) and the resulting mixture was stirred at the same temperature for 30 min. A solution of tert-butyl 3-(2,8-difluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)quinazolin-4-yl) -3,8-diazabicyclo[3.2.1]octane-8- carboxylate (680 mg, 0.894 mmol) in THF (5 mL) was added to the above mixture and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0 °C, ice-cold water (40 mL) was added, and the mixture was extracted with ethyl acetate (2 x 80 mL). The organic layer was washed with brine (25 mL), dried over sodium sulfate, fdtered, 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-l-yl)-2-(((6'R,7a' R)-6'-fluorodihydro-rH,3'H- spiro[cyclopropane-l,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)quin azolin-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] ⁺ .

[0224] Preparation of intermediate 39: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro- 2-(((6'R,7a'R)-6'-fluorodihydro-rH,3'H-spiro[cyclopropane-l, 2'-pyrrolizin]-7a'(5'H)- yl)methoxy)quinazolin-7-yl)-6-fluoro-5-((triisopropylsilyl)e thynyl)naphthalen-2-ol [0225] To a stirring solution of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((6'R,7a'R)- 6'-fluorodihydro-rH,3'H- spiro[cyclopropane-l,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)quin azolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (350 mg, 0.38 mmol) in DCM (3 mL) was added HC1 (0.945 mL, 3.78 mmol, 4.0 M in dioxane) and the reaction mixture was allowed to stir at room temperature for 2 h. The reaction mixture was diluted with DCM (25 mL) and washed with saturated sodium bicarbonate (1x8 mL), dried over sodium sulfate, filtered, and concentrated to afford 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((6'R,7 a'R)-6'-fluorodihydro-rH,3'H- spiro[cyclopropane-l,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)quin azolin-7-yl)-6-fluoro-5- ((triisopropylsilyl)ethynyl)naphthalen-2-ol (290 mg, 94% yield) . LCMS (ESI) m/z: 782.2 [M+H] ⁺ .

EXAMPLE 4-1

[0226] This examples describes a synthesis of 4-(2-{[(6'R,7'aR)-6'-fluoro- hexahydrospiro[cyclopropane-l,2'-pyrrolizine]-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

4-1.

[0227] To a stirring solution of 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((6'R,7a'R)-6'-fluorodihydro-TH,3'H-spiro[cyclopropane-l,2' -pyrrolizin]-7a'(5'H)- yl)methoxy)quinazolin-7-yl)-6-fluoro-5-((triisopropylsilyl)e thynyl)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 allowed to stir at room temperature for 3 h. The reaction mixture was diluted with water (5 mL) and extracted with DCM (2x10 mL). The organic layer was washed with brine (1x5 mL), dried over sodium sulfate, filtered, and concentrated. Purification by prep-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) afforded 4-(2- {[(6'R,7'aR)-6'-fluoro-hexahydrospiro[cyclopropane-l,2'-pyrr olizine]-7'a-yl]methoxy}-4-{3,8- diazabicyclo[3.2.1]octan-3-yl}-8-fluoroquinazolin-7-yl)-5-et hynyl-6-fluoronaphthalen-2- ol.2TFA (28 mg, 0.032 mmol, 9% yield) as an off-white solid. LCMS (ESI) m/z: 626.3 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO-d6): 5 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, 6.0 Hz, 1H), 7.84 (d, J = 8.51 Hz, 1H), 7.48 (dd, J = 9.0, 9.0 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.32-7.36 (m, 1H), 7.08 (d, J = 2.4 Hz, 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 = 13.0 Hz, 1H), 0.80-0.90 (m, 2H), 0.60-0.75 (m, 2H).

[0228] Preparation of intermediate 40: methyl (6'R,7a'R)-2,2,6'-trifluorodihydro-rH,3'H- spiro[cyclopropane-l,2'-pyrrolizine]-7a'(5'H)-carboxylate

40.

[0229] To a stirred solution of methyl (2R,7aR)-2-fluoro-6-methylenetetrahydro-lH- pyrrolizine-7a(5H)-carboxylate (2.0 g, 10.0 mmol) in THF (25 mL) was 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 h. The reaction mixture was cooled to room temperature, water (80 mL) and ethyl acetate (2 x 200 mL) were added. The two layers were separated, and the organic layer was washed with aqueous sodium thiosulfate (1x100 mL, 0.1 M), brine (1x100 mL), dried over NaiSCU, filtered, and concentrated. Purification by silica gel chromatography by eluting with 20% ethyl acetate and petroleum ether afforded methyl (6'R,7a'R)- 2,2,6'-trifluorodihydro-rH,3'H-spiro[cyclopropane-l,2'-pyrro lizine]-7a'(5'H)-carboxylate (1.6 g, 6.34 mmol, 63.2% yield) as a mixture of diastereomers in 63:37 ratio. LCMS (ESI) m/z: 250.2 [M+H] ⁺ .

[0230] Preparation of intermediate 41: methyl (6'R,7a'R)-2,2,6'-trifluorodihydro-rH,3'H- spiro[cyclopropane-l,2'-pyrrolizine]-7a'(5'H)-carboxylate

41.

[0231] To a stirred solution of methyl (6'R,7a'R)-2,2,6'-trifluorodihydro-rH,3'H spiro[cyclopropane-l,2'-pyrrolizine]-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 and 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 afford ((6'R,7a'R)-2,2,6'-trifluorodihydro- l'H,3'H-spiro[cyclopropane-l,2'-pyrrolizin]-7a'(5'H)-yl)meth anol (1.3 g, 89%) as a mixture of diastereomers in 63:37 ratio. LCMS (ESI) m/z: 222.1 [M+H] ⁺ .

[0232] Preparation of intermediate 42 and 43: tert-butyl 3-(8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l- yl)-2-(((lR,6'R,7aR)-2,2,6'- trifluorodihydro-rH,3'H-spiro[cyclopropane-l,2'-pyrrolizin]- 7a'(5'H)-yl)methoxy)quinazolin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 42) and tert-butyl 3-(8-fluoro-7-(7- fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naph thalen-l-yl)-2-(((lS,6'R,7a'R)- 2,2,6'-trifluorodihydro-rH,3'H-spiro[cyclopropane-l,2'-pyrro lizin]-7a'(5'H)- yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2. l]octane-8-carboxylate (Intermediate 43)

[0233] To a stirred solution of ((6'R,7a'R)-2,2,6'-trifluorodihydro-rH,3'H- spiro[cyclopropane-l,2'-pyrrolizin]-7a'(5'H)-yl)methanol (1.047 g, 4.73 mmol) in THF (20 mL) at 0 °C was added NaH (0.189 g, 4.73 mmol) and the reaction mixture was stirred at the same temperature for 30 min. A solution of tert-butyl 3-(2,8-difluoro-7-(7-fluoro-3-(methoxymethoxy)- 8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)quinazolin-4-y l)-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 was stirred at room temperature for 2 h. The reaction mixture was then cooled to 0 °C, ice-cold water (50 mL) was added, and the mixture was stirred for 10 min, and then extracted with ethyl acetate (2x80 mL). The organic layer was washed with brine (1x45 mL), dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography on neutral alumina by eluting with 14% ethyl acetate in petroleum ether afforded tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)- 8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((lR,6'R,7 a'R)-2,2,6'-trifluorodihydro-l'H,3'H- spiro[cyclopropane-l,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)quin azolin-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] ⁺ . The minor diastereomer tert-butyl 3-(8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l- yl)-2-(((lS,6'R,7a'R)-2,2,6'- trifluorodihydro-l'H,3'H-spiro[cyclopropane-l,2'-pyrrolizin] -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) was also isolated. LCMS (ESI) m/z: 962.4 [M+H] ⁺ . The stereochemistry shown at the spirocyclic centre in intermediates 42 and 43 was arbitrarily assigned.

[0234] Preparation of intermediate 44: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro- 2-(((lR, 6'R,7a'R)-2, 2, 6'-tri fluorodihydro- 1'H, 3'H-spiro[cyclopropane- l,2'-pyrrolizin]-7a'(5'H)- yl)methoxy)quinazolin-7-yl)-6-fluoro-5-((triisopropylsilyl)e thynyl)naphthalen-2-ol

[0235] To a stirred solution of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((lR,6'R,7a' R)-2,2,6'-trifluorodihydro- TH,3'Hspiro[cyclopropane-l,2'-pyrrolizin]-7a'(5'H)-yl)methox y)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 HC1 (3.90 mL, 15.6 mmol, 4 M in dioxane) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with DCM (35 mL) and washed with saturated sodium bicarbonate solution (1x10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to afford 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((1R, 6'R,7a'R)-2, 2, 6'-tri fluorodihydro- 1'H, 3'H-spiro[cyclopropane-l,2'-pyrrolizin]-7a'(5'H)- yl)methoxy)quinazolin-7-yl)-6-fluoro-5-((triisopropylsilyl)e thynyl)naphthalen-2-ol (1.2 g).

LCMS (ESI) m/z: 818.2 [M+H] ⁺ .

EXAMPLE 5-1

[0236] This examples describes a synthesis of 4-(2-{[(lR,6'R,7'aR)-3,3,6'-trifluoro- hexahydrospiro[cyclopropane-l,2'-pyrrolizine]-7'a-yl]methoxy }-4-{3,8- diazabicyclo[3.2.1]octan-3-yl}-8-fluoroquinazolin-7-yl)-5-et hynyl-6-fluoronaphthalen-2-ol

5-1. [0237] 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'-tri fluorodihydro- 1H,3H-spiro[cyclopropane-l,2'-pyrrolizin]-7a'(5H)- yl)methoxy)quinazolin-7-yl)-6-fluoro-5-((triisopropylsilyl)e thynyl)naphthalen-2-ol (1.2 g, 1.47 mmol) in DCM (10 mL) at 0 °C was added TBAF (7.33 mL, 7.33 mmol, 1 M in THF), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with DCM (2x15 mL). The organic layer was washed with brine (1x5 mL), dried over sodium sulfate, filtered, and concentrated to afford the crude residue. Purification by prep-HPLC (eluent: THF: water :MeCN (50:20:30); column: X-bridge C18 (250 x 19)mm, 5 micron; mobile phase A: 0.1% TFA in water, mobile phase B: acetonitrile; flow: 20 mL/min; gradient) afforded the desired product as a bis-TFA salt. Further purification by SFC (CHIRALPAK™ AD-H (Daicel, Japan) (250 x 4.6)mm, 5 micron; mobile phase-0.1% NHrOH in

2-propanol) afforded 4-(4-(3,8- 4-(2-{[(lR,6'R,7'aR)-3,3,6'-trifluoro- hexahydrospiro[cyclopropane-l,2'-pyrrolizine]-7'a-yl]methoxy }-4-{3,8-diazabicyclo[3.2.1]octan-

3-yl}-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthal en-2-ol (250 mg, 26%) as an off-white solid. LCMS (ESI) m/z: 662.2 [M+H] ⁺ . ’H-NMR (400 MHz, DMSO-de): 5 10.17 (br s, 1H), 7.96 (dd, J = 9.2, 6.0 Hz, 1H), 7.40 (d, J = 8.40 Hz, 1H), 7.46 (dd, J = 9.2, 9.2 Hz, 1H), 7.36 (d, J = 2.4 Hz, 1H), 7.15-7.21 (m, 1H), 7.07 (d, J = 2.4 Hz, 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.

[0238] Preparation of intermediate 45: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro- 2-(((lS,6'R,7a'R)-2,2,6'-trifluorodihydro-rH,3'H-spiro[cyclo propane-l,2'-pyrrolizin]-7a'(5'H)- yl)methoxy)quinazolin-7-yl)-6-fluoro-5-((triisopropylsilyl)e thynyl)naphthalen-2-ol

[0239] To a stirred solution of tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((lS,6'R,7a' R)-2,2,6'-trifluorodihydro-l'H,3'H- spiro[cyclopropane-l,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)quin azolin-4-yl)-3,8- diazabicyclo[3 2.1]octane-8-carboxylate (450 mg, 0 468 mmol) in DCM (5 mL) at 0 °C was added HC1 (1.17 mL, 4.68 mmol, 4 M in dioxane) and the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with DCM (35 mL) and washed with saturated aqueous sodium bicarbonate (1x10 mL), dried over sodium sulfate, filtered, and concentrated to afford 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((lS,6' R,7a'R)-2,2,6'- trifluorodihydro-rH,3'H-spiro[cyclopropane-l,2'-pyrrolizin]- 7a'(5'H)-yl)methoxy)quinazolin-7- yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (370 mg, crude). LCMS (ESI) m/z: 818.2 [M+H] ⁺ .

EXAMPLE 6-1

[0240] This examples describes a synthesis of 4-(2-{[(lS,6'R,7'aR)-3,3,6'-trifluoro- hexahydrospiro[cyclopropane-l,2'-pyrrolizine]-7'a-yl]methoxy }-4-{3,8-diazabicyclo[3.2.1]octan- 3-yl}-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen- 2-ol

6-1.

[0241] To a stirred solution of 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2 (((1 S,6'R,7a'R)-2, 2, 6'-tri fluorodihydro- rH,3'H-spiro[cyclopropane-l,2'-pyrrolizin]-7a'(5'H)- yl)methoxy)quinazolin-7-yl)-6-fluoro-5-((triisopropylsilyl)e thynyl)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 h. The reaction mixture was diluted with water (ImL) and extracted with DCM (2x8 mL). The organic layer was washed with brine (1x1 mL), dried over sodium sulfate, filtered, and concentrated. Purification by prep-HPLC (eluent: THF:water:MeCN (50:20:30); column: Xbridge C18 (150 x 19) mm, 5 micron; mobile phase A:0.1% TFA in water; mobile phase B: acetonitrile; flow: 15 mL/min, gradient) afforded 4-(2- {[(lS,6'R,7'aR)-3,3,6'-trifluoro-hexahydrospiro[cyclopropane -l,2'-pyrrolizine]-7'a-yl]methoxy}- 4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoroquinazolin-7-y l)-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 (400 MHz, 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, 6.0 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.48 (dd, J = 9.2, 9.2 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.31-7.38 (m, 1H), 7.08 (d, J = 2.4 Hz, 1H), 5.53-5.70 (m, 1H), 3.45-4.70 (m, 14 H), 2.46-2.70 (m, 2H), 2.33-2.40 (m, 1H), 1.81-2.05 (m, 6H).

[0242] Preparation of intermediate 46: tert-butyl 3-(7-chloro-8-fluoro-2-(((6'R,7a'R)-6'- fluorodihydro-rH,3'H-spiro[cyclopropane-l,2'-pyrrolizin]-7a' (5'H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylat e

46.

[0243] To a stirred solution of ((6'R,7a'R)-6'-fluorodihydro-rH,3'H-spiro[cyclopropane- l,2'-pyrrolizin]-7a'(5H)-yl)methanol (0.649 g, 3.50 mmol) in THF (15 mb) at 0 °C was added LiHMDS (4.67 mL, 4.67 mmol, 1 M in THF), and the resulting mixture was stirred at the same temperature for 10 min. 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 above solution at 0 °C, and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0 °C and ice-cold water (50 mL) was added and the mixture was extracted with ethyl acetate (3x50 mL). The organic layer was washed with brine (1x50 mL), dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography by eluting with 15% ethyl acetate and petroleum ether afforded tert-butyl 3-(7- chloro-8-fluoro-2-(((6'R,7a'R)-6'-fluorodihydro-rH,3'H-spiro [cyclopropane-l,2'-pyrrolizin]- 7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-azabicy clo[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] ⁺ .

[0244] Preparation of intermediate 47: tert-butyl 3-(8-fluoro-7-(7-fluoro-3-

(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen -l-yl)-2-(((6'R,7a'R)-6'- fluorodihydro-rH,3'H-spiro[cyclopropane-l,2'-pyrrolizin]-7a' (5'H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylat e

[0245] To a mixture of tert-butyl 3-(7-chloro-8-fluoro-2-(((6'R,7aR)-6'-fluorodihydro- 11,3'H-spiro[cyclopropane-l,2'-pyrrolizin]-7a'(5'H)-yl)metho xy)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.52 mmol) and ((2-fluoro-6- (methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2 -yl)naphthalen-l- yl)ethynyl)triisopropylsilane (666 mg, 1.30 mmol) in THF (10 mL) was added tripotassium phosphate (1.04 mL, 1.56 mmol, 1.5 M aqueous solution) at room temperature and purged with nitrogen for 5 min. 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 h. The reaction mixture was cooled to room temperature, ice-cold water (50 mL) was added and the mixture was extracted with ethyl acetate (3x50 mL). The organic layer was washed with brine (1x50 mL), dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography on neutral alumina by eluting with 15% ethyl acetate in petroleum ether afforded tert-butyl 3-(8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-triisopropylsilyl)ethynyl)naphthalen-l-yl )-2-(((6R,7aR)-6'-fluorodihydro- rH,3'H-spiro[cyclopropane-l,2'-pyrrolizin]-7a'(5'H)-yl)metho xy)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] ⁺ .

[0246] Preparation of intermediate 48: tert-butyl 3-(7-(8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-8-fluoro-2-(((6R,7aR)-6'-fl uorodihydro-rH,3'H- spiro[cyclopropane-l,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)pyri do[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1 ]octane-8-carboxylate

[0247] To a solution of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((6'R,7a'R)- 6'-fhjorodihydro-l'H,3'H- spiro[cyclopropane-l,2'-pyrrolizin]-7a'(5'H)-l)methoxy)pyrid o[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 was added TBAF (0.647 mL, 0.647 mmol,l M in THF) and the resulting mixture was stirred for 30 min at the same temperature. The reaction mixture was diluted with ice-cold water (50 mL) and extracted with ethyl acetate (3x50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to afford tert-butyl 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)- 8-fluoro-2-(((6'R,7a'R)-6'-fluorodihydro-rH,3'H-spiro[cyclop ropane-l,2'-pyrrolizin]-7a'(5'H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2 . l]octane-8-carboxylate (200 mg, crude). LCMS (ESI) m/z: 771.2 [M+H] ⁺ .

EXAMPLE 7-1

[0248] This examples describes a synthesis of 4-(2-{[(6'R,7'aR)-6'-fluoro- hexahydrospiro[cyclopropane-l,2'-pyrrolizine]-7'a-yl]methoxy }-4-{3,8-diazabicyclo[3.2.1]octan- 3-yl}-8-fhjoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluor onaphthalen-2-ol

[0249] To tert-butyl 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)- 8- fluoro-2-(((6'R,7a'R)-6'-fluorodihydro-rH,3'H-spiro[cyclopro pane-l,2'-pyrrolizin]-7a'(5'H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2 . l]octane-8-carboxylate (200 mg, 0.259 mmol) in acetonitrile (5 mL) 0 °C was added HC1 (0.52 mL, 2.08 mmol, 4 M in dioxane) and the resulting mixture was stirred at the same temperature for 2 h. Triethylamine (0.1 mL) and ice-cold water (10 mL) were added and the mixture was extracted with ethyl acetate (3x50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by prep- HPLC (eluent: THF:water:MeCN (50:20:30); column: Symmetry (300x19mm) 7 pm, mobile phase A: 0.1% TFA in water, mobile phase B: MeCN; flow rate: 15 mL/min, gradient) afforded the desired product as a bis-TFA salt. The bis-TFA salt was taken into DCM (3 mL) and solid ammonium bicarbonate (50 mg) was added. After stirring the suspension for 15 min at room temperature, the suspension was filtered, and the filtrate was concentrated. After lyophilization, 4- (2-{[(6'R,7'aR)-6'-fluoro-hexahydrospiro[cyclopropane-l,2'-p yrrolizine]-7'a-yl]methoxy}-4-{3,8- diazabicyclo[3.2.1]octan-3-yl}-8-fluoropyrido[4,3-d]pyrimidi n-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+l] ⁺ . ¹ H-NMR (400 MHz, DMSO-d6): 5 10.14 (s, 1H), 9.04 (s, 1H), 7.98 (dd, J = 9.2, 6.00 Hz, 1H), 7.47 (t, J = 9.20 Hz, 1H), 7.40 (d, J = 2.80 Hz, 1H), 7.18 (t, J = 2.00 Hz, 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 = 10 Hz, 1H), 2.64 (d, J = 10 Hz, 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.

[0250] Preparation of intermediates 49 and 50: tert-butyl 3-(7-chloro-8-fluoro-2- (((lR,6'R,7a'R)-2,2,6'-trifluorodihydro-rH,3'H-spiro[cyclopr opane-l,2'-pyrrolizin]-7a'(5'H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2 . l]octane-8-carboxylate (49) and tert-butyl 3-(7-chloro-8-fluoro-2-(((lS,6'R,7aR)-2,2,6'-trifluorodihydr o-1H,3H- spiro[cyclopropane-l,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)pyri do[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (50)

[0251] To a stirred solution of ((6'R,7a'R)-2,2,6'-trifluorodihydro-TH,3'H- spiro[cyclopropane-l,2'-pyrrolizin]-7a'(5'H)-yl)methanol (1.30 g, 5.88 mmol) in THF (10 rnL) at 0 °C was added LiHMDS (6.54 mL, 6.54 mmol, 1 M in THF) and the reaction mixture was stirred at the same temperature for 20 min. A solution of tert-butyl 3-(2,7-dichloro-8- fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oc tane-8-carboxylate (1.4 g, 3.27 mmol) in THF (10 mL) was added at 0 °C and the reaction was stirred at room temperature for 16 h. The reaction mixture was then cooled to 0 °C and ice-cold water (50 mL) was added, stirred for 10 minutes and then extracted with ethyl acetate (2x80 mL). The organic layer was washed with brine (1x45 mL), dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography on neutral alumina by eluting with 32% ethyl acetate in petroleum ether afforded tert-butyl 3 -(7-chloro-8-fluoro-2-((( 1R, 6'R, 7 a'R)-2,2, 6'-trifluorodihy dro- 1 'H, 3 'H- spiro[cyclopropane-l,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)pyri do[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] ⁺ . The minor diastereomer tert-butyl 3-(7-chloro-8-fluoro-2- (((lS,6'R,7a'R)-2,2,6'-trifluorodihydro-rH,3'H-spiro[cyclopr opane-l,2'-pyrrolizin]-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) was also isolated. LCMS (ESI) m/z: 613.2 [M+H] ⁺ . The stereochemistry shown at the spirocyclic centre in intermediates 62 and 63 was arbitrarily assigned.

[0252] Preparation of intermediate 51 : tert-butyl 3-(8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l- yl)-2-(((lR,6'R,7a'R)-2,2,6'- trifluorodihydro-rH,3'H-spiro[cyclopropane-l,2'-pyrrolizin]- 7a'(5'H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylat e

[0253] To a mixture of tert-butyl 3-(7-chloro-8-fluoro-2-(((lR,6'R,7a'R)-2,2,6'- trifluorodihydro-rH,3'H-spiro[cyclopropane-l,2'-pyrrolizin]- 7a'(5'H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylat e (300 mg, 0.49 mmol) and ((2- fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxa borolan-2-yl)naphthalen-l- yl)ethynyl)triisopropylsilane (502 mg, 0.98 mmol) in THF (10 mL) was added tripotassium phosphate (0.98 mL, 1.47 mmol, 1.5 M aqueous solution) at room temperature and the mixture was purged with nitrogen for 5 min. 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 h. The reaction mixture was cooled to room temperature, ice-cold water (10 mL) was added and extracted with ethyl acetate (3x20 mL). The organic layer was washed with brine (1x10 mL), dried over sodium sulfate, filtered, and concentrated. Purification by silica gel column chromatography by eluting with 42% EtOAc in petroleum ether afforded tert-butyl 3-(8-fluoro-7- (7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)n aphthalen-l-yl)-2-(((lR,6R,7aR)- 2,2,6'-trifluorodihydro-rH,3'H-spiro[cyclopropane-l,2'-pyrro lizin]-7a'(5'H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2 . l]octane-8-carboxylate (400 mg, 0.407 mmol, 83% yield) as a pale-yellow solid. LCMS (ESI) m/z: 963.3 [M+H] ⁺ .

[0254] Preparation of intermediate 52: tert-butyl 3-(7-(8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-8-fluoro-2-(((lR,6'R,7a'R)- 2,2,6'-trifluorodihydro-rH,3'H- spiro[cyclopropane-l,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)pyri do[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1 ]octane-8-carboxylate

[0255] To a solution of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((lR,6'R,7aR )-2,2,6'-trifluorodihydro- TH,3'Hspiro[cyclopropane-l,2'-pyrrolizin]-7a'(5'H)-yl)methox y)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 h. The reaction mixture was cooled to room temperature and diluted with EtOAc (30 mL). The organic layer was washed with saturated aqueous NaHCO ₃ (1x10 mL), dried over sodium sulfate, filtered, and concentrated to afford tert-butyl 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l- yl)-8-fluoro-2-(((lR,6'R,7a'R)-2,2,6'-trifluorodihydro-TH,3' H-spiro[cyclopropane-l,2'- pyrrolizin]-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 taken to the next step without further purification. LCMS (ESI) m/z: 807.2 [M+H] ⁺ .

EXAMPLE 8-1

[0256] This examples describes a synthesis of 4-(2-{[(lR,6'R,7'aR)-3,3,6'-trifluoro- hexahydrospiro[cyclopropane-l,2'-pyrrolizine]-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-fluor onaphthalen-2-ol [0257] To a solution of tert-butyl 3-(7-(8-ethynyl-7-fluoro-3 (methoxymethoxy)naphthalen-l-yl)-8-fluoro-2-(((lR, 6'R,7a'R)-2, 2, 6'-tri fluorodihydro- l'H, 3'H- spiro[cyclopropane-l,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)pyri do[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 was added HC1 (0.744 mL, 2.97 mmol, 4.0 M in dioxane) and the reaction mixture was allowed to stir at room temperature for 2 h. The reaction mixture was concentrated under vacuum and diluted with dichloromethane (20 mL). The organic layer was washed with saturated aqueous NaHCCh (5 mL), dried over sodium sulfate, fdtered, and concentrated. Purification by prep-HPLC (eluent: THF:water:MeCN (50:20:30); column: Symmetry C8 (300 x 19)mm, 7 pm; mobile phase A: 5 mM aqueous ammonium formate, mobile phase B: MeCN; flow: 15 mL/min, gradient) afforded 4-(4- (3, 8-diazabicyclo[3.2. l]octan-3-yl)-8-fluoro-2-(((lR, 6'R,7a'R)-2, 2, 6'-tri fluorodihydro- TH, 3'H- spiro[cyclopropane-l,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)pyri do[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+l] ⁺ . H-NMR (400 MHz, DMSO-d6): 8 9.06 (s, 1H), 7.98 (dd, J = 9.2, 5.6 Hz, 1H), 7.47 (dd, J = 8.8, 8.8 Hz, 1H), 7.40 (d, J = 2.4 Hz, 1H), 7.18 (d, J = 2.4 Hz, 1H), 5.37 (dt, J = 53.6, 3.75 Hz, 1H), 4.52 (d, J = 12.4 Hz, 1H), 4.22-4.38 (m, 3H), 3.94 (dd, J = 2.4, 0.8 Hz, 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.

[0258] Preparation of intermediate 53: tert-butyl 3-(8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l- yl)-2-(((lS,6'R,7a'R)-2,2,6'- trifluorodihydro-rH,3'H-spiro[cyclopropane-l,2'-pyrrolizin]- 7a'(5'H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylat e

[0259] To a mixture of tert-butyl 3-(7-chloro-8-fluoro-2-(((lS,6'R,7a'R)-2,2,6'- trifluorodihydro-rH,3'H-spiro[cyclopropane-l,2'-pyrrolizin]- 7a'(5'H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylat e (290 mg, 0.47 mmol) and ((2- fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxa borolan-2-yl)naphthalen-l- 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 min. 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 h. The reaction mixture was cooled to room temperature, ice-cold water (10 mL) was added, and the mixture was extracted with ethyl acetate (3x20 mL). The organic layer was washed with brine (1x10 mL), dried over sodium sulfate, filtered, and concentrated. Purification by silica gel column chromatography by eluting with 42% EtOAc in petroleum ether afforded tert-butyl 3-(8-fluoro-7- (7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)n aphthalen-l-yl)-2-(((lS,6'R,7a'R)- 2,2,6'-trifluorodihydro-1H,3'H-spiro[cyclopropane-l,2'-pyrro lizin]-7a'(5'H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2 . l]octane-8-carboxylate (310 mg, 0.29 mmol, 61% yield) as a pale-yellow solid. LCMS (ESI) m/z: 963.3 [M+H] ⁺ .

[0260] Preparation of intermediate 54: tert-butyl 3-(7-(8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-8-fluoro-2-(((lS,6R,7a'R)-2 ,2,6'-trifluorodihydro-1H,3'H- spiro[cyclopropane-l,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)pyri do[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1 ]octane-8-carboxylate

[0261] To tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-

((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((lS,6'R, 7a'R)-2,2,6'-trifluorodihydro- l'H,3'Hspiro[cyclopropane-l,2'-pyrrolizin]-7a'(5'H)-yl)metho xy)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 h. The reaction mixture was cooled to room temperature and diluted with EtOAc (30 mL). The organic layer was washed with saturated aqueous NaHCOi (1x10 mL), dried over sodium sulfate, filtered, and concentrated to afford tert-butyl 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l- yl)-8-fluoro-2-(((l S,6R,7aR)-2,2,6'-trifluorodihydro-l'H,3'H-spiro[cyclopropane -l,2'- pyrrolizin]-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 taken to the next step without further purification. LCMS (ESI) m/z: 807.2 [M+H] ⁺ .

EXAMPLE 9-1

[0262] This examples describes a synthesis of 4-(2-{[(lS,6'R,7'aR)-3,3,6'-trifluoro- hexahydrospiro[cyclopropane-l,2'-pyrrolizine]-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-fluor onaphthalen-2-ol

[0263] To a solution of tert-butyl 3-(7-(8-ethynyl-7-fluoro-3 (methoxymethoxy)naphthalen-l-yl)-8-fluoro-2-(((l S,6R,7a'R)-2, 2, 6'-tri fluorodihydro- l'H,3'H- spiro[cyclopropane-l,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)pyri do[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 was added HC1 (0.713 mL, 2.85 mmol, 4.0 M in dioxane) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum and diluted with dichloromethane (20 mL). The organic layer was washed with saturated aqueous NaHCOi (5 mL), dried over sodium sulfate, filtered, and concentrated. Purification by prep-HPLC (eluent: THF:water:MeCN (50:20:30); column: Symmetry C8 (300 x 19)mm, 7 pm; mobile phase A: 5 mM aqueous ammonium formate, mobile phase B: MeCN; flow: 15 mL/min, gradient) afforded 4-(4- (3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((lS,6'R,7a' R)-2,2,6'-trifluorodihydro-1H,3'H- spiro[cyclopropane-l,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)pyri do[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+l] ⁺ . ¹ H-NMR (400 MHz, DMSO-d6): 5 10.2 (br s, 1H), 9.05 (s, 1H), 7.95-8.00 (m, 1H), 7.47 (dd, J = 8.8, 8.8 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.18 (t, J = 2.4, 2.4 Hz, 1H), 5.43 (dt, J = 56, 3.6 Hz, 1H), 4.47-4.58 (m, 1H), 4.26-4.38 (m, 1H), 4.16 (d, J = 10.8 Hz, 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.

BIOLOGICAL ACTIVITY

KRAS ^G12D RAF Disruption Assay

[0264] Recombinant GMPPNP -loaded KRAS G12D (5 nM) was treated with compound at room temperature for 20 minutes in assay buffer (50mM Tris pH 7.5, lOOmM NaCl, ImM MgCh, ImM DTT, lOOug/ml BSA). Recombinant GST-RAF1 RBD (9 nM) was added, followed by the addition of SA-Tb (0.25 nM), and the reaction mixture was incubated for 3 hours. Homogeneous Time Resolved Fluorescence (HTRF) signal was measured (PerkinElmer Envision), the signal ratio (Am 520/ Am 495) was calculated, and IC50 values were calculated from the doseresponse curve.

KRAS ^G12D Nucleotide Exchange Assay

[0265] Recombinant GDP -loaded KRAS G12D (20 nM) was treated with compound at room temperature for 20 minutes in assay buffer (10 mM Hepes pH 7.4, 150 mM NaCl, 5 mM MgCh, 0.0025% Igepal-CA630, 0.05% BSA, 1 mM DTT, 0.5 nM SA-Tb). BODIPY™-labeled GDP (Thermofisher, Waltham, MA) (400 nM) and recombinant SOS (10 nM) were added, and the reaction was incubated for 30 minutes. HTRF signal was measured (PerkinElmer Envision), the signal ratio (Am 520/ Am 495) was calculated, and IC50 values were calculated from the doseresponse curve.

[0266] The IC50 values for compounds described herein for the KRAS ^G12D RAF disruption and KRAS ^G12D nucleotide exchange assays are shown in Table 3.

Table 3

[0267] It is to be appreciated 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 can set forth one or more but not all exemplary aspects of the present disclosure as contemplated by the inventor(s), and thus, are not intended to limit the present disclosure and the appended claims in any way.

[0268] The present disclosure has been described above with the aid of functional building blocks illustrating the implementation of specified functions and relationships thereof. The boundaries of these functional building blocks have been arbitrarily defined herein for the convenience of the description. Alternate boundaries can be defined so long as the specified functions and relationships thereof are appropriately performed.

[0269] The foregoing description of the specific aspects will so fully reveal the general nature of the disclosure that others can, by applying knowledge within the skill of the art, readily modify and/or adapt for various applications such specific aspects, without undue experimentation, without departing from the general concept of the present disclosure. Therefore, such adaptations and modifications are intended to be within the meaning and range of equivalents of the disclosed aspects, based on the teaching and guidance presented herein. It is to be understood that the phraseology or terminology herein is for the purpose of description and not of limitation, such that the terminology or phraseology of the present specification is to be interpreted by the skilled artisan in light of the teachings and guidance.

[0270] 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.