KRAS modulating compounds

Abstract

Provided herein are compounds, and pharmaceutically acceptable salts thereof, useful as KRAS inhibitors, methods of making and using the same (singly or in combination with additional agents), and pharmaceutical compositions thereof.

Description

Attorney Docket No. 1587-WO-PCT KRAS MODULATING COMPOUNDSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U. S. Provisional Application No. 63 / 738,266, filed December 23, 2024, which is incorporated herein in its entireties for all puiposes.BACKGROUND

[0002] The KRAS protein, Kirsten Rat Sarcoma 2 Viral Oncogene Homolog (“KRAS”), is a GTPase. KRAS gene mutations have been observed in a number of conditions including, for instance, pancreatic cancer, endometrial cancer, lung adenocarcinoma, colorectal cancer, rectal carcinoma, gall bladder cancer, thyroid cancer, bile duct cancer, small cell lung cancer, and nonsmall cell lung cancer (NSCLC). Accordingly, there is a need for compounds, pharmaceutical compositions, and methods for inhibiting KRAS (e.g., wild type, KRAS G12C, KRAS G12D, and / or KRAS G12V) and treating associated cancers.SUMMARY

[0003] In one embodiment, the present disclosure provides a compound of Formula (lib):or a pharmaceutically acceptable salt thereof,whereinR1is F;Rlband R2bare each independently H or Me, wherein at least one of Rlband R2bis Me;RA2is -NH2; and-O-Lc-Rcis:Attorney Docket No. 1587-WO-PCTalternatively, whereinR1is H;Rlband R2bare each Me;RA2is -NH2; and-O-Lc-Rcis:alternatively, whereinR1is H or F;Rlband R2bare each independently H or Me, wherein at least one of Rlband R2bis Me; RA2is -OH; and-O-Lc-Rcis:alternatively, whereinR1is H or F;R1band R2bare each H;RA2is -OH; and-O-Lc-Rcis:Attorney Docket No. 1587-WO-PCT

[0004] In another embodiment, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, and a pharmaceutically acceptable excipient.

[0005] In another embodiment, the present disclosure provides a method of inhibiting KRAS wild type, G12C, G12D, or G12V protein in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0006] In another embodiment, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0007] In another embodiment, the present disclosure provides a method for manufacturing a medicament for treating cancer in a subject in need thereof, characterized in that a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is used.

[0008] In another embodiment, the present disclosure provides a method for manufacturing a medicament for inhibiting cancer metastasis in a subject in need thereof, characterized in that a compound of the present invention, or a pharmaceutically acceptable salt thereof, is used.

[0009] In another embodiment, the present disclosure provides use of the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer in a subject.

[0010] In another embodiment, the present disclosure provides use of the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting cancer metastasis in a subject.

[0011] In another embodiment, the present disclosure provides the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in a subject in need thereof.Attorney Docket No. 1587-WO-PCT

[0012] In another embodiment, the present disclosure provides the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in inhibiting cancer metastasis in a subject in need thereof.

[0013] In another embodiment, the present disclosure provides the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in therapy.

[0014] Also disclosed herein are compounds and pharmaceutically acceptable salts thereof of subformulas of Formula (lib).DETAILED DESCRIPTIONI. General

[0015] The disclosure relates generally to methods and compounds, and pharmaceutically acceptable salts thereof, for inhibiting KRAS wild type, KRASG12D, KRASG12Cand / or KRASG12V. The following description sets forth exemplary methods, parameters and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.II. Definitions

[0016] As used in the present specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0017] A dashthat is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONFb is attached through the carbon atom. A dash at the front or end of a chemical group is a matter of convenience; chemical groups can be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line drawn through a line in a structure indicates a point of attachment of a group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which a chemical group is written or named.

[0018] A squiggly line on a chemical group as shown below, for example,indicates a point of attachment, i.e., it shows the broken bond by which the group is connected to another described group.Attorney Docket No. 1587-WO-PCT

[0019] As used herein, “a compound of the disclosure” can mean a compound of any of the Formula (lib) or a pharmaceutically acceptable salt thereof. Similarly, the phrase “a compound of Formula (number)” means a compound of that formula and pharmaceutically acceptable salts thereof.

[0020] The prefix “CuCv” indicates that the following group has from u to v carbon atoms. For example, “Ci-Cs alkyl” indicates that the alkyl group has from 1 to 8 carbon atoms.

[0021] “Alkyl” refers to an unbranched or branched saturated hydrocarbon chain. For example, an alkyl group can have 1 to 20 carbon atoms (i.e., C1-C20 alkyl), 1 to 8 carbon atoms (i.e., Ci-Cs alkyl), 1 to 6 carbon atoms (i.e., Ci-Ce alkyl), or 1 to 3 carbon atoms (i.e., C1-C3 alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1 -propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (z-Pr, / -propyl, -CH(CH3)2), 1 -butyl (zi-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (.y-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (Z-Bu, / -butyl, -C(CH3)3), 1 -pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl- 1 -butyl (-CH2CH2CH(CH3)2), 2-methyl-l -butyl (-CH2CH(CH3)CH2CH3), 1 -hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3 -methyl-3 -pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), and 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3. Other alkyl groups include, but are not limited to, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, pentadcyl, hexadecyl, heptadecyl and octadecyl.

[0022] “Alkenyl” refers to an unbranched or branched hydrocarbon chain containing at least two carbon atoms and at least one carbon-carbon double bond. As used herein, alkenyl can have from 2 to 20 carbon atoms (i.e., C2-20 alkenyl), 2 to 8 carbon atoms (i.e., C2-8 alkenyl), 2 to 6 carbon atoms (i.e., C2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C2-4 alkenyl). Alkenyl can include any number of carbons, such as C2, C3, C4, C5, Ce, C7, Cs, C9, C10, Cu, C12, C13, C14, C15, Ci6, C17, Cis, C19, C20, or any range therein. Alkenyl groups can have any suitable number of double bonds, including, but not limited to, 1, 2, 3, 4, 5 or more. Examples of alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1 -pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1 -hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatrienyl.Attorney Docket No. 1587-WO-PCT

[0023] “Alkynyl” refers to an unbranched or branched hydrocarbon chain containing at least one carbon-carbon triple bond. For example, an alkynyl group can have from 2 to 20 carbon atoms (i.c., C2-20 alkynyl), 2 to 8 carbon atoms (i.c., C2-8 alkynyl), 2 to 6 carbon atoms (i.c., C2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C2-4 alkynyl). The term “alkynyl” also includes those groups having one triple bond and one double bond. Examples of C2-6alkynyl include, but are not limited to, ethynyl, prop-l-ynyl, but-l-ynyl, pent-l-ynyl, pent-4-ynyl and penta- 1,4-diynyl.

[0024] “Alkoxy" means a group having the formula -O-alkyl, in which an alkyl group, as defined above, is attached to the parent molecule via an oxygen atom. The alkyl portion of an alkoxy group can have 1 to 20 carbon atoms (i.e., C1-C20 alkoxy), 1 to 12 carbon atoms (i.e., C1-C12 alkoxy), 1 to 8 carbon atoms (i.e., Ci-Cs alkoxy), 1 to 6 carbon atoms (i.e., Ci-Ce alkoxy) or 1 to 3 carbon atoms (i.e., C1-C3 alkoxy). Examples of suitable alkoxy groups include, but are not limited to, methoxy (-O-CH3 or -OMe), ethoxy (-OCH2CH3 or -OEt), isopropoxy (-O-CH(CH3)2), t-butoxy (-O-C(CH3)3or -OtBu) and the like. Other examples of suitable alkoxy groups include, but are not limited to, sec-butoxy, tert-butoxy, pentoxy, hexoxy, and the like.

[0025] “Alkoxyalkyl” refers an alkoxy group linked to an alkyl group which is linked to the remainder of the compound. Alkoxyalkyl can have any suitable number of carbon, such as from 2 to 6 (C2-6 alkoxyalkyl), 2 to 5 (C2-5 alkoxyalkyl), 2 to 4 (C2-4 alkoxyalkyl), or 2 to 3 (C2-3 alkoxyalkyl). Alkoxy and alkyl are as defined above. Examples of “alkoxyalkyl” include, but are not limited to, methoxymethyl (CH3OCH2-), and methoxyethyl (CH3OCH2CH2).

[0026] “Bridged” means a ring system in which non-adjacent atoms on a ring are connected by a divalent substituent, such as an alkylenyl or heteroalkylenyl group or a single heteroatom.

[0027] “Hydroxyalkyl” refers to a hydroxy group, -OH, linked to an alkyl group which is linked to the remainder of the compound such that the alkyl group is divalent. Hydroxyalkyl can have any suitable number of carbons, such as from 1 to 8 (C1-8 hydroxy alkyl), 1 to 6 (Ci-6 hydroxyalkyl), 2 to 6 (C2-6 hydroxyalkyl), 2 to 4 (C2-4 hydroxy alkyl), or 2 to 3 (C2- 3 hydroxy alkyl). Alkyl is as defined above where the alkyl is divalent.

[0028] “Halo” or “halogen” as used herein refers to fluoro (-F), chloro (-C1), bromo (-Br) and iodo (-1).

[0029] “Haloalkyl” is an alkyl group, as defined above, in which one or more hydrogen atoms of the alkyl group is replaced with a halogen atom. The alkyl portion of a haloalkyl group can have 1 to 20 carbon atoms (i.e., C1-C20 haloalkyl), 1 to 12 carbon atoms (i.e., C1-C12 haloalkyl), 1 to 8Attorney Docket No. 1587-WO-PCT carbon atoms (i.e., Ci-Cs haloalkyl), 1 to 6 carbon atoms (i.e., Ci-Ce alkyl) or 1 to 3 carbon atoms (i.e., C1-C3 alkyl). The alkyl groups can be substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9 or more halogens. Examples of suitable haloalkyl groups include, but arc not limited to, -CF3, -CHF2, -CFH2, -CH2CF3, fluorochloromethyl, difluorochloromethyl, and pentafluoroethyl.

[0030] “Haloalkoxy” refers to an alkoxy group where some or all of the hydrogen atoms are substituted with halogen atoms. As for an alkyl group, haloalkoxy groups can have any suitable number of carbon atoms, such as C1-6. The alkoxy groups can be substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9 or more halogens. When all the hydrogens are replaced with a halogen, for example by fluorine, the compounds are per-substituted, for example, perfluorinated. Haloalkoxy includes, but is not limited to, trifluoromethoxy, 2, 2, 2, -trifluoroethoxy, perfluoroethoxy, etc.

[0031] “Thioalkyl” refers to a thio group, -SH, linked to an alkyl group which is linked to the remainder of the compound such that the alkyl group is divalent. Thioalkyl can have any suitable number of carbons, such as from 1 to 8 (Ci-s thioalkyl), 1 to 6 (C1-6 thioalkyl), 2 to 6 (C2-6 thioalkyl), 2 to 4 (C2-4 thioalkyl), or 2 to 3 (C2-3 thioalkyl). Alkyl is as defined above where the alkyl is divalent.

[0032] “Haloalkylthio” is an alkylthio group, as defined above, in which one or more hydrogen atoms of the alkyl group is replaced with a halogen atom. The alkyl portion of a haloalkylthio group can have 1 to 20 carbon atoms (i.e., C1-C20 haloalkylthio), 1 to 12 carbon atoms (i.e., Ci-C12 haloalkylthio), 1 to 8 carbon atoms (i.e., Ci-Cs haloalkylthio), 1 to 6 carbon atoms (i.e., Ci-Ce alkylthio) or 1 to 3 carbon atoms (i.e., C1-C3 alkylthio). The alkylthio groups can be substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9 or more halogens.

[0033] “Heteroalkyl” refers to an unbranched or branched saturated hydrocarbon chain containing from 1 to 4 heteroatoms.

[0034] “Cyanoalkyl” refers to a cyano group, -CN, linked to an alkyl group which is linked to the remainder of the compound such that the alkyl group is divalent. Cyanoalkyl can have any suitable number of carbons, such as from 1 to 8 (C1-8 cyanoalkyl), 1 to 6 (C1-6 cyanoalkyl), 2 to 6 (C2-6 cyanoalkyl), 2 to 4 (C2-4 cyanoalkyl), or 2 to 3 (C2-3 cyanoalkyl). Alkyl is as defined above where the alkyl is divalent.

[0035] “Cycloalkyl” refers to a saturated or partially saturated cyclic alkyl group having a single ring or multiple rings, such as 2, 3, 4 or more, wherein the multiple rings can be fused, bridged,Attorney Docket No. 1587-WO-PCT spiro, or any combination thereof. As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.c., C3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-6 cycloalkyl). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl groups also include partially unsaturated ring systems containing one or more double bonds, including fused ring systems with one aromatic ring and one non-aromatic ring, but not fully aromatic ring systems.

[0036] The term “fused” refers to a ring system in which two or more rings in the system share a pair of adjacent ring atoms.

[0037] “Spiro” refers to at least two rings are linked together by one common atom. “Spiro” also refers to a ring substituent which is joined by two bonds at the same carbon atom. Examples of spiro groups include, but are not limited to, 1, 1 -diethylcyclopentane, dimethyl-di oxolane, and 4-benzyl-4-methylpiperidine, wherein the cyclopentane and piperidine, respectively, are the spiro substituents.

[0038] “Alkyl-cycloalkyl” refers to a radical having an alkyl component and a cycloalkyl component, where the alkyl component links the cycloalkyl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene, to link to the cycloalkyl component and to the point of attachment. In some instances, the alkyl component can be absent. The alkyl component can include any number of carbons, such as Ci-6, C1-2, C1-3, Ci-4, Ci-5, C2-3, C24, C2-5, C26, C34, C3-5, C3-6, C4 -5, C4 -6 and C5-6. The cycloalkyl component is as defined within. Exemplary alkyl-cycloalkyl groups include, but are not limited to, methyl-cyclopropyl, methyl-cyclobutyl, methyl-cyclopentyl and methyl-cyclohexyl.

[0039] “Heterocycle” or “heterocyclyl” or “heterocycloalkyl” refer to a saturated or unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen, sulfur and silicon. A heterocyclyl can be a single ring or multiple rings, such as 2, 3, 4 or more, wherein the multiple rings can be fused, bridged, spiro, or any combination thereof. As used herein, heterocyclyl has 3 to 20 ring atoms (i.e., 3 to 20 membered heterocyclyl), 3 to 12 ring atoms (i.e., 3 to 12 membered heterocyclyl), 3 to 10 ring atoms (i.e., 3 to 10 membered heterocyclyl), 3 to 8 ring atoms (i.e., 3 to 8 membered heterocyclyl), 4 to 12 ring carbon atoms (i.e., 4 to 12 membered heterocyclyl), 4 to 8 ring atoms (i.e., 4 to 8 membered heterocyclyl), or 4 to 6 ring atoms (i.e., 4 to 6 membered heterocyclyl). Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl.Attorney Docket No. 1587-WO-PCT

[0040] “Alkyl-heterocycloalkyl” refers to a radical having an alkyl component and a heterocycloalkyl component, where the alkyl component links the heterocycloalkyl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene, to link to the heterocycloalkyl component and to the point of attachment. The alkyl component can include any number of carbons, such as Co-6. C1-2, C1-3, Ci-4, C1-5, C1-6, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6 and C5-6. In some instances, the alkyl component can be absent. The heterocycloalkyl component is as defined above.

[0041] “Aryl” means an aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. For example, an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms. Exemplary aryl groups include, but are not limited to, radicals derived from benzene (e.g., phenyl), naphthalene, anthracene, biphenyl, and the like.

[0042] “Alkyl-aryl” refers to a radical having an alkyl component and an aryl component, where the alkyl component links the aryl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene, to link to the aryl component and to the point of attachment. The alkyl component can include any number of carbons, such as Co-6, C1-2, C1-3, C1-4, C1-5, Ci-6, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6 and C5-6. In some instances, the alkyl component can be absent. The aryl component is as defined above. Examples of alkyl-aryl groups include, but are not limited to, benzyl and ethyl-benzene.

[0043] “Heteroaryl” refers to an aromatic group, including groups having an aromatic tautomer or resonance structure, having a single ring, multiple rings, or multiple fused rings, with at least one heteroatom in the ring, i.e., one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the nitrogen or sulfur can be oxidized. Thus, the term includes rings having one or more annular O, N, S, S(O), S(O)2, and N-oxide groups. The term includes rings having one or more annular C(O) groups. As used herein, heteroaryl include 5 to 20 ring atoms (i.e., 5- to 20-membered heteroaryl), 5 to 12 ring atoms (i.e., 5- to 12-membered heteroaryl), or 5 to 10 ring atoms (i.e., 5- to 10-membered heteroaryl), and 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and oxidized forms of the heteroatoms. Examples of heteroaryl groups include, but are not limited to, pyridin-2(lH)-one, pyridazin-3(2H)-one, pyrimidin-4(3H)-one, quinolin-2(lH)-one, pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does not encompass or overlap with aryl as defined above.Attorney Docket No. 1587-WO-PCT

[0044] “Alkyl-heteroaryl” refers to a radical having an alkyl component and a heteroaryl component, where the alkyl component links the heteroaryl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene, to link to the heteroaryl component and to the point of attachment. The alkyl component can include any number of carbons, such as C0-6, C1-2, C1-3, C1-4, C1-5, C1-6, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6and C5-6. In some instances, the alkyl component can be absent. The heteroaryl component is as defined within.

[0045] ‘ ‘KRAS G12C” refers to the G12C mutation of the KRAS protein, where cysteine replaces glycine at amino acid position 12.

[0046] “KRAS G12C inhibitor’’ refers to compounds of the present disclosure, including compounds of Formula (lib). The compounds modulate or inhibit some or all of the activity of KRAS G12C.

[0047] “KRAS G12C-associated disease or disorder’’ refers to diseases or disorders associated with or mediated by or having a KRAS G12C mutation. Representative diseases or disorders include, but are not limited to, KRAS G12C-associated cancer.

[0048] “KRAS G12D’’ refers to the G12D mutation of the KRAS protein, where aspartic acid replaces glycine at amino acid position 12.

[0049] “KRAS G12D inhibitor” refers to compounds of the present disclosure, including compounds of Formula (lib). The compounds modulate or inhibit some or all of the activity of KRAS G12D.

[0050] “KRAS G12D-associated disease or disorder” refers to diseases or disorders associated with or mediated by or having a KRAS G12D mutation. Representative diseases or disorders include, but are not limited to, KRAS G12D-associated cancer.

[0051] “KRAS G12V” refers to the G12V mutation of the KRAS protein, where aspartic acid replaces valine at amino acid position 12.

[0052] “KRAS G12V inhibitor” refers to compounds of the present disclosure, including compounds of Formula (lib). The compounds modulate or inhibit some or all of the activity of KRAS G12V.Attorney Docket No. 1587-WO-PCT

[0053] “KRAS G12V-associated disease or disorder” refers to diseases or disorders associated with or mediated by or having a KRAS G12V mutation. Representative diseases or disorders include, but are not limited to, KRAS G12V-associated cancer.

[0054] ‘ ‘Oxo” refers to the group (=0) or (O).

[0055] Provided are also pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein. “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, formulations, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.

[0056] The compounds described herein can be prepared and / or formulated as pharmaceutically acceptable salts or when appropriate as a free base. Pharmaceutically acceptable salts are nontoxic salts of a free base form of a compound that possess the desired pharmacological activity of the free base. These salts can be derived from inorganic or organic acids or bases. For example, a compound that contains a basic nitrogen can be prepared as a pharmaceutically acceptable salt by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne- 1,4-dioates, hexyne- 1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates, besylates, xylenesulfonates, naphthalene- 1 -sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, y-hydroxybutyrates, glycolates, tartrates, and mandelates. Lists of other suitable pharmaceutically acceptable salts are found in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, 21stEdition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.

[0057] Examples of “pharmaceutically acceptable salts” of the compounds disclosed herein also include salts derived from an appropriate base, such as an alkali metal (for example, sodium, potassium), an alkaline earth metal (for example, magnesium), ammonium and NX4+(wherein X is C1-C4 alkyl). Also included are base addition salts, such as sodium or potassium salts.Attorney Docket No. 1587-WO-PCT

[0058] Provided are also compounds described herein or pharmaceutically acceptable salts, isomers, or a mixture thereof, in which from 1 to n hydrogen atoms attached to a carbon atom can be replaced by a deuterium atom or D, in which n is the number of hydrogen atoms in the molecule. As known in the art, the deuterium atom is a non-radioactive isotope of the hydrogen atom. Such compounds can increase resistance to metabolism, and thus can be useful for increasing the halflife of the compounds described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof when administered to a mammal. See, e.g., Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,’’ TRENDS PHARMACOL. SCI., 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0059] Examples of isotopes that can be incorporated into the disclosed compounds also include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as2H,3H, “C,13C,14C,13N,15N,15O,17O,18O,31P,32P,35S,18F,36C1,123I, and125I, respectively. Substitution with positron emitting isotopes, such as11C,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of Formula (lib) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the nonlabeled reagent previously employed.

[0060] The compounds of the embodiments disclosed herein, or their pharmaceutically acceptable salts can contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), ( / ?)- and (5)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. Where compounds are represented in their chiral form, it is understood that the embodiment encompasses, but is not limited to, the specific diastereomerically orAttorney Docket No. 1587-WO-PCT enantiomencally enriched form. Where chirality is not specified but is present, it is understood that the embodiment is directed to either the specific diastereomerically or enantiomencally enriched form; or a racemic or scalcmic mixture of such compound(s). As used herein, “scalcrnic mixture” is a mixture of stereoisomers at a ratio other than 1:1.

[0061] “Racemates” refers to a mixture of enantiomers. The mixture can comprise equal or unequal amounts of each enantiomer.

[0062] “Stereoisomer” and “stereoisomers” refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers. The compounds can exist in stereoisomeric form if they possess one or more asymmetric centers or a double bond with asymmetric substitution and, therefore, can be produced as individual stereoisomers or as mixtures. Unless otherwise indicated, the description is intended to include individual stereoisomers as well as mixtures. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art see, e.g., Chapter 4 of ADVANCED ORGANIC CHEMISTRY, 4th ed., J. March, John Wiley & Sons, New York, 1992).

[0063] A “subject” or “patient” is meant to describe a human or vertebrate animal including a dog, cat, pocket pet, marmoset, horse, cow, pig, sheep, goat, elephant, giraffe, chicken, lion, monkey, owl, rat, squirrel, slender loris, and mouse. A “pocket pet” refers to a group of vertebrate animals capable of fitting into a commodious coat pocket such as, for example, hamsters, chinchillas, ferrets, rats, guinea pigs, gerbils, rabbits and sugar gliders.

[0064] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. A dash at the front or end of a chemical group is a matter of convenience: chemical groups can be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line drawn through a line in a structure indicates a point of attachment of a group. A dashed line indicates an optional bond. Unless chemically or structurally required, no directionality is indicated or implied by the order in which a chemical group is written or the point at which it is attached to the remainder of the molecule. For instance, the group “-SO2CH2-” is equivalent to “-CH2SO2-” and both can be connected in either direction. Similarly, an “arylalkyl” group, for example, can be attached to the remainder of the molecule at either an aryl or an alkyl portion of the group. A prefix such as “Cu-Cv” or “(Cu-Cv)” indicates that the following group has from u to v carbon atoms. For example, “C1-6 alkyl” and “Ci-Ce alkyl” both indicate that the alkyl group has from 1 to 6 carbon atoms.Attorney Docket No. 1587-WO-PCT

[0065] Unless otherwise specified, the carbon atoms of the compounds of Formula (lib), are intended to have a valence of four. If in some chemical structure representations, carbon atoms do not have a sufficient number of variables attached to produce a valence of four, the remaining carbon substituents needed to provide a valence of four should be assumed to be hydrogen.

[0066] “Treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results may include one or more of the following: (a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and / or diminishing the extent of the disease or condition); (b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and / or (c) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival.

[0067] The term “therapeutically effective amount,” as used herein, is the amount of compound disclosed herein present in a formulation described herein that is needed to provide a desired level of drug in the secretions and tissues of the airways and lungs, or alternatively, in the bloodstream of a subject to be treated to give an anticipated physiological response or desired biological effect when such a formulation is administered by the chosen route of administration. The precise amount will depend upon numerous factors, for example the particular compound disclosed herein, the specific activity of the formulation, the delivery device employed, the physical characteristics of the formulation, its intended use, as well as subject considerations such as severity of the disease state, subject cooperation, etc., and can readily be determined by one skilled in the art based upon the information provided herein. The term “therapeutically effective amount” or “effective amount” also means amounts that eliminate or reduce the subject’s viral burden and / or viral reservoir.

[0068] “Administering” refers to oral administration, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, intrathecal administration, or the implantation of a slow-release device e.g., a mini-osmotic pump, to the subject. The administration can be carried out according to a schedule specifying frequency of administration, dose for administration, and other factors.Attorney Docket No. 1587-WO-PCT

[0069] “Co-administration” as used herein refers to administration of unit dosages of the compounds disclosed herein before or after administration of unit dosages of one or more additional therapeutic agents, for example, administration of the compound disclosed herein within seconds, minutes, or hours of the administration of one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound of the present disclosure is administered first, followed within seconds or minutes by administration of a unit dose of one or more additional therapeutic agents. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound of the present disclosure within seconds or minutes. In some embodiments, a unit dose of a compound of the present disclosure is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more additional therapeutic agents. In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of a compound of the present disclosure. Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents, such that therapeutically effective amounts of each agent are present in the body of the patient.

[0070] “Subject” refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In some embodiments, the subject is a human.

[0071] “Disease” or “condition” refer to a state of being or health status of a patient or subject capable of being treated with a compound, pharmaceutical composition, or method provided herein. The disease may be an autoimmune, inflammatory, cancer, infectious (e.g., a viral infection), metabolic, developmental, cardiovascular, liver, intestinal, endocrine, neurological, or other disease. In some embodiments, the disease is cancer (e.g. lung cancer, ovarian cancer, osteosarcoma, bladder cancer, cervical cancer, liver cancer, kidney cancer, skin cancer (e.g., Merkel cell carcinoma), testicular cancer, leukemia, lymphoma, head and neck cancer, colorectal cancer, prostate cancer, pancreatic cancer, melanoma, breast cancer, neuroblastoma).

[0072] “C ancer” refers to all types of cancer, neoplasm or malignant tumors found in mammals, including leukemias, lymphomas, melanomas, neuroendocrine tumors, carcinomas and sarcomas. Exemplary cancers that may be treated with a compound, pharmaceutical composition, or method provided herein include lymphoma, sarcoma, bladder cancer, bone cancer, brain tumor, cervical cancer, colon cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer,Attorney Docket No. 1587-WO-PCT myeloma, thyroid cancer, leukemia, prostate cancer, breast cancer (e.g. triple negative, ER positive, ER negative, chemotherapy resistant, herceptin resistant, HER2 positive, doxorubicin resistant, tamoxifen resistant, ductal carcinoma, lobular carcinoma, primary, metastatic), ovarian cancer, pancreatic cancer, liver cancer (e.g. hepatocellular carcinoma), lung cancer (e.g. nonsmall cell lung carcinoma, squamous cell lung carcinoma, adenocarcinoma, large cell lung carcinoma, small cell lung carcinoma, carcinoid, sarcoma), glioblastoma multiforme, glioma, melanoma, prostate cancer, castration-resistant prostate cancer, breast cancer, triple negative breast cancer, glioblastoma, ovarian cancer, lung cancer, squamous cell carcinoma (e.g., head, neck, or esophagus), colorectal cancer, leukemia, acute myeloid leukemia, lymphoma, B cell lymphoma, or multiple myeloma.

[0073] “Metastasis,” “metastatic,” and “metastatic cancer” can be used interchangeably and refer to the spread of a proliferative disease or disorder, e.g., cancer, from one organ or another non-adjacent organ or body part. Cancer occurs at an originating site, e.g., breast, which site is referred to as a primary tumor, e.g., primary breast cancer. Some cancer cells in the primary tumor or originating site acquire the ability to penetrate and infiltrate surrounding normal tissue in the local area and / or the ability to penetrate the walls of the lymphatic system or vascular system circulating through the system to other sites and tissues in the body. A second clinically detectable tumor formed from cancer cells of a primary tumor is referred to as a metastatic or secondary tumor. When cancer cells metastasize, the metastatic tumor and its cells are presumed to be similar to those of the original tumor. Thus, if lung cancer metastasizes to the breast, the secondary tumor at the site of the breast consists of abnormal lung cells and not abnormal breast cells. The secondary tumor in the breast is referred to a metastatic lung cancer. Thus, the phrase metastatic cancer refers to a disease in which a subject has or had a primary tumor and has one or more secondary tumors. The phrases non-mctastatic cancer or subjects with cancer that is not metastatic refers to diseases in which subjects have a primary tumor but not one or more secondary tumors. For example, metastatic lung cancer refers to a disease in a subject with or with a history of a primary lung tumor and with one or more secondary tumors at a second location or multiple locations, e.g., in the breast.

[0074] “ Associated” or “associated with” in the context of a substance or substance activity or function associated with a disease (e.g., diabetes, cancer (e.g. prostate cancer, renal cancer, metastatic cancer, melanoma, castration-resistant prostate cancer, breast cancer, triple negative breast cancer, glioblastoma, ovarian cancer, lung cancer, squamous cell carcinoma (e.g., head, neck, or esophagus), colorectal cancer, leukemia, acute myeloid leukemia, lymphoma, B cell lymphoma, or multiple myeloma)) means that the disease (e.g. lung cancer, ovarian cancer,Attorney Docket No. 1587-WO-PCT osteosarcoma, bladder cancer, cervical cancer, liver cancer, kidney cancer, skin cancer (e.g., Merkel cell carcinoma), testicular cancer, leukemia, lymphoma, head and neck cancer, colorectal cancer, prostate cancer, pancreatic cancer, melanoma, breast cancer, neuroblastoma) is caused by (in whole or in part), or a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function.

[0075] The term “adjacent carbons’" as used herein refers to consecutive carbons atoms that are H H H H H H.4 X. 2 X.H Hdirectly attached to each other. For example, in H H H H, Ci and C2 are adjacent carbons, C2 and C3 are adjacent carbons, C3 and C4 are adjacent carbons, and C4 and C5 are adjacent 62 ( \^ J4carbons. Similarly, in3Ci and C2 are adjacent carbons, C2 and C3 are adjacent carbons, C and C4 are adjacent carbons, and C4 and C5 are adjacent carbons, C5 and C> are adjacent carbons and Ce and Ci are adjacent carbons.

[0076] “Solvate’" as used herein refers to the result of the interaction of a solvent and a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0077] “Prodrug” as used herein refers to a derivative of a drug that upon administration to the human body is converted to the parent drug according to some chemical or enzymatic pathway.

[0078] As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes, but is not limited to, any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and combinations thereof. The use of pharmaceutically acceptable carriers and pharmaceutically acceptable excipients for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic formulations is contemplated. Supplementary active ingredients can also be incorporated into the formulations. The carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.III. Compounds

[0079] Disclosed herein are, among other things, compounds of Formula (lib). In some embodiments, the present disclosure provides a compound of Formula (lib):Attorney Docket No. 1587-WO-PCTor a pharmaceutically acceptable salt thereof,whereinR1is F;R1band R2bare each independently H or Me, wherein at least one of R1band R2bis Me; RA2is -NH2; and-O-Lc-Rcis:alternatively, whereinR1is H;Rlband R2bare each Me;RA2is -NH2; and-O-Lc-Rcis:alternatively, whereinR1is H or F;Rlband R2bare each independently H or Me, wherein at least one of Rlband R2bis Me; RA2is -OH; and-O-Lc-Rcis:Attorney Docket No. 1587-WO-PCTalternatively, whereinR1is H or F;R1band R2bare each H;RA2is -OH; and-O-Lc-Rcis:

[0080] In some embodiments, the present disclosure provides the compound of Formula (lib), or a pharmaceutically acceptable salt thereof, wherein R1is H. In some embodiments, the present disclosure provides the compound of Formula (lib), or a pharmaceutically acceptable salt thereof, wherein R1is F.

[0081] In some embodiments, the present disclosure provides the compound of Formula (Uh), or a pharmaceutically acceptable salt thereof, wherein R1bis H; and R2bis Me. In some embodiments, the present disclosure provides the compound of Formula (lib), or a pharmaceutically acceptable salt thereof, wherein R1bis Me; and R2bis Me.

[0082] In some embodiments, the present disclosure provides the compound of Formula (lib), or a pharmaceutically acceptable salt thereof, wherein-O-Lc-Rcis:FAttorney Docket No. 1587-WO-PCT

[0083] In some embodiments, the present disclosure provides a compound, or a pharmaceutically acceptable salt thereof, having the structure:Attorney Docket No. 1587-WO-PCT

[0084] Also falling within the scope herein are the in vivo metabolic products of the compounds described herein. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, esterification and the like of the administered compound, primarily due to enzymatic processes. Accordingly, included are novel and unobvious compounds produced by a process comprising contacting a compound with a mammal for a period of time sufficient to yield aAttorney Docket No. 1587-WO-PCT metabolic product thereof. Such products typically are identified by preparing a radiolabelled (e.g., or 3] i) compound, administering it parenterally in a detectable dose (e.g., greater than about 0.5 mg / kg) to an animal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from the urine, blood or other biological samples. These products are easily isolated since they are labeled (others are isolated by the use of antibodies capable of binding epitopes surviving in the metabolite). The metabolite structures are determined in conventional fashion, e.g., by MS or NMR analysis. In general, analysis of metabolites is done in the same way as conventional drug metabolism studies. The conversion products, so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds even if they possess no HSV antiviral activity of their own.

[0085] Recipes and methods for determining stability of compounds in surrogate gastrointestinal secretions are known. Compounds are defined herein as stable in the gastrointestinal tract where less than about 50 mole percent of the protected groups are deprotected in surrogate intestinal or gastric juice upon incubation for 1 hour at 37°C. Simply because the compounds are stable to the gastrointestinal tract does not mean that they cannot be hydrolyzed in vivo. The prodrugs typically will be stable in the digestive system but may be substantially hydrolyzed to the parental drug in the digestive lumen, liver, lung or other metabolic organ, or within cells in general. As used herein, a prodrug is understood to be a compound that is chemically designed to efficiently liberate the parent drug after overcoming biological barriers to oral deliver}'.IV. Pharmaceutical Compositions

[0086] Also disclosed herein are pharmaceutical compositions comprising a pharmaceutically effective amount of a compound of the present disclosure (e.g., a compound of Formula (lib)), or a pharmaceutically acceptable salt thereof), and a pharmaceutically acceptable carrier or excipient. Also provided herein is a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0087] The compounds disclosed herein can be formulated with conventional carriers and excipients. Tablets can contain, for instance, excipients, glidants, fillers, binders, or a combination thereof. Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. Exemplary excipients include, but are not limited to, those set forth in the “HANDBOOK OF PHARMACEUTICAL EXCIPIENTS” (1986).Attorney Docket No. 1587-WO-PCT

[0088] In some embodiments, the compounds disclosed herein have pharmacokinetic properties (e.g., oral bioavailability) suitable for oral administration of the compounds. Formulations suitable for oral administration can, for instance, be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient can also be administered, for instance, as a bolus, electuary, or paste.

[0089] A tablet can be made by compression or molding, optionally with at least accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as, for instance, a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active, dispersing agent, or a combination thereof. Molded tablets can be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets can optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom.

[0090] For infections of the eye or other external tissues (e.g., mouth and skin), the formulations can be applied as a topical ointment or cream containing the active ingredient(s). When formulated in an ointment, the active ingredients can be employed in some embodiments with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients can be formulated in a cream with an oil-in-water cream base.

[0091] In some embodiments, the cream base can include, for instance, a compound that enhances absorption or penetration of the active ingredient through the skin or other affected areas. In some embodiments, the cream or emulsion does not include water.

[0092] The oily phase of the emulsions can be constituted from known ingredients in a known manner. In some embodiments, the phase comprises merely an emulsifier (otherwise known as an emulgent). In some embodiments, the phase comprises a mixture of at least one emulsifier with a fat, an oil, or a combination thereof. In some embodiments, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. Together, the emulsifier(s) with or without stabilizer(s) can make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base that can form the oily dispersed phase of the cream formulations.Attorney Docket No. 1587-WO-PCT

[0093] The choice of suitable oils or fats for the formulation can be based on achieving the desired cosmetic properties.

[0094] In some embodiments, the compounds disclosed herein are administered alone. In some embodiments, the compounds disclosed herein are administered in pharmaceutical compositions. In some embodiments, the pharmaceutical compositions are for veterinary use. In some embodiments, the pharmaceutical compositions are for human use. In some embodiments, the pharmaceutical compositions disclosed herein include at least one additional therapeutic agent. In some embodiments, the pharmaceutical compositions disclosed herein include one or more additional therapeutic agent. In some embodiments, the one or more additional therapeutic agents is independently a chemotherapeutic agent, an immunotherapeutic agent, a hormonal agent, an anti-hormonal agent, a targeted therapy agent, or an anti-angiogenesis agent.

[0095] Pharmaceutical compositions disclosed herein can be in any form suitable for the intended method of administration. The pharmaceutical compositions disclosed herein can be presented in unit dosage form and can be prepared by any of the methods well known in the art of pharmacy. Exemplary techniques and formulations can be found, for instance, in REMINGTON’S PHARMACEUTICAL SCIENCES (Mack Publishing Co., Easton, PA). Such methods can include the step of bringing into association a compound disclosed herein with the carrier that constitutes at least accessory ingredients. In general, the formulations can be prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

[0096] When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, solutions, syrups or elixirs can be prepared. Formulations intended for oral use can be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such formulations can contain at least agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. Tablets can be uncoated or can be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.

[0097] Formulations for oral use can be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium.Attorney Docket No. 1587-WO-PCT

[0098] Aqueous suspensions can contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. The aqueous suspension can also contain, for example, at least preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents, one or more sweetening agents (such as sucrose or saccharin), or combinations thereof.

[0099] Oil suspensions can be formulated by suspending the active ingredient in a vegetable oil, a mineral oil, or a combination thereof. The oral suspensions can contain, for instance, a thickening agent. In some embodiments, sweetening agents, such as those set forth above, and / or flavoring agents, are added to provide a palatable oral preparation. In some embodiments, the formulations disclosed herein are preserved by the addition of an antioxidant such as ascorbic acid.

[0100] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water can provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, a preservative, and combinations thereof. Additional excipients, for example sweetening, flavoring and coloring agents, can also be present.

[0101] The pharmaceutical compositions can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil, such as olive oil or arachis oil, a mineral oil, or a mixture of these. The emulsion can also contain sweetening and flavoring agents. Such formulations can also contain, for instance, a demulcent, a preservative, a flavoring, a coloring agent, or a combination thereof.

[0102] The pharmaceutical compositions can be in the form of a sterile injectable or intravenous preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable or intravenous preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, or prepared as a lyophilized powder.

[0103] The amount of active ingredient that can be combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. The pharmaceutical composition can be prepared to provide easily measurable amounts for administration.Attorney Docket No. 1587-WO-PCT

[0104] Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient.

[0105] Formulations suitable for topical administration in the mouth include lozenges can comprise an active ingredient (i.e., a compound disclosed herein and / or additional therapeutic agents) in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0106] Formulations for rectal administration can be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.

[0107] Formulations suitable for vaginal administration can be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

[0108] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions that can contain anti-oxidants, buffers, bacteriostats and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and nonaqueous sterile suspensions that can include suspending agents and thickening agents.

[0109] The formulations can be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately before use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit-dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.

[0110] It should be understood that in addition to the ingredients particularly mentioned above the formulations can include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration can include flavoring agents.

[0111] Further provided are veterinary formulations comprising a compound disclosed herein together with a veterinary carrier therefor.Attorney Docket No. 1587-WO-PCT

[0112] Veterinary carriers are materials useful for the purpose of administering the formulation and can be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and arc compatible with the active ingredient. These veterinary formulations can be administered orally, parenterally, or by any other desired route.

[0113] Compounds herein are used to provide controlled release pharmaceutical compositions containing as active ingredient one or more of the compounds (“controlled release formulations”) in which the release of the active ingredient can be controlled and regulated to allow less frequency dosing or to improve the pharmacokinetic or toxicity profile of a given active ingredient.

[0114] Effective dose of active ingredient depends at least on the nature of the condition being treated, toxicity, the method of delivery, and the pharmaceutical composition, and will be determined by the clinician using conventional dose escalation studies.V. Kits

[0115] Also provided herein are kits that includes a compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments the kits described herein can comprise a label and / or instructions for use of the compound in the treatment of a disease or condition in a subject (e.g., human) in need thereof. In some embodiments, the disease or condition is viral infection.

[0116] In some embodiments, the kit can also comprise one or more additional therapeutic agents and / or instructions for use of additional therapeutic agents in combination with the compound disclosed herein in the treatment of the disease or condition in a subject (e.g., human) in need thereof.

[0117] In some embodiments, the kits provided herein comprise individual dose units of a compound as described herein, or a pharmaceutically acceptable salt, racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate or solvate thereof. Examples of individual dosage units can include pills, tablets, capsules, prefilled syringes or syringe cartridges, IV bags, inhalers, nebulizers etc., each comprising a therapeutically effective amount of the compound in question, or a pharmaceutically acceptable salt, racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate or solvate thereof. In some embodiments, the kit can contain a single dosage unit and in others multiple dosage units are present, such as the number of dosage units required for a specified regimen or period.Attorney Docket No. 1587-WO-PCT

[0118] Also provided are articles of manufacture that include a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or tautomer thereof; and a container. In some embodiments, the container of the article of manufacture is a vial, jar, ampoule, preloaded syringe, blister package, tin, can, bottle, box, an intravenous bag, an inhaler, or a nebulizer.VI. Administration

[0119] One or more of the compounds of Formula (lib), or a pharmaceutically acceptable salt thereof (herein referred to as the active ingredients), are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It will be appreciated that the route may vary with for example the condition of the recipient. An advantage of the compounds herein is that they are orally bioavailable and can be dosed orally.

[0120] The compounds of the present disclosure (also referred to herein as the active ingredients), can be administered by any route appropriate to the condition to be treated.

[0121] Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It will be appreciated that the route may vary with for example the condition of the recipient. An advantage of certain compounds disclosed herein is that they are orally bioavailable and can be dosed orally.

[0122] A compound of the present disclosure may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration.

[0123] The dosage or dosing frequency of a compound of the present disclosure may be adjusted over the course of the treatment, based on the judgment of the administering physician.

[0124] The compound may be administered to an individual (e.g., a human) in an effective amount. In some embodiments, the compound is administered once daily.

[0125] The compound can be administered by any useful route and means, such as by oral or parenteral (e.g., intravenous) administration.Attorney Docket No. 1587-WO-PCT

[0126] A compound of the present disclosure may be combined with one or more additional therapeutic agents in any dosage amount of the compound of the present disclosure). A single dose can be administered hourly, daily, or weekly.

[0127] The frequency of dosage of the compound of the present disclosure can be determined by the needs of the individual patient and can be, for example, once per day or twice, or more times, per day. Administration of the compound continues for as long as necessary to treat the disease or condition.

[0128] Administration can be intermittent, with a period of several or more days during which a patient receives a daily dose of the compound of the present disclosure followed by a period of several or more days during which a patient does not receive a daily dose of the compound. Alternating periods of administration of the compound, followed by non-administration of the compound, can be repeated as clinically required to treat the patient.

[0129] In some embodiments, pharmaceutical compositions comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents, and a pharmaceutically acceptable excipient are provided.

[0130] In some embodiments, kits comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents are provided.

[0131] In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four or more additional therapeutic agents. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents. The one, two, three, four or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, and / or they can be selected from different classes of therapeutic agents.

[0132] In some embodiments, when a compound of the present disclosure is combined with one or more additional therapeutic agents as described herein, the components of the composition areAttorney Docket No. 1587-WO-PCT administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations.

[0133] In some embodiments, a compound of the present disclosure is combined with one or more additional therapeutic agents in a unitary dosage form for simultaneous administration to a patient, for example as a solid dosage form for oral administration.

[0134] In some embodiments, a compound of the present disclosure is co-administered with one or more additional therapeutic agents.

[0135] In order to prolong the effect of a compound of the present disclosure, it is often desirable to slow the absorption of a compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending a compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of a compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping a compound in liposomes or microemulsions that are compatible with body tissues.VII. Methods of Use

[0136] The disclosure further relates to the use of compounds disclosed herein for the treatment of diseases and / or conditions through inhibition of KRAS G12C, G12D and / or G12V. Further, the present disclosure relates to the use of said compounds for the preparation of a medicament for the treatment of cancer.

[0137] Medicaments as referred to herein can be prepared by conventional processes, including the combination of a compound according to the present disclosure and a pharmaceutically acceptable carrier.

[0138] In some embodiments, provided herein is a method of inhibiting KRAS G12C, G12D and / or G12V protein in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (lib), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (lib).Attorney Docket No. 1587-WO-PCT

[0139] In some embodiments, provided herein is treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (Uh), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (lib).

[0140] In some embodiments, provided herein is a method of treating a cancer.

[0141] In some embodiments, provided herein is a method of treating a KRAS G12C-, G12D-and / or G12V-associated cancer.

[0142] In some embodiments, provided herein is a method of reducing the proliferation of a cell comprising contacting the cell with a compound of Formula (lib), or a pharmaceutically acceptable salt thereof.

[0143] In some embodiments, the KRAS G12C, G12D and / or G12V associated disease or condition includes cancer. In some embodiments, the cancer is a hematological cancer. In some embodiments, the cancer includes a solid tumor. In some embodiments, the cancer includes a malignant tumor. In some embodiments the cancer includes a metastatic cancer. In some embodiments, the cancer is resistant or refractory to one or more anticancer therapies. In some embodiments, greater than about 50% of the cancer cells detectably express one or more cell surface immune checkpoint receptors (e.g., so-called “hot” cancer or tumor). In some embodiments, greater than about 1% and less than about 50% of the cancer cells detectably express one or more cell surface immune checkpoint receptors (e.g., so called “warm” cancer or tumor). In some embodiments, less than about 1% of the cancer cells detectably express one or more cell surface immune checkpoint receptors (e.g., so called “cold” cancer or tumor).

[0144] In some embodiments, the KRAS G12C, G12D and / or G12V associated disease or condition is colorectal cancer, lung cancer, pancreatic cancer, ovarian cancer, endometrial cancer, esophageal cancer, gastric cancer, biliary cancer, brain cancer, melanoma, or hepatocellular cancer.

[0145] In some embodiments, the KRAS G12C, G12D and / or G12V associated disease or condition is colorectal cancer, non-small cell lung cancer, pancreatic cancer, or ovarian cancer.

[0146] In some embodiments, the KRAS G12C, G12D and / or G12V associated disease or condition is a cancer selected from a lung cancer, a colorectal cancer, a breast cancer, an endometrial cancer, a prostate cancer, a cervical cancer, a pancreatic cancer and a head and neck cancer. In some embodiments, the cancer is metastatic.Attorney Docket No. 1587-WO-PCT

[0147] In some embodiments, the compound or pharmaceutically acceptable salt thereof of the present disclosure is administered in combination with one or more additional therapeutic agent or therapeutic modality.

[0148] In some embodiments, the present disclosure provides the pharmaceutical composition or the method wherein the one or more more additional therapeutic agent or additional therapeutic modality comprises one, two, three, or four additional therapeutic agents and / or therapeutic modalities.

[0149] In another embodiment, the present disclosure provides a method for manufacturing a medicament for treating cancer in a subject in need thereof, characterized in that a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is used.

[0150] In another embodiment, the present disclosure provides a method for manufacturing a medicament for inhibiting cancer metastasis in a subject in need thereof, characterized in that a compound of the present invention, or a pharmaceutically acceptable salt thereof, is used.

[0151] In another embodiment, the present disclosure provides use of the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer in a subject.

[0152] In another embodiment, the present disclosure provides use of the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting cancer metastasis in a subject.

[0153] In another embodiment, the present disclosure provides the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in a subject in need thereof.

[0154] In another embodiment, the present disclosure provides the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in inhibiting cancer metastasis in a subject in need thereof.

[0155] In another embodiment, the present disclosure provides the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in therapy.Attorney Docket No. 1587-WO-PCT VIII. Combination Therapy

[0156] In some embodiments, a compound of Formula (lib), provided herein, or pharmaceutically acceptable salt thereof, is administered in combination with one or more additional therapeutic agents to treat a disease or condition disclosed herein. In some embodiments, the one or more additional therapeutic agents are one, two, three, or four additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are one additional therapeutic agent. In some embodiments, the one or more additional therapeutic agents are two additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are three additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are four additional therapeutic agents.

[0157] In some embodiments, the pharmaceutical compositions provided herein have a compound of Formula (lib), provided herein, or pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are one, two, three, or four additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are one additional therapeutic agent. In some embodiments, the one or more additional therapeutic agents are two additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are three additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are four additional therapeutic agents.

[0158] In some embodiments the additional therapeutic agent includes, EGFR inhibitors, topoisomerase inhibitors, AURKA inhibitors, AKT inhibitors, PD-L1 inhibitors, PD-1 inhibitors, CDK4 / 6 inhibitors, CXCR1 / CXCR2 inhibitors, ERK inhibitors, FAK inhibitors, MEK inhibitors, mTOR inhibitors, PARP inhibitors, PI3Ka inhibitors, PIM inhibitors, PRMT5 inhibitors, RAF / MEK inhibitors, RAS inhibitors, RTK inhibitors, SOS1 inhibitors, SHP2 inhibitors, ULK1 / 2 inhibitors, VEGF inhibitors, famesyl transferase inhibitors, immunotherapy, chemotherapy, proteasome inhibitors, radiation therapy, antibody-drug conjugate, or any combination thereof. In some embodiments, the chemotherapy is gemcitabine, taxanes (docetaxel and paclitaxel), 5FU, or any combination thereof.

[0159] In some embodiments the compound provided herein is administered with one or more therapeutic agents selected from a PI3K inhibitor, a Trop-2 binding agent, a FLT3R agonist, a PD- 1 antagonist, a PD-L1 antagonist, an MCL1 inhibitor, a CCR8 binding agent, an HPK1 antagonist, a DGKa inhibitor, a CISH inhibitor, a PARP-1 inhibitor, a PARP-7 inhibitor, a Cbl-b inhibitor, a KRAS inhibitor (e.g., a KRAS G12C or G12D inhibitor), a KRAS degrader, a beta-catenin degrader, a helios degrader, a CD73 inhibitor, an adenosine receptor antagonist, a TIGITAttorney Docket No. 1587-WO-PCT antagonist, a CD 137 agonist, an 0X40 binding agent, a PRMT5 inhibitor, a WRN inhibitor, an IL-2v inhibitor, an IL-18BP inhibitor, a LIV-1 TCE inhibitor, a CDK2 / E1 inhibitor, an FAP inhibitor, a LRRC15 binding agent, a SLC7A11 inhibitor, a TREX1 inhibitor, and a CAR-T cell therapy.IX. Compound Preparation

[0160] In some embodiments, the present disclosure provides processes and intermediates useful for preparing the compounds disclosed herein or pharmaceutically acceptable salts thereof.

[0161] Compounds disclosed herein can be purified by any of the means known in the art, including chromatographic means, including but not limited to high-performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography, ion exchange chromatography, and supercritical fluid chromatography (SFC). Any suitable stationary phase can be used, including but not limited to, normal and reversed phases as well as ionic resins. In some embodiments, the disclosed compounds are purified via silica gel and / or alumina chromatography.

[0162] During any of the processes for preparation of the compounds provided herein, it can be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved by means of conventional protecting groups as described in standard works, such as T. W. Greene and P. G. M. Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, 4th ed., Wiley, New York 2006. The protecting groups can be removed at a convenient subsequent stage using methods known from the art.

[0163] Exemplary chemical entities useful in methods of the embodiments will now be described by reference to illustrative synthetic schemes for their general preparation herein and the specific examples that follow. Skilled artisans will recognize that, to obtain the various compounds herein, starting materials can be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it can be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that can be carried through the reaction scheme and replaced as appropriate with the desired substituent. Furthermore, one of skill in the art will recognize that the transformations shown in the schemes below can be performed in any order that is compatible with the functionality of the particular pendant groups.Attorney Docket No. 1587-WO-PCT

[0164] The methods of the present disclosure generally provide a specific enantiomer or diastereomer as the desired product, although the stereochemistry of the enantiomer or diastereomer was not determined in all cases. When the stereochemistry of the specific stereocenter in the enantiomer or diastereomer is not determined, the compound is drawn without showing any stereochemistry at that specific stereocenter even though the compound can be substantially enantiomerically or disatereomerically pure.

[0165] Compounds disclosed herein can be prepared from commercially available reagents using the synthetic methods and reaction schemes described herein, or using other reagents and conventional methods known to persons of ordinary skill in the art. For instance, representative syntheses of compounds of the present disclosure are described in the schemes below, and the particular examples that follow.EXAMPLESI. Abbreviations

[0166] Certain abbreviations and acronyms are used in describing the experimental details. Although most of these would be understood by one skilled in the art, Table 1 contains a list of many of these abbreviations and acronyms.Table 1. List of Abbreviations and AcronymsAbbreviation Meaning°C degree(s) CelsiusPg or ug microgram(s)pL or uL microliter(s)pm or urn micron(s)p mol or umol micromole(s)ACN acetonitrileaq aqueousBoc tert-butoxycarbonylbr s broad singletcataCXium A Pd G3 mesylate[(di(1-adamantyl)-n-butylphosphine)-2-(2′-amino-1,1′-biphenyl)]palladium(II)Cbz benzyloxycarbonylCOD 1,5 -cyclooctadiened doubletDCM dichloromethanedd doublet of doubletsAttorney Docket No. 1587-WO-PCT ddd doublet of doublet of doubletsddt doublet of doublet of tripletsDIPEA N, N -diisopropylethylamineDMAP 4-dimethylaminopyridineDMB 2,4-dimethoxybenzylDMF dimethylformamideDMP Dess-Martin periodinaneDMSO dimethyl sulfoxidedt doublet of tripletsEt ethylEtOAc ethyl acetateg gram(s)h hour(s)HATU hexafluorophosphate aza benzo triazole tetramethyl uroniumHPLC high-performance liquid chromatographyHz Hertz'Pr isopropylIPA or iPrOH isopropyl alcoholJ coupling constantKHMDS potassium bis(trimethylsilyl)amideKOAc potassium acetateLAH lithium aluminum hydrideLCMS liquid chromatography mass spectrometryLDA lithium diisopropylamideLiHMDS lithium bis(trimethylsilyl)amidem multipletM molarityMe methylMeCN acetonitrileMeOH methanolmg milligram(s)MHz megahertzmin minute(s)mL milliliter(s)mm millimeter(s)mmol millimole(s)MOMO or OMOM methoxymethylNaOMe sodium methoxiden-BuLi n-butyllithiumNMR nuclear magnetic resonanceOSEM 2-(trimethylsilyl)ethoxymethoxyAttorney Docket No. 1587-WO-PCT OTf tri fluoromethane sulfon atePiv pivaloylqd quartet of doubletsrt or RT room temperature[dicyclohexyl(2′,6′-diisopropoxy-2-biphenylyl)phosphine-κP](methanesulfonato-κO)[2′-(methylamino-κN)-2-biphenylyl-κC²]palladium (CAS # 1599466-85-9)s singletsat. saturatedsec-BuLi sec-butyllithiumt tripletTBAF tetrabutylammonium fluorideTBS tert-butyldimethylsilylTBSC1 tert-Butyldimethylsilyl chloride'Bu tert-butyltd triplet of doubletsTES triethylsilaneTF₂O or Tf₂O tri f 1 uorom e than e sulfon ic anhydri deTFA trifluoroacetic acidTHF tetrahydrofuranTIPS triisopropylsilylTMEDA tetramethylethylenediamineTMS trimethylsilyltt triplet of tripletsv / v volume / volumewt weight5 parts per million referenced to residual non-deuterated solvent peakII. IntermediatesIntermediates 1-1 - 1-4.ci Br 0 step 1 step 3F F INT 1-1 INT 1-3Br Cl step 4FINT 1-4Attorney Docket No. 1587-WO-PCT

[0167] Step 1: 7-chloro-2-(ethylthio)-8-fluoro-4-methoxypyrido[4,3-d]pyrimidine (Intermediate 1-1). Sodium methoxide solution (25% wt in methanol, 20 mmol) was added over 15 min via syringe pump to a vigorously stirred solution of 2,4,7-trichloro-8-fluoropyrido[4,3-<7|pyrimidinc (19.8 mmol) in 2-methyltetrahydrofuran (70 mL) at -20°C. After 11 min, ethanethiol (59.5 mmol) was added over 1 min via syringe. After 1 min, N, N-diisopropylethylamine (63.5 mmol) was added over 2 min via syringe. After 11 min, the resulting mixture was warmed to room temperature. After 20 min, the resulting mixture was heated to 70°C. After 22 h, the resulting mixture was cooled to room temperature, and citric acid (3.0 g), diethyl ether (200 mL), and ethyl acetate (25 mL) were added sequentially. The organic layer was washed with water (200 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 11% ethyl acetate in hexanes) to afford the title compound. LCMS: 274.0.

[0168] Step 2: 5-bromo-7-chloro-2-(ethylthio)-8-fluoro-4-methoxypyrido[4,3-d]pyrimidine (Intermediate 1-2).2,2,6,6-Tetramethylpiperidinylmagnesium chloride lithium chloride complex solution (1.0 M in tetrahydrofuran, 14 mmol) was added over 20 min via syringe pump to a vigorously stirred solution of Intermediate 1-1 (3.65 mmol) in tetrahydrofuran (3.0 mL) at 0°C. After 60 min, a solution of l,2-dibromo-l,1.2,2-tetrachloroethane (14.6 mmol) in tetrahydrofuran (8.0 mL) was added via syringe. After 120 min, citric acid (5.0 g), diethyl ether (200 mL), and ethyl acetate (25 mL) were added sequentially. The organic layer was washed with water (2 x 150 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 5% ethyl acetate in hexanes) to give the title compound. LCMS: 351.9.

[0169] Step 3: 5-bromo-7-chloro-2-(ethylthio)-8-fluoropyrido[4,3-rf]pyrimidin-4(3H)-one (Intermediate 1-3). Sodium iodide (1.90 g, 12.7 mmol) was added to a vigorously stirred solution of Intermediate 1-2 (895 mg, 2.54 mmol) in acetic acid (12.0 mL) at room temperature, and the resulting mixture was heated to 80°C. After 2.5 h, the resulting mixture was cooled to room temperature, and ethyl acetate (100 mL) and aqueous sodium thiosulfate solution (1.0 M, 2.0 mL) were added sequentially. The organic layer was washed with water (100 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure to give the title compound. LCMS: 337.9.

[0170] Step 4: 5-bromo-4,7-dichIoro-2-(ethylthio)-8-fluoropyrido[4,3-d]pyrimidine (Intermediate 1-4). A, A- Diisopropylethylamine (5.08 mmol) was added via syringe to a mixture of Intermediate 1-3 (2.48 mmol) and phosphorous(V) oxychloride (10 mL) at room temperature,Attorney Docket No. 1587-WO-PCT and the resulting mixture was stirred at rt for 15 min before it was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 13% ethyl acetate in hexanes) to give the title compound. LCMS: 357.9.Intermediate 4-1.INT 4-1

[0171] Step 1: 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-l,3-diyl bis(trifluoromethanesulfonate). To a solution of 7-fluoro-8- ((triisopropylsilyl)ethynyl)naphthalene-l,3-diol (61.4 mmol) in DCM (154 mL) at 0 °C were added sequentially DIPEA (245 mmol) and Tf2O (129 mmol). Upon completion, the reaction was partitioned between water and DCM. The organic fraction was washed with brine, then dried over sodium sulfate and concentrated under reduced pressure to afford the title compound which was used without further purification. 'H NMR (CDCI3, 400 MHz) 57.95 - 7.75 (m, 2H), 7.55 - 7.45 (m, 2H), 1.40 - 1.15 (m, 21H) ppm.

[0172] Step 2: 3-((diphenylmethylene)amino)-7-fluoro-8 ((triisopropylsilyl)ethynyl)naphthalen-l-yl trifluoromethanesulfonate. To a mixture of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene- 1, 3-diy 1 bis(trifluoromethanesulfonate) (41.8 mmol), diphenylmethanimine (45.9 mmol), and toluene (260 mL) were added CS2CO3 (125 mmol), Xantphos (8.35 mmol) and Pd2(dba)3. The mixture was evacuated and backfilled with N2 three times, then heated to 100 °C under N2. Upon completion, volatiles were removed under reduced pressure and the resulting residue was purified by silica gel chromatography eluting with petroleum ether / EtOAc. Fractions containing the product were pooled and concentrated under reduced pressure to afford the title compound.

[0173] Step 3: N-(6-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaboroIan-2-yl)-5- ((triisopropylsilyl)ethynyl)naphthalen-2-yl)-l,l-diphenylmethanimine (Intermediate 4-1).3-((diphenylmethylene)amino)-7-tluoro-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl trifluoromethanesulfonate (28.2 mmol), bis(pinacolato)diboron (61.2 mmol), KOAc (61.2 mmol),Attorney Docket No. 1587-WO-PCT and Pd(dppf)C12 (3.06 mmol), were combined in a flask and diluted with toluene (200 mL). The mixture was evacuated and backfilled with N2 three times, then heated to 110 °C under N2. Upon completion, volatiles were removed under reduced pressure and the resulting residue was purified by silica gel chromatography eluting with petroleum ether / EtOAc. Fractions containing the product were pooled and concentrated under reduced pressure to afford the title compound.NMR (DMSO-de, 400 MHz) 57.87 - 7.80 (m, 1H), 7.74 - 7.68 (m, 2H), 7.62 - 7.55 (m, 1H), 7.53 - 7.47 (m, 2H), 7.47 - 7.39 (m, 1H), 7.35 - 7.27 (m, 4H), 7.23 - 7.18 (m, 2H), 7.15 - 7.10 (m, 1H), 1.26 (s, 12H), 1.15 - 1.07 (m, 21H) ppm. LCMS: 632.Intermediate 5-1.INT 4-1

[0174] Step 1: 6-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaboroIan-2-yl)-5- ((triisopropylsilyl)ethynyl)naphthalen-2-amine (Intermediate 5-1). To a solution of Intermediate 4-1 (0.510 mmol) in EtOAc (2.00 mL) was added HC1 in dioxane (1.30 mL of 4 M solution) and water (1.02 mmol). Upon completion, the reaction mixture was filtered and rinsed with hexanes to afford the title compound. LCMS 468.3.Intermediates 6-1 - 6-2.CO2Me step 2 AvCbz

[0175] Step 1: 1-benzyl 2-methyl 2-(but-3-en-l-yl)pyrrolidine-l,2-dicarboxylate. 1-benzyl 2-methyl (S)-pyrrolidine-l,2-dicarboxylate (3.8 mol) in THF (2 L) was added dropwise to a solutionAttorney Docket No. 1587-WO-PCT of LiHMDS (5.7 mol) in THF (5.7 L) at -60 °C. 4-Bromo-l -butene was added to the mixture. Upon completion, the reaction was partitioned between NH4CI (aq)and EtOAc. The organic fraction was washed with brine, then dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography eluting with petroleum ether / EtOAc. Fractions containing the product were pooled and concentrated under reduced pressure to afford the title compound.

[0176] Step 2: 1-benzyl 2-methyl 2-(2-(oxiran-2-yl)ethyl)pyrrolidine-l,2-dicarboxylate. To a stirred solution of 1-benzyl 2-methyl 2-(but-3-en-l-yl)pyrrolidine-l,2-dicarboxylate (0.94 mol) in DCM (1.8 L) was added m-CPBA (1.13 mol) portionwise while maintaining the temperature between 20 - 30 °C. Upon completion, the reaction was quenched by the dropwise addition of 10% NaHSO₃ (9 L) over Ih then extracted with DCM (9 L). The organic fraction was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography eluting with petroleum ether / EtOAc. Fractions containing the product were pooled and concentrated under reduced pressure to afford the title compound. ¹H NMR (CDCl₃, 400 MHz) δ 7.38 - 7.29 (m, 5 H), 5.19 - 5.06 (m, 2 H), 3.86 - 3.67 (m, 3 H), 3.56 - 3.43 (m, 2 H), 2.99 - 2.64 (m, 2 H), 2.56 - 2.20 (m, 3 H), 2.19 - 1.77 (m, 7 H), 1.68 - 1.39 (m, 3 H) ppm.

[0177] Step 3: methyl 3-(hydroxymethyl)tetrahydro-lH-pyrrolizine-7a(5H)-carboxylate. To a mixture of 1-benzyl 2-methyl 2-(2-(oxiran-2-yl)ethyl)pyrroli dine- 1,2-dicarboxy late in MeOH (3 L) was added Pd / C (50.5 g of 10% Pd / C) under N2. The mixture was pressurized to 50 Psi under H2 atmosphere. Upon completion, the mixture was filtered and the filtrate concentrated under reduced pressure to afford the title compound, which was used without further purification.

[0178] Step 4: rel-methyl (3S,7aS)-3-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-lH-pyrrolizine-7a(5H)-carboxylate. To a solution of methyl 3-(hydroxymethyl)tetrahydro-lH-pyrrolizine-7a(5H)-carboxylate (2.51 mol) and imidazole (2.76 mol) in DCM (3 L) was added TBSC1 (2.51 mol). Upon completion, the reaction was diluted with water and extracted twice with DCM (2 x 1 L). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography eluting with petroleum ether / EtOAc. Fractions containing the product were pooled and concentrated under reduced pressure to afford the title compound. ¹H NMR (CDCl₃, 400 MHz) δ 3.90 (dd, J = 10.4, 4.4 Hz, 1 H) 3.79 (br dd, J = 10.4, 6.0 Hz, 1 H) 3.72 (s, 3 H) 3.37 - 3.27 (m, 1 H) 3.01 - 2.92 (m, 1 H) 2.84 (q, J = 8.4 Hz, 1 H) 2.46 (dt, J = 12.4, 4.8 Hz, 1 H) 2.18Attorney Docket No. 1587-WO-PCT (dt, J = 12.4, 7.6 Hz, 1 H) 1.96 - 1.68 (m, 7 H) 1.66 - 1.55 (m, 1 H) 0.90 (s, 9 H) 0.06 (s, 6 H) ppm.

[0179] Step 5: rel-((3S,7aS)-3-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-lH-pyrrolizin-7a(5H)-yl)inethanol. To a stirred mixture of LiAlH (688 mmol) in THF (1.1 L) at -30 °C was added methyl (3S,7aS)-3-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-lH-pyrrolizine-7a(5H)-carboxylate (574 mmol) dropwise under N2 maintaining the temperature between -30 and -20 °C. Upon completion, the reaction was quenched with water at -20 °C, then gradually warmed to -10 °C. The mixture was then filtered and the filter cake was rinsed with EtOAc (3 x 200 mL). The resulting filtrate was concentrated under reduced pressure, and the residue purified by silica gel chromatography eluting with petroleum ether / EtOAc. Fractions containing the product were pooled and concentrated under reduced pressure to afford the title compound. ¹H NMR (CDCl₃, 400 MHz) δ 3.87 (dd, J = 10.4, 6.0 Hz, 1 H) 3.72 (dd, J = 10.4, 6.0 Hz, 1 H) 3.34 - 3.23 (m, 2 H) 3.18 - 3.07 (m, 1 H) 3.04 (br d, J = 6.4 Hz, 1 H) 2.90 - 2.81 (m, 1 H) 2.75 (td, J = 9.6, 6.4 Hz, 1 H) 2.01 - 1.93 (m, 1 H) 1.49 - 1.85 (m, 8 H) 0.90 (s, 9 H) 0.07 (s, 6 H) ppm.

[0180] Step 6: ((3R,7aR)-3-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (Intermediate 6-1). Rel-((3S,7aS)-3-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (455 mmol) was purified by chiral SFC. Column: (s.s) WHELK-01 (250 mm x 50 mm, 10 um); mobile phase:[0.1% NH3H2O / IPA]; B% = 40; 3.6 min. Early-eluting isomer. The title compound was obtained after concentration of product-containing fractions under reduced pressure. ¹H NMR (400 MHz, DMSO-d₆): δ 4.36 (br s, 1 H) 3.78 (dd, J = 10.4, 5.6 Hz, 1 H) 3.64 (dd, J = 10.4, 6.4 Hz, 1 H) 3.16 - 3.07 (m, 1 H) 3.07 - 2.91 (m, 2 H) 2.70 - 2.62 (m, 2 H) 1.90 (ddd, J = 12.4, 7.2, 2.0 Hz, 1 H) 1.72 - 1.43 (m, 7 H) 1.30 (td, J = 11.2, 7.6 Hz, 1 H) 0.87 (s, 9 H) 0.04 (s, 6 H).

[0181] ((3S,7aS)-3-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (Intermediate 6-2). The title compound was obtained from the purification of Rel-((3S,7aS)-3-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (455 mmol) as the late eluting isomer using the conditions described above for Intermediate 6-1. ¹H NMR (400 MHz, DMSO-d₆): δ 4.36 (br s, 1 H) 3.78 (dd, J = 10.4, 5.6 Hz, 1 H) 3.64 (dd, J = 10.4, 6.4 Hz, 1 H) 3.15 - 3.08 (m, 1 H) 3.07 - 2.93 (m, 2 H) 2.69 - 2.63 (m, 2 H) 1.90 (ddd, J = 12.4, 7.2, 2.0 Hz, 1 H) 1.70 - 1.43 (m, 7 H) 1.36 - 1.25 (m, 1 H) 0.87 (s, 10 H) 0.04 (s, 6 H) ppm.Attorney Docket No. 1587-WO-PCT Intermediate 7-1.HOOTBS INT 6-2 INT 7-1

[0182] Step 1: (3S,7aS)-3-(((tert-butyldimethylsilyl)oxy)methyl)-7a- ((trityloxy)methyl)hexahydro-lH-pyrrolizine. Triphenylmethyl chloride (4.20 mmol) was added to a vigorously stirred mixture of Intermediate 6-2 (3.50 mmol), triethylamine (5.25 mmol), 4-(dimethylamino)pyridine (701 pmol), and dichloromethane (5.0 mL) at room temperature, and the resulting mixture was heated to 40 °C. After 95 min, the resulting mixture was heated to 65 °C. After 120 min, the resulting mixture was cooled to room temperature, and diethyl ether (100 mL) and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with water (100 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 5% methanol in dichloromethane). Fractions containing the product were pooled and lyophilized to give the title compound. LCMS: 528.3.

[0183] Step 2: ((3S,7aS)-7a-((trityloxy)methyl)hexahydro-lH-pyrrolizin-3-yl)methanol (Intermediate 7-1). Tetrabutylammonium fluoride solution (1.0 M in tetrahydrofuran, 10.5 mL, 11 mmol) was added via syringe to a stirred solution of (3S,7aS)-3-(((tert-butyldimethylsilyl)oxy)methyl)-7a-((trityloxy)methyl)hexahydro-lH-pyrrolizine (1.16 g, 2.20 mmol) in tetrahydrofuran (2.0 mL) at room temperature. After 30 min, the resulting mixture was heated to 50 °C. After 15 min, the resulting mixture was cooled to room temperature, and diethyl ether (100 mL), ethyl acetate (20 mL), saturated aqueous ammonium chloride solution (2.0 mL), and saturated aqueous sodium carbonate solution (10 mL) were added sequentially. The organic layer was washed with water (2 x 100 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 100% methanol in dichloromethane) to give the title compound.LCMS: 414.2.Attorney Docket No. 1587-WO-PCT Intermediate 8-1step 1 step 2

[0184] Step 1: (3S,7aS)-3-((pyrimidin-4-yloxy)methyl)-7a-((trityloxy)methyl)hexahydro-IH-pyrrolizidine. To a mixture of Intermediate 7-1 (2.42 mmol) in THF (10 mL) was added sodium hydride (60% dispersion in mineral oil, 12.1 mmol) at 0 °C, and the resulting mixture was stirred at 0°C for 30 mins, then 4-chloro-pyrimidine (3.63 mmol) was added, then the reaction mixture was stirred at 70 °C for 12 h. The reaction mixture was then slowly mixed with ice water and extracted 4x with EtOAc. The residue was purified by flash silica gel chromatography (20 g Silica Flash Column, Eluent of 0 to 54% Ethyl acetate / Petroleum ether). Fractions containing the product were pooled and concentrated under reduced pressure to give the title compound. LCMS: 492.3.

[0185] Step 2: ((3S,7aS)-3-((pyrimidin-4-yloxy)methyl)tetrahydro-lH-pyrroIizin-7a(5H)-yl)methanol (Intermediate 8-1). To a solution of (3S,7aS)-3-((pyrimidin-4-yloxy)methyl)-7a-((trityloxy)methyl)hexahydro-lH-pyrrolizidine (1.63 mmol) in EtOAc (8.0 mL) was added HCl / EtOAc (1.22 mL of 4M solution). Upon completion, the filtered and the cake was washed with EtOAc and petroleum ether successively. The cake was then dissolved in MeCN and basic resin, K2CO3 were added to adjust the pH to 9, then stirred for 30 m. The resulting mixture was filtered and concentrated under reduced pressure to afford the title compound which was used without further purification. ’ll NMR (400 MHz, DMSO-de) 8.78 (s, 1 H), 8.51 (d, J=5.88 Hz, 1 H), 6.97 (d,.1=5.75 Hz, 1 H), 4.41 - 4.55 (m, 3 H), 3.16 (br dd,.1=9.82, 3.56 Hz, 1 H), 3.06 (br dd, J=10.38, 5.13 Hz, 1 H), 2.64 - 2.70 (m, 2 H), 1.95 (br dd,.1=11.94, 6.44 Hz, 1 H), 1.49 - 1.74 (m, 7 H), 1.35 (td,.1=11.54, 7.57 Hz, 1 H) ppm. LCMS: 250.1.Intermediate 9-1.step 1Attorney Docket No. 1587-WO-PCT

[0186] Step 1: (3S,7a5)-3-(fluoromethyl)-7a-((trityloxy)methyl)hexahydro-lH-pyrrolizine.To a solution of Intermediate 7-1 (241.81 umol) in DCM (5 mL) were added sequentially triethylamine (483.62 umol) and methanesulfonyl chloride (362.71 umol) at 0°C. The mixture was stirred at 25 °C for 1 hr. The reaction mixture was quenched with sat. aq. NaHCO₃ (10 ml) and extracted with DCM (3 x 10 mL), the combined organic phase was washed with brine (10 ml), and then dried over Na2SO4, filtered and concentrated. To one third of the residue at room temperature was added tetrabutylammonium fluoride solution (1.0 M in tetrahydrofuran, 10 mmol), and the resulting mixture was stirred vigorously and was heated to 70 °C. After 12 h, the reaction mixture was concentrated under reduced pressure. The residue was diluted with NaHCO₃ (10 mL) and extracted with EtOAc 30 mL (3 x 10 mL). The combined organic layers were washed with brine 20 mL (2 x 10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by RP-HPLC (eluting with water(NH₄HCO₃)-ACN]; B%: 35%-75%, over 8 min). Fractions containing the product were pooled and lyophilized to give the title compound. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.32 - 7.27 (m, 6H), 7.13 - 7.08 (m, 6H), 7.06 - 7.01 (m, 3H), 4.48 - 4.33 (m, 2H), 3.14 - 2.99 (m, 1H), 2.83 (d, 1H, J = 8.4 Hz), 2.68 (d, 2H, J = 8.4 Hz), 2.51 (dt, 1H, J = 6.0, 9.2 Hz), 1.98 -1.89 (m, 1H), 1.66 - 1.44 (m, 6H), 1.34 - 1.20 (m, 1H).

[0187] Step 2: ((3. S.7a. S)-3-(fluoromethyl)tetraliydro-l / / -pyrrolizin-7a(5 / / )-yl)methanol trifluoroacetic acid salt (Intermediate 9-1). (3S,7aS)-3-(fluoromethyl)-7a-((trityloxy)methyl)hexahydro-lH-pyrrolizine (336.91 umol) was dissolved in EtOAc (1.6 mL) and HCl / EtOAc (0.4 mL). The mixture was stirred at 25°C for 1 hr. The residue was purified by RP-HPLC (eluting with water(NH4HCO3)-ACN]; B%: l%-10%, over lOmin) to give the title compound. LCMS: 174.1.Attorney Docket No. 1587-WO-PCT Intermediates 23-1 - 23-8.Boc Boc Boc Boc BocINT 23-1 INT 23-2 INT 23-3 INT 23-4INT 23-5 INT 23-6 INT 23-7

[0188] Step 1: tert-butyl (lR,2R,5S)-2,3-diallyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 23-1). A sealed tube was charged with tert-butyl (lR,2R,5S)-2-allyL3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5.50 mmol), K2CO3 (19.2 mmol), allyl bromide (11.0 mmol) and acetone (20.0 mL). The reaction was heated at 56 °C for 18 hours. The reaction was cooled to RT, filtered and concentrated. The residue was purified by silica gel chromatography to afford the title compound. LCMS 293.0.

[0189] Step 2: tert-butyl (lS,4R,5S)-3,4-diallyl-l-fluoro-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 23-2). A flask charged with Intermediate 23-1 (4.67 mmol) was purged with nitrogen. TMEDA (9.34 mmol) and degassed THF (19.0 mL) were added and the solution was cooled to -55 °C. Sec-BuLi (9.34 mmol, 1.0 M in cyclohexane) was added dropwise and the solution was stirred for 10 min. A solution of N-fluorobenzenesulfonimide (9.34 mmol) in degassed THF (11.0 mL) was added. The solution was stirred until reaction completion. The reaction was quenched with water at -45 °C and was warmed up to RT. Saturated NH₄Cl (aq) was added and the mixture was extracted with EtOAc (3x). The combined organic layer was washed with brine, dried over MgSO₄, filtered and concentrated. The residue was purified by silica gel chromatography to afford the title compound. LCMS 311.0.

[0190] Step 3: tert-butyl (lR,2R,5S)-2,3-diallyl-l,5-difluoro-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 23-3). A flask charged with Intermediate 23-2 (3.89 mmol) was purged with nitrogen. TMEDA (7.77 mmol) and degassed THF (16.0 mL) were added and theAttorney Docket No. 1587-WO-PCT solution was cooled to -60 °C. Sec-BuLi (7.77 mmol, 1 M in cyclohexane) was added dropwise and the solution was stirred for 90 min. The reaction was cooled to -70 °C and a solution of N-fluorobenzenesulfonimide (7.77 mmol) in degassed THF (11.0 mL) was added. The solution was stirred until reaction completion. The reaction was quenched with water at -45 °C and was warmed up to RT. Sat. NH₄Cl (aq) was added and the mixture was extracted with EtOAc (3x). The combined organic layer was washed with brine, dried over MgSO₄, filtered and concentrated. The residue was purified by silica gel chromatography to afford the title compound. LCMS 329.0.

[0191] Step 4: tert-butyl (lR,2R,5S)-2-allyl-l,5-difluoro-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 23-4). A vial charged with Intermediate 23-3 (1.05 mmol), Pd(PPh3)4 (0.105 mmol) and 1,3 -dimethylbarbituric acid (3.15 mmol) was purged with nitrogen. Degassed DCM (10.0 mL) was added and the reaction was heated at 30 °C. Upon completion, the reaction was cooled to RT and washed with sat. Na₂CO₃ (aq) (3x). The organic layer was dried over MgSO₄, filtered and concentrated. The residue was purified by silica gel chromatography to yield the title compound. LCMS 232.9 (M - tBu).

[0192] Step 5: tert-butyl (lR,2R,5S)-2-allyl-3-(5-bromo-7-chloro-2-(ethylthio)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-l,5-difhioro-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 23-5). A vial was charged with Intermediate 1-4 (0.975 mmol), Intermediate 23-4 (0.975 mmol), 4A molecular sieves and 2-MeTHF (5.0 mL). The mixture was stirred at RT for 1 hour. N,N-diisopropylethylamine (4.87 mmol) was added and the reaction was heated at 80 °C for 18 hours. The reaction was cooled to RT, filtered over celite and concentrated. The residue was purified by silica gel chromatography to afford the title compound. LCMS 608.0 / 610.0.

[0193] Step 6: tert-butyl (lR,2R,5S)-2-(3-(9-borabicyclo[3.3.1]nonan-9-yl)propyl)-3-(5-bromo-7-chloro-2-(ethylthio)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-l,5-difluoro-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 23-6). A vial was charged with Intermediate 23-5 (0.430 mmol) and 1,4-dioxane (14.0 mL). 9-Borabicyclo(3.3.1)nonane (0.615 mmol, 0.5 M solution in THF) was added and the reaction was heated at 60 °C. Upon reaction completion, the mixture was cooled to RT and was used directly in the subsequent reaction. LCMS 654.1 / 656.0.

[0194] Step 7: tert-butyl (6aR,7R,10S)-2-chloro-13-(ethylthio)-l,7,10-trifluoro- 5,6,6a,7,8,9,10,ll-octahydro-4H-3,lla,12,14,15-pentaaza-7,10-methanocyclohepta[4,5]cycloocta[l,2,3-de]naphthalene-15-carboxylate (Intermediate 23-7).To a crude solution of Intermediate 23-6 (0.430 mmol) in 1,4-dioxane (14.0 mL) was addedAttorney Docket No. 1587-WO-PCT water (2.80 mL). [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.043 mmol) and K3PO4 (1.29 mmol) were added. The resulting mixture was sparged with argon gas for 5 minutes. The reaction was heated at 90 °C. Upon reaction completion, the reaction was cooled to RT, quenched with sat. NH₄Cl (aq), extracted with EtOAc (3x), washed with brine, dried over MgSO₄, filtered and concentrated. The residue was purified by silica gel chromatography to afford the title compound. LCMS 530.1.

[0195] The following Intermediates were made in a similar fashion to Intermediates 23-1 - 23-7 and are shown below in Table 2. To prepare the below Intermediates, different reagents / starting materials were used than some of those described in the steps toward Intermediates 23-1 - 23-7 and are noted in the last column of Table 2 - “Changes to Procedure: Different Reagents / Starting Materials”. A person of ordinary skill in the art will readily recognize which reagents / starting materials used for the synthesis of Intermediates 23-1 - 23-7 were replaced with the different reagents / starting materials noted below.Table 2. IntermediatesIntermediate Structure LCMS Changes to Procedure:Different Reagents / Starting MaterialsFY- NBocF tert-butyl (lR,2S,5S)-2-vinyl-3,8- \ H N— ' 516.1 diazabicyclo[3.2. l]octane-8- 23-8carboxylate (prepared according to j J J US 2023 / 0374036) in step 1. CI'x^yX'N'X^SEtFAttorney Docket No. 1587-WO-PCT Intermediates 24-1 to 24-4.INT 23-7 INT 24-1

[0196] Step 1: tert-butyl (6aR,7R,10S)-2-chloro-13-(ethylsulfonyl)-l,7,10-trifluoro-5,6,6a,7,8,9,10,ll-octahydro-4H-3,lla,12,14,15-pentaaza-7,10-methanocyclohepta[4,5]cycloocta[l,2,3-de]naphthalene-15-carboxylate (Intermediate 24-1).3-Chloroperbenzoic acid (77% wt, 1.01 mmol) was added in three portions to a stirred solution of Intermediate 23-7 (0.245 mmol) in dichloromethane (5.0 mL) at 0 °C. Upon reaction completion, the reaction was quenched with sat. sodium thiosulfate (aq) and extracted with EtOAc. The organic layer was washed with sat. NaHCO₃ (aq) (3x), brine, dried over MgSO₄, filtered and concentrated. The residue was purified by silica gel chromatography to afford the title compound. LCMS 561.9.

[0197] Step 2: tert-butyl (6aR,7R,10S)-2-chloro-l,7,10-trifluoro-13-(((3S,7aS)-3- (fluoromethyl)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5,6,6a,7,8,9,10,ll-octahydro-4H-3,lla,12,14,15-pentaaza-7,10-methanocyclohepta[4,5]cycloocta[l,2,3-de]naphthalene-15-carboxylate (Intermediate 24-2). ((3S,7aS)-3-(fluoromethyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (0.854 mmol) and toluene (5 mL) were combined and the mixture was concentrated under reduced pressure (2x). 2-MeTHF (5.0 mL) was added and the solution was cooled to 0 °C. Lithium bis(trimethylsilyl)amide solution (1.0 M in THF, 0.641 mmol) was added and the mixture was stirred for 20 min. A solution of tert-butyl (6aR,7R,10S)-2-chloro-13-(ethylsulfonyl)-l,7, 10-trifluoro-5,6,6a,7,8,9, 10,11 -octahydro-4H-3,l la, 12,14,15-pentaaza-7, 10-Attorney Docket No. 1587-WO-PCT methanocyclohepta[4,5]cycloocta[l,2,3-de]naphthalene-15-carboxylate (0.427 mmol) in 2-Me THF (5 ml) was slowly added to the solution and stirred at 0 °C for 30 min. The reaction was quenched with water at 0 °C, extracted with EtOAc (3x), washed with brine, dried over MgSO₄, filtered and concentrated. The residue was purified on basic alumina chromatography to afford the title compound. LCMS: 641.3.

[0198] Step 3: tert-butyl (6aR,7R,10S)-2-(3-((tert-butoxycarbonyl)amino)-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-l,7,10-trifluoro-13-(((3S,7aS)-3-(fluoromethyI)tetrahydro-lH-pyrrolizin-7a(5H)-yI)methoxy)-5,6,6a,7,8,9,10,ll-octahydro-4H-3,lla,12,14,15-pentaaza-7,10-methanocyclohepta[4,5]cycloocta[l,2,3-de]naphthalene-15-carboxylate (Intermediate 24-3). A vial was charged with Intermediate 24-2 (0.187 mmol), tert-butyl (6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- ((triisopropylsilyl)ethynyl)naphthalen-2-yl)carbamate (0.842 mmol), K3PO4 (0.749 mmol) and cataCXium A Pd G3 (0.037 mmol). 1,4-Dioxane (5 mL) and water (1 mL) were added and the mixture was sparged with argon gas for 5 minutes. The reaction then was heated to 90 °C. Upon completion, the mixture was partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgSO₄, filtered and concentrated under reduced pressure. The residue was purified by basic alumina chromatography to afford the title compound. LCMS: 1046.11.

[0199] Step 4: 6-fluoro-4-((6aR,7R,10S)-l,7,10-trifluoro-13-(((3S,7aS)-3- (fluoromethyl)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5,6,6a,7,8,9,10,ll-octahydro-4H-3,lla,12,14,15-pentaaza-7,10-methanocyclohepta[4,5]cycloocta[l,2,3-de]naphthalen-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-amine (Intermediate 24-4). Intermediate 24-3 (0.086 mmol) was dissolved in toluene (5ml) and 4N HC1 in 1,4-dioxane was added at 0 °C. Upon completion, water (5 mL) was added to the reaction and the resulting mixture was extracted with EtOAc (3x). The combined organic layer was washed with 5% LiCl (aq) (2x), dried over MgSO₄, filtered and concentrated. The residue was used without further purification. LCMS: 846.15.Attorney Docket No. 1587-WO-PCT Intermediates 26-1 - 26-7.Boc I step 1INT 26-1 INT 26-2 INT 26-3 INT 26-4INT 26-5 INT 26-6 INT 26-7

[0200] Step 1: tert-butyl (lR,2S,5S)-3-allyl-2-(prop-l-en-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 26-1). A sealed tube was charged with tert-butyl (lR,2S,5S)-2-(prop-l-en-2-yl)-3,8-diazabicyclo[3.2. l]octane-8-carboxylate (18.8 mmol, prepared according to US 2023 / 0374036), K2CO3 (65.9 mmol), allyl bromide (37.6 mmol) and acetone (40.0 mL). The reaction was heated at 60 °C for 18 hours. The reaction was cooled to RT, filtered and concentrated. The residue was purified by silica gel chromatography to afford the title compound. LCMS: 293.1.

[0201] Step 2: tert-butyl (lS,4S,5S)-3-allyl-l-fluoro-4-(prop-l-en-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 26-2). A flask charged with Intermediate 26-1 (0.877 mmol) was purged with nitrogen. TMEDA (1.75 mmol) and degassed THE (3.70 mL) were added and the solution was cooled to -78 °C. Sec-BuLi (1.75 mmol, 1.1 M in cyclohexane) was added dropwise and the solution was stirred for 20 min. A solution of N-fluorobenzenesulfonimide (1.75 mmol) in degassed THF (3.00 mL) was added. The solution was stirred until reaction completion. The reaction was quenched at 0 °C with water and was warmed up to RT. Saturated NH4CI (aq) was added and the mixture was extracted with EtOAc (3x). The combined organic layer was washed with brine, dried over MgSO₄, filtered and concentrated. The residue was purified by silica gel chromatography to afford the title compound. LCMS: 311.0.

[0202] Step 3: tert-butyl (lR,2S,5S)-3-allyl-l,5-difluoro-2-(prop-l-en-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 26-3). A flask charged withAttorney Docket No. 1587-WO-PCT Intermediate 26-2 (0.459 mmol) was purged with nitrogen. TMEDA (0.918 mmol) and degassed THF (1.90 mL) were added and the solution was cooled to -78 °C. Sec-BuLi (0.835 mmol, 1.1 M in cyclohexane) was added dropwise and the solution was stirred for 60 min. A solution of N-fluorobenzenesulfonimide (0.918 mmol) in degassed THF (2.00 mL) was added at -78 °C. The solution was stirred until reaction completion. The reaction was quenched at 0 °C with water and was warmed up to RT. Sat. NH4CI (aq) was added and the mixture was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated. The residue was purified by silica gel chromatography to afford the title compound.LCMS: 329.0.

[0203] Step 4: tert-butyl (lR,2S,5S)-l,5-difluoro-2-(prop-l-en-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 26-4). A vial charged with Intermediate 26-3 (0.344 mmol), Pd(PPh3)4 (0.017 mmol) and 1,3-dimethylbarbituric acid (0.688 mmol) was purged with nitrogen. Degassed DCM (3.40 mL) was added and the reaction was heated at 45 °C. Upon completion, the reaction was cooled to RT and washed with sat. Na2CO3 (aq) (2x). The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography to yield the title compound. LCMS: 233.0.

[0204] Step 5: tert-butyl (lR,2S,5S)-3-(5-bromo-7-chloro-2-(ethylthio)-8-fluoropyrido[4,3-d]pyrimidin-4-yI)-l,5-difluoro-2-(prop-l-en-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 26-5). A vial was charged with Intermediate 1-4 (0.486 mmol), Intermediate 26-4 (0.277 mmol), 4A molecular sieves and 2-MeTHF (2.00 mL). The mixture was stirred at RT for 1 hour. N,N-diisopropylethylamine (0.832 mmol) was added and the reaction was heated at 80 °C. Upon completion, the reaction was cooled to RT, filtered over celite and concentrated. The residue was purified by silica gel chromatography to afford the title compound, which was used without further purification. LCMS: 608.0 / 610.0.

[0205] Step 6: tert-butyl (lR,2S,5S)-2-((S)-l-(9-borabicyclo[3.3.1]nonan-9-yl)propan-2-yl)-3-(5-bromo-7-chloro-2-(ethylthio)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-l,5-difluoro-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 26-6). A vial was charged with Intermediate 26-5 (0.085 mmol) and 9-borabicyclo(3.3.1)nonane (0.217 mmol, 0.5 M solution in THF) under nitrogen. The reaction was heated at 60 °C. Upon completion, the title compoundcontaining mixture was cooled to RT and was used directly in the subsequent reaction. LCMS:654.1 / 656.1.

[0206] Step 7: tert-butyl (5S,5aS,6R,9S)-2-chloro-12-(ethylthio)-l,6,9-trifluoro-5-methyl-4,5,5a,6,7,8,9,10-octahydro-3,10a,ll,13,14-pentaaza-6,9-methanonaphtho[l,8-Attorney Docket No. 1587-WO-PCT ab]heptalene-14-carboxylate (Intermediate 26-7). To crude Intermediate 26-6 (0.085 mmol) was added 1,4-dioxane (2.50 mL) and water (0.50 mL). [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.009 mmol) and K3PO4 (0.256 mmol) were added. The resulting mixture was sparged with argon gas for 5 minutes. The reaction was heated at 90 °C. Upon completion, the reaction was cooled to RT, quenched with sat. NH4CI (aq), extracted with EtOAc (3x), washed with brine, dried over MgSO₄, filtered and concentrated. The residue was purified by silica gel chromatography to afford the title compound. LCMS: 530.1.Intermediates 27-1 to 27-11.

[0207] Step 1: tert-butyl (5S,5aS,6R,9S)-2-chloro-12-(ethylsulfonyl)-l,6,9-trifluoro-5-methyl-4,5,5a,6,7,8,9,10-octahydro-3,10a,ll,13,14-pentaaza-6,9-methanonaphtho[l,8-ab]heptalene-14-carboxylate (Intermediate 27-1). 3 -Chloroperbenzoic acid (77% wt, 0.074 mmol) was added to a stirred solution of Intermediate 26-7 (0.032 mmol) in dichloromethane (1.5 mL) at 0 °C. The reaction was gradually warmed to RT. Upon reaction completion, the mixture was purified by silica gel chromatography to afford the title compound. LCMS: 562.0.

[0208] Step 2: tert-butyl (5S,5aS,6R,9S)-2-chloro-l,6,9-trifluoro-12-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methyl-4,5,5a,6,7,8,9,10-octahydro-3,10a,ll,13,14-pentaaza-6,9-methanonaphtho[l,8-ab]heptalene-14-carboxylate (Intermediate 27-2). Intermediate 27-1 (0.151 mmol), ((2R,7aS)-2-fluorotetrahydro-lH-Attorney Docket No. 1587-WO-PCT pyrrolizin-7a(5H)-yl)methanol (0.378 mmol) and toluene (5 mL) were combined and the mixture was concentrated under reduced pressure (2x). 2-MeTHF (3.0 mL) was added and the solution was cooled to 0 °C. Lithium bis(trimethylsilyl)amide solution (1.0 M in THF, 0.348 mmol) was added and the mixture was stirred until completion. The reaction was quenched with water at 0 °C, extracted with EtOAc (3x), washed with brine, dried over MgSO₄, filtered and concentrated. The residue was purified by silica gel chromatography to afford the title compound. LCMS:627.3.

[0209] Step 3: tert-butyl (5S,5aS,6R,9S)-2-(3-amino-7-fluoro-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-l,6,9-trifluoro-12-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methyl-4,5,5a,6,7,8,9,10-octahydro-3.10a.l 1.13.14-pentaaza-6.9-methanonapht ho| L8-ab|heptalene- 14-carboxy late (Intermediate 27-3). A vial was charged with Intermediate 27-2 (0.102 mmol), Intermediate 5-1 (0.204 mmol), K3PO4 (0.408 mmol) and cataCXium A Pd G3 (0.026 mmol). 1,4-Dioxane (2.5 mL) and water (0.5 mL) were added and the mixture was degassed with argon gas for 5 minutes. The reaction was heated at 90 °C. Upon completion, the mixture was partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography to afford the title compound.LCMS: 932.3.

[0210] Step 4: tert-butyl (5S,5aS,6R,9S)-2-(3-amino-8-ethynyI-7-fluoronaphthalen-l-yl)-l,6,9-trifluoro-12-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methyl-4,5,5a,6,7,8,9,10-octahydro-3,10a,ll,13,14-pentaaza-6,9-methanonaphtho[l,8-ab]heptalene-14-carboxylate (Intermediate 27-4). A vial charged with Intermediate 27-3 (0.102 mmol), CsF (0.510 mmol) and DMF (2.0 mL) was heated at 45 °C. Upon completion, the mixture was cooled, quenched with water and extracted with EtOAc (3x). The combined organic layer was washed with 5% LiCl (aq) (2x), dried over MgSO4, filtered and concentrated. The residue was used without further purification. LCMS: 776.1.

[0211] The following Intermediates were made in a similar fashion to Intermediates 27-1 - 4 and are shown below in Table 3. To prepare the below Intermediates, different reagents / starting materials were used than some of those described in the steps toward Intermediates 27-1 - 4 and are noted in the last column of Table 3- “Changes to Procedure: Different Reagents / Starting Materials”. A person of ordinary skill in the art will readily recognize which reagents / starting materials used for the synthesis of Intermediates 27-1 - 4 were replaced with the different reagents / starting materials noted below.Attorney Docket No. 1587-WO-PCT Table 3. IntermediatesIntermediate Structure LCMS Changes to Procedure:Different Reagents / Starting MaterialsF.V-NBoc_ A Ff7 N— ’ 2-(8-ethynyl-7-fluoro-3- (methoxymethoxy )naphthalen- 1 - 27-5 A / AA 820.6I A ^rA yl)-4,4,5,5-tetramethyl- 1,3,2- dioxaborolane used in step 3. LJ G OMOM F>0oz[(3S,8S)-3-(pyrimidin-4- f y loxymethy 1) -1,2,3, 5, 6, 7- 27-6 866.0hcxahydropyrrolizin-8- / > co A_ - yl]methanol used in step 2.Intermediate 23-8 in step 1. F Boc ((3S,4S)-4-(difluoromethyl)-l,3- N%. V- F dimethylpiperidin-3-yl)methanol \ (prepared according to 27-7 841.1 WO2024 / 067714) in step 2. 2-(8- ( 1 u 1 JlFethynyl-7-fluoro-3 - VFM (methoxymethoxy)naphthalen- 1 - OMOM1yl)-4,4,5,5-tetramethyl- 1,3,2- dioxaborolane used in step 3. BocIntermediate 32-7 used in step 1. F Ilf. v < H^ ITrF(S)-(2-methylenetetrahydro- 1 H- 27-8 766.4 pyrrolizin-7a(5H)-yl)methanol in Q ^ rA step 2. TBAF (2.0 equiv.) in THF YX FN°7 / used in step 4. NH2' 'r~ NBoc1 \H'N~~^ Intermediate 32-7 used in step 1.[(3S,8S)-3-(pyrimidin-4- 27-9 (Xl Xl CGXT fN°^>y 862.0 yloxymethyl)-l,2,3,5,6,7- hcxahydropyrrolizin-8- NH, yl]methanol used in step 2.o\=NAttorney Docket No. 1587-WO-PCT Intermediate Structure LCMS Changes to Procedure:Different Reagents / Starting MaterialsBocIntermediate 32-7 used in Step 1. 2-(8-ethynyl-7-fluoro-3- f 111. / h? (methoxymethoxy)naphthalen- 1 - 27-10 817.5 yl)-4,4,5,5-tetramethyl- 1,3,2- Q x U dioxaborolane used in step 3.TBAF (2.0 equiv.) in THF used y tN 00in step 4.OMOM FBoc / TN"Intermediate 32-7 used in step 1. F N— (S, E)-(4-(fluoromethylene)- 1,3- 27-11 786.3 dimethylpiperidin-3-yl)methanol O' ] ] (prepared according to WO2024 / 067714) used in Step 2. YfVNH21Intermediates 32-1 to 32-7.Boc step 1

[0212] Step 1: tert-butyl (lR,2S,5S)-3-allyl-2-((S)-but-3-en-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 32-1). A sealed tube was charged with tert-butyl (lR,2S,5S)-2-((S)-but-3-en-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (prepared according to US 2023 / 0374036, 3.75 mmol), K2CO3 (13.1 mmol), allyl bromide (7.51 mmol), and acetone (9.4 mL). The reaction was heated to 60 °C for 18 hours. The reaction wasAttorney Docket No. 1587-WO-PCT cooled to ambient temperature and filtered. The filter cake was washed with additional acetone and the combined filtrates were concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexanes / EtOAc) to afford the title compound. LCMS 307.4.

[0213] Step 2: tert-butyl (lS,4S,5S)-3-allyl-4-((S)-but-3-en-2-yl)-l-fluoro-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 32-2). To a -41 °C cooled mixture of Intermediate 32-1 (2.71 mmol) and TMEDA (5.42 mmol) in THF (13.6 mL) was added sec-BuLi (1.2 M in cyclohexanes) (8.13 mmol) dropwise over 5 min. The mixture was stirred for 10 min, followed by the dropwise addition of N-fluorobenzenesulfonimide (6.77 mmol) in THF (10.8 mL). The mixture was stirred for 20 min then the cooling bath was removed and the reaction mixture was quenched with saturated NH4CI (aq)(10 mL) slowly. The mixture was added to H2O (150) and extracted with EtOAc (3 x 80 mL). The combined organic extracts were washed with brine (50 mL), dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel chromatography (hexanes / EtOAc) to afford the title compound. LCMS 325.3.

[0214] Step 3: tert-butyl (lS,4S,5S)-4-((S)-but-3-en-2-yl)-l-fluoro-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 32-3). To a mixture of Intermediate 32-2 (4.65 mmol) in MeOH (46.5 mL) was added 1,3 -dimethylbarbituric acid (14.0 mmol), followed by Pd(PPh3)4 (0.465 mmol). The mixture was heated to 45 °C with stirring for 40 min, then cooled to ambient temperature and concentrated under reduced pressure. EtOAc (300 mL) was added, and the mixture was washed with saturated NaHCO3 (aq) (3 x 40 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. Et20 was added (100 mL) and the resulting mixture was filtered over celite. The filter cake was washed with additional Et2O, and the combined filtrates was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexanes / EtOAc) to afford the title compound. LCMS 285.3.

[0215] Step 4: tert-butyl (lS,4S,5S)-3-(5-bromo-7-chloro-2-(ethylthio)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-4-((S)-but-3-en-2-yl)-l-fluoro-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 32-4). To a mixture of Intermediate 32-3 (3.36 mmol) in 2-MeTHF (33.6 mL) was added Intermediate 1-4 (7.39 mmol) followed by DIPEA (13.4 mL). The mixture was heated to 80 °C with stirring for 2 hours then cooled to ambient temperature. The mixture was added to H2O (300 mL) and extracted with EtOAc (3 x 120 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexanes / EtOAc) to afford the title compound. LCMS 606.2.Attorney Docket No. 1587-WO-PCT

[0216] Step 5: tert-butyl (5S,5aS,6S,9S)-2-chloro-12-(ethylthio)-l,9-difluoro-5-methyl-4-methylene-4,5,5a,6,7,8,9,10-octahydro-3,10a,ll,13,14-pentaaza-6,9-methanonaphtho[l,8-ab]heptalene-14-carboxylate (Intermediate 32-5). To a mixture of Intermediate 32-4 (0.827 mmol) in DMF (27.5 mL) was added tetrabutylammonium bromide (1.65 mmol) and Et3N (1.82 mmol). The mixture was sparged with argon. bis(tri-t -butylphosphine)palladium(0) (0.165 mmol) was added, and the mixture was heated to 90 °C with stirring for 20 min. The mixture was cooled to ambient temperature, added to H2O (150 mL), and extracted with EtOAc (3 x 80 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexanes / EtOAc) to afford the title compound and Intermediate 32-6 as a mixture. LCMS 524.2.

[0217] Step 6: tert-butyl (4R,5S,5aS,6S,9S)-2-chloro-12-(ethylthio)-l,9-difluoro-4,5-dimethyl-4,5,5a,6,7,8,9,10-octahydro-3,10a,1143,14-pentaaza-6,9-methanonaphtho[l,8-ab]heptalene-14-carboxylate (Intermediate 32-7). To a mixture of Intermediates 32-5 and 32-6 (0.513 mmol) in MeCN (25.7 mL) and H2O (12.8 mL) was added 4-methylbenzenesulfonohydrazide (5.13 mmol) and NaOAc (7.70 mmol). The mixture was heated to 85 °C for 2.5 h with vigorous stirring. Additional 4-methylbenzenesulfonohydrazide (5.13 mmol) and NaOAc (7.70 mmol) were added, and the reaction was continued for 3 additional hours. The mixture was cooled to ambient temperature, added to H2O (150 mL) and extracted with EtOAc (4 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexanes / EtOAc) to afford the title compound. LCMS 526.2.Attorney Docket No. 1587-WO-PCT Intermediate 33-1 to 33-11.Boc step 1INT 33-1 INT 33-2

[0218] Step 1: tert-butyl (lR,5S)-3-allyl-2-oxo-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 33-1). To a 0 °C cooled mixture of tert-butyl (lS,5R)-2-oxo-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (88.4 mmol) in THF (402 mL) was added NaH (60% dispersion in mineral oil) (106 mmol) in 4 portions over 20 min with vigorous stirring. The mixture was warmed to ambient temperature and stirred for 40 min, followed by the addition of allyl bromide (133 mmol) slowly. The mixture was stirred for 18 hours, then saturated aqueous NH4CI (200 mL), H2O (200 mL), and EtOAc (200 mL) were added sequentially with vigorous stirring. The organic and aqueous layers were separated, and the aqueous layer was further extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with brine (2 x 200 mL), dried over Na2SO4, filtered over celite, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexanes / EtOAc) and fractions containing the product were concentrated under reduced pressure to afford the title compound. LCMS: 267.2.

[0219] Step 2: tert-butyl (lR,2S,5S)-3-allyl-2-(but-2-en-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 33-2). To a vigorously stirring mixture of magnesium turnings (62.0 mmol) in THF (31.3 mL) was added I2 (0.09 mmol). The mixture was heated to 45 °C, and a solution of 2-bromo-2-butene (mixture of E and Z isomers) (56.3 mmol) in THF (9.4 mL) wasAttorney Docket No. 1587-WO-PCT added slowly dropwise. Once 1 / 3 of the solution was added, an exothermic reaction initiated and the remainder of the 2-bromo-2-butene solution was added dropwise at a rate sufficient to maintain reflux. Upon completion of the addition, the mixture was heated to 70 °C for an additional 30 minutes, then cooled to ambient temperature and allowed to sit for 1 hour to afford but-2-en-2-ylmagnesium bromide as a mixture of E and Z isomers.

[0220] In a separate vessel, to a 0 °C cooled mixture of Intermediate 33-1 (9.39 mmol) in THF (63 mL) was added LiAlH4 (1M in THF) (4.69 mmol). The mixture was stirred at 0°C for 1 hour, then diluted with Et2O (63 mL). H2O (0.2 mL), 15% aqueous NaOH (0.2 mL), and additional H2O (0.6 mL) were added sequentially very carefully dropwise. The mixture was warmed to ambient temperature and anhydrous magnesium sulfate (33.23 mmol) was added. The mixture was stirred vigorously for 10 min then filtered. The filter cake was washed with additional Et2O, and the combined organic extracts were concentrated under reduced pressure. To a 0 °C cooled solution of the resulting residue in THF (47 mL), was added diethyl chlorophosphate (16.9 mmol). The mixture was stirred for 20 min. Subsequently, the but-2-en-2-ylmagnesium bromide in THF solution was added slowly via cannula, and the resulting mixture was stirred at 0°C for 30 min. The mixture was diluted with Et2O (100 mL), followed by the sequential slow addition of saturated aqueous NH4CI (50 mL) and H2O (100 mL). The layers were separated, and the aqueous layer was further extracted with Et2O (2 x 100 mL). The combined organic extracts were washed with brine (50 mL), dried over Na2SC>4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexanes / EtOAc) and fractions containing the product were concentrated under reduced pressure to afford the title compound as a mixture of E and Z isomers.LCMS: 307.3.

[0221] Step 3: tert-butyl (lS,4S,5S)-3-allyl-4-(but-2-en-2-yl)-l-fluoro-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 33-3). To a -41 °C cooled mixture of Intermediate 33-2 (4.63 mmol) andTMEDA (9.27 mmol) in THF (23.2 mL) was added sec-BuLi (1.2 M in cyclohexane) (13.9 mmol) dropwise over 5 min. The mixture was stirred for 15 min followed by the addition of N-fluorobenzenesulfonimide (11.6 mmol) in THF (18.5 mL). The mixture was stirred for 20 min. The cooling bath was removed and the reaction was quenched by the dropwise addition of saturated aqueous NH4CI (20 mL). The mixture was warmed to ambient temperature and added to saturated aqueous NH4CI (75 mL) and H2O (75 mL) then extracted with EtOAc (3 x 80 mL). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was suspended in methyl tert-butyl ether (100 mL) and filtered over celite. The filter cake was washed with additional methyl tertbutyl ether, and the combined filtrates were concentrated under reduced pressure. The residueAttorney Docket No. 1587-WO-PCT was purified by silica gel chromatography (hexanes / EtOAc) and fractions containing the product were concentrated under reduced pressure to afford the title compound as a mixture of E and Z isomers. LCMS: 325.3.

[0222] Step 4: tert-butyl (lR,2S,5S)-3-allyl-2-(but-2-en-2-yl)-l,5-difluoro-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 33-4). To a -41 °C cooled mixture of Intermediate 33-3 (3.99 mmol) and TMEDA (7.98 mmol) in THF (20.0 mL) was added sec-BuLi (1.2 M in cyclohexane) (12.0 mmol) dropwise over 5 min. The mixture was stirred for 20 min followed by the addition of N-fluorobenzenesulfonimide (9.98 mmol) in THF (16.0 mL). The mixture was stirred for 20 min. The cooling bath was removed and the reaction was quenched by the dropwise addition of saturated aqueous NH4CI (20 mL). The mixture was warmed to ambient temperature and added to saturated aqueous NH₄Cl (75 mL) and H₂O (75 mL) then extracted with EtOAc (3 x 80 mL). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was suspended in methyl tert-butyl ether (100 mL) and filtered over celite. The filter cake was washed with additional methyl tertbutyl ether, and the combined filtrates were concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexanes / EtOAc) and fractions containing the product were concentrated under reduced pressure to afford the title compound as a mixture of E and Z isomers. LCMS: 381.3.

[0223] Step 5: tert-butyl (lR,2S,5S)-2-(but-2-en-2-yl)-l,5-difluoro-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 33-5). To a stirring mixture of Intermediate 33-4 (2.80 mmol) in MeOH (28 mL) was added 1,3 -dimethylbarbituric acid (5.61 mmol), followed by Pd(PPh3)4 (0.140 mmol). The mixture was heated to 45 °C for 1 hour, then cooled to ambient temperature and concentrated under reduced pressure. EtOAc (350 mL) was added, and the mixture was washed with saturated aqueous NaHCO₃ (3 x 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. Methyl tert-butyl ether (100 mL) was added and the resulting mixture was filtered over celite. The filter cake was washed with additional methyl tert-butyl ether, and the combined filtrates were concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexanes / EtOAc) and fractions containing the product were concentrated under reduced pressure to afford the title compound as a mixture of E and Z isomers. LCMS: 325.2.

[0224] Step 6: tert-butyl (lR,2S,5S)-3-(5-bromo-7-chloro-2-(ethylthio)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-2-((Z)-but-2-en-2-yl)-l,5-difluoro-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate 33-6). To a stirring mixture of Intermediate 33-5 (1.82 mmol) andAttorney Docket No. 1587-WO-PCT Intermediate 1-4 (3.64 mmol) in 2-Me-THF (18.2 mL) was added DIPEA (7.28 mmol). The mixture was heated to 80 °C for 5 h. The mixture was cooled to ambient temperature followed by the sequential dropwise addition of saturated aqueous NaHCO₃ (4.6 mL) and 1-methylimidazole (3.64 mmol). The mixture was stirred vigorously for 10 min followed by the addition of 2-Me-THF (100 mL) and saturated aqueous NaHCO₃ (300 mL). The layers were separated, and the aqueous layer was further extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was suspended in methyl tert-butyl ether (50 mL) and stirred for 10 min then filtered over celite. The filter cake was washed with additional methyl tert-butyl ether, and the combined filtrates were concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexanes / EtOAc) and fractions containing the product were concentrated under reduced pressure to afford the title compound. LCMS: 622.1 / 624.2.

[0225] Step 7: tert-butyl (4R,5S,5aS,6R,9S)-2-chloro-12-(ethylthio)-l,6,9-trifluoro-4,5-dimethyl-4,5,5a,6,7,8,9,10-octahydro-3,10a,ll,13,14-pentaaza-6,9-methanonaphtho[l,8-ab]heptalene-14-carboxylate (Intermediate 33-7). To Intermediate 33-6 (0.586 mmol) was added 9-borabicyclo(3.3.1)nonane (0.5 M solution in THF) (2.93 mmol) and the mixture was heated at 70 °C for 18 hours. The mixture was cooled to ambient temperature followed by the addition of 1,4-dioxane (9.8 mL), H2O (2.93 mL), K3PO4 (5.86 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.088 mmol). The mixture was heated to 90 °C with vigorous stirring for 1 hour then cooled to ambient temperature. The mixture was added to saturated aqueous NH4CI (150 mL) and extracted with EtOAc (3 x 80 mL). The combined organic extracts were washed with NH4CI (50 mL) and brine (50 mL), dried over Na2SO4, filtered over celite and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexanes / EtOAc) and fractions containing the product were concentrated under reduced pressure to afford the title compound. LCMS: 544.2.

[0226] Step 8: tert-butyl (4R,5S,5aS,6R,9S)-2-chIoro-12-(ethylsulfonyl)-l,6,9-trifluoro-4,5-dimethyl-4.5.5a.6.7.8.9.10-octahydro-3.10a.11.13.14-pentaaza-6.9-methanonaphtho| 1 -8-ab]heptalene-14-carboxylate (Intermediate 33-8). To a mixture of Intermediate 33-7 (0.16 mmol) in DCM (1.6 mL) was added 3-Chloroperbenzoic acid (77% wt) (0.63 mmol) and the mixture was stirred at ambient temperature for 2 hours. The mixture was added to saturated aqueous NaHCO₃ (200 mL) and extracted with DCM (4 x 50 mL). The combined organic extracts were washed with saturated aqueous NaHCO₃ (50 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gelAttorney Docket No. 1587-WO-PCT chromatography (hexanes / EtOAc) and fractions containing the product were concentrated under reduced pressure to afford the title compound. LCMS: 576.2.

[0227] Step 9: tert-butyl (4R,5S,5aS,6R,9S)-2-chloro-l,6,9-trifluoro-12-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-4,5-dimethyl-4,5,5a,6,7,8,9,10-octahydro-3, 10a, 11, 13, 14- pentaaza-6,9-methanonaphtho[l,8-ab]heptalene-14-carboxylate (Intermediate 33-9). To a 0 °C cooled mixture of Intermediate 33-8 (0.066 mmol) and ((2R,7aS)-2-fhiorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (0.119 mmol) in 2-MeTHF (0.7 mL) was added LiHMDS (IM in THF) (0.106 mmol). The mixture was stirred for 30 min at 0 °C then quenched with saturated aqueous NH4CI (10 mL). The mixture was added to saturated aqueous NaHCO₃ (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexanes / EtOAc / MeOH) and fractions containing the product were concentrated under reduced pressure to afford the title compound. LCMS: 641.3.

[0228] Step 10: tert-butyl (4R,5S,5aS,6R,9S)-2-(3-amino-7-fluoro-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-l,6,9-trifluoro-12-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-4,5-dimethyl-4,5,5a,6,7,8,9,10-octahydro-3, 10a, 11, 13, 14- pentaaza-6,9-methanonaphtho[l,8-ab]heptalene-14-carboxylate (Intermediate 33-10). A vigorously stirring mixture of Intermediate 33-9 (0.042 mmol), Intermediate 5-1 (0.084 mmol) and K3PO4 (0.19 mmol) in dioxane (1 mL) and H2O (0.25 mL) was sparged with argon, followed by the addition of cataCXium A Pd G3 (0.0105 mmol). The mixture was heated to 95 °C for 1 h then cooled to ambient temperature. The mixture was added to saturated aqueous NaHCO₃ (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH) and fractions containing the product were concentrated under reduced pressure to afford the title compound. LCMS: 946.6.

[0229] Step 11: tert-butyl (4R,5S,5aS,6R,9S)-2-(3-amino-8-ethynyl-7-fluoronaphthalen-l-yl)-l,6,9-trifluoro-12-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-4,5-dimethyl-4,5,5a,6,7,8,9,10-octahydro-3,10a,ll,13,14-pentaaza-6,9-methanonaphtho[l,8-ab]heptalene-14-carboxylate (Intermediate 33-11). To a 0 °C mixture of Intermediate 33-10 (0.031 mmol) in THF (1 mL) was added TBAF (1 M in THF) (0.061 mmol). The mixture was warmed to ambient temperature and stirred for 40 min. The mixture was added to saturatedAttorney Docket No. 1587-WO-PCT aqueous NaHCCh (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / McOH) and fractions containing the product were concentrated under reduced pressure to afford the title compound. LCMS: 790.4.III. CompoundsExample 1-1 to 1-8.INT 27-4 1-1

[0230] Step 1: 5-ethynyl-6-fluoro-4-((5S,5aS,6R,9S)-l,6,9-trifluoro-12-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methyl-4,5,5a,6,7,8,9,10-octahydro-3,10a,ll,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-amine (Example 1-1). To Intermediate 27-4 (0.102 mmol) was added DCM (3.0 mL) and TFA (6.53 mmol) at RT. The reaction was stirred until completion, then cooled to 0 °C. Pyrrolidine was added (7.65 mmol), the mixture was stirred for 2 minutes, then concentrated under reduced pressure. The residue was purified by RP-HPLC (0.1% TFA in ACN / water) to afford the title compound.!H NMR (400 MHz, Acetonitrile- di) 8 12.20 - 11.90 (bm, 1H), 7.81 - 7.74 (m, 1H), 7.28 (t, 7= 9.1 Hz, 1H), 7.19 - 6.99 (m, 2H), 5.60 - 5.41 (m, 1H), 5.15 - 5.04 (m, 1H), 4.65 (s, 2H), 3.92 - 3.52 (m), 3.52 - 3.20 (m), 3.14 - 2.98 (m), 2.90 - 1.66 (m), 1.28 - 1.16 (m, 311).LCMS 676.1.

[0231] The following Examples were made in a similar fashion to Example 1-1 and are shown below in Table 4. To prepare the below Examples, different reagents / starting materials were used than some of those described in the steps toward Example 1-1 and are noted in the last column of Table 4 - “Changes to Procedure: Different Reagents / Starting Materials”. A person of ordinary skill in the art will readily recognize which reagents / starting materials used for the synthesis of Example 1-1 were replaced with the different reagents / starting materials noted below.Attorney Docket No. 1587-WO-PCT Table 4. CompoundsChanges to Procedure: Different Ex. Structure LCMS ‘H-NMRReagents / Starting Materials E VNHF / / / ( HQ XXI JXFx'fzV | 'N^ 1 1 'll NMR (400 MHz,V Acetonitrile-d3) 5 10.37- OHF1 9.90 (m, 1H), 8.01-7.88(m, 1H), 7.57 - 7.14 (m,Intermediate 1-2 4-((5aS,6R,9S)-12-(((3S,4S)-4- 697.1 3H), 6.47 - 5.94 (m, 1H),(difluoromethyl)- 1,3- 27-7 in step 1.5.31 - 5.10 (m, 1H), 4.95- dimethylpiperidin-3- 4.80 (m, 1H), 4.28 (d, J = yl)methoxy)-l,6,9-trifluoro- 12.5 Hz, 1H), 4.00 - 1.674, 5, 5 a, 6, 7, 8, 9, 10-octahydro- (m, 21H), 1.35 (s, 3H).3, 10a, 11, 13, 14-pentaaza-6,9- methanonaphtho[l,8- ab]heptalen-2-yl)-5-ethynyl-6- fluoronaphthalen-2-olH ’ll NMR (400 MHz,Methanol-cU) 58.08 - 7.96F III "" / H y (m, 1H), 7.83 - 7.70 (m, Intermediate 1H), 7.58 - 7.32 (m, 2H), 27-8 in step 1.5.43 (d, J = n.l Hz, 1H), Deprotection 5.37 - 5.26 (m, 2H), 4.85 was NH2" - 4.68 (m, 2H), 4.49 - perfomred in 4.37 (m, 1H), 4.25 - 4.12 2:1 4-((4R,5S.5aS,6S.9S)-1.9- (m, 1H), 3.97 - 3.88 (m, DCM / TFA.1-3 666.4difluoro-4,5-dimethyl-12-(((S)- 1H), 3.88 - 3.73 (m, 2H), The reaction 2-methylenetetrahydro- 1 H- 3.68 - 3.51 (m, 2H), 3.31 was pyrrolizin-7a(5H)- - 3.19 (m, 1H), 3.18 - concentrated yl)methoxy)-4,5,5a,6,7,8,9, 10- 3.02 (m, 1H), 3.02 - 2.87 and purified octahydro-3, 10a, 11, 13, 14- (m, 2H), 2.87 - 2.73 (m, without the pentaaza-6,9- 1H), 2.52 - 2.32 (m, 3H), addition of an methanonaphtho[l,8- 2.32 - 2.08 (m, 4H), 1.84 amine base. ab]heptalen-2-yl)-5-ethynyl-6- - 1.62 (m, 1H). 1.38 - fluoronaphthalen-2-amine 1.28 (m, 3H), 1.08 - 0.95(m, 3H) ppm.Attorney Docket No. 1587-WO-PCT Changes to Procedure: Different Ex. Structure LCMS 'H-WIRReagents / Starting Materials ’ll NMR (400 MHz,MeOD) 58.80 (dd, J = / ^NH7.4, 1.0 Hz, 1H), 8.44 (t, J= 5.8 Hz, 1H), 8.01 (ddd, J= 12.0, 9.1, 5.7 Hz, 1H), CX l Xl FA 7.73 (dd, J = 13.7, 2.3 Hz,XY jN 0Intermediate 1H), 7.54 - 7.38 (m, 2H),NH227-9)" A, in step 6.88 (ddd, J = 18.2, 5.9,o 1. \=N 1.2 Hz, 1H), 5.42 (dd,.1 =Deprotection 12.7, 1.5 Hz, 1H), 4.99 - was 1-4 4-((4R,5S,5aS,6S,9S)-l,9- 4.90 (m, 3H), 4.82 (dd, J =performed in difluoro-4,5-dimethyl- 12- 762.0 16.6, 12.4 Hz, 1H), 4.75 - 20% (((3S,7aS)-3-((pyrimidin-4- 4.64 (m, 2H), 4.47 (d, J =TFA / DCM. yloxy)methyl)tetrahy dro- 1 H- 9.0 Hz, 1H). 4.17 (t. J =Triethylamine pyrrolizin-7a(5H)- 6.1 Hz, 1H), 3.88 - 3.79was used yl)methoxy)-4,5,5a,6,7,8,9,10- (m, 1H), 3.66 - 3.53 (m,instead of octahydro-3, 1 Oa, 11, 13, 14- 3H), 3.50 (dd,.1 = 11.3,pyrrolidine. pentaaza-6,9- 5.7 Hz, 1H), 3.08 - 2.86 methanonaphtho[l,8- (m, 2H), 2.54 - 2.29 (m, ab]heptalen-2-yl)-5-ethynyl-6- 3H), 2.30 - 2.02 (m, 6H), fluoronaphthalen-2-amine 1.80 - 1.62 (m, 1H), 1.34(t, J = 6.7 Hz, 3H), 1.01(dd, J = 16.3, 5.9 Hz, 3H). / — NH Intermediate F 1H NMR (400 MHz,27-11 in step Methanol-d4) 57.96 (dd, J1 1H' 1.= 9.5, 5.1 Hz, 2H), 7.60 (s, CYYTA Deprotection 2H), 7.50 - 7.35 (m, 3H), was 7.26 (s, III), 6.94 (d, J =VFperformed NH21 83.4 Hz, 3H), 5.36 (d, J = with 4M HC112.5 Hz, 311), 4.71 - 4.52 in dioxane (20 4-((4R,5S,5aS,6S,9S)-l,9- (m, 3H), 4.46 (d, J = 11.4 equiv.) using 1-5 difluoro-12-(((S, E)-4- 686.3 Hz, 1H), 4.07 (d, J = 6.4 acetonitrile as (fluoromethylene)-l,3- Hz, 2H), 3.83 - 3.50 (m, solvent. The dimethylpiperidin- 3 - 8H), 3.21 - 2.77 (m, 14H), reaction yl)methoxy)-4,5-dimethyl- 2.61 (s, 2H), 2.50 - 2.23 mixture was 4,5,5a,6,7,8,9,10-octahydro- (m, 4H), 2.16 (d, J = 13.8 concentrated 3, 1 Oa, 11,13,14-pentaaza- 6, 9- Hz, 3H), 1.43 - 1.29 (m, and diluted methanonaphtho[l,8- 10H), 1.02 (d, J = 6.2 Hz, with 1:1 ab]heptalen-2-yl)-5-ethynyl-6- 3H). 0.98 (d, J = 4.7 Hz, MeCN / H2O fluoronaphthalen-2-amine 2H). thenneutralizedAttorney Docket No. 1587-WO-PCT Changes to Procedure: Different Ex. Structure LCMS 'H-MIRReagents / Starting Materials with triethylamine.Intermediate 27-10 in step H 1.Deprotection F III. / pN. was ’ll NMR (400 MHz, performed Q CA Methanol -Yq 57.93 - 7.84 with 4M HC1 XJ JN 0(m, 1H), 7.39 - 7.10 (m, in dioxane (40 cquiv.) using OH F 3H), 5.71 - 5.51 (m, 1H),5.43 (d, J= acetonitrile as 12.8 Hz, 1H),4 solvent. The 4-((.82 - 4.65 (m, 2H), 4.214R,5S,5aS,6S,9S)-l,9- 1-6 673.4 reaction dif - 3.80 (m, 5H), 3.64 -luoro-12-(((2R.7aS)-2- mixture was 3.43 (m, 3H), 3.11 - 2.87 fluorotetrahydro- 1 H- concentrated (m, 2H), 2.85 - 2.54 (m, pyrrolizin-7a(5H)- and diluted 2H), 2.53 - 2.11 (m, 7H), yl)methoxy)-4,5-dimethyl- with 1:11.81 - 1.62 (m, 1H), 1.424, 5, 5 a, 6,7, 8, 9, 10-octahydro- MeCN / H2O - 1.28 (m, 3H), 1.02 (dd, J 3, 10a, 11, 13, 14-pentaaza-6,9- then = 17.1, 5.9 Hz, 3H) ppm. methanonaphtho[l,8- neutralized ab]heptalen-2-yl)-5-ethynyl-6- with fluoronaphthalen-2-ol triethylamine prior to purification. Fy- NHy ' _ / y F Intermediate 27-5 in step 1. *7 ft \H'’ll NMR (400 MHz, Deprotection CDjCN) 8 11.93 (m, III), was 7.94 (m, 1H), 7.49 - 7.16 performed U CJN(m, 3H), 5.69 - 5.39 (m, with 4M HC1 OH F 1H), 5.23 - 5.04 (m, 1H), in dioxane 4.82 - 4.60 (m, 2H), 3.971-7 5-ethynyl-6-fluoro-4- 676.6 (100 eq.)- 3.60 (m, 3H), 3.60 - ((5S,5aS,6R,9S)-l,6,9- using 2.97 (m, 4H), 2.97 - 2.50 trifluoro-12-(((2R,7aS)-2- acetonitrile as (m, 5H), 2.50 - 2.02 (m, fluorotetrahydro- III- solvent and 6H), 1.26 (m, 3H). pyrrolizin-7a(5H)- quenched y l)methoxy )- 5 -methyl- with 4, 5, 5a, 6, 7, 8, 9, 10-octahydro- triethylamine 3, 10a, 11, 13, 14-pcntaaza-6,9- (150 eq.).methanonaphtho[ 1,8- ab]heptalen-2-yl)naphthalen-2-Attorney Docket No. 1587-WO-PCT Changes to Procedure: Different Ex. Structure LCMS 'H-NMRReagents / Starting Materials ol1H NMR (400 MHz,MeOD) 58.79 (dt, J =12.1, 0.9 Hz, 1H), 8.43 (d,J = 5.9 Hz, 1H), 7.91 (td, JU TI LAANA = 9.7, 5.7 Hz, 1H), 7.50O 2 (dd, J = 7.1, 2.4 Hz, 1H),U T Q 7.43 - 7.25 (m, 2H), 6.85 Intermediate (ddd, J = 39.3, 6.0, 1.2 Hz, 27-6 in step 1. O 1H), 5.22 - 5.13 (m, 1H), Deprotection 4.99 - 4.77 (m, 4H), 4.77 was 5-ethynyl-6-fluoro-4- - 4.57 (m, 2H), 4.47 (t, J = performed in 1-8 ((5S.5aS.6R.9S)- 1,6.9- 766.0 8.8 Hz, 1H), 3.77 (d, J = 20%trifluoro-5 -methyl- 12- 1.0 Hz, 1H), 3.63 - 3.51 TFA / DCM. (((3S,7aS)-3-((pyrimidin-4- (m, 2H), 3.49 - 3.34 (m, Triethylamine yloxy)methyl)tetrahydro- 1 H- 2H), 3.31 (dd, J = 3.3, 1.3 was used pyrrolizin-7a(5H)- Hz, 1H), 3.21 (dt, J = 12.0, instead of yl)methoxy)-4,5,5a,6,7,8,9,10- 6.1 Hz, 1H), 2.90 - 2.76 pyrrolidine. octahydro-3,10a,ll,13,14- (m, 1H), 2.50 - 2.40 (m,pentaaza-6,9- 1H), 2.34 (dq, J = 11.7, methanonaphtho[l,8- 5.3 Hz, 1H), 2.26 - 2.03ab]heptalen-2-yl)naphthalen-2- (m, 6H), 1.94 (d, J = 14.8amine Hz, 1H), 1.31 (ddd, J =12.0, 6.4, 2.4 Hz, 4H).Example 2-1.

[0232] Step 1: 5-ethynyl-6-fluoro-4-((6aR,7R,10S)-l,7,10-trifluoro-13-(((3S,7aS)-3- (fluoromethyl)tetrahydro-lH-pyirolizin-7a(5H)-yl)methoxy)-5,6,6a,7,8,9,10,ll-octahydro- 4H-3,lla,12,14,15-pentaaza-7,10-methanocyclohepta[4,5]cycloocta[l,2,3-de]naphthalen-2-Attorney Docket No. 1587-WO-PCT yl)naphthalen-2-amine (Example 2-1). A vial charged with Intermediate 24-4 (0.0768 mmol), CsF (1.54 mmol) and DMF (3.0 mL) was stirred at room temperature. Upon completion, the mixture quenched with water and extracted with EtOAc (3x). The combined organic layer was washed with saturated aqueous solution of LiCl (3x), dried over MgSO₄, filtered and concentrated. The residue was purified by RP-HPLC to afford the title compound. 'H NMR (400 MHz, Methanol-d4) 57.83 (dd, J = 9.2, 5.8 Hz, 1H), 7.41 - 7.08 (m, 3H), 5.43 (s, 2H), 4.75 (d, J = 13.0 Hz, 2H), 4.31 (s, 2H), 3.90 (s, 2H), 3.65 (s, 2H), 3.47 (s, 2H), 3.00 (d, J = 49.4 Hz, 3H), 2.63 -2.34 (m, 3H), 2.36 - 2.07 (m, 6H), 1.96 (s, 3H), 1.64 (d, J = 43.2 Hz, 4H). LCMS: 690.0.Example 3-1.step 1

[0233] Step 1: 5-ethynyl-6-fluoro-4-((4R,5S,5aS,6R,9S)-l,6,9-trifluoro-12-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-4,5-dimethyl-4,5,5a,6,7,8,9,10-octahydro-3, 10a, 11, 13,14- pentaaza-6,9-methanonaphtho[l,8-ab]heptalen-2-yl)naphthalen-2-amine (Example 3-1). To a 0 °C mixture of Intermediate 33-11 (0.027 mmol) in DCM (1 mL) was added TFA (0.5 mL). The mixture was warmed to ambient temperature and stirred for 1 hour, then concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (0.1% TFA in MeCN / H2O). Fractions containing the product were pooled and lyophilized to afford the title compound. *H NMR (400 MHz, Methanol-d4) 5 8.00 - 7.91 (m, 1H), 7.65 - 7.56 (m, 1H), 7.46 - 7.23 (m, 2H), 5.70 - 5.49 (m, 1H), 5.26 - 5.13 (m, 1H), 4.81 - 4.62 (m, 2H), 4.13 - 3.82 (m, 4H), 3.64 - 3.41 (m, 3H). 3.31 - 3.13 (m, 2H), 3.12 - 2.98 (m, 1H), 2.82 - 2.55 (m, 2H), 2.50 - 1.91 (m, 5H), 1.36 (d, J = 6.8 Hz, 3H), 1.15 - 1.03 (m, 3H) ppm. LCMS: 690.4.Attorney Docket No. 1587-WO-PCT IV. Biological ExamplesKRAS (GDP) Biochemical Assays:

[0234] Compounds are tested for binding to GDP-loaded wild-type KRAS (WT), KRAS-G12C, KRAS -G12D, and KRAS-G12V in a 384-well assay format using a TR-FRET probe displacement assay in buffer consisting of 50 mM Hepes (pH 7.4), 150 mM NaCl, 5 mM MgCl₂ and 0.005% Tween- 20. 0.03 nM KRAS is used in this assay with 0.02 nM Eu-streptavidin and 12 nM Cy-5 labelled probe. Compounds are serially diluted (1:3) in DMSO. The LabCyte ECHO Acoustic dispenser was used to pre-spot the assay plates (384-well Non-Binding Surface plates, Coming, Catalog #3824) with 50 nL of compound. 5 pL of 2X enzyme concentration is added to the prespotted plates and incubated for 30 minutes before adding 5 pL of 2X concentration of Eu-streptavidin and Cy-5 labelled probe (10 pL final reaction volume). The plates are incubated at room temperature for 2 hours before measuring TR-FRET ratio (665nm / 615nm) on the Envision multimode plate reader. The ratios are normalized to a positive (saturating concentration of known inhibitor) and negative (DMSO) control and plotted against the log of compound concentration. IC50 values are defined as the compound concentration that causes a 50% decrease in normalized signal and are calculated using a sigmoidal dose-response model to generate curve fits.Cell Based pERK Assays:

[0235] Compounds were tested in a 384-well assay format for their ability to inhibit cellular pERK in Kuramochi (WT KRAS), MIA-PaCa-2 (KRAS-G12C), ASPC-1 (KRAS G12D), and NCI-H441 (KRAS-G12V) cell-lines. Compounds were serially diluted (1:3) in DMSO. On day -1, 80 uL of cells were plated per well in the 384 well tissue-culture plates (Greiner: Cat# 781080) to seed 5000 cells per wells of AsPC-1 or 7500 cells of MIA-PaCa-2, NCI-H441, and Kuramochi cell lines in RPMI (Corning: Cat# 10-040-CM) with 10% fetal bovine serum (FBS) (HyClone: Cat# SH30071-03) and IX penicillin-streptomycin-glutamate (PSG) (Corning: Cat# 30-009-CI) for AsPC2, NCI-H440 and Kuramochi cell lines and DMEM (Coming: Cat# 15-018-CM) with 10% FBS and IX PSG for MIA-PaCa-2 cell line. The plates were then incubated overnight at 37°C and 5% CO2. On day 0, 400nL of compound / well was added into the cell plates and mixed 5 times by pipetting using a Beckmann Biomek FX. The cell plates were then incubated for 2 hours at 37°C and 5% CO2. HTRF Advanced Phospho-ERKl / 2 (THR202 / TYR204) Detection Kits (PerkinElmer: Cat# 64AERPEG) were used to prepare the lysis and detection solution according to manufacturer protocol. Following the 2 hour incubation, 70uL of medium was aspirated from the plates and lOuL of lysis and detection solution was added to the plates using a Biotek EL406 washer and dispenser. Plates were sealed and stored overnight at room temperature.Attorney Docket No. 1587-WO-PCT HTRF ratio (665nm / 615nm) was read by Envision multimode reader (PerkinElmer) the next day. The TR-FRET ratios were normalized to a positive (saturating concentration of known inhibitor) and negative (DMSO) control and plotted against the log of compound concentration. EC50 values were defined as the compound concentration that causes a 50% decrease in normalized signal and were calculated using a sigmoidal dose-response model to generate curve fits.Table 5. Biological DataKRAS KRAS KRAS H441Kuramochi MIAPaCa2 AsPC1 Example WT KRAS G12C G12V G12D pERK pERK No. pERK EC50 pERK EC50IC50(nM) IC50IC50IC50EC50EC50(nM) (nM) (nM) (nM) (nM) (nM) (nM) 1-1 0.128 0.192 0.230 0.436 1.364 0.26 1.16 1.87 1-2 0.351 0.427 0.287 0.744 1.48 0.20 0.70 1.53 1-3 0.104 0.159 0.186 0.425 1.17 0.18 0.94 2.73 1-4 0.179 0.302 0.346 0.705 2.98 0.39 2.59 10.49 1-5 0.770 2.176 3.735 20.369 2.54 2.79 5.24 30.06 1-6 0.156 0.174 0.153 0.302 1.34 0.15 0.62 0.70 1-7 0.154 0.199 0.216 0.406 1.54 0.21 0.90 0.92 1-8 0.340 0.500 0.364 0.765 4.53 0.23 1.23 3.25 2-1 0.148 0.415 0.839 1.417 1.13 0.51 3.67 6.013-1 0.573 0.889 0.387 0.842 1.15 0.22 0.77 0.60

[0236] The present disclosure provides reference to various embodiments and techniques. However, it should be understood that many variations and modifications can be made while remaining within the spirit and scope of the present disclosure. The description is made with the understanding that it is to be considered an exemplification of the claimed subject matter, and is not intended to limit the appended claims to the specific embodiments illustrated.

Claims

Attorney Docket No. 1587-WO-PCT CLAIMS1. A compound of Formula (lib):or a pharmaceutically acceptable salt thereof,whereinR1is F;R1band R2bare each independently H or Me, wherein at least one of R1band R2bis Me; RA2is -NH2; and-O-Lc-Rcis:alternatively, whereinR1is H;R1band R2bare each Me;RA2is -NH2; and-O-Lc-Rcis:alternatively, whereinAttorney Docket No. 1587-WO-PCT R1is H or F;R1band R2bare each independently H or Me, wherein at least one of R1band R2bis Me;RA2is -OH; and-O-Lc-Rcis:alternatively, whereinR1is H or F;R1band R2bare each H;RA2is -OH; and-O-Lc-Rcis:

2. The compound of of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is H.

3. I’he compound of of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is F.

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R1bis H; and R2bis Me.

5. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R1bis Me; and R2bis Me.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein -O-Lc-Rcis:Attorney Docket No. 1587-WO-PCT7. A compound, or a pharmaceutically acceptable salt thereof, having the structure:Attorney Docket No. 1587-WO-PCTAttorney Docket No. 1587-WO-PCT8. A pharmaceutical composition comprising a compound of any one of claims 1 to 7, and a pharmaceutically acceptable excipient.

9. The pharmaceutical composition of claim 8, further comprising one or more additional therapeutic agents.

10. A method of inhibiting KRAS G12C, G12D, or G12V protein in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claims 8 or 9.

11. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claims 8 or 9.

12. The method of claim 11, wherein the cancer is a KRAS G12C-, G12D-, or G12V-associated cancer.

13. The method of claim 11 or 12, wherein the cancer is colorectal cancer, lung cancer, pancreatic cancer, ovarian cancer, endometrial cancer, esophageal cancer, gastric cancer, biliary cancer, brain cancer, melanoma, or hepatocellular cancer.

14. Use of the compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer in a subject.

15. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for use in therapy.

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