Small molecule protein degraders of kras g12d mutant

Abstract

Compounds disclosed herein or their pharmaceutically acceptable salts can modulate the G12D mutant of Kirsten rat sarcoma (KRAS) protein and are expected to have utility as therapeutic agents, for example, for treating cancer. The disclosure also provides pharmaceutical compositions which comprise compounds disclosed herein or pharmaceutically acceptable salts thereof. The disclosure also relates to methods for use of the compounds or their pharmaceutically acceptable salts in the therapy and prophylaxis of cancer and for preparing pharmaceuticals for this purpose.

Description

145021.598160 (002000.PC) SMALL MOLECULE PROTEIN DEGRADERS OF KRAS G12D MUTANT CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 527,954, filed July 20, 2023, the disclosure of which is incorporated herein by reference in its entirety. FIELD OF THE INVENTION

[0002] The present disclosure relates to certain compounds and pharmaceutically acceptable salts thereof that modulate the G12D mutant of Kirsten rat sarcoma (KRAS) protein and are expected to have utility as therapeutic agents, for example, for treatment of cancer. The present application also relates to pharmaceutical compositions containing such compounds as well as methods of using the compounds for treating cancer. BACKGROUND

[0003] The KRAS gene belongs to the RAS family, is one of the common gene mutations in human cancers and encodes a small GTPase. RAS proteins are membrane-associated guanine nucleotide-binding proteins which function as molecular switches. RAS proteins function as components of signaling pathways transmitting signals from cell-surface receptors to regulate cellular proliferation, survival and differentiation. RAS proteins cycle between an inactive GDP-bound state and an active GTP-bound state. The KRAS gene is involved in the kinase signaling pathway that controls gene transcription, thereby regulating cell growth and differentiation. Within the cell, KRAS protein transitions between an inactive and an active state - when KRAS binds to Guanosine Diphosphate (GDP), it is in the inactive state; when it binds to Guanosine Triphosphate (GTP), it is in the active state and can activate downstream signaling pathways. KRAS in most cells is inactivated and when activated, downstream signaling pathways that can be activated include the MAPK signaling pathway, the PI3K signaling pathway, and the Ral-GEFs signaling pathway. These signaling pathways play an important role in promoting cell survival, proliferation and cytokine release, thereby affecting tumorigenesis and progression.

[0004] In human cancers, KRAS gene mutations occur in nearly 90% of pancreatic cancers, about 30% to 40% of colon cancers, about 17% of endometrial cancers, and about 15% to 20% of Lung cancers (mostly Non-Small Cell Lung Cancer, NSCLC). It also appears in cancer types such as cholangiocarcinoma, cervical cancer, bladder cancer, liver cancer, and145021.598160 (002000.PC) breast cancer. That is, in many of the cancers described above, there is a high proportion of KRAS gene mutations. Most KRAS missense mutations occur in codon 12, resulting in glycine to other amino acids, for example, exchange of glycine for an aspartate at residue 12 of RAS (the G12D mutation). Depending on the particular mutation present, G12C, G12D and G12R are the most common KRAS mutations in patients, e.g., KRAS G12D and KRAS G12V mutations, both found in about 90% of pancreatic cancers, and KRAS G12D is the most common KRAS mutation in colon cancer.

[0005] Currently in relation to KRAS G12D, in the case of anticancer drugs, small molecules traditionally inhibit the activity of target protein by targeted binding to induce cancer cell apoptosis, but target proteins in tumor cells often recover their activity and acquire drug resistance through overexpression of the target protein or incorporation of a new mutation in the target protein.

[0006] Targeted protein degraders (TPDs) are heterobifunctional molecules containing two small molecule binding moieties, joined together by a linker. One of the small molecule components is designed to bind with high affinity to a target protein in the cell and the other can bind with high affinity to an E3 ligase. In the cell, the TPD selectively binds to the target protein of interest. The TPD then recruits a specific E3 ligase to the target protein to form a ternary complex with both the target protein and the E3 ligase held in close proximity. The E3 ligase then recruits an E2 conjugating enzyme to the ternary complex. E2 is then able to ubiquitinate the target protein, labelling an available lysine residue on the protein, and then dissociates from the ternary complex. E3 can then recruit additional E2 molecules resulting in poly-ubiquitination of the target protein, labelling the target protein for potential degradation by the cell’s proteasome activity. A TPD is then able to dissociate from the target protein and initiate another catalytic cycle. The poly-ubiquitinated target protein is then recognized and degraded by the proteasome.

[0007] Accordingly, while progress has been made in this field, there remains a need in the art for small molecules that enable targeted degradation therapy for KRAS G12D mutation- related diseases or disorders. Embodiments of the present disclosure fulfill this need and provide further related advantages. SUMMARY OF THE DISCLOSURE

[0008] The present disclosure provides small molecule protein degraders which modulate mutant KRAS proteins and may be valuable pharmaceutically active compounds for the145021.598160 (002000.PC) treatment of cancer. The compounds of the disclosure, including compounds of Formula (I):and their pharmaceutically acceptable salts, can modulate the KRAS activity and thereby affect the signaling pathway which regulates cell growth, differentiation, and proliferation associated with oncological disorders. In certain embodiments, the compounds of the disclosure can modulate the KRAS (G12D) protein. The disclosure furthermore provides processes for preparing compounds of the disclosure, methods for using such compounds to treat oncological disorders, and pharmaceutical compositions which comprise compounds of the disclosure. DETAILED DESCRIPTION OF THE INVENTION Compounds of the Disclosure

[0009] In one embodiment, the present disclosure provides a compound having structural Formula (I), or a pharmaceutically acceptable salt thereof, as shown above, wherein: MLis selected from the group consisting of:Ring CLis selected from:(i) a 7- to 14-membered spiroheterocycloalkyl containing 0 to 2 additional heteroatoms independently selected from the group consisting of N, O, and S in addition to the illustrated N atom; and145021.598160 (002000.PC) (ii) a 4- to 6-membered saturated monocyclic heterocycloalkyl containing 0 to 1 additional heteroatom selected from the group consisting of N, O, and S in addition to the illustrated N atom; wherein Ring CLis unsubstituted or substituted by 1 to 3 RCLsubstituents independentlyselected from the group consisting of halo, C1-C3alkyl, C1-C3fluoroalkyl, and C1-C3alkoxy;Lb is -CH2-, -O-, -CH2-O-, -CH2CH2-O-, -O-piperidinylene-, -(C3-C7cycloalkylene)-, orabsent;Lc is C1-C3alkyl;Ldis selected from the group consisting of:(i) -CH2-;(ii) -CF2-;(iii) -O-; (iv) -phenylene-; (v) -O-phenylene-; and (vi) -piperidinylene-;Leis selected from the group consisting of:selected from the group consisting of C(H), C(RLe),N, S, and O; wherein at least one of Xe, Xf, Xg, and Xhis C(H) or C(RLe); andeach RLesubstituent is independently selected from the group consisting of halo, C1-C3alkyl, C1-C3fluoroalkyl, and C1-C3alkoxy;R1 is C1-C6alkyl, -CH2-C1, C3-C7cycloalkyl, or C3-C7heterocycloalkyl containing 1 to 2heteroatoms selected from the group consisting of N, O, and S; wherein C1 is C3-C7cycloalkyl;145021.598160 (002000.PC) each is H, C1-C6alkyl, or -CH2OH, or alternatively, two R2, together with the carbon atom to which both are attached, form a 3- to 7- membered saturated monocyclic ring;each R3 is independently H, fluoro, C1-C3alkyl, or C1-C3fluoroalkyl;each Rcis independently fluoro or C1-C3alkyl;Xa, Xb, Xc, Xd, and Xiare independently selected from the group consisting of C(H), C(R4),N, N(R4), S and O; wherein at least one of Xa, Xb, Xc, Xd, and Xiis C(H) or C(R4);R4 is halo, C1-C3alkyl or C1-C3fluoroalkyl;X1is N or C(H);Rx is halo, C1-C3alkyl or C1-C3fluoroalkyl;Ring Y is (i) phenyl or naphthyl; or (ii) a 5- to 6-membered mono- or a 9- to 10-membered bicyclic heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; wherein Ring Y is unsubstituted or substituted by 1 to 4 RYsubstituents selected from the group consisting of halo, hydroxy, C1-C3alkyl, C2-C3alkynyl, C1-C3fluoroalkyl, C1-C3alkoxy, C1-C3fluoroalkoxy, C1-C3alkylthio, C1-C3fluoroalkylthio, amino, C1-C3alkylamino, C1-C3dialkylamino and cyano;A is selected from the group consisting of:Ring A is a saturated 8- to 10-membered N-containing bridged bicyclic ring which contains at least one further N atom in addition to the illustrated N atom;RA is selected from the group consisting of C1-C3alkyl,GC2-C4alkenyl, C1-C3alkoxy, C1-C3alkoxy(C1-C3)alkyl, halo, C1-C3fluoroalkyl, hydroxy, C1-C3hydroxyalkyl, CF3-C(H)(OH)-, C(H)(F2)-C(H)(OH)-, cyano, and C1-C3cyanoalkyl;each Ra* is independently C1-C3alkyl;subscript i is 0, 1, or 2; subscript j is 1, 2, or 3; subscript k is 0, 1, or 2; subscript m is 0, 1, or 2;145021.598160 (002000.PC) subscript o is 0, 1, 2, 3, 4, or 5; subscript r is 0, 1, 2, or 3; subscript s is 0, 1, 2, or 3; subscript t is 1, 2, 3, 4, or 5; subscript u is 0 or 1; and subscript v is 0, 1, 2, or 3;

[0010] In one embodiment, the present disclosure provides a compound having structural formula (I), or a pharmaceutically acceptable salt thereof, wherein MLis.

[0011] In one embodiment, the present disclosure provides a compound having structural formula (I), or a pharmaceutically acceptable salt thereof, whereinis, wherein: subscripts p and q are independently 1, 2, or 3; andring CL2is a 4- to 6-membered saturated ring containing 0 to 1 heteroatom selected fromthe group consisting of N, S, and O.

[0012] In one embodiment, the present disclosure provides a compound having structural formula (I), or a pharmaceutically acceptable salt thereof, wherein MLis, wherein subscript n is 1, 2, or 3.

[0013] In one embodiment, the present disclosure provides a compound having structural formula (I), or a pharmaceutically acceptable salt thereof, wherein MLis.

[0014] In one embodiment, the present disclosure provides a compound having structural formula (I), or a pharmaceutically acceptable salt thereof, wherein Lcis methyl.145021.598160 (002000.PC)

[0015] In one embodiment, the present disclosure provides a compound having structural formula (I), or a pharmaceutically acceptable salt thereof, wherein Ldis -CH2-.

[0016] In one embodiment, the present disclosure provides a compound having structuralformula (I), or a pharmaceutically acceptable salt thereof, wherein Leis .

[0017] In one embodiment, the present disclosure provides a compound having structuralformula (I), or a pharmaceutically acceptable salt thereof, whereinis H.

[0018] In one embodiment, the present disclosure provides a compound having structural formula (I), or a pharmaceutically acceptable salt thereof, wherein.

[0019] In one embodiment, the present disclosure provides a compound having structural formula (I), or a pharmaceutically acceptable salt thereof, wherein Leis selected from the group consisting

[0020] In one embodiment, the present disclosure provides a compound having structural formula (I), or a pharmaceutically acceptable salt thereof, wherein subscript u is 0.

[0021] In one embodiment, the present disclosure provides a compound having structural formula (I), or a pharmaceutically acceptable salt thereof, wherein the moiety.

[0022] In one embodiment, the present disclosure provides a compound having structural formula (I), or a pharmaceutically acceptable salt thereof, wherein the moietyis selected from the group consisting of:145021.598160 (002000.PC)145021.598160 (002000.PC)

[0023] In one embodiment, the present disclosure provides a compound having structural formula (I), or a pharmaceutically acceptable salt thereof, wherein the moiety.

[0024] In one embodiment, the present disclosure provides a compound having structural formula (I), or a pharmaceutically acceptable salt thereof, wherein the moietyselected from the group consisting of:145021.598160 (002000.PC)

[0025] In one embodiment, the present disclosure provides a compound having structural formula (I), or a pharmaceutically acceptable salt thereof, wherein the moiety.145021.598160 (002000.PC)

[0026] In one embodiment, the present disclosure provides a compound having structural formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring Y is selected from

[0027] In one embodiment, the present disclosure provides a compound having structural formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring Y is selected from.

[0028] In one embodiment, the present disclosure provides a compound having structural formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring Y is selected from

[0029] In one embodiment, the present disclosure provides a compound having structural formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring Y is selected from145021.598160 (002000.PC)

[0030] In one embodiment, the present disclosure provides a compound having structural formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring, wherein subscript v is 0, 1, or 2.

[0031] In one embodiment, the present disclosure provides a compound having structural formula (I), or a pharmaceutically acceptable salt thereof, wherein R1is t-butyl.

[0032] In one embodiment, the present disclosure provides a compound having structural formula (I), or a pharmaceutically acceptable salt thereof, wherein each R2is H.

[0033] In one embodiment, the present disclosure provides a compound having structural formula (I), or a pharmaceutically acceptable salt thereof, wherein subscript j is 1 and eachR3is H.

[0034] In one embodiment, the present disclosure provides a compound having structural formula (I), or a pharmaceutically acceptable salt thereof, wherein the moiety145021.598160 (002000.PC)

[0035] In specific embodiments, the present disclosure provides a compound as described in any one of Examples 1-115 as set forth below, or a pharmaceutically acceptable salt thereof.

[0036] The present disclosure also provides compounds of Formula (II):or a pharmaceutically acceptable salt thereof, wherein:MLis selected from the group consisting of:Ring CLis selected from:(i) a 7- to 14-membered spiroheterocycloalkyl containing 0 to 2 additional heteroatoms independently selected from the group consisting of N, O, and S in addition to the illustrated N atom; and (ii) a 4- to 6-membered saturated monocyclic heterocycloalkyl containing 0 to 1 additional heteroatom selected from the group consisting of N, O, and S in addition to the illustrated N atom; wherein Ring CLis unsubstituted or substituted by 1 to 3 RCLsubstituents independentlyselected from the group consisting of halo, C1-C3alkyl, C1-C3fluoroalkyl, and C1-C3alkoxy;Lbis -CH2-, -O-, or absent;Lc is C1-C3alkyl;Ldis selected from the group consisting of: (i) -CH2-;(ii) -CF2-;145021.598160 (002000.PC) (iii) -O-; (iv) -phenylene-; and (v) -O-phenylene-;Leis selected from the group consisting of:R5is H or C1-C3alkyl;Xe, Xf, Xg, and Xhare independently selected from the group consisting of C(H), C(RLe),N, S, and O; wherein at least one of Xe, Xf, Xg, and Xhis C(H) or C(RLe); andeach RLesubstituent is independently selected from the group consisting of halo, C1-C3alkyl, C1-C3fluoroalkyl, and C1-C3alkoxy;is C1-C6alkyl, -CH2-C1, C3-C7cycloalkyl, or C3-C7heterocycloalkyl containing 1 to 2heteroatoms selected from the group consisting of N, O, and S; wherein C1is C3-C7cycloalkyl;R2 is H, C1-C6alkyl, or -CH2OH;each R3is independently H, fluoro, C1-C3alkyl, or C1-C3fluoroalkyl;each Rc is independently fluoro or C1-C3alkyl;Xa, Xb, Xcand Xdare independently selected from the group consisting of C(H), C(R4), N,N(R4), S and O; wherein at least one of Xa, Xb, Xcand Xdis C(H) or C(R4);R4 is halo, C1-C3alkyl or C1-C3fluoroalkyl;X1is N or C(H);Rx is halo, C1-C3alkyl or C1-C3fluoroalkyl;Ring Y is (i) phenyl or naphthyl; or (ii) a 5- to 6-membered mono- or a 9- to 10-membered bicyclic heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S;145021.598160 (002000.PC) wherein Ring Y is unsubstituted or substituted by 1 to 4 RYsubstituents selected from the group consisting of halo, hydroxy, C1-C3alkyl, C2-C3alkynyl, C1-C3fluoroalkyl, C1-C3alkoxy, C1-C3fluoroalkoxy, C1-C3alkylthio, C1-C3fluoroalkylthio, amino, C1-C3alkylamino, C1-C3dialkylamino and cyano;A is selected from the group consisting of:Ring A is a saturated 8- to 10-membered N-containing bridged bicyclic ring which contains at least one further N atom in addition to the illustrated N atom;RA is selected from the group consisting of C1-C3alkyl,GC2-C4alkenyl, C1-C3alkoxy, C1-C3alkoxy(C1-C3)alkyl, halo, C1-C3fluoroalkyl, hydroxy, C1-C3hydroxyalkyl, CF3-C(H)(OH)-, C(H)(F2)-C(H)(OH)-, cyano, and C1-C3cyanoalkyl;each Ra* is independently C1-C3alkyl;subscript i is 0, 1, or 2; subscript j is 1, 2, or 3; subscript k is 0, 1, or 2; subscript m is 0, 1, or 2; subscript o is 0, 1, 2, 3, 4, or 5; subscript r is 0, 1, 2, or 3; subscript s is 0, 1, 2, or 3; subscript t is 1, 2, 3, 4, or 5; subscript u is 0 or 1; and subscript v is 0, 1, 2, or 3.

[0037] The present disclosure includes the pharmaceutically acceptable salts of the compounds defined herein, including the pharmaceutically acceptable salts of all structural formulas, embodiments and classes defined herein. Definitions

[0038] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.145021.598160 (002000.PC)

[0039] As used throughout this disclosure, “compound(s) of Formula (I) or (II)”, “compound(s) disclosed herein”, “compound(s) described herein”, “compound(s) of the disclosure”, etc., are used interchangeably and are to be understood to include the disclosed compounds of Formula (I) or (II). The compounds of Formula (I) or (II) can form salts which are also within the scope of the present disclosure. Reference to a compound of the disclosure (or compound of Formula (I) or (II)) herein is understood to include reference to salts thereof, unless otherwise indicated.

[0040] “Alkenyl” means an aliphatic hydrocarbon group containing at least one carbon- carbon double bond and which may be straight or branched. Non-limiting examples include ethenyl, propenyl, and butenyl.

[0041] “Alkyl”, as well as other groups having the prefix “alk”, such as alkoxy, and the like, means carbon chains which may be linear or branched, or combinations thereof, containing the indicated number of carbon atoms. For instance, a C1-C6 alkyl means an alkyl group having one (i.e., methyl) up to 6 carbon atoms (i.e., hexyl). In particular embodiments, linear alkyl groups have 1-6 carbon atoms and branched alkyl groups have 3- 7 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl and the like.

[0042] “Alkylamino” means an alkyl group linked to an amine, wherein the nitrogen atom is substituted by one or more alkyl substituents. The bond to the parent group is through the nitrogen atom of the amino component.

[0043] “Alkylthio” means an alkyl group linked to a sulfur. “Fluoroalkylthio” means an alkylthio that is mono-or multiple-fluoro-substituted. The bond to the parent group is through the sulfur atom of the group.

[0044] “Alkoxy” and “alkyl-O-” are used interchangeably and refer to an alkyl group linked to oxygen. “Fluoroalkoxy” means an alkoxy that is mono-or multiple-fluoro- substituted. The bond to the parent group is through the oxygen atom of the group.

[0045] “Alkoxyalkyl” means and alkoxy group linked to an alkyl. The bond to the parent group is through the carbon atom of the alkyl component.

[0046] “Alkynyl” means an aliphatic hydrocarbon group containing at least one carbon- carbon triple bond and which may be straight or branched. Non-limiting examples include ethynyl, propynyl, and butynyl.

[0047] “Amino” means an amine group that contains two substituents bonded to a nitrogen atom via two single covalent bonds. The bond to the parent group is through the nitrogen atom of the group.145021.598160 (002000.PC)

[0048] “Aryl” means a monocyclic, bicyclic, tricyclic, or tetracyclic carbocyclic aromatic ring or ring system containing 5-17 carbon atoms, wherein at least one of the rings is aromatic. Non-limiting examples include phenyl and naphthyl.

[0049] “Bicyclic ring system” refers to two joined rings. “Tricyclic ring system” refers to three joined rings. “Tetracyclic ring system” refers to four joined rings. The rings may be fused, i.e., share two adjacent atoms, or “spirocyclic”, i.e., share only a single atom, or “bridged”, i.e., share three or more atoms with two bridgehead atoms being connected by a bridge containing at least one atom. Likewise the bicyclic or tricyclic rings may be aryl rings, heterocyclic rings, cycloalkyl rings, etc.

[0050] “Carbamoyl” means a H2N-C(O)- group, which is the univalent group formed by loss of -OH group of carbamic acid. The bond to the parent group is through the carbon atom of the carbonyl component.

[0051] “Cyanoalkyl” means and cyano group linked to an alkyl. The bond to the parent group is through the carbon atom of the alkyl component.

[0052] “Cycloalkyl” means a saturated cyclic hydrocarbon radical. In particular embodiments, the cycloalkyl group has 3-12 carbon atoms, forming 1-3 carbocyclic rings, wherein cyclic systems having 2-3 rings can be fused. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and the like. “Fluorocycloalkyl” means a saturated cyclic hydrocarbon radical that is mono- or multiple- fluoro-substituted, e.g., doubly fluoro-substituted cyclopentyl. “Cycloalkoxy” refers to a cycloalkyl group linked through an oxygen to the parent moiety. “Spirocycloalkyl” means a saturated spirocyclic hydrocarbon radical having at least two rings sharing only a single atom.

[0053] “Cycloalkylene” means a divalent saturated cyclic hydrocarbon radical having two single bonds, where each single bond attaches to a different parent moiety.

[0054] “Dialkylamino” means an alkylamino as previously defined, wherein the nitrogen atom of the amine is substituted by two alkyl substituents, which substitutions can be the same or different, e.g., -N(CH3)2 or -N(CH3)(CH2CH3). The bond to the parent group is through the nitrogen atom of the amino component.

[0055] “Fluoroalkyl” includes mono-substituted as well as multiple fluoro-substituted alkyl groups, up to perfluoro substituted alkyl. For example, fluoromethyl, 1,1-difluoroethyl, trifluoromethyl or 1,1,1,2,2-pentafluorobutyl are included. The bond to the parent group is through one of the carbon atoms of the alkyl component.145021.598160 (002000.PC)

[0056] “Halogen” or “halo”, unless otherwise indicated, includes fluorine (fluoro), chlorine (chloro), bromine (bromo) and iodine (iodo). In one embodiment, halo is fluoro (-F) or chloro (-Cl).

[0057] “Heteroaryl” refers to aromatic monocyclic, bicyclic and tricyclic ring structures in which one or more atoms in the ring, the heteroatom(s), is an element other than carbon. Heteroatoms are typically O, S, or N atoms. Examples of heteroaryl groups include pyrazolyl, oxadiazolonyl, pyridinyl, pyrimidinyl, pyrrolyl, pyridazinyl, isoxazolyl, thiazolyl, oxazolyl, indolyl, benzoxazolyl, benzothiazolyl, and imidazolyl.

[0058] “Heterocycloalkyl” or “heterocyclic ring” or “heterocycle” means a non-aromatic monocyclic, bicyclic, tricyclic or tetracyclic ring system comprising about 3 to about 17 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example, nitrogen, oxygen, phosphorus or sulfur, alone or in combination. There are no adjacent oxygen and / or sulfur atoms present in the ring system. In some embodiments, heterocycloalkyls contain about 5 to about 6 ring atoms. The prefix aza, oxa, phospha or thia before the heterocyclyl root name means that at least a nitrogen, oxygen, phosphorus or sulfur atom respectively is present as a ring atom. In some embodiments, the nitrogen or sulfur atom of the heterocycloalkyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. For instance, in some embodiments the heterocycloalkyl can contain N, S, S(O), S(O)2and / or O (which are referred to herein as “heteroatom groups”). Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, phosphorinane, phosphinane, 1-oxophosphinan-1-ium and the like. “Spiroheterocycloalkyl” refers to a fused ring system in which the rings share only a single atom and at least one of the rings is a heterocycloalkyl.

[0059] “Hydroxyalkyl” means a HO-alkyl- group in which alkyl is as previously defined. The bond to the parent moiety is through one of the carbon atoms of the alkyl component. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl. “Hydroxyfluoroalkyl” means a HO-fluoroalkyl- group in which fluoroalkyl is as previously defined. “Hydroxycycloalkyl” means a HO-cycloalkyl- group in which cycloalkyl is as previously defined. “Hydroxyfluorocycloalkyl” means a HO-fluorocycloalkyl- group in which fluorocycloalkyl is as previously defined.145021.598160 (002000.PC)

[0060] “Piperidinylene” means a divalent piperidine-based radical having two single bonds, where each single bond attaches to a different parent moiety

[0061] “Phenylene” means a divalent benzene radical, -C6H4-, wherein each of the two hydrogen atoms of the benzene is substituted by a substituent. Any of the remaining four hydrogen atoms of phenylene can be further substituted by optional substituents. Phenylene can exist in ortho-, meta-, or para- form.

[0062] When any variable (e.g., Rx) occurs more than one time in any constituent or in Formula (I) or (II) or other generic formulas herein, its definition on each occurrence is independent of its definition at every other occurrence. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. In choosing compounds of the present disclosure, one of ordinary skill in the art will recognize that the various substituents, e.g., Rx, are to be chosen in conformity with well-known principles of chemical structure connectivity and stability. Unless expressly stated to the contrary, substitution by a named substituent is permitted on any atom in a ring (e.g., aryl, a heteroaryl ring, or a saturated heteroaryl ring) provided such ring substitution is chemically allowed and results in a stable compound. A “stable” compound is a compound which can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic or prophylactic administration to a subject).

[0063] The term “substituted” shall be deemed to include multiple degrees of substitution by a named substituent. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different.

[0064] Unless expressly depicted or described otherwise, variables depicted in a structural formula with a “floating” bond, such as RX, are permitted on any available carbon atom in the ring to which the variable is attached. When a moiety is noted as being “optionally substituted” in Formula (I) or (II) or any embodiment thereof, it means that Formula (I) or (II) or the embodiment thereof encompasses compounds that contain the noted substituent (or substituents) on the moiety and also compounds that do not contain the noted substituent (or substituents) on the moiety.

[0065] The wavy line , as used herein, indicates a point of attachment to the rest of the compound.145021.598160 (002000.PC)

[0066] The compounds of Formula (I) or (II) may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereoisomeric mixtures and individual diastereoisomers. Centers of asymmetry that are present in the compounds of Formula (I) or (II) can all independently of one another have S configuration or R configuration. The compounds of Formula (I) or (II) include all possible enantiomers and diastereomers and mixtures of two or more stereoisomers, for example, mixtures of enantiomers and / or diastereomers, in all ratios. Thus, enantiomers are a subject of the disclosure in enantiomerically pure form, both as levorotatory and as dextrorotatory antipodes, in the form of racemates and in the form of mixtures of the two enantiomers in all ratios. In the case of a cis / trans isomerism, the disclosure includes both the cis form and the trans form as well as mixtures of these forms in all ratios. The present disclosure is meant to comprehend all such stereoisomeric forms of the compounds of Formula (I) or (II). Where a structural formula or chemical name specifies a particular configuration at a stereocenter, the enantiomer or stereoisomer of the compound resulting from that specified stereocenter is intended. Where a structural formula of the compounds of Formula (I) or (II) indicates a straight line at a chiral center, the structural formula includes both the S and R stereoisomers associated with the chiral center and mixtures thereof.

[0067] The compounds of Formula (I) or (II) may be separated into their individual diastereoisomers by, for example, fractional crystallization from a suitable solvent, for example, methanol or ethyl acetate or a mixture thereof, or via chiral chromatography using an optically active stationary phase. Absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. Vibrational circular dichroism (VCD) may also be used to determine the absolute stereochemistry. Alternatively, any stereoisomer or isomers of the compounds of Formula (I) or (II) may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known absolute configuration.

[0068] If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereoisomeric mixture, followed by separation of the individual diastereoisomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diasteromeric derivatives may then be145021.598160 (002000.PC) converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.

[0069] The compounds of Formula (I) or (II) which contain olefinic double bonds, unless specified otherwise, they are meant to include both E and Z geometric isomers.

[0070] Some of the compounds described herein may exist as tautomers which have different points of attachment of hydrogen accompanied by one or more double bond shifts. For example, a ketone and its enol form are keto-enol tautomers. The individual tautomers as well as mixtures thereof are encompassed by the compounds of Formula (I) or (II).

[0071] Some of the compounds of Formula (I) or (II) described herein may exist as atropisomers when the rotational energy barrier around a single bond is sufficiently high to prevent free rotation at a given temperature, thus allowing isolation of individual conformers with distinct properties. The individual atropisomers as well as mixtures thereof are encompassed with compounds of Formula (I) or (II) of the present disclosure. When resolved, individual atropisomers can be designated by established conventions such as those specified by the International Union of Pure Applied Chemistry (IUPAC) 2013 Recommendations.

[0072] In the compounds of Formula (I) or (II), the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present disclosure as described and claimed herein is meant to include all suitable isotopic variations of the compounds of Formula (I) or (II) and embodiments thereof. For example, different isotopic forms of hydrogen (H) include protium (1H) and deuterium (2H, also denoted herein as D). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and / or intermediates.

[0073] The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When a compound of Formula (I) or (II) is acidic, its corresponding salt can be conveniently prepared from pharmaceutically145021.598160 (002000.PC) acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc and the like salts. Preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts prepared from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines derived from both naturally occurring and synthetic sources. Pharmaceutically acceptable organic non-toxic bases from which salts can beformed include, for example, arginine, betaine, caffeine, choline, N,N'- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, dicyclohexylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

[0074] When a compound of Formula (I) or (II) is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic inorganic and organic acids. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids. If a compound of Formula (I) or (II) simultaneously contains acidic and basic groups in the molecule, the disclosure also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). Salts can be obtained from the compounds of Formula (I) or (II) by customary methods which are known to the person skilled in the art, for example, by combination with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange from other salts. The present disclosure also includes all salts of the compounds of Formula (I) or (II) which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

[0075] Furthermore, the compounds of Formula (I) or (II) may exist in amorphous form and / or one or more crystalline forms, and as such all amorphous and crystalline forms and mixtures thereof of the compounds of Formula (I) or (II), including the Examples, are intended to be included within the scope of the present disclosure. In addition, some of the145021.598160 (002000.PC) compounds of Formula (I) or (II) may form solvates with water (i.e., a hydrate) or common organic solvents such as but not limited to ethyl acetate. Such solvates and hydrates, particularly the pharmaceutically acceptable solvates and hydrates, of the instant compounds are likewise encompassed within the scope of this disclosure, along with un- solvated and anhydrous forms.

[0076] Any pharmaceutically acceptable pro-drug modification of a compound of Formula (I) or (II) which results in conversion in vivo to a compound within the scope of this disclosure is also within the scope of this disclosure.

[0077] The present disclosure also relates to processes for the preparation of the compounds of the disclosure which are described in the following and by which the compounds of the disclosure are obtainable.

[0078] The terms “therapeutically effective (or efficacious) amount” and similar descriptions such as “an amount efficacious for treatment” or “an effective dose” are intended to mean that amount of a compound of Formula (I) or (II) that will elicit the biological or medical response of a tissue, a system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. In a preferred embodiment, the term “therapeutically effective amount” means an amount of a compound of Formula (I) or (II) that alleviates at least one clinical symptom in a human patient. The terms “prophylactically effective (or efficacious) amount” and similar descriptions such as “an amount efficacious for prevention” are intended to mean that amount of a compound of Formula (I) or (II) that will prevent or reduce the risk of occurrence of the biological or medical event that is sought to be prevented in a tissue, a system, animal or human by a researcher, veterinarian, medical doctor or other clinician. Dosages of the compounds of Formula (I) or (II)

[0079] The dosage regimen utilizing a compound of Formula (I) or (II) is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the potency of the compound chosen to be administered; the route of administration; and the renal and hepatic function of the patient. A consideration of these factors is well within the purview of the ordinarily skilled clinician for the purpose of determining the therapeutically effective or prophylactically effective dosage amount needed to prevent, counter, or arrest the progress of the condition. It is understood that a specific daily dosage amount can simultaneously be145021.598160 (002000.PC) both a therapeutically effective amount, e.g., for treatment of an oncological condition, and a prophylactically effective amount, e.g., for prevention of an oncological condition.

[0080] While individual needs vary, determination of optimal ranges of effective amounts of the compounds of Formula (I) or (II) is within the skill of the art. For administration to a human in, for example, the curative or prophylactic treatment of the conditions and disorders identified herein, the typical dosages of the compounds of Formula (I) or (II) can be about 0.05 mg / kg / day to about 50 mg / kg / day, or at least 0.05 mg / kg, or at least 0.08 mg / kg, or at least 0.1 mg / kg, or at least 0.2 mg / kg, or at least 0.3 mg / kg, or at least 0.4 mg / kg, or at least 0.5 mg / kg, and any amount therebetween, to about 50 mg / kg or less, or about 40 mg / kg or less, or about 30 mg / kg or less, or about 20 mg / kg or less, or about 10 mg / kg or less and any amount therebetween, which can be, for example, about 2.5 mg / day (0.5 mg / kg x 5 kg) to about 5000 mg / day (50 mg / kg x 100 kg). For example, dosages of the compounds can be about 0.1 mg / kg / day to about 50 mg / kg / day, or about 0.05 mg / kg / day to about 10 mg / kg / day, or about 0.05 mg / kg / day to about 5 mg / kg / day, or about 0.05 mg / kg / day to about 3 mg / kg / day, or about 0.07 mg / kg / day to about 3 mg / kg / day, or about 0.09 mg / kg / day to about 3 mg / kg / day, or about 0.05 mg / kg / day to about 0.1 mg / kg / day, or about 0.1 mg / kg / day to about 1 mg / kg / day, or about 1 mg / kg / day to about 10 mg / kg / day, or about 1 mg / kg / day to about 5 mg / kg / day, or about 1 mg / kg / day to about 3 mg / kg / day, or about 3 mg / day to about 500 mg / day, or about 5 mg / day to about 250 mg / day, or about 10 mg / day to about 100 mg / day, or about 3 mg / day to about 10 mg / day, or about 100 mg / day to about 250 mg / day. Such doses may be administered in a single dose or may be divided into multiple doses. Pharmaceutical Compositions

[0081] The compounds of Formula (I) or (II) and their pharmaceutically acceptable salts can be administered to animals, preferably to mammals, and in particular to humans, as pharmaceuticals by themselves, in mixtures with one another or in the form of pharmaceutical compositions. The term “subject” or “patient” includes animals, preferably mammals and especially humans, who use the instant active agents for the prevention or treatment of a medical condition. Administering of the drug to the subject includes both self-administration and administration to the patient by another person. The subject may be in need of, or desire, treatment for an existing disease or medical condition, or may be in need of or desire prophylactic treatment to prevent or reduce the risk of occurrence of said disease or medical condition. As used herein, a subject “in need” of treatment of an existing145021.598160 (002000.PC) condition or of prophylactic treatment encompasses both a determination of need by a medical professional as well as the desire of a patient for such treatment.

[0082] The present disclosure therefore also provides the compounds of the disclosure and their pharmaceutically acceptable salts for use as pharmaceuticals, their use for modulating the activity of mutant KRAS proteins and in particular their use in the therapy and prophylaxis of the below-mentioned diseases or disorders as well as their use for preparing medicaments for these purposes. In certain embodiments, the compounds of the disclosure and their pharmaceutically acceptable salts inhibit the KRAS G12D protein.

[0083] Furthermore, the present disclosure provides pharmaceutical compositions which comprise as active component an effective dose of at least one compound of Formula (I) or (II) and / or a pharmaceutically acceptable salt thereof and a customary pharmaceutically acceptable carrier, i.e., one or more pharmaceutically acceptable carrier substances and / or additives.

[0084] Thus, the present disclosure provides, for example, said compound and its pharmaceutically acceptable salts for use as pharmaceutical compositions which comprise as active component an effective dose of at least one compound of Formula (I) or (II) and / or a pharmaceutically acceptable salt thereof and a customary pharmaceutically acceptable carrier, and the uses of said compound and / or a pharmaceutically acceptable salt thereof in the therapy or prophylaxis of the below-mentioned diseases or disorders, e.g., cancer, as well as their use for preparing medicaments for these purposes.

[0085] The pharmaceutical compositions according to the disclosure can be administered orally, for example, in the form of pills, tablets, lacquered tablets, sugar-coated tablets, granules, hard and soft gelatin capsules, aqueous, alcoholic or oily solutions, syrups, emulsions or suspensions, or rectally, for example, in the form of suppositories. Administration can also be carried out parenterally, for example subcutaneously, intramuscularly or intravenously in the form of solutions for injection or infusion.

[0086] Other suitable administration forms are, for example, percutaneous or topical administration, for example, in the form of ointments, tinctures, sprays or transdermal therapeutic systems, or, for example, microcapsules, implants or rods. The preferred administration form depends, for example, on the disease to be treated and on its severity.

[0087] The amount of active compound of a compound described herein and / or its pharmaceutically acceptable salts in the pharmaceutical composition normally is from 0.01 to 200 mg, or from 0.1 to 200 mg, or from 1 to 200 mg, per dose, but depending on the type of the pharmaceutical composition, it can also be higher. In some embodiments, the amount145021.598160 (002000.PC) of active compound of a compound of Formula (I) or (II) and / or its pharmaceutically acceptable salts in the pharmaceutical composition is from 0.01 to 10 mg per dose. The pharmaceutical compositions usually comprise 0.5 to 90 percent by weight of at least one compound of Formula (I) or (II) and / or its pharmaceutically acceptable salts. The preparation of the pharmaceutical compositions can be carried out in a manner known per se. For this purpose, one or more compounds of Formula (I) or (II) and / or their pharmaceutically acceptable salts, together with one or more solid or liquid pharmaceutical carrier substances and / or additives (or auxiliary substances) and, if desired, in combination with other pharmaceutically active compounds having therapeutic or prophylactic action, are brought into a suitable administration form or dosage form which can then be used as a pharmaceutical in human or veterinary medicine.

[0088] For the production of pills, tablets, sugar-coated tablets and hard gelatin capsules, it is possible to use, for example, lactose, starch, for example, maize starch, or starch derivatives, talc, stearic acid or its salts, etc. Carriers for soft gelatin capsules and suppositories are, for example, fats, waxes, semisolid and liquid polyols, natural or hardened oils, etc. Suitable carriers for the preparation of solutions, for example, of solutions for injection, or of emulsions or syrups are, for example, water, physiologically acceptable sodium chloride solution, alcohols such as ethanol, glycerol, polyols, sucrose, invert sugar, glucose, mannitol, vegetable oils, etc. It is also possible to lyophilize the compounds of Formula (I) or (II) and their pharmaceutically acceptable salts and to use the resulting lyophilisates, for example, for preparing preparations for injection or infusion. Suitable carriers for microcapsules, implants or rods are, for example, copolymers of glycolic acid and lactic acid.

[0089] Besides the active compounds and carriers, the pharmaceutical compositions can also contain customary additives, for example, fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, dispersants, preservatives, sweeteners, colorants, flavorings, aromatizers, thickeners, diluents, buffer substances, solvents, solubilizers, agents for achieving a depot effect, salts for altering the osmotic pressure, coating agents and / or antioxidants. Methods of Using the Compounds of Formula (I) or (II)

[0090] The present application provides a method of modulating RAS-mediated cell signaling comprising contacting a cell with a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof. Modulation of RAS-mediated signal transduction145021.598160 (002000.PC) can be assessed and demonstrated by a wide variety of ways known in the art. Non-limiting examples include (a) a decrease in GTPase activity of RAS; (b) a decrease in GTP bindingaffinity or an increase in GDP binding affinity; (c) an increase in Koffof GTP or a decreasein Koffof GDP; (d) a decrease in the levels of signaling transduction moleculesdownstream in the RAS pathway, such as a decrease in pMEK, pERK, or pAKT levels; and / or (e) a decrease in binding of RAS complex to downstream signaling molecules including but not limited to Raf. Kits and commercially available assays can be utilized for determining one or more of the above.

[0091] The present application also provides methods of using the compounds of the disclosure (or their pharmaceutically acceptable salts) or pharmaceutical compositions containing such compounds to treat disease conditions, including but not limited to, conditions implicated by mutant KRAS proteins (e.g., cancer), and in some embodiments the KRAS G12D mutant.

[0092] In some embodiments, a method of degrading a KRAS G12D protein in a cell is provided, comprising administering a therapeutically effective amount a compound of the disclosure (or a pharmaceutically acceptable salt thereof) or any of the foregoing pharmaceutical compositions comprising such a compound to a subject in need of such treatment, resulting in degradation of the KRAS G12D protein in the cell.

[0093] In some embodiments, a method of inhibiting a KRAS G12D protein in a cell is provided, comprising administering a therapeutically effective amount of a compound of the disclosure (or a pharmaceutically acceptable salt thereof) or any of the foregoing pharmaceutical compositions comprising such a compound to a subject in need of such treatment, resulting in inhibition of the KRAS G12D protein in the cell.

[0094] In some embodiments, a method for treatment of cancer is provided, the method comprising administering a therapeutically effective amount a compound of the disclosure (or a pharmaceutically acceptable salt thereof) or any of the foregoing pharmaceutical compositions comprising such a compound to a subject in need of such treatment. In some embodiments, the cancer is mediated by a KRAS mutation, e.g., the KRAS G12D mutation. In various embodiments, the cancer is pancreatic cancer, colorectal cancer or lung cancer. In some embodiments, the cancer is gall bladder cancer, thyroid cancer, or bile duct cancer.

[0095] In some embodiments the present disclosure provides a method of treating a disorder in a subject in need thereof, wherein said method comprises determining if the subject has a KRAS mutation (e.g., KRAS G12D mutation) and if the subject is determined145021.598160 (002000.PC) to have the KRAS mutation, then administering to the subject a therapeutically effective amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof.

[0096] The disclosed compounds inhibit anchorage-independent cell growth and therefore have the potential to inhibit tumor metastasis. Accordingly, another embodiment of the present disclosure provides a method for inhibiting tumor metastasis, the method comprising administering an effective amount a compound of Formula (I) or (II).

[0097] KRAS mutations have also been identified in hematological malignancies (e.g., cancers that affect blood, bone marrow and / or lymph nodes). Accordingly, certain embodiments are directed to administration of the compounds of the disclosure (e.g., in the form of a pharmaceutical composition) to a subject in need of treatment of a hematological malignancy. Such malignancies include, but are not limited to leukemias and lymphomas. For example, the presently disclosed compounds can be used for treatment of diseases such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL) and / or other leukemias. In other embodiments, the compounds are useful for treatment of lymphomas such as Hodgkins lymphoma or non-Hodgkins lymphoma. In various embodiments, the compounds are useful for treatment of plasma cell malignancies such as multiple myeloma, mantle cell lymphoma, and Waldenstrom's macroglubunemia.

[0098] Determining whether a tumor or cancer comprises a KRAS mutation (e.g., the KRAS G12D mutation) can be undertaken by assessing the nucleotide sequence encoding the KRAS protein, by assessing the amino acid sequence of the KRAS protein, or by assessing the characteristics of a putative KRAS mutant protein. The sequences of wild- type human KRAS are known in the art.

[0099] Methods for detecting a mutation in a KRAS nucleotide sequence are also known by those of skill in the art. These methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) assays, real-time PCR assays, PCR sequencing, mutant allele-specific PCR amplification (MASA) assays, direct sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high resolution melting assays and microarray analyses. In some embodiments, samples are evaluated for KRAS mutations (e.g., the KRAS G12D mutation) by real-time PCR. In real-time PCR, fluorescent probes specific for the KRAS mutation are used. When a mutation is present,145021.598160 (002000.PC) the probe binds and fluorescence is detected. In some embodiments, the KRAS mutation is identified using a direct sequencing method of specific regions (e.g., exon 2 and / or exon 3) in the KRAS gene.

[0100] Methods for detecting a mutation in a KRAS protein (e.g., the KRAS G12D mutation) are known by those of skill in the art. These methods include, but are not limited to, detection of a KRAS mutant using a binding agent (e.g., an antibody) specific for the mutant protein, protein electrophoresis and Western blotting, and direct peptide sequencing.

[0100] A number of tissue samples can be assessed for determining whether a tumor or cancer comprises a KRAS mutation (e.g., the KRAS G12D mutation). In some embodiments, the sample is taken from a subject having a tumor or cancer. In some embodiments, the sample is a fresh tumor / cancer sample. In some embodiments, the sample is a frozen tumor / cancer sample. In some embodiments, the sample is a formalin- fixed paraffin-embedded sample. In some embodiments, the sample is a circulating tumor cell (CTC) sample. In some embodiments, the sample is processed to a cell lysate. In some embodiments, the sample is processed to DNA or RNA.

[0101] The present application also provides a method of treating a hyperproliferative disorder comprising administering a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof to a subject in need thereof. In some embodiments, said method relates to the treatment of a subject who suffers from a cancer such as acute myeloid leukemia, cancer in adolescents, adrenocortical carcinoma childhood, AIDS- related cancers (e.g., Lymphoma and Kaposi's Sarcoma), anal cancer, appendix cancer, astrocytomas, atypical teratoid, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumors, Burkitt lymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germ cell tumor, primary lymphoma, cervical cancer, childhood cancers, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myleoproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gall bladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell145021.598160 (002000.PC) tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary, midline tract carcinoma, mouth cancer; multiple endocrine neoplasia syndromes, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplasia syndromes, myelodysplastic / myeloproliferative neoplasms, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, Non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach (gastric) cancer, small cell lung cancer; small intestine cancer, soft tissue sarcoma, T-Cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, trophoblastic tumor, unusual cancers of childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or viral-induced cancer. In some embodiments, said method relates to the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)).

[0102] In some embodiments, the methods for treatment are directed to treating lung cancers, and the methods comprise administering a therapeutically effective amount of the compounds of Formula (I) or (II) (or pharmaceutical composition comprising such compounds) to a subject in need thereof. In certain embodiments, the lung cancer is a non- small cell lung carcinoma (NSCLC), for example, adenocarcinoma, squamous-cell lung carcinoma or large-cell lung carcinoma. In some embodiments, the lung cancer is a small cell lung carcinoma. Other lung cancers which the compounds of Formula (I) or (II) may provide therapeutic benefit for include, but are not limited to, glandular tumors, carcinoid tumors and undifferentiated carcinomas.

[0103] The present disclosure also provides methods of modulating a mutant KRAS protein activity (e.g., activity resulting from the KRAS G12D mutation) by contacting the protein with an effective amount of a compound of the disclosure. Modulation can be inhibiting or activating protein activity, or degrading targeted polypeptides or proteins. In some embodiments, the present disclosure provides methods of inhibiting protein activity or145021.598160 (002000.PC) degrading the mutant KRAS protein by contacting the mutant KRAS protein (e.g., KRAS G12D mutant) with an effective amount of a compound of the disclosure in solution. In some embodiments, the present disclosure provides methods of inhibiting the mutant KRAS protein activity or degrading the mutant KRAS protein by contacting a cell, tissue, or organ that expresses the protein of interest. In some embodiments, the disclosure provides methods of inhibiting protein activity or degrading targeted polypeptides or proteins in subjects including, but not limited to, rodents and mammals (e.g., humans) by administering into the subjects an effective amount of a compound of the disclosure. Combination Therapies

[0104] One or more additional pharmacologically active agents may be administered in combination with a compound of Formula (I) or (II) (or a pharmaceutically acceptable salt thereof). An additional active agent (or agents) is intended to mean a pharmaceutically active agent (or agents) that is active in the body, including pro-drugs that convert to pharmaceutically active form after administration, which are different from the compound of Formula (I) or (II). The additional active agents also include free-acid, free-base and pharmaceutically acceptable salts of said additional active agents. Generally, any suitable additional active agent or agents, including chemotherapeutic agents or therapeutic antibodies, may be used in any combination with the compound of Formula (I) or (II) in a single dosage formulation (e.g., a fixed dose drug combination), or in one or more separate dosage formulations which allows for concurrent or sequential administration of the active agents (co-administration of the separate active agents) to subjects. In addition, the compounds of Formula (I) or (II) (or pharmaceutically acceptable salts thereof) can be administered in combination with radiation therapy, hormone therapy, surgery or immunotherapy.

[0105] The present application also provides methods for combination therapies in which the additional active agent is known to modulate other pathways, or other components of the same pathway, or even overlapping sets of target enzymes which are used in combination with a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof. In one embodiment, such therapy includes, but is not limited to, the combination of one or more compounds of Formula (I) or (II) with chemotherapeutic agents, immunotherapeutic agents, hormonal and anti-hormonal agents, targeted therapy agents, and anti-angiogenesis agents, to provide a synergistic or additive therapeutic effect. In145021.598160 (002000.PC) another embodiment, such therapy includes radiation treatment to provide a synergistic or additive therapeutic effect.

[0106] Examples of additional active agents (i.e., additional anti-cancer agents) include chemotherapeutic agents (e.g., cytotoxic agents), immunotherapeutic agents, hormonal and anti-hormonal agents, targeted therapy agents, and anti-angiogenesis agents. Many anti- cancer agents can be classified within one or more of these groups. While certain anti- cancer agents have been categorized within a specific group(s) or subgroup(s) herein, many of these agents can also be listed within one or more other group(s) or subgroup(s), as would be presently understood in the art. It is to be understood that the classification herein of a particular agent into a particular group is not intended to be limiting. Many anti-cancer agents are presently known in the art and can be used in combination with the compounds of the present disclosure.

[0107] Further, an agent can be an agonist, antagonist, allosteric modulator, toxin or, more generally, may act to inhibit or stimulate its target (e.g., receptor or enzyme activation or inhibition). For example, suitable for use are one or more agents (e.g., antibodies, antigen binding regions, or soluble receptors) that specifically bind and inhibit the activity of growth factors, such as antagonists of hepatocyte growth factor (HGF, also known as Scatter Factor), and antibodies or antigen binding regions that specifically bind its receptor “c-met”.

[0108] In an embodiment, the additional anti-cancer agent is a chemotherapeutic agent, an immunotherapeutic agent, a hormonal agent, an anti-hormonal agent, a targeted therapy agent, or an anti-angiogenesis agent (or angiogenesis inhibitor). In an embodiment, the additional anti-cancer agent is selected from the group consisting of a chemotherapeutic agent, a mitotic inhibitor, a plant alkaloid, an alkylating agent, an anti-metabolite, a platinum analog, an enzyme, a topoisomerase inhibitor, a retinoid, an aziridine, an antibiotic, a hormonal agent, an anti-hormonal agent, an anti-estrogen, an anti-androgen, an anti-adrenal, an androgen, a targeted therapy agent, an immunotherapeutic agent, a biological response modifier, a cytokine inhibitor, a tumor vaccine, a monoclonal antibody, an immune checkpoint inhibitor, an anti-PD-1 agent, an anti-PD-L1 agent, a colony- stimulating factor, an immunomodulator, an immunomodulatory imide (IMiD), an anti- CTLA4 agent, an anti-LAGl agent, an anti-LAG3 agent, an anti-ILT4 agent, an anti-OX40 agent, a GITR agonist, a CAR-T cell, a BiTE, a signal transduction inhibitor, a growth factor inhibitor, a tyrosine kinase inhibitor, an EGFR inhibitor, a histone deacetylase (HDAC) inhibitor, a proteasome inhibitor, a cell-cycle inhibitor, an anti-angiogenesis agent,145021.598160 (002000.PC) a matrix-metalloproteinase (MMP) inhibitor, a hepatocyte growth factor inhibitor, a TOR inhibitor, a KDR inhibitor, a VEGF inhibitor, a HIF-1Į inhibitor, a HIF-2Į inhibitor, a fibroblast growth factor (FGF) inhibitor, a RAF inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, an AKT inhibitor, an MCL-1 inhibitor, a BCL-2 inhibitor, an SHP2 inhibitor, a HER-2 inhibitor, a BRAF-inhibitor, a gene expression modulator, an autophagy inhibitor, an apoptosis inducer, an antiproliferative agent, and a glycolysis inhibitor.

[0109] In one embodiment, the additional anti-cancer agent(s) is a chemotherapeutic agent. Non-limiting examples of chemotherapeutic agents include mitotic inhibitors and plant alkaloids, alkylating agents, anti-metabolites, platinum analogs, enzymes, topoisomerase inhibitors, retinoids, aziridines, and antibiotics.

[0110] Non-limiting examples of mitotic inhibitors and plant alkaloids include taxanes such as cabazitaxel, docetaxel, larotaxel, ortataxel, paclitaxel, and tesetaxel; demecolcine; epothilone; eribulin; etoposide (VP- 16); etoposide phosphate; navelbine; noscapine; teniposide; thaliblastine; vinblastine; vincristine; vindesine; vinflunine; and vinorelbine.

[0111] Non-limiting examples of alkylating agents include nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, cytophosphane, estramustine, ifosfamide, mannomustine, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, tris(2-chloroethyl)amine, trofosfamide, and uracil mustard; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine, streptozotocin, and TA-07; ethylenimines and methylamelamines such as altretamine, thiotepa, triethylenemelamine, triethylenethiophosphaoramide, trietylenephosphoramide, and trimethylolomelamine; ambamustine; bendamustine; dacarbazine; etoglucid; irofulven; mafosfamide; mitobronitol; mitolactol; pipobroman; procarbazine; temozolomide; treosulfan; and triaziquone.

[0112] Non-limiting examples of anti-metabolites include folic acid analogues such as aminopterin, denopterin, edatrexate, methotrexate, pteropterin, raltitrexed, and trimetrexate; purine analogs such as 6-mercaptopurine, 6-thioguanine, fludarabine, forodesine, thiamiprine, and thioguanine; pyrimidine analogs such as 5-fluorouracil (5-FU), 6- azauridine, ancitabine, azacytidine, capecitabine, carmofur, cytarabine, decitabine, dideoxyuridine, doxifiuridine, doxifluridine, enocitabine, floxuridine, galocitabine, gemcitabine, and sapacitabine; 3-aminopyridine-2-carboxaldehyde thiosemicarbazone;145021.598160 (002000.PC) broxuridine; cladribine; cyclophosphamide; cytarabine; emitefur; hydroxyurea; mercaptopurine; nelarabine; pemetrexed; pentostatin; tegafur; and troxacitabine.

[0113] Non-limiting examples of platinum analogs include carboplatin, cisplatin, dicycloplatin, heptaplatin, lobaplatin, nedaplatin, oxaliplatin, satraplatin, and triplatin tetranitrate.

[0114] Non-limiting examples of enzymes include asparaginase and pegaspargase.

[0115] Non-limiting examples of topoisomerase inhibitors include acridine carboxamide, amonafide, amsacrine, belotecan, elliptinium acetate, exatecan, indolocarbazole, irinotecan, lurtotecan, mitoxantrone, razoxane, rubitecan, SN-38, sobuzoxane, and topotecan.

[0116] Non-limiting examples of retinoids include alitretinoin, bexarotene, fenretinide, isotretinoin, liarozole, RII retinamide, and tretinoin.

[0117] Non-limiting examples of aziridines include benzodopa, carboquone, meturedopa, and uredopa.

[0118] Non-limiting examples of antibiotics include intercalating antibiotics; anthracenediones; anthracycline antibiotics such as aclarubicin, amrubicin, daunomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril, nogalamycin, pirarubicin, and valrubicin; 6-diazo-5-oxo- L-norleucine; aclacinomysins; actinomycin; authramycin; azaserine; bleomycins; cactinomycin; calicheamicin; carabicin; carminomycin; carzinophilin; chromomycins; dactinomycin; detorubicin; esorubicin; esperamicins; geldanamycin; marcellomycin; mitomycins; mitomycin C; mycophenolic acid; olivomycins; novantrone; peplomycin; porfiromycin; potfiromycin; puromycin; quelamycin; rebeccamycin; rodorubicin; streptonigrin; streptozocin; tanespimycin; tubercidin; ubenimex; zinostatin; zinostatin stimalamer; and zorubicin.

[0119] In one embodiment, the additional anti-cancer agent(s) is a hormonal and / or anti- hormonal agent (i.e., hormone therapy). Non-limiting examples of hormonal and anti- hormonal agents include anti-androgens such as abiraterone, apalutamide, bicalutamide, darolutamide, enzalutamide, flutamide, goserelin, leuprolide, and nilutamide; anti-estrogens such as 4- hydroxy tamoxifen, aromatase inhibiting 4(5)-imidazoles, EM-800, fosfestrol, fulvestrant, keoxifene, LY 117018, onapristone, raloxifene, tamoxifen, toremifene, and trioxifene; anti-adrenals such as aminoglutethimide, dexaminoglutethimide, mitotane, and trilostane; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; abarelix; anastrozole; cetrorelix; deslorelin; exemestane; fadrozole; finasteride; formestane; histrelin (RL 0903); human chorionic gonadotropin;145021.598160 (002000.PC) lanreotide; LDI 200 (Milkhaus); letrozole; leuprorelin; mifepristone; nafarelin; nafoxidine; osaterone; prednisone; thyrotropin alfa; and triptorelin.

[0120] In one embodiment, the additional anti-cancer agent(s) is an immunotherapeutic agent (i.e., immunotherapy). Non-limiting examples of immunotherapeutic agents include biological response modifiers, cytokine inhibitors, tumor vaccines, monoclonal antibodies, immune checkpoint inhibitors, colony-stimulating factors, and immunomodulators.

[0121] Non-limiting examples of biological response modifiers, including cytokine inhibitors (cytokines) such as interferons and interleukins, include interferon alfa / interferon alpha such as interferon alfa-2, interferon alfa-2a, interferon alfa-2b, interferon alfa-nl, interferon alfa-n3, interferon alfacon-1, peginterferon alfa-2a, peginterferon alfa-2b, and leukocyte alpha interferon; interferon beta such as interferon beta-1a, and interferon beta- 1b; interferon gamma such as natural interferon gamma-1a, and interferon gamma-1b; aldesleukin; interleukin-1 beta; interleukin-2; oprelvekin; sonermin; tasonermin; and virulizin.

[0122] Non-limiting examples of tumor vaccines include APC 8015, AVICINE, bladder cancer vaccine, cancer vaccine (Biomira), gastrin 17 immunogen, Maruyama vaccine, melanoma lysate vaccine, melanoma oncolysate vaccine (New York Medical College), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering Institute), TICE® BCG (Bacillus Calmette-Guerin), and viral melanoma cell lysates vaccine (Royal Newcastle Hospital).

[0123] Non-limiting examples of monoclonal antibodies include abagovomab, adecatumumab, aflibercept, alemtuzumab, blinatumomab, brentuximab vedotin, CA 125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), daclizumab, daratumumab, denosumab, edrecolomab, gemtuzumab zogamicin, HER- 2 and Fc MAb (Medarex), ibritumomab tiuxetan, idiotypic 105AD7 MAb (CRC Technology), idiotypic CEA MAb (Trilex), ipilimumab, quavonlimab, vibostolimab, favezelimab, lintuzumab, LYM-1 -iodine 131 MAb (Techni clone), mitumomab, moxetumomab, ofatumumab, polymorphic epithelial mucin-yttrium 90 MAb (Antisoma), ranibizumab, rituximab, and trastuzumab.

[0124] Non-limiting examples of immune checkpoint inhibitors include anti-PD-1 agents or antibodies such as cemiplimab, nivolumab, and pembrolizumab; anti-PD-L1 agents or antibodies such as atezolizumab, avelumab, and durvalumab; anti-CTLA-4 agents or antibodies such as ipilumumab and quavonlimab; anti-LAG1 agents; anti-LAG3 agents such as favezelimab, and anti-OX40 agents.145021.598160 (002000.PC)

[0125] Non-limiting examples of colony-stimulating factors include darbepoetin alfa, epoetin alfa, epoetin beta, filgrastim, granulocyte macrophage colony stimulating factor, lenograstim, leridistim, mirimostim, molgramostim, nartograstim, pegfilgrastim, and sargramostim.

[0126] Non-limiting examples of additional immunotherapeutic agents include BiTEs, CAR-T cells, GITR agonists, imiquimod, immunomodulatory imides (IMiDs), mismatched double stranded RNA (Ampligen), resiquimod, SRL 172, and thymalfasin.

[0127] In one embodiment, the additional anti-cancer agent(s) is a targeted therapy agent (i.e., targeted therapy). Targeted therapy agents include, for example, monoclonal antibodies and small molecule drugs. Non-limiting examples of targeted therapy agents include signal transduction inhibitors, growth factor inhibitors, tyrosine kinase inhibitors, EGFR inhibitors, histone deacetylase (HDAC) inhibitors, proteasome inhibitors, cell-cycle inhibitors, angiogenesis inhibitors, matrix-metalloproteinase (MMP) inhibitors, hepatocyte growth factor inhibitors, TOR inhibitors, KDR inhibitors, VEGF inhibitors, fibroblast growth factors (FGF) inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, MCL-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, HER-2 inhibitors, BRAF- inhibitors, BTK inhibitors (e.g., nemtabrutinib), gene expression modulators, autophagy inhibitors, apoptosis inducers, antiproliferative agents, and glycolysis inhibitors.

[0128] Non-limiting examples of signal transduction inhibitors include tyrosine kinase inhibitors, multiple-kinase inhibitors, anlotinib, avapritinib, axitinib, dasatinib, dovitinib, imatinib, lenvatinib, lonidamine, nilotinib, nintedanib, pazopanib, pegvisomant, ponatinib, vandetanib, and EGFR inhibitory agents.

[0129] Non-limiting examples of EGFR inhibitory agents include small molecule antagonists of EGFR such as afatinib, brigatinib, erlotinib, gefitinib, lapatinib, and osimertinib; and antibody-based EGFR inhibitors, including any anti-EGFR antibody or antibody fragment that can partially or completely block EGFR activation by its natural ligand. Antibody-based EGFR inhibitory agents may include, for example, those described in Modjtahedi, H., et al., 1993, Br. J. Cancer 67:247-253; Teramoto, T., et al., 1996, Cancer 77:639-645; Goldstein et al, 1995, Clin. Cancer Res.1 : 1311-1318; Huang, S. M., et al., 1999, Cancer Res.15:59(8): 1935-40; and Yang, X., et al., 1999, Cancer Res.59: 1236- 1243; monoclonal antibody Mab E7.6.3 (Yang, 1999 supra); Mab C225 (ATCC Accession No. HB-8508), or an antibody or antibody fragment having the binding specificity thereof; specific antisense nucleotide or siRNA; afatinib, cetuximab; matuzumab; necitumumab; nimotuzumab; panitumumab; and zalutumumab.145021.598160 (002000.PC)

[0130] Non-limiting examples of histone deacetylase (HDAC) inhibitors include belinostat, panobinostat, romidepsin, and vorinostat.

[0131] Non-limiting examples of proteasome inhibitors include bortezomib, carfilzomib, ixazomib, marizomib (salinosporamide a), and oprozomib.

[0132] Non-limiting examples of cell-cycle inhibitors, including CDK inhibitors, include abemaciclib, alvocidib, palbociclib, and ribociclib.

[0133] In one embodiment, the additional anti-cancer agent(s) is an anti-angiogenic agent (or angiogenesis inhibitor) including, but not limited to, matrix-metalloproteinase (MMP) inhibitors; VEGF inhibitors; EGFR inhibitors; TOR inhibitors such as everolimus and temsirolimus; PDGFR kinase inhibitory agents such as crenolanib; HIF-lĮ inhibitors such as PX 478; HIF-2Į inhibitors such as belzutifan and the HIF-2Į inhibitors described in WO 2015 / 035223; fibroblast growth factor (FGF) or FGFR inhibitory agents such as B-FGF and RG 13577; hepatocyte growth factor inhibitors; KDR inhibitors; anti-Ang1 and anti-Ang2 agents; anti-Tie2 kinase inhibitory agents; Tek antagonists (US 2003 / 0162712; US 6,413,932); anti-TWEAK agents (US 6,727,225); ADAM distintegrin domain to antagonize the binding of integrin to its ligands (US 2002 / 0042368); anti-eph receptor and / or anti- ephrin antibodies or antigen binding regions (US 5,981,245; 5,728,813; 5,969,110; 6,596,852; 6,232,447; and 6,057,124); and anti-PDGF-BB antagonists as well as antibodies or antigen binding regions specifically binding to PDGF-BB ligands.

[0134] Non-limiting examples of matrix-metalloproteinase (MMP) inhibitors include MMP-2 (matrix-metalloproteinase 2) inhibitors, MMP-9 (matrix-metalloproteinase 9) inhibitors, prinomastat, RO 32-3555, and RS 13-0830. Examples of useful matrix metalloproteinase inhibitors are described, for example, in WO 96 / 33172, WO 96 / 27583, EP 1004578 , WO 98 / 07697, WO 98 / 03516, WO 98 / 34918, WO 98 / 34915, WO 98 / 33768, WO 98 / 30566, EP 0606046, EP 0931788, WO 90 / 05719, WO 99 / 52910, WO 99 / 52889, WO 99 / 29667, WO 1999 / 007675 , EP 1786785, EP 1181017, US 2009 / 0012085 , US 5,863,949, US 5,861,510, and EP 0780386. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1. More preferred, are those that selectively inhibit MMP-2 and / or MMP-9 relative to the other matrix-metalloproteinases (i.e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP- 7, MMP- 8, MMP-10, MMP-11, MMP-12, and MMP-13).

[0135] Non-limiting examples of VEGF and VEGFR inhibitory agents include bevacizumab, cediranib, CEP 7055, CP 547632, KRN 633, orantinib, pazopanib,145021.598160 (002000.PC) pegaptanib, pegaptanib octasodium, semaxanib, sorafenib, sunitinib, VEGF antagonist (Borean, Denmark), and VEGF-TRAP™.

[0136] The additional anti-cancer agent(s) may also be another anti-angiogenic agent including, but not limited to, 2-methoxyestradiol, AE 941, alemtuzumab, alpha-D148 Mab (Amgen, US), alphastatin, anecortave acetate, angiocidin, angiogenesis inhibitors, (SUGEN, US), angiostatin, anti-Vn Mab (Crucell, Netherlands), atiprimod, axitinib, AZD 9935, BAY RES 2690 (Bayer, Germany, BC 1 (Genoa Institute of Cancer Research, Italy), beloranib, benefin (Lane Labs, US), cabozantinib, CDP 791 (Celltech Group, UK), chondroitinase AC, cilengitide, combretastatin A4 prodrug, CP 564959 (OSI, US), CV247, CYC 381 (Harvard University, US), E 7820, EHT 0101, endostatin, enzastaurin hydrochloride, ER-68203-00 (IVAX, US), fibrinogen-E fragment, Flk-1 (ImClone Systems, US), forms of FLT 1 (VEGFR 1), FR-111142, GCS-100, GW 2286 (GlaxoSmithKline, UK), IL-8, ilomastat, IM- 862, irsogladine, KM-2550 (Kyowa Hakko, Japan), lenalidomide, lenvatinib, MAb alpha5beta3 integrin, second generation (Applied Molecular Evolution, USA and Medlmmune, US), MAb VEGF (Xenova, UK), marimastat, maspin (Sosei, Japan), metastatin, motuporamine C, M-PGA, ombrabulin, OXI4503, PI 88, platelet factor 4, PPI 2458, ramucirumab, rBPI 21 and BPI-derived antiangiogenic (XOMA, US), regorafenib, SC-236, SD-7784 (Pfizer, US), SDX 103 (University of California at San Diego, US), SG 292 (Telios, US), SU-0879 (Pfizer, US), TAN-1120, TBC-1635, tesevatinib, tetrathiomolybdate, thalidomide, thrombospondin 1 inhibitor, Tie-2 ligands (Regeneron, US), tissue factor pathway inhibitors (EntreMed, US), tumor necrosis factor-alpha inhibitors, tumstatin, TZ 93, urokinase plasminogen activator inhibitors, vadimezan, vandetanib, vasostatin, vatalanib, VE-cadherin-2 antagonists, xanthorrhizol, XL 784 (Exelixis, US), ziv-aflibercept, and ZD 6126.

[0137] In embodiments, the additional anti-cancer agent(s) is an additional active agent that disrupts or inhibits RAS-RAF-ERK or PI3K-AKT-TOR signaling pathways or is a PD-1 and / or PD-L1 antagonist. In embodiments, the additional anti-cancer agent(s) is a RAF inhibitor, EGFR inhibitor, MEK inhibitor, ERK inhibitor, PI3K inhibitor, AKT inhibitor, TOR inhibitor, MCL-1 inhibitor, BCL-2 inhibitor, SHP2 inhibitor, proteasome inhibitor, or immune therapy, including monoclonal antibodies, immunomodulatory imides (IMiDs), anti-PD-1, anti-PDL-1, anti-CTLA4, anti-LAGl, anti-LAG3, and anti-OX40 agents, GITR agonists, CAR-T cells, and BiTEs.

[0138] Non-limiting examples of RAF inhibitors include dabrafenib, encorafenib, regorafenib, sorafenib, and vemurafenib.145021.598160 (002000.PC)

[0139] Non-limiting examples of MEK inhibitors include binimetinib, CI-1040, cobimetinib, PD318088, PD325901, PD334581, PD98059, refametinib, selumetinib, and trametinib.

[0140] Non-limiting examples of ERK inhibitors include LY3214996, LTT462, MK-8353, SCH772984, ravoxertinib, ulixertinib, and an ERKi as described in WO 2017 / 068412.

[0141] Non-limiting examples of PI3K inhibitors include 17-hydroxywortmannin analogs (e.g., WO 06 / 044453); AEZS-136; alpelisib; AS-252424; buparlisib; CAL263; copanlisib; CUDC-907; dactolisib (WO 06 / 122806); demethoxyviridin; duvelisib; GNE-477; GSK1059615; IC87114; idelalisib; INK1117; LY294002; Palomid 529; paxalisib; perifosine; PI-103; PI-103 hydrochloride; pictilisib (e.g., WO 09 / 036,082; WO 09 / 055,730); PIK 90; PWT33597; SF1126; sonolisib; TGI 00-115; TGX-221; XL147; XL-765; wortmannin; and ZSTK474.

[0142] Non-limiting examples of AKT inhibitors include Akt-1-1 (inhibits Aktl) (Barnett et al. (2005) Biochem. J., 385 (Pt.2), 399-408); Akt-1-1,2 (Barnett et al. (2005) Biochem. J. 385 (Pt.2), 399-408); API-59CJ-Ome (e.g., Jin et al. (2004) Br. J. Cancer 91, 1808-12); l- H-imidazo[4,5-c]pyridinyl compounds (e.g., WO05011700); indole-3-carbinol and derivatives thereof (e.g., U.S. Patent No.6,656,963; Sarkar and Li (2004) J Nutr.134(12 Suppl), 3493S-3498S); perifosine, Dasmahapatra et al. (2004) Clin. Cancer Res.10(15), 5242-52, 2004); phosphatidylinositol ether lipid analogues (e.g., Gills and Dennis (2004) Expert. Opin. Investig. Drugs 13, 787-97); triciribine (Yang et al. (2004) Cancer Res.64, 4394-9); imidazooxazone compounds including trans-3-amino-1-methyl-3-[4-(3-phenyl- 5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)phenyl]-cyclobutanol hydrochloride (WO 2012 / 137870) ; afuresertib;; capivasertib; MK2206; patasertib, and those disclosed in WO 2011 / 082270 and WO 2012 / 177844.

[0143] Non-limiting examples of TOR inhibitors include deforolimus; ATP-competitive TORC1 / TORC2 inhibitors, including PI-103, PP242, PP30, and Torin 1; TOR inhibitors in FKBP12 enhancer, rapamycins and derivatives thereof, including temsirolimus, everolimus, WO 9409010; rapalogs, e.g. as disclosed in WO 98 / 02441 and WO 01 / 14387, e.g. AP23573, AP23464, or AP23841; 40-(2-hydroxyethyl)rapamycin, 40-[3- hydroxy(hydroxymethyl)methylpropanoate]-rapamycin ; 40-epi-(tetrazolyl)-rapamycin (also called ABT578); 32-deoxorapamycin; 16-pentynyloxy-32(S)-dihydrorapanycin, and other derivatives disclosed in WO 05 / 005434; derivatives disclosed in US 5,258,389, WO 94 / 090101, WO 92 / 05179, US 5,118,677, US 5,118,678, US 5,100,883, US 5,151,413, US 5,120,842, WO 93 / 111130, WO 94 / 02136, WO 94 / 02485, WO 95 / 14023, WO 94 / 02136,145021.598160 (002000.PC) WO 95 / 16691, WO 96 / 41807, WO 96 / 41807 and US 5,256,790; and phosphorus-containing rapamycin derivatives (e.g., WO 05 / 016252).

[0144] Non-limiting examples of MCL-1 inhibitors include AMG-176, MIK665, and S63845.

[0145] Non-limiting examples of SHP2 inhibitors include SHP2 inhibitors described in WO 2019 / 167000 and WO 2020 / 022323.

[0146] Additional non-limiting examples of anti-cancer agents that are suitable for use include 2-ethylhydrazide, 2,2',2"-trichlorotriethylamine, ABVD, aceglatone, acemannan, aldophosphamide glycoside, alpharadin, amifostine, aminolevulinic acid, anagrelide, ANCER, ancestim, anti-CD22 immunotoxins, antitumorigenic herbs, apaziquone, arglabin, arsenic trioxide, azathioprine, BAM 002 (Novelos), bcl-2 (Genta), bestrabucil, biricodar, bisantrene, bromocriptine, brostallicin, bryostatin, buthionine sulfoximine, calyculin, cell- cycle nonspecific antineoplastic agents, celmoleukin, clodronate, clotrimazole, cytarabine ocfosfate, DA 3030 (Dong-A), defofamine, denileukin diftitox, dexrazoxane, diaziquone, dichloroacetic acid, dilazep, discodermolide, docosanol, doxercalciferol, edelfosine, eflornithine, EL532 (Elan), elfomithine, elsamitrucin, eniluracil, etanidazole, exisulind, ferruginol, folic acid replenisher such as frolinic acid, gacytosine, gallium nitrate, gimeracil / oteracil / tegafur combination (S-1), glycopine, histamine dihydrochloride, HIT diclofenac, HLA-B7 gene therapy (Vical), human fetal alpha fetoprotein, ibandronate, ibandronic acid, ICE chemotherapy regimen, imexon, iobenguane, IT-101 (CRLX101), laniquidar, LC 9018 (Yakult), leflunomide, lentinan, levamisole + fluorouracil, lovastatin, lucanthone, masoprocol, melarsoprol, metoclopramide, miltefosine, miproxifene, mitoguazone, mitozolomide, mopidamol, motexafin gadolinium, MX6 (Galderma), naloxone + pentazocine, nitracrine, nolatrexed, NSC 631570 octreotide (Ukrain), olaparib, P-30 protein, PAC-1, palifermin, pamidronate, pamidronic acid, pentosan polysulfate sodium, phenamet, picibanil, pixantrone, platinum, podophyllinic acid, porfimer sodium, PSK (Polysaccharide-K), rabbit antithymocyte polyclonal antibody, rasburiembodiment, retinoic acid, rhenium Re 186 etidronate, romurtide, samarium (153 Sm) lexidronam, sizofiran, sodium phenylacetate, sparfosic acid, spirogermanium, strontium-89 chloride, suramin, swainsonine, talaporfin, tariquidar, tazarotene, tegafur-uracil, temoporfin, tenuazonic acid, tetrachlorodecaoxide, thrombopoietin, tin ethyl etiopurpurin, tirapazamine, TLC ELL-12, tositumomab-iodine 131, trifluridine and tipiracil combination, troponin I (Harvard University, US), urethan, valspodar, verteporfin, zoledronic acid, and zosuquidar.145021.598160 (002000.PC)

[0147] The present disclosure further provides a method for using the compounds of Formula (I) or (II) or pharmaceutical compositions provided herein, in combination with radiation therapy to treat cancer. Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein. The administration of the compound of Formula (I) or (II) in this combination therapy can be determined as described herein.

[0148] Radiation therapy can be administered through one of several methods, or a combination of methods, including, without limitation, external-beam therapy, internal radiation therapy, implant radiation, stereotactic radiosurgery, systemic radiation therapy, radiotherapy and permanent or temporary interstitial brachy therapy. The term "brachytherapy," as used herein, refers to radiation therapy delivered by a spatially confined radioactive material inserted into the body at or near a tumor or other proliferative tissue disease site. The term is intended, without limitation, to include exposure to radioactive isotopes (e.g., At-211, I-131, I -125, Y-90, Re-186, Re-188, Sm- 153, Bi-212, P-32, and radioactive isotopes of Lu). Suitable radiation sources for use as a cell conditioner of the present disclosure include both solids and liquids. By way of non-limiting example, the radiation source can be a radionuclide, such as I-125, I -131, Yb-169, Ir-192 as a solid source, I-125 as a solid source, or other radionuclides that emit photons, beta particles, gamma radiation, or other therapeutic rays. The radioactive material can also be a fluid made from any solution of radionuclide(s), e.g., a solution of I-125 or I-131, or a radioactive fluid can be produced using a slurry of a suitable fluid containing small particles of solid radionuclides, such as Au-198, Y-90. Moreover, the radionuclide(s) can be embodied in a gel or radioactive microspheres.

[0149] The present disclosure also provides methods for combination therapies in which the additional active agent is known to modulate other pathways, or other components of the same pathway, or even overlapping sets of target enzymes which are used in combination with a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof. In one embodiment, such therapy includes, but is not limited to, the combination of one or more compounds of Formula (I) or (II) with chemotherapeutic agents, immunotherapeutic agents, hormonal therapy agents, therapeutic antibodies, targeted therapy agents, and radiation treatment, to provide a synergistic or additive therapeutic effect.

[0150] The compounds of the disclosure can be used in combination with the agents disclosed herein or other suitable agents, depending on the condition being treated. Hence,145021.598160 (002000.PC) in some embodiments the one or more compounds of the disclosure will be co-administered with other agents as described above. When used in combination therapy, the compounds described herein are administered with the second agent simultaneously or separately. This administration in combination can include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, a compound of Formula (I) or (II) and any of the agents described above can be formulated together in the same dosage form and administered simultaneously. Alternatively, a compound of Formula (I) or (II) and any of the agents described above can be simultaneously administered, wherein both the agents are present in separate formulations. In another alternative, a compound of Formula (I) or (II) can be administered just followed by and any of the agents described above, or vice versa. In some embodiments of the separate administration protocol, a compound of Formula (I) or (II) and any of the agents described above are administered a few minutes apart, or a few hours apart, or a few days apart.

[0151] As one aspect of the present disclosure contemplates the treatment of the disease / conditions with a combination of pharmaceutically active compounds that may be administered separately, the disclosure further relates to combining separate pharmaceutical compositions in kit form. The kit comprises two separate pharmaceutical compositions: a compound of Formula (I) or (II), and a second pharmaceutical compound. The kit comprises a container for containing the separate compositions such as a divided bottle or a divided foil packet. Additional examples of containers include syringes, boxes, and bags. In some embodiments, the kit comprises directions for the use of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing health care professional.

[0152] The present disclosure also provides for the compound of Formula (I) or (II), or the pharmaceutically acceptable salt thereof, for use in therapy, or use of the compound of Formula (I) or (II), or the pharmaceutically acceptable salt thereof, in therapy. The present disclosure also provides for the compound of Formula (I) or (II), or the pharmaceutically acceptable salt thereof, for use in treating cancer, or use of a compound of Formula (I) or (II), or the pharmaceutically acceptable salt thereof, for treating cancer. The present disclosure also provides for the compound of Formula (I) or (II), or the pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of cancer, or145021.598160 (002000.PC) use of the compound of Formula (I) or (II), or the pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of cancer. The present disclosure also provides for the compound of Formula (I) or (II), or the pharmaceutically acceptable salt thereof, and an additional anti-cancer agent, for use in the treatment of cancer, or use of the compound of Formula (I) or (II), or the pharmaceutically acceptable salt thereof, and the additional anti-cancer agent for treating cancer. The disclosure also provides the compound of Formula (I) or (II), or the pharmaceutically acceptable salt thereof, and an additional anti- cancer agent, for the preparation of a medicament for the treatment of cancer, or use of the compound of Formula (I) or (II), or the pharmaceutically acceptable salt thereof, and the additional anti-cancer agent, for the preparation of a medicament for the treatment of cancer. The present disclosure also provides for a pharmaceutical composition comprising the compound of Formula (I) or (II), or the pharmaceutically acceptable salt thereof, for use in the treatment of cancer, or use of the pharmaceutical composition comprising the compound of Formula (I) or (II), or the pharmaceutically acceptable salt thereof, for treating cancer. The present disclosure also provides for a pharmaceutical composition comprising the compound of Formula (I) or (II), or the pharmaceutically acceptable salt thereof, and an additional anti-cancer agent, for use in the treatment of cancer, or use of the pharmaceutical composition comprising the compound of Formula (I) or (II), or the pharmaceutically acceptable salt thereof, and the additional anti-cancer agent, for treating cancer. Methods of Preparing the Compounds of the Disclosure

[0153] The compounds described herein can be prepared according to the procedures of the following schemes and examples, using appropriate materials and are further exemplified by the following specific examples. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the disclosure. The examples further illustrate details for the preparation of the compounds of the present disclosure. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. For instance, in some cases, the order of carrying out the steps of reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. These examples are provided for the purpose of further illustration only and are not intended to be limitations on the disclosure. Any intermediates described below may be referred to herein by their number preceded by "Int-."145021.598160 (002000.PC)

[0154] Throughout the synthetic schemes and examples, abbreviations and acronyms may be used with the following meanings unless otherwise indicated: s = singlet; d = doublet; t = triplet; q = quartet; sep = septet; dd = double doublet; dt = double triplet; td = triple doublet; tt = triple triplet; ddd = double double doublet; ddt = double double triplet; dtd = double triple doublet; tdd = triple double doublet; m = multiplet; br = broad; brs = broad singlet; Ac = acetyl; AcO = acetate; AcOH = acetic acid; BI-DIME = 3-(tert-butyl)-4-(2,6- dimethoxyphenyl)-2,3-dihydrobenzo[d][1,3]oxaphosphole; Bn = benzyl; BnO = benzyloxy; Boc = tert-butyloxycarbonyl; Boc2O = di-tert-butyl decarbonate; BOP = benzotriazol-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate; Bpin: pinacol boronic ester; B2pin2= bis(pinacolato)diboron; Bu = butyl; tBu = tert-butyl; tBuO = OtBu = tert-butoxide; calc’d = calculated; Cbz = benzyloxycarbonyl; conc. = concentrated; DCE = 1,2- dichloroethane; DCM = dichloromethane; Dess-Martin periodinane = 1,1,1-tris(acetyloxy)- 1,1-dihydro-1,2-benziodoxol-3-(1H)-one; DIPEA = = DIEA = N,N-diisopropylethylamine; DMF = N,N-dimethylformamide; DMSO = dimethylsulfoxide; DMSO-d6 = deuterated dimethyl sulfoxide; dppf = 1,1'-bis(diphenylphosphino)ferrocene; EDC = 1-[3- (dimethylamino)propyl]-3-ethylcarbodiimide methiodide; ESI = electrospray ionization; Et = ethyl; EtOAc = ethyl acetate; EtOH = ethanol; Ex. = example; Fmoc = fluorenylmethoxycarbonyl; GDP = guanosine diphosphate; h = hour; HATU: N- [(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N- methylmethanaminium hexafluorophosphate N-oxide; HOBt = 1-hydroxybenzotriazole hydrate; HPLC = high pressure liquid chromatography; Int = intermediate; iPr = isopropyl; i-PrOH = IPA = isopropyl alcohol; KHMDS = potassium bis(trimethylsilyl)amide; LiHMDS = Lithium bis(trimethylsilyl)amide; M = Molar; mCPBA = 3- chlorobenzoperoxoic acid = m-chloroperoxybenzoic acid; Me = methyl; MeCN = acetonitrile; MeOH = methanol; min = minute; MO = methoxy; MOM = methoxymethyl; MP-cyanoborohydride = polymer supported cyanoborohydride, BIOTAGE® Part No. 800407; MS = mass spectrometry; Ms = methanesulfonyl; MsCl = methanesulfonyl chloride; N = Normal; NCS = N-chlorosuccinimide; NIS = N-iodosuccinimide; NMP = N- methyl-2-pyrrolidone; NMR = nuclear magnetic resonance; Pd-C = palladium on carbon; PdCl2(DPEPhos) = dichloro[bis(2-(diphenylphosphino)phenyl)ether]palladium(II); Pd(dppf)Cl2 = [1,1ƍ-bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pd2dba3 = tris(dibenzylideneacetone)dipalladium(0); pet. ether = petroleum ether; PMB = 4- methoxybenzyl = p-methoxybenzyl; PPTS = pyridinium p-toluenesulfonate; PyAOP = (7- azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate; PyBOP =145021.598160 (002000.PC) (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate; rac = racemic; RT = room temperature; RuPhos Pd G2 = chloro(2-dicyclohexylphosphino-2’,6’-diisopropoxy- 1,1’-biphenyl)[2-(2’-amino-1,1’-biphenyl)]palladium(II); sat’d = saturated; sc = supercritical; scCO2= supercritical carbon dioxide; SFC = supercritical fluid chromatography; SPhos Pd G3 = (2-dicyclohexylphosphino-2ƍ,6ƍ-dimethoxybiphenyl)[2-(2ƍ- amino-1,1ƍ-biphenyl)]palladium(II) methanesulfonate; TBAF = tetrabutylammonium fluoride; TBDPS = tert-butyldiphenylsilyl; TBS = tert-butyldimethylsilyl; Tf = trifluoromethanesulfonyl; TfO = trifluoromethanesulfonate; TF = 2,2,2-trifluoroethanol; TFA = trifluoroacetic acid; TFE = 2,2,2-trifluoroethanol; THF = tetrahydrofuran; THP = tetrahydropyran; TIPS = triisopropypsilyl; THF = tetrahydrofuran; TLC = thin layer chromatography; TMP: 2,2,6,6-tetramethylpiperidinyl; TMS = trimethylsilyl; pTsOH = p- toluenesulfonic acid = 4-methylbenzenesulfonic acid; XPhos Pd G2 = chloro(2- dicyclohexylphosphino-2ƍ,4ƍ,6ƍ-triisopropyl-1,1ƍ-biphenyl)[2-(2ƍ-amino-1,1ƍ- biphenyl)]palladium(II); Xphos Pd G3 = (2-dicyclohexylphosphino-2’,4’,6’-triisopropyl- 1,1’-biphenyl)[2-(2’-amino-1,1’-biphenyl)]palladium(II) methanesulfonate; Xphos Pd G3 = (2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1’-biphenyl)[2-(2’-amino-1,1’- biphenyl)]palladium(II) methanesulfonate; Xphos Pd G4 = (2-dicyclohexylphosphino- 2’,4’,6’-triisopropyl-1,1’-biphenyl)[2-(2’-methylamino-1,1’-biphenyl)]palladium(II) methanesulfonate; μm = micrometer.

[0155] The reagents used in the Examples are commercially available products unless indicated otherwise. Prepacked columns manufactured by Teledyne ISCO or Biotage were used in silica gel column chromatography and basic silica gel column chromatography. AVANCE III HD 500 spectrometer (500 MHz; BRUKER) were used for NMR spectra. For a deuterated solvent containing tetramethylsilane, tetramethylsilane was used as the internal reference. For other cases, measurement was performed using an NMR solvent as the internal reference. All į values are indicated in ppm. Microwave reactions were performed using an Initiator (trademark) manufactured by Biotage. RediSepRf C18 High Performance GOLD columns manufactured by Teledyne ISCO Inc. were used for preparative reversed- phase HPLC. EXAMPLES

[0156] Methyl 7-(methylamino)heptanoate145021.598160 (002000.PC)

[0157] To stirred N,N,N',N'-tetramethylmethanediamine (12.7 g, 125 mmol) at 0 °C were added TFA (52.0 mL, 31.2 mmol) and methyl hex-5-enoate (4.00 g, 31.2 mmol). The resulting mixture was heated to 75 °C for 16 h and then concentrated in vacuo. The residue was re-dissolved in DCM and washed with 5M NaOH. The organic layer was separated, and the aqueous layer was extracted with DCM (2x). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 10-12% MeOH / DCM) to give methyl 7-(methylamino)heptanoate (2 g). ESI-MS m / z calc’d for C9H20NO2[M+H]+: 174; found: 174.

[0159] Step A: Ethyl 7-(benzyl(methyl)amino)heptanoate

[0160] To a stirred solution of N-methyl-1-phenylmethanamine (2.00 g, 16.5 mmol) in DMF (20 mL) were added ethyl 7-bromoheptanoate (3.91 g, 16.5 mmol) and K2CO3 (3.42 g, 24.8 mmol). The resulting mixture was stirred at RT for 16 h, diluted with EtOAc, and then washed with water (5x). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give ethyl 7-(benzyl(methyl)amino)heptanoate (4.10 g), which was used directly in the next step without further purification. ESI-MS m / z calc’d for C17H28NO2 [M+H]+: 278; found:NMR (400MHz, CDCl3) į 7.35 – 7.29 (m, 4H), 7.27 – 7.22 (m, 1H), 4.13 (q, J = 7.2 Hz, 2H), 3.49 (s, 2H), 2.41 – 2.33 (m, 2H), 2.29 (t, J = 7.6 Hz, 2H), 2.19 (s, 3H), 1.66 – 1.59 (m, 2H), 1.56 – 1.49 (m, 2H), 1.36 – 1.30 (m, 4H), 1.26 (t, J = 7.2 Hz, 3H).

[0161] Step B: Ethyl 7-(methylamino)heptanoate

[0162] To a stirred solution of ethyl 7-(benzyl(methyl)amino)heptanoate (4.00 g, 14.4 mmol) in TFE (60 mL) were added Pd-C (10 wt%, 1.53 g, 1.44 mmol) and HCl (4 M in dioxane, 2 drops). The reaction vessel was stirred at 15 psi H2at RT for 16 h, filtered, and concentrated in vacuo to give ethyl 7-(methylamino)heptanoate (2.5 g), which was used directly in subsequent step(s) without further purification. ESI-MS m / z calc’d for145021.598160 (002000.PC) C10H22NO2 [M+H]+: 188; found: 188.1H NMR (400MHz, CDCl3) į 4.12 (d, J = 7.2 Hz, 2H), 2.62 – 2.52 (m, 2H), 2.42 (s, 3H), 2.28 (t, J = 7.5 Hz, 2H), 1.68 – 1.57 (m, 2H), 1.54 – 1.45 (m, 2H), 1.38 – 1.30 (m, 4H), 1.25 (t, J = 7.2 Hz, 3H).

[0163] Ethyl 3-(2-azaspiro[3.3]heptan-6-yl)propanoate

[0164] Step A: Tert-butyl (E)-6-(3-ethoxy-3-oxoprop-1-en-1-yl)-2-azaspiro[3.3]heptane-2- carboxylate

[0165] To a stirred solution of KOtBu (3.74 g, 33.3 mmol) in THF (30 mL) was added triethyl phosphonoacetate (7.46 g, 33.3 mmol). The resulting mixture was heated to 35 °C for 1 h, and then tert-butyl 6-formyl-2-azaspiro[3.3]heptane-2-carboxylate (3.00 g, 13.3 mmol) was added. The resulting mixture was stirred at 35 °C, cooled to RT, and then quenched by addition of water. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0-35% EtOAc / pet. ether) to give tert-butyl (E)-6-(3-ethoxy-3-oxoprop-1-en-1-yl)-2- azaspiro[3.3]heptane-2-carboxylate (1.5 g).1H NMR (400MHz, CDCl3): į 6.96 (dd, J = 15.6, 6.8 Hz, 1H), 5.74 (dd, J = 15.6, 1.4 Hz, 1H), 4.23 – 4.13 (m, 2H), 3.97 (s, 2H), 3.82 (s, 2H), 3.03 – 2.88 (m, 1H), 2.44 – 2.37 (m, 2H), 2.15 – 2.06 (m, 2H), 1.43 (s, 9H), 1.29 (t, J = 7.2 Hz, 3H).

[0166] Step B: Tert-butyl 6-(3-ethoxy-3-oxopropyl)-2-azaspiro[3.3]heptane-2-carboxylate

[0167] To a stirred solution of tert-butyl (E)-6-(3-ethoxy-3-oxoprop-1-en-1-yl)-2- azaspiro[3.3]heptane-2-carboxylate (1.5 g, 5.1 mmol) in TFE (10 mL) was added Pd-C (10 wt%, 540 mg, 0.51 mmol). The reaction mixture was stirred at 50 psi H2at RT for 16 h, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 15% EtOAc / pet. ether) to give tert-butyl 6-(3-ethoxy-3-oxopropyl)-2- azaspiro[3.3]heptane-2-carboxylate (1.3 g).1H NMR (400MHz, CDCl3) į 4.14 – 4.08 (m, 2H), 3.94 – 3.88 (m, 2H), 3.79 (s, 2H), 2.30 – 2.22 (m, 2H), 2.19 (t, J = 7.6 Hz, 2H), 2.15 – 2.06 (m, 1H), 1.79 – 1.72 (m, 2H), 1.67 (q, J = 7.5 Hz, 2H), 1.48 – 1.39 (m, 9H), 1.28 – 1.22 (m, 3H).

[0168] Step C: Ethyl 3-(2-azaspiro[3.3]heptan-6-yl)propanoate

[0169] To a stirred solution of tert-butyl 6-(3-ethoxy-3-oxopropyl)-2-azaspiro[3.3]heptane- 2-carboxylate (1.20 g, 4.04 mmol) in DCM (10 mL) was added TFA (3 mL). The resulting145021.598160 (002000.PC) mixture was stirred at RT for 2 h and then concentrated in vacuo. The residue was re- dissolved in DCM and quenched by addition of sat’d NaHCO3. The organic layer was separated, and the aqueous layer was extracted with DCM (2x). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give ethyl 3-(2- azaspiro[3.3]heptan-6-yl)propanoate (700 mg), which was used directly in subsequent step(s) without further purification.1H NMR (400MHz, CDCl3) į 4.13 – 4.08 (m, 2H), 4.05 (br s, 2H), 3.93 (br s, 2H), 2.44 – 2.34 (m, 2H), 2.19 (t, J = 7.6 Hz, 2H), 2.15 – 2.08 (m, 1H), 1.86 (br d, J = 10.8 Hz, 2H), 1.67 (q, J = 7.4 Hz, 2H), 1.29 – 1.24 (m, 3H).

[0170] 7-bromo-8-fluoro-2-(methylthio)-6-(trifluoromethyl)quinazolin-4-ol

[0171] Step A: 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid

[0172] To a stirred solution of 2-amino-4-bromo-3-fluorobenzoic acid (30.0 g, 128 mmol) in DMF (100 mL) was added NIS (86.5 g, 385 mmol). The resulting mixture was heated to 100 °C for 5 h, cooled to RT, and then quenched by addition of water. The precipitate was filtered, rinsed with water, and then dried in vacuo to give 2-amino-4-bromo-3-fluoro-5- iodobenzoic acid (44.5 g), which was used directly in the next step without further purification.

[0173] Step B: Methyl 2-acetamido-4-bromo-3-fluoro-5-iodobenzoate

[0174] To a stirred solution of 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid (3.00 g, 8.34 mmol) and K2CO3 (3.46 g, 25.0 mmol) in DMF (30 mL) was added MeI (0.57 mL, 9.2 mmol). The resulting mixture was stirred at RT for 2 h, and then additional MeI (0.10 mL, 1.6 mmol) was added. The resulting mixture was stirred at RT for 1 h, diluted with EtOAc, and quenched by addition of water. The organic layer was separated, washed with water, and then concentrated in vacuo to give a crude ester.

[0175] To a stirred solution of the crude ester and pyridine (2.02 mL, 25 mmol) in DCM (930 mL) was added AcCl (0.77 mL, 11 mmol). The resulting mixture was stirred at RT for 2 days and then concentrated in vacuo. The residue was re-dissolved in EtOAc, washed with145021.598160 (002000.PC) water, and then concentrated in vacuo. The residue was suspended in MeCN, heated to 80 °C for 30 min, and then cooled to RT. The precipitate was filtered and dried in vacuo to give methyl 2-acetamido-4-bromo-3-fluoro-5-iodobenzoate (1.96 g). ESI-MS m / z calc’d for C10H9BrFINO3[M+H]+: 416; found: 416.1H NMR (400 MHz, DMSO-d6) į 10.02 (s, 1H), 8.04 (d, J = 1.6 Hz, 1H), 3.77 (s, 3H), 2.05 (s, 3H).

[0176] Step C: Methyl 2-acetamido-4-bromo-3-fluoro-5-(trifluoromethyl)benzoate

[0177] To a stirred mixture of methyl 2-acetamido-4-bromo-3-fluoro-5-iodobenzoate (1.95 g, 4.69 mmol) and CuI (536 mg, 2.81 mmol) in NMP (20 mL) was added methyl 2,2- difluoro-2-fluorosulfonyl acetate (1.78 mL, 14.1 mmol). The resulting mixture was heated to 90 °C for 2.5 h, cooled to RT, diluted with EtOAc, and then quenched by addition of water. The organic layer was separated, washed with brine, and then concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 10-65% EtOAc / hexanes) to give methyl 2-acetamido-4-bromo-3-fluoro-5-(trifluoromethyl)benzoate (1.36 g). ESI-MS m / z calc’d for C11H9BrF4NO3 [M+H]+: 358; found: 358.1H NMR (400 MHz, DMSO-d6) į 10.39 (s, 1H), 7.89 (d, J = 1.2 Hz, 1H), 3.80 (s, 3H), 2.11 (s, 3H).

[0178] Step D: 2-amino-4-bromo-3-fluoro-5-(trifluoromethyl)benzoic acid

[0179] A stirred solution of methyl 2-acetamido-4-bromo-3-fluoro-5- (trifluoromethyl)benzoate (1.36 g, 3.08 mmol) in 10% HCl in MeOH (20 mL) was heated to 80 °C for 4 h, cooled to RT, and then concentrated in vacuo to give a crude ester.

[0180] To a stirred solution of the crude ester in THF (20 mL) and water (5 mL) was added LiOH ā H2O (797 mg, 19.0 mmol). The resulting mixture was heated to 70 °C for 3 h, cooled to RT, and then quenched by addition of HCl (2 M in water) until neutral. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and then concentrated in vacuo to give 2-amino-4-bromo-3-fluoro-5- (trifluoromethyl)benzoic acid (1.15 g). ESI-MS m / z calc’d for C8H5BrF4NO2[M+H]+: 302; found: 302.1H NMR (400 MHz, DMSO-d6) į 13.62 (br s, 1H), 7.90 (s, 1H), 7.46 (br s, 2H).

[0181] Step E: 7-bromo-8-fluoro-2-(methylthio)-6-(trifluoromethyl)quinazolin-4-ol

[0182] A stirred solution of 2-amino-4-bromo-3-fluoro-5-(trifluoromethyl)benzoic acid (9.34 g, 30.9 mmol) from multiple batches in thionyl chloride (22.5 mL, 310 mmol) was heated to 80 °C for 1 h, cooled to RT, and then concentrated in vacuo (after repeated concentration with toluene) to give a crude acid chloride.145021.598160 (002000.PC)

[0183] To a stirred mixture of the crude acid chloride in acetone (30 mL) at 0 °C was added NH4SCN (2.50 g, 33.0 mmol) in acetone (10 mL). The resulting mixture was stirred at RT for 2 h and then diluted with water. The precipitate was filtered to give a crude quinazoline.

[0184] To a stirred solution of the crude quinazoline in NaOH (2.0 M in water, 60 mL, 120 mmol) was added MeI (2.31 mL, 37.1 mmol). The resulting mixture was stirred at RT for 1 h, and then additional MeI (0.75 mmol, 12.1 mmol) was added. The resulting mixture was stirred at RT for 15 min and then filtered. To the filtrate was added 2.0 M HCl until pH = 3. The precipitate was filtered, rinsed with water, and then dried in vacuo at 60 °C to give 7- bromo-8-fluoro-2-(methylthio)-6-(trifluoromethyl)quinazolin-4-ol (10.1 g). ESI-MS m / z calc’d for C10H5BrF4N2OS [M+H]+: 357; found: 357.

[0185] (2S,4R)-1-((S)-2-amino-4,4,4-trifluorobutanoyl)-4-hydroxy-N-(4-(4-methylthiazol- 5-yl)benzyl)pyrrolidine-2-carboxamide-

[0187] To a stirred solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4,4,4- trifluorobutanoic acid (25 mg, 0.066 mmol) and (2S,4R)-4-hydroxy-2-((4- (4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-ium chloride (42 mg, 0.12 mmol) in MeCN (1.3mL) were added HATU (48 mg, 0.13 mmol) and DIPEA (92 uL, 0.53 mmol). The reaction mixture was stirred at RT for 1 h and then purified by reverse-phase preparative HPLC (C18, MeCN / water with 0.05% TFA modifier) to give (9H-fluoren-9- yl)methyl ((S)-4,4,4-trifluoro-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)-1-oxobutan-2-yl)carbamate (45 mg). ESI-MS m / z calc’d for C35H34F3N4O5S [M+H]+: 679; found: 679.

[0188] Step B: (2S,4R)-1-( -2-amino-4,4,4-trifluorobutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl) 2-carboxamide

[0189] To a stirred solution of (9H-fluoren-9-yl)methyl ((S)-4,4,4-trifluoro-1-((2S,4R)-4- hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-1-oxobutan-2-145021.598160 (002000.PC) yl)carbamate (45 mg, 0.066 mmol) in THF (0.15 mL) was added Me2NH (2 M in THF, 0.13 mL, 0.26 mmol). The resulting mixture was stirred at RT for 1 h, diluted with ether / hexanes, and then cooled to –20 °C. The top layer was separated, and the bottom layer was concentrated in vacuo to give (2S,4R)-1-((S)-2-amino-4,4,4-trifluorobutanoyl)-4- hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (25 mg). ESI-MS m / z calc’d for C20H24F3N4O3S [M+H]+: 457; found: 457.

[0190] Compounds in the table below were synthesized via a similar route as described in the above synthesis by making the appropriate substitutions for the corresponding amino acid. Appropriate substitutions are available commercially, synthesized as described in the literature, synthesized using methods available to those skilled in the art, or synthesized as described herein.145021.598160 (002000.PC)

[0191] (2S,4R)-1-(L-valyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)- 4-hydroxypyrrolidine-2-carboxamide

[0192] Step A: Tert-butyl (R)-(1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2- hydroxyethyl)carbamate

[0193] To a stirred solution of 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole (420 mg, 1.9 mmol), tert-butyl (R)-(1-(4-bromophenyl)-2-hydroxyethyl)carbamate (300 mg, 0.95 mmol) and XPhos Pd G2 (75 mg, 0.095 mmol) in dioxane (4.3 mL) and water (0.43 mL) was added Cs2CO3 (1.0 M in water, 1.9 mL, 1.9 mmol). The resulting mixture was heated to 80 °C for 1 h, cooled to RT, filtered through a pad of MgSO4 / silica gel (rinsing with EtOAc), and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0-100% EtOAc / hexanes) to give tert-butyl (R)-(1-(4-(1-ethyl-145021.598160 (002000.PC) 1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)carbamate (262 mg). ESI-MS m / z calc’d for C18H26N3O3 [M+H]+: 332; found: 332.

[0194] Step B: (R)-2-amino-2-(4- ethyl-1H-pyrazol-5-yl)phenyl)ethan-1-ol

[0195] To a stirred solution of tert- (R)-(1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2- hydroxyethyl)carbamate (260 mg, 0.80 mmol) in DCM (2.6 mL) was added HCl (4 M in dioxane, 1.4 mL, 5.6 mmol). The resulting mixture was stirred at RT for 30 min and then concentrated in vacuo to give (R)-2-amino-2-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)ethan-1-ol (213 mg), which was used directly in the next step without further purification. ESI-MS m / z calc’d for C13H18N3O [M+H]+: 232; found: 232.

[0196] Step C: Tert-butyl ((S)-1-((2S,4R)-2-(((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2- hydroxyethyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate

[0197] To a stirred solution of (R)-2-amino-2-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)ethan-1- ol (100 mg, 0.37 mmol) and (2S,4R)-1-((tert-butoxycarbonyl)-L-valyl)-4- hydroxypyrrolidine-2-carboxylic acid (150 mg, 0.45 mmol) in DMF (1.2 mL) was added DIPEA (200 μL, 1.1 mmol), followed by HATU (190 mg, 0.49 mmol). The resulting mixture was stirred at RT for 15 min, quenched by addition of sat’d NaHCO3. The organic layer was separated, and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0-15% MeOH / DCM) to give tert-butyl ((S)-1- ((2S,4R)-2-(((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)carbamoyl)-4- hydroxypyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (183 mg). ESI-MS m / z calc’d for C28H42N5O6[M+H]+: 544; found: 544.

[0198] Step D: (2S,4R)-1-(L-valyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2- hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0199] To a stirred solution of tert-butyl ((S)-1-((2S,4R)-2-(((R)-1-(4-(1-ethyl-1H-pyrazol- 5-yl)phenyl)-2-hydroxyethyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3-methyl-1-oxobutan- 2-yl)carbamate (180 mg, 0.34 mmol) in DCM (1.1 mL) was added HCl (4 M in dioxane, 590 μL, 2.4 mmol). The resulting mixture was stirred at RT for 1 h and then concentrated in vacuo to give (2S,4R)-1-(L-valyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2- hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide (162 mg), which was used directly in subsequent step(s) without further purification. ESI-MS m / z calc’d for C23H34N5O4 [M+H]+: 444; found: 444.1H NMR (500 MHz, DMSO-d6) į 8.60 (d, J = 7.9 Hz, 1H), 8.11 (s, 3H), 7.51 (d, J = 1.8 Hz, 1H), 7.42 (s, 3H), 6.33 (d, J = 1.8 Hz, 1H), 4.87 (q, J = 6.2 Hz, 1H), 4.60 (t, J = 8.3 Hz, 1H), 4.34 (s, 1H), 4.13 (q, J = 7.2 Hz, 2H), 4.05 – 4.00 (m, 1H),145021.598160 (002000.PC) 3.75 – 3.58 (m, 3H), 3.54 (dd, J = 10.8, 3.9 Hz, 1H), 2.13 (tt, J = 12.2, 6.2 Hz, 2H), 1.79 (ddd, J = 13.1, 9.0, 4.3 Hz, 1H), 1.32 (t, J = 7.2 Hz, 3H), 1.03 (d, J = 6.9 Hz, 3H), 0.95 (d, J = 6.8 Hz, 3H).

[0200] The compound in the table below was synthesized via a similar route as described in the above synthesis by making the appropriate substitutions for the corresponding precursor. Appropriate substitutions are available commercially, synthesized as described in the literature, synthesized using methods available to those skilled in the art, or synthesized as described herein.

[0201] The NMR spectrum is provided below.

[0202] (2S,4R)-1-(L-valyl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0203] 1H NMR (500 MHz, DMSO-d6) į 9.03 (s, 1H), 8.58 (d, J = 7.8 Hz, 1H), 8.09 (d, J = 4.3 Hz, 3H), 7.45 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H), 4.85 (q, J = 6.2 Hz, 1H), 4.59 (t, J = 8.3 Hz, 1H), 4.34 (s, 1H), 4.03 (t, J = 5.3 Hz, 1H), 3.75 – 3.58 (m, 3H), 3.56 – 3.45 (m, 1H), 2.48 (s, 3H), 2.14 (dt, J = 14.1, 7.2 Hz, 2H), 1.78 (ddd, J = 13.0, 9.0, 4.3 Hz, 1H), 1.03 (d, J = 6.9 Hz, 3H), 0.95 (d, J = 6.9 Hz, 3H).

[0204] (2S,4R)-1-((S)-2-azido-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide145021.598160 (002000.PC)

[0205] To a stirred solution of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy- N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (1.00 g, 2.32 mmol) and 1H- imidazole-1-sulfonyl azide hydrochloride (974 mg, 4.65 mmol) in DMF (7.7 mL) was added K2CO3 (3 M in water, 3.1 mL, 9.3 mmol). The resulting mixture was stirred at RT for 1 h and then diluted with EtOAc. The organic layer was separated and washed with water. The aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0-10% MeOH / DCM) to give (2S,4R)-1-((S)-2- azido-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (714 mg). ESI-MS m / z calc’d for C22H29N6O3S [M+H]+: 457; found: 457. Synthesis of Alcohol Intermediates

[0206] Intermediate A001: Methyl (R)-7-(((2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)(methyl)amino)heptanoate (Int-A001)

[0207] Step A: (S)-(1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl methanesulfonate

[0208] To a stirred solution of (R)-(1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methanol (1.17 g, 5.13 mmol) in DCM (10 mL) at 0 °C was added NEt3 (1.43 mL, 10.3 mmol), followed by MsCl (640 μL, 8.22 mmol) dropwise. The resulting mixture was stirred at RT for 2 h and then quenched by addition of sat’d NaHCO3. The organic layer was separated, and the aqueous layer was extracted with DCM (2x). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to145021.598160 (002000.PC) give (S)-(1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl methanesulfonate, which was used directly in the next step without further purification.

[0209] Step B: (R)-1-(1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)-N- methylmethanamine

[0210] To a stirred solution of (S)-(1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl methanesulfonate in EtOH (5.1 mL) was added MeNH2(33% in EtOH, 16 mL, 128 mmol). The resulting mixture was stirred at RT overnight and then concentrated in vacuo. The residue was purified by flash chromatography (C18, 10-100% MeCN / water with 0.05% TFA modifier) to give (R)-1-(1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)-N- methylmethanamine (1.71 g). ESI-MS m / z calc’d for C13H18F2NO [M+H]+: 242; found: 242.1H NMR (400 MHz, CDCl3) į 7.29 – 7.24 (m, 5H), 4.49 (s, 2H), 3.61 (br d, J = 10.61 Hz, 1H), 3.53 – 3.49 (m, 1H), 2.96 (br d, J = 12.87 Hz, 1H), 2.83 – 2.77 (m, 1H), 2.44 (s, 3H), 1.35 – 1.20 (m, 2H).

[0211] Step C: Methyl (R)-7-(((1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)(methyl)amino)heptanoate

[0212] To a stirred solution of (R)-1-(1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)-N- methylmethanamine (1.71 g, 4.82 mmol) in MeCN (32.1 mL) was added methyl 7- bromoheptanoate (2.15 g, 9.64 mmol) followed by K2CO3 (2.67 g, 19.3 mmol). The resulting mixture was heated to 90 °C overnight, cooled to RT, filtered through a pad of CELITE®, and concentrated in vacuo. The residue was purified by flash chromatography (C18, 10-100% MeCN / water with 0.05% TFA modifier) to give methyl (R)-7-(((1- ((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl)(methyl)amino)heptanoate (2.39 g). ESI-MS m / z calc’d for C21H32F2NO3[M+H]+: 384; found: 384.

[0213] Step D: Methyl (R)-7-(((2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)(methyl)amino)heptanoate (Int-A001)

[0214] To a stirred solution of methyl (R)-7-(((1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)(methyl)amino)heptanoate (2.39 g, 4.81 mmol) in TFE (32 mL) were added HCl (4 M in dioxane, 1.20 mL, 4.81 mmol) and Pd-C (10 wt%, 1.53 g, 1.44 mmol). The reaction vessel was evacuated under vacuum and purged with H2 (3x). The resulting mixture was stirred at RT overnight, filtered through a pad of celite (rinsing with MeOH), and concentrated in vacuo. The residue was re-dissolved in EtOAc, washed with sat’d NaHCO3, dried over Na2SO4, filtered and concentrated in vacuo to give methyl (R)-7- (((2,2-difluoro-1-(hydroxymethyl)cyclopropyl)methyl)(methyl)amino)heptanoate (Int-145021.598160 (002000.PC) A001) (1.28 g), which was used directly in the next step without further purification. ESI- MS m / z calc’d for C14H26F2NO3 [M+H]+: 294; found: 294.

[0215] Compounds in the table below were synthesized via a similar route as described in the above synthesis of Int-A001 by making the appropriate substitutions for the corresponding alcohol such as using (1-((benzyloxy)methyl)cyclopropyl)methanol or (R or S)-(1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methanol and the corresponding alkyl halides. Appropriate substitutions are available commercially, synthesized as described in the literature, synthesized using methods available to those skilled in the art, or synthesized as described herein.

[0216] A representative NMR spectrum is provided below.

[0217] Int-A037

[0218] 1H NMR (400MHz, CDCl3) į 4.10 – 4.02 (m, 2H), 3.84 (br dd, J = 3.87, 11.62 Hz, 1H), 3.60 (br d, J = 11.68 Hz, 1H), 2.95 (br dd, J = 4.47, 13.17 Hz, 1H), 2.53 – 2.43 (m,145021.598160 (002000.PC) 2H), 2.42 – 2.35 (m, 1H), 2.30 (s, 3H), 2.23 (t, J = 7.45 Hz, 2H), 1.68 – 1.45 (m, 4H), 1.37 – 1.22 (m, 5H), 1.19 (t, J = 7.15 Hz, 3H), 1.05 – 0.96 (m, 1H).

[0219] Intermediate A002: Ethyl 3-(1-((1-(hydroxymethyl)cyclopropyl)methyl)piperidin- 4-yl)propanoate (Int-A002)

[0220] Step A: 1-((benzyloxy)methyl)cyclopropane-1-carbaldehyde

[0221] To a stirred solution of (1-((benzyloxy)methyl)cyclopropyl)methanol (500 mg, 2.60 mmol) in DCM (17 mL) at 0 °C was added Dess-Martin periodinane (1.43 g, 3.38 mmol). The resulting mixture was stirred at RT overnight, diluted with DCM, washed with Na2S2O3, washed with sat’d NaHCO3, dried over Na2SO4, filtered, and concentrated in vacuo to give 1-((benzyloxy)methyl)cyclopropane-1-carbaldehyde, which was used directly in the next step without further purification.

[0222] Step B: Ethyl 3-(1-((1-((benzyloxy)methyl)cyclopropyl)methyl)piperidin-4- yl)propanoate

[0223] To a stirred solution of 1-((benzyloxy)methyl)cyclopropane-1-carbaldehyde (200 mg, 1.05 mmol) in DCM (5.3 mL) and MeOH (5.3 mL) were added ethyl 3-(piperidin-4- yl)propanoate hydrochloride (233 mg, 1.05 mmol), AcOH (181 μL, 3.15 mmol), and 4Å molecular sieves. The resulting mixture was stirred at RT for 10 min and then BIOTAGE® MP-cyanoborohydride (1.32 g, 3.15 mmol) was added. The resulting mixture was stirred at RT for 4.5 h, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (C18, 10-100% MeCN / water) to give ethyl 3-(1-((1- ((benzyloxy)methyl)cyclopropyl)methyl)piperidin-4-yl)propanoate (176 mg). ESI-MS m / z calc’d for C22H34NO3 [M+H]+: 360; found: 360.

[0224] Step C: Ethyl 3-(1-((1-(hydroxymethyl)cyclopropyl)methyl)piperidin-4- yl)propanoate (Int-A002)

[0225] To a stirred solution of ethyl 3-(1-((1- ((benzyloxy)methyl)cyclopropyl)methyl)piperidin-4-yl)propanoate (176 mg, 0.490 mmol) in TFE (6.1 mL) were added HCl (4 M in dioxane, 122 uL, 0.490 mmol) and Pd-C (10 wt%, 52 mg, 0.049 mmol). The reaction vessel was evacuated under vacuum and purged with H2 (3x). The resulting mixture was stirred at RT overnight, filtered through a pad of CELITE® (rinsing with MeOH), and concentrated in vacuo to give ethyl 3-(1-((1-145021.598160 (002000.PC) (hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)propanoate (Int-A002) (112 mg), which was used directly in subsequent step(s) without further purification. ESI-MS m / z calc’d for C15H28NO3 [M+H]+: 270; found: 270.

[0226] Compounds in the table below were synthesized via a similar route as described in the above synthesis of Int-A002 by making the appropriate substitutions for the corresponding alcohol such as using (R)-(1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methanol or (1-((benzyloxy)methyl)cyclopropyl)methanol. Appropriate substitutions are available commercially, synthesized as described in the literature, synthesized using methods available to those skilled in the art, or synthesized as described herein. In Step C, alternatively, MeOH may be used as the solvent.145021.598160 (002000.PC)

[0227] Intermediate A003: Methyl 2-(3-((1-(hydroxymethyl) methyl)-3-azaspiro[5.5]undecan-9-yl)acetate (Int-A003)

[0228] Step A: (1-((benzyloxy)methyl)cyclopropyl)methyl methanesulfonate145021.598160 (002000.PC)

[0229] To a stirred solution of (1-((benzyloxy)methyl)cyclopropyl)methanol (52 mg, 0.27 mmol) in DCM (2 mL) were added NEt3 (75 uL, 0.54 mmol) and MsCl (34 uL, 0.43 mmol). The resulting mixture was stirred at RT for 30 min and then quenched by addition of sat’d NaHCO3. The organic layer was separated, and the aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give (1-((benzyloxy)methyl)cyclopropyl)methyl methanesulfonate, which was used directly in the next step without further purification.

[0230] Step B: Methyl 2-(3-((1-((benzyloxy)methyl)cyclopropyl)methyl)-3- azaspiro[5.5]undecan-9-yl)acetate

[0231] To a stirred solution of (1-((benzyloxy)methyl)cyclopropyl)methyl methanesulfonate, methyl 2-(3-azaspiro[5.5]undecan-9-yl)acetate (61 mg, 0.27 mmol) in THF was added K3PO4 (0.81 mmol). The resulting mixture was heated to 80 °C for 16 h, cooled to RT, filtered, and concentrated in vacuo. Several batches were combined, and the residue was purified by flash chromatography (10-100% MeCN / water with 0.05% TFA modifier) to give methyl 2-(3-((1-((benzyloxy)methyl)cyclopropyl)methyl)-3- azaspiro[5.5]undecan-9-yl)acetate (140 mg). ESI-MS m / z calc’d for C25H38NO3 [M+H]+: 400; found: 400.

[0232] Step C: Methyl 2-(3-((1-(hydroxymethyl)cyclopropyl)methyl)-3- azaspiro[5.5]undecan-9-yl)acetate (Int-A003)

[0233] To a stirred solution of methyl 2-(3-((1-((benzyloxy)methyl)cyclopropyl)methyl)-3- azaspiro[5.5]undecan-9-yl)acetate (140 mg) in TFE (3.5 mL) were added HCl (4 M in dioxane, 88 uL, 0.35 mmol) and Pd-C (10 wt%, 75 mg, 0.070 mmol). The reaction vessel was evacuated under vacuum and purged with H2(3x). The resulting mixture was stirred at RT for 4 h, filtered through a pad of CELITE® (rinsing with MeOH), and concentrated in vacuo to give methyl 2-(3-((1-(hydroxymethyl)cyclopropyl)methyl)-3- azaspiro[5.5]undecan-9-yl)acetate (Int-A003) (91 mg). ESI-MS m / z calc’d for C18H31NO3 [M+H]+: 310; found: 310.

[0234] Compounds in the table below were synthesized via a similar route as described in the above synthesis of Int-A003 by making the appropriate substitutions for the corresponding alcohol such as using (R)-(1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methanol or (1-((benzyloxy)methyl)cyclopropyl)methanol. Appropriate substitutions are available commercially, synthesized as described in the literature,145021.598160 (002000.PC) synthesized using methods available to those skilled in the art, or synthesized as described herein. In Step B, alternatively, K2CO3 may be used as the base.145021.598160 (002000.PC)

[0235] Representative NMR spectra are provided below.145021.598160 (002000.PC)

[0236] Int-A049

[0237] 1H NMR (400MHz, CDCl3) į 4.04 (q, J = 7.15 Hz, 2H), 3.62 – 3.48 (m, 2H), 3.39 – 3.17 (m, 2H), 2.87 (br d, J = 10.49 Hz, 1H), 2.67 – 2.55 (m, 1H), 2.28 (br d, J = 8.46 Hz, 1H), 2.20 – 2.00 (m, 4H), 1.78 – 1.57 (m, 4H), 1.28 – 1.15 (m, 5H), 1.13 – 1.01 (m, 1H), 0.84 (t, J = 7.39 Hz, 1H).

[0241] Step A: Methyl (R)-6-(((1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)(methyl)amino)hexanoate

[0242] To a stirred solution of (R)-1-(1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)-N- methylmethanamine (Step B of Int-A001) (200 mg, 0.829 mmol) in DCE (4.2 mL) and MeOH (4.2 mL) were added methyl 6-oxohexanoate (120 mg, 0.829 mmol), AcOH (142 μL, 2.49 mmol), and 4Å molecular sieves. The resulting mixture was stirred at RT for 10 min and then BIOTAGE® MP-cyanoborohydride (1.04 g, 2.49 mmol) was added. The resulting mixture was stirred at RT overnight, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (C18, 10-100% MeCN / water) to give methyl (R)-6-(((1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl)(methyl)amino)hexanoate (208 mg). ESI-MS m / z calc’d for C20H30F2NO3 [M+H]+: 370; found: 370.

[0243] Step B: Methyl (R)-6-(((2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)(methyl)amino)hexanoate (Int-A012)

[0244] To a stirred solution of methyl (R)-6-(((1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)(methyl)amino)hexanoate (208 mg, 0.563 mmol) in TFE (7.0 mL) were added HCl (4 M in dioxane, 141 uL, 0.56 mmol) and Pd-C (10 wt%, 60 mg, 0.056 mmol). The reaction vessel was evacuated under vacuum and purged with H2(3x).145021.598160 (002000.PC) The resulting mixture was stirred at RT overnight, and then subjected to additional Pd-C (10 wt%, 10 mg). The reaction vessel was evacuated under vacuum and purged with H2 (3x). The resulting mixture was stirred at RT for 4 h, filtered through a pad of CELITE® (rinsing with MeOH), and concentrated in vacuo to give methyl (R)-6-(((2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)(methyl)amino)hexanoate (Int-A012), which was used directly in subsequent step(s) without further purification. ESI-MS m / z calc’d for C13H24F2NO3[M+H]+: 280; found: 280.

[0245] The compound in the table below was synthesized via a similar route as described in the above synthesis of Int-A012 by making the appropriate substitutions that are available commercially, synthesized as described in the literature, synthesized using methods available to those skilled in the art, or synthesized as described herein. In Step B, alternatively, BCl3 in DCM / MeOH may be used.

[0246] Intermediate A025: Methyl 6-(((1- (hydroxymethyl)cyclopropyl)methyl)(methyl)amino)hexanoate (Int-A025)

[0247] Step A: Methyl 6-(((1-((benzyloxy)methyl)cyclopropyl)methyl)amino)hexanoate

[0248] To a stirred solution of methyl 6-aminohexanoate hydrochloride (3.50 g, 19.3 mmol) in MeOH (35 mL) were added 1-((benzyloxy)methyl)cyclopropane-1-carbaldehyde145021.598160 (002000.PC) (Step A of Int-A002) (3.30 g, 17.3 mmol) and AcOH (221 uL, 3.85 mmol). The resulting mixture was stirred at RT for 2 h, and then 2-picoline borane complex (2.38 mL, 28.9 mmol) was added. The resulting mixture was stirred at RT for 16 h and then concentrated in vacuo. The residue was diluted with water and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with sat’d NaHCO3and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0-8% MeOH / DCM) to give methyl 6-(((1- ((benzyloxy)methyl)cyclopropyl)methyl)amino)hexanoate (3.50 g). ESI-MS m / z calc’d for C19H30NO3[M+H]+: 320; found: 320.

[0249] Step B: Methyl 6-(((1- ((benzyloxy)methyl)cyclopropyl)methyl)(methyl)amino)hexanoate

[0250] To a stirred solution of methyl 6-(((1- ((benzyloxy)methyl)cyclopropyl)methyl)amino)hexanoate (4.5 g, 14 mmol) from multiple batches in MeOH was added formaldehyde (5.3 mL, 70 mmol). The resulting mixture was stirred at RT for 1 h, and then NaBH3CN (4.4 g, 70 mmol) was added. The resulting mixture was stirred at RT for 3 h and then concentrated in vacuo. The residue was diluted with water and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with sat’d NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0-6% MeOH / DCM) to give methyl 6-(((1- ((benzyloxy)methyl)cyclopropyl)methyl)(methyl)amino)hexanoate (4.1 g). ESI-MS m / z calc’d for C20H32NO3[M+H]+: 334; found: 334.

[0251] Step C: Methyl 6-(((1- (hydroxymethyl)cyclopropyl)methyl)(methyl)amino)hexanoate (Int-A025)

[0252] To a stirred solution of methyl 6-(((1- ((benzyloxy)methyl)cyclopropyl)methyl)(methyl)amino)hexanoate (1.5 g, 4.5 mmol) in MeOH (100 mL) was added Pd-C (10 wt%, 1.44 g, 14 mmol). The reaction mixture was stirred in a Parr shaker at 60 psi H2 at RT for 48 h, filtered through a pad of CELITE® (rinsing with MeOH), and concentrated in vacuo to give methyl 6-(((1- (hydroxymethyl)cyclopropyl)methyl)(methyl)amino)hexanoate (Int-A025), which was used directly in subsequent step(s) without further purification. ESI-MS m / z calc’d for C13H26NO3 [M+H]+: 244; found: 244.145021.598160 (002000.PC)

[0253] Intermediate A026: Benzyl (R)-((2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)(methyl)carbamate (Int-A026)

[0254] Step A: (R)-(2,2-difluoro-1-((methylamino)methyl)cyclopropyl)methanol

[0255] To a stirred solution of (R)-1-(1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)-N- methylmethanamine (Step B of Int-A001) (1.80 g, 6.49 mmol) in TFE (40 mL) was added Pd-C (10 wt%, 1.38 g, 1.30 mmol) (10%). The reaction mixture was stirred at 15 psi H2 at RT for 16 h, filtered, and concentrated in vacuo to give (R)-(2,2-difluoro-1- ((methylamino)methyl)cyclopropyl)methanol (1.5 g) as a yellow oil, which was used directly in the next step without further purification. ESI-MS m / z calc’d for C6H12F2NO [M+H]+: 152; found: 152.

[0256] Step B: Benzyl (R)-((2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)(methyl)carbamate (Int-A026)

[0257] To a stirred solution of (R)-(2,2-difluoro-1- ((methylamino)methyl)cyclopropyl)methanol (1.8 g, 7.14 mmol) in DCM (20 mL) at 0 °C was added NEt3 (2.99 ml, 21.4 mmol) and Cbz-Cl (1.53 mL, 10.7 mmol). The resulting mixture was stirred at RT for 1 h and then quenched by addition of sat’d NaHCO3. The organic layer was separated, and the aqueous layer was extracted with DCM (3x). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 23% EtOAc / pet. ether) to give benzyl (R)-((2,2-difluoro-1-(hydroxymethyl)cyclopropyl)methyl)(methyl)carbamate (Int- A026) (1.27 g). ESI-MS m / z calc’d for C14H18F2NO3 [M+H]+: 286; found: 286.1H NMR (500MHz, CD3OD) į 7.39 – 7.31 (m, 5H), 5.14 (br s, 2H), 3.86 (dd, J = 2.7, 15.0 Hz, 1H), 3.59 (br d, J=12.4 Hz, 1H), 3.54 – 3.45 (m, 1H), 3.42 – 3.33 (m, 1H), 3.02 – 2.88 (m, 3H), 1.44 – 1.24 (m, 2H).

[0258] The compound in the table below was synthesized via a similar route as described in the above synthesis of Int-A026 by making the appropriate substitutions that are available commercially, synthesized as described in the literature, synthesized using methods available to those skilled in the art, or synthesized as described herein.145021.598160 (002000.PC)

[0259] The NMR spectrum is provided below.

[0260] Int-A027

[0261] 1H NMR (400MHz, CDCl3) į 7.03 – 6.87 (m, 5H), 4.75 (s, 2H), 2.88 (s, 2H), 2.83 (br d, J = 7.1 Hz, 2H), 2.57 (s, 3H), 1.63 (s, 1H), 0.08 – –0.02 (m, 4H).

[0262] Intermediate A029: Methyl 4,4-difluoro-7-(((1- (hydroxymethyl)cyclopropyl)methyl)(methyl)amino)heptanoate (Int-A029)

[0263] Step A: Dimethyl 4,4-difluoroheptanedioate

[0264] To a stirred solution of diethyl 4,4-difluoroheptanedioate (25 g, 99 mmol) in MeOH (200 mL) was added conc. H2SO4 (1.0 mL, 20 mmol). The resulting mixture was heated to 65 °C for 12 h, cooled to RT, and concentrated in vacuo. The residue was diluted with water and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with sat’d NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo to give dimethyl 4,4-difluoroheptanedioate (20 g), which was used directly in the next step without further purification.

[0265] Step B: 4,4-difluoro-7-methoxy-7-oxoheptanoic acid

[0266] To a stirred solution of dimethyl 4,4-difluoroheptanedioate (20 g, 89 mmol) in MeOH (200 mL) was added KOH (5.0 g, 89 mmol). The resulting mixture was stirred at RT for 16 h and then concentrated in vacuo. The residue was diluted with water and the aqueous layer was washed with ether. To the aqueous layer was added 1N HCl until acidic.145021.598160 (002000.PC) The aqueous layer was extracted with DCM (2x). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give 4,4-difluoro-7-methoxy-7- oxoheptanoic acid (10 g), which was used directly in the next step without further purification.

[0267] Step C: Methyl 4,4-difluoro-7-hydroxyheptanoate

[0268] To a stirred solution of 4,4-difluoro-7-methoxy-7-oxoheptanoic acid (10 g, 48 mmol) in THF (100 mL) at 0 °C was added BH3· THF (1 M in THF 95 mL, 95 mmol). The resulting mixture was stirred at RT for 12 h, quenched by addition of MeOH, and then concentrated in vacuo. The residue was diluted with water, and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with sat’d NaHCO3and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0-70% EtOAc / pet. ether) to give methyl 4,4-difluoro-7- hydroxyheptanoate (6.1 g).

[0269] Step D: Methyl 4,4-difluoro-7-oxoheptanoate

[0270] To a stirred solution of methyl 4,4-difluoro-7-hydroxyheptanoate (6.0 g, 31 mmol) in DCM (100 mL) at 0 °C was added Dess-Martin periodinane (19 g, 46 mmol). The resulting mixture was stirred at RT for 2 h and then concentrated in vacuo. The residue was diluted with water, and the aqueous layer was extracted with ether (2x). The combined organic layers were washed with sat’d NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0-20% EtOAc / pet. ether) to give methyl 4,4-difluoro-7-oxoheptanoate (4.1 g).

[0271] Step E: Methyl 4,4-difluoro-7-(((1- (hydroxymethyl)cyclopropyl)methyl)amino)heptanoate

[0272] To a stirred solution of methyl 4,4-difluoro-7-oxoheptanoate (2.0 g, 10 mmol) in MeOH (20 mL) was added (1-(aminomethyl)cyclopropyl)methanol (1.0 g, 10 mmol). The resulting mixture was stirred at RT for 1 h, and then NaBH3CN (1.94 g, 30.9 mmol) was added. The resulting mixture was stirred at RT for 3 h and then concentrated in vacuo. The residue was diluted with water, and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with sat’d NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0-6% MeOH / DCM) to give methyl 4,4-difluoro-7-(((1- (hydroxymethyl)cyclopropyl)methyl)amino)heptanoate (1.2 g). ESI-MS m / z calc’d for C13H24F2NO3 [M+H]+: 280; found: 280.145021.598160 (002000.PC)

[0273] Step F: Methyl 4,4-difluoro-7-(((1- (hydroxymethyl)cyclopropyl)methyl)(methyl)amino)heptanoate (Int-A029)

[0274] To a stirred solution of methyl 4,4-difluoro-7-(((1- (hydroxymethyl)cyclopropyl)methyl)amino)heptanoate (2.3 g, 8.2 mmol) from multiple batches in MeOH (50 mL) was added formaldehyde (3.1 mL, 41 mmol). The resulting mixture was stirred at RT for 1 h, and then NaBH3CN (2.6 g, 41 mmol) was added. The resulting mixture was stirred at RT for 3 h and then concentrated in vacuo. The residue was diluted with water, and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with sat’d NaHCO3and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0-5% MeOH / DCM) to give methyl 4,4-difluoro-7-(((1- (hydroxymethyl)cyclopropyl)methyl)(methyl)amino)heptanoate (Int-A029) (780 mg). ESI- MS m / z calc’d for C14H26F2NO3 [M+H]+: 294; found: 294.

[0275] Intermediate A124: (R)-(2,2-difluoro-1-((4-(3-(triisopropylsilyl)prop-2-yn-1- yl)piperidin-1-yl)methyl)cyclopropyl)methanol (Int-A124)

[0276] Step 4-(3-(triisopropylsilyl)prop-2-yn-1-yl)piperidine-1-carboxylate

[0277] To a of tert-butyl 4-(prop-2-yn-1-yl)piperidine-1-carboxylate (892 mg, 3.99 mmol) in THF (13.3 mL) at –78 °C was added n-BuLi (2.5 M in hexanes, 2.40 mL, 5.99 mmol) dropwise. The resulting mixture was stirred at –78 °C for 30 min, and then TIPS-Cl (1.69 mL, 7.99 mmol) was added. The resulting mixture was stirred at RT overnight and then quenched by addition of sat’d NH4Cl and water. The aqueous layer was extracted with EtOAc (2x). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0- 20% EtOAc / hexanes) to give tert-butyl 4-(3-(triisopropylsilyl)prop-2-yn-1-yl)piperidine-1- carboxylate.1H NMR (500 MHz, CDCl3) į 4.13 (d, J = 13.3 Hz, 2H), 3.70 (t, J = 6.6 Hz, 1H), 2.72 (td, J = 13.1, 2.5 Hz, 2H), 2.24 (d, J = 6.6 Hz, 2H), 1.78 (d, J = 12.8 Hz, 2H), 1.72 – 1.58 (m, 2H), 1.48 (s, 9H), 1.08 (d, J = 4.6 Hz, 37H).

[0278] Step B: 4-(3-(triisopropylsilyl)prop-2-yn-1-yl)piperidine145021.598160 (002000.PC)

[0279] To a stirred solution of tert-butyl 4-(3-(triisopropylsilyl)prop-2-yn-1-yl)piperidine- 1-carboxylate (1.60 g, 4.21 mmol) in DCM (8.4 mL) was added HCl (4 M in dioxane, 7.4 mL, 30 mmol). The resulting mixture was stirred at RT for 1 h and then concentrated in vacuo. The residue was triturated with ether and then collected by vacuum filtration to give 4-(3-(triisopropylsilyl)prop-2-yn-1-yl)piperidine, which was used directly in the next step without further purification.1H NMR (500 MHz, CD3OD) į 3.43 (d, J = 12.7 Hz, 2H), 3.03 (td, J = 13.0, 3.1 Hz, 2H), 2.36 (d, J = 6.7 Hz, 2H), 2.09 (d, J = 14.3 Hz, 2H), 1.86 (ttt, J = 10.6, 7.1, 3.7 Hz, 1H), 1.57 – 1.47 (m, 2H), 1.14 – 1.00 (m, 21H).

[0280] Step C: (R)-1-((2,2-difluoro-1-((methoxymethoxy)methyl)cyclopropyl)methyl)-4- (3-(triisopropylsilyl)prop-2-yn-1-yl)piperidine

[0281] To a stirred solution of (S)-(2,2-difluoro-1- ((methoxymethoxy)methyl)cyclopropyl)methyl methanesulfonate (191 mg, 0.734 mmol) in MeCN (4.9 mL) were added 4-(3-(triisopropylsilyl)prop-2-yn-1-yl)piperidine (348 mg, 1.10 mmol) and then K2CO3 (406 mg, 2.94 mmol). The resulting mixture was heated to 90 °C overnight, cooled to RT, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc / hexanes) to give (R)-1-((2,2-difluoro-1- ((methoxymethoxy)methyl)cyclopropyl)methyl)-4-(3-(triisopropylsilyl)prop-2-yn-1- yl)piperidine (113 mg). ESI-MScalc’d for C24H44F2NO2Si [M+H]+: 444; found: 444.

[0282] Step D: (R)-(2,2-difluoro-1-((4-(3-(triisopropylsilyl)prop-2-yn-1-yl)piperidin-1- yl)methyl)cyclopropyl)methanol (Int-A124)

[0283] To a stirred solution of (R)-1-((2,2-difluoro-1- ((methoxymethoxy)methyl)cyclopropyl)methyl)-4-(3-(triisopropylsilyl)prop-2-yn-1- yl)piperidine (113 mg, 0.255 mmol) in i-PrOH (1.0 mL) was added HCl (4 M in dioxane, 1.0 mL, 4.0 mmol). The resulting mixture was stirred at RT for 2 h and then concentrated in vacuo. The residue was re-dissolved in DCM, washed with sat’d NaHCO3, dried over MgSO4, filtered and concentrated in vacuo to give (R)-(2,2-difluoro-1-((4-(3- (triisopropylsilyl)prop-2-yn-1-yl)piperidin-1-yl)methyl)cyclopropyl)methanol (Int-A124), which was used directly in subsequent step(s) without further purification. ESI-MS m / z calc’d for C22H40F2NOSi [M+H]+: 400; found: 400.

[0284] Intermediate A125: (R)-(2,2-difluoro-1-((methyl(8-(triisopropylsilyl)oct-7-yn-1- yl)amino)methyl)cyclopropyl)methanol (Int-A125)145021.598160 (002000.PC)

[0285] Step A: 8-(triisopropylsilyl)oct-7-yn-1-ol

[0286] To a stirred solution of oct-7-yn-1-ol (500 mg, 3.96 mmol) in THF (5 mL) at –78 °C was added n-BuLi (2.5 M in hexanes, 3.33 mL, 8.32 mmol). The resulting mixture was warmed to 0 °C and stirred at 0 °C for 20 min and then cooled to –78 °C and then TIPS-Cl (930 uL, 4.36 mmol) was added. The resulting mixture was warmed to RT for 1 h and then quenched by addition of NH4Cl (1 M in water). The aqueous layer was extracted with EtOAc, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 10% EtOAc / pet. ether) to give 8-(triisopropylsilyl)oct-7- yn-1-ol (820 mg).1H NMR (400 MHz, CDCl3) į 3.65 (t, J = 6.6 Hz, 2H), 2.28 – 2.25 (t, J = 6.8 Hz, 2H), 1.63 – 1.53 (m, 4H), 1.52 – 1.42 (m, 2H), 1.40 – 1.36 (m, 2H), 1.13 – 1.03 (m, 21H).

[0287] Step B: 8-(triisopropylsilyl)oct-7-yn-1-yl methanesulfonate

[0288] To a stirred solution of 8-(triisopropylsilyl)oct-7-yn-1-ol (820 mg, 2.90 mmol) in DCM (8 mL) at 0 °C were added DIPEA (1.01 mL, 5.80 mmol) and MsCl (0.42 mL, 5.3 mmol). The resulting mixture was warmed to RT, stirred at RT for 30 min, and then quenched by addition of water. The aqueous layer was extracted with DCM, dried overNa2SO4, filtered, and concentrated in vacuo. The residue was purified by flashchromatography (silica gel, 10% EtOAc / pet. ether) to give 8-(triisopropylsilyl)oct-7-yn-1-yl methanesulfonate (902 mg).1H NMR (400 MHz, CD3OD) į 4.23 (t, J = 6.4 Hz, 2H), 3.05 (s, 3H), 2.29 (t, J = 6.4 Hz, 2H), 1.80 – 1.70 (m, 2H), 1.61 – 1.41 (m, 6H), 1.17 – 1.01 (m, 21H).

[0289] Step C: (R)-(2,2-difluoro-1-((methyl(8-(triisopropylsilyl)oct-7-yn-1- yl)amino)methyl)cyclopropyl)methanol (Int-A125)

[0290] To a solution of (R)-(2,2-difluoro-1-((methylamino)methyl)cyclopropyl)methanol (Step A of Int-A026) (140 mg, 0.926 mmol) in MeCN (2 mL) were added 8- (triisopropylsilyl)oct-7-yn-1-yl methanesulfonate (367 mg, 1.02 mmol) and K2CO3 (768 mg, 5.56 mmol). The resulting mixture was heated to 50 °C for 12 h, cooled to RT, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 100% EtOAc) to give (R)-(2,2-difluoro-1-((methyl(8-(triisopropylsilyl)oct-7-yn-1- yl)amino)methyl)cyclopropyl)methanol (Int-A125) (101 mg). ESI-MS m / z calc’d for145021.598160 (002000.PC) C23H44F2NOSi [M+H]+: 416; found: 416.1H NMR (400 MHz, CD3OD) į 3.81 – 3.73 (m, 1H), 3.71 – 3.63 (m, 1H), 2.96 – 2.89 (m, 1H), 2.51 – 2.43 (m, 1H), 2.42 – 2.32 (m, 2H), 2.31 –2.18 (m, 5H), 1.62 – 1.45 (m, 6H), 1.43 – 1.26 (m, 4H), 1.20 –1.12 (m, 3H), 1.11 – 1.01 (m, 18H).

[0291] Intermediate A126: Ethyl (R)-4-(1-((2,2-difluoro-1-

[0292] Step A: (S)-(1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl methanesulfonate

[0293] To a solution of (1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methanol (2.0 g, 8.76 mmol) in DCM (20 mL) was added TEA (4.89 mL, 35.1 mmol) and MsCl (1.925 mL, 24.71 mmol) at 0 °C under N2atmosphere. The mixture was stirred at 25 °C for 3 h. TLC (SiO2; petroleum ether: ethyl acetate = 3:1) showed the starting material was consumed and a new spot was formed. The mixture was quenched with H2O (5 mL), then extracted with DCM (3 x 20 mL). The combined organic layer was dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 10% ethyl acetate in petroleum ether gradient @ 30 mL / min) to give (1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl methanesulfonate.1H NMR (400 MHz, CDCl3) į 7.21-7.32 (m, 5H), 4.43-4.52 (m, 2H), 4.28-4.36 (m, 2H), 3.58-3.64 (m, 1H), 3.45 (d, J=10.61 Hz, 1H), 2.91 (s, 3H), 1.43-1.49 (m, 1H), 1.30-1.38 (m, 1H).

[0294] Step B: Ethyl (R)-4-(1-((1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)butanoate

[0295] To a solution of (S)-(1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl methanesulfonate (100 mg, 0.326 mmol) in MeCN (1 mL) was added K2CO3(135 mg, 0.979 mmol) and ethyl 4-(piperidin-4-yl)butanoate hydrochloride (92 mg, 0.392 mmol) at 25 °C. Then the mixture was stirred at 75 °C for 15 h. LCMS showed the starting material was consumed and the desired MS was found. The reaction mixture was cooled to room temperature, and diluted with water (2 mL), then extracted with EtOAc (10 mL * 2). The145021.598160 (002000.PC) combined organic layer was dried with Na2SO4, filtered and the solvent was removed under reduced pressure. The crude was purified by flash silica gel chromatography (ISCO®, 4 g Agela Flash Colum, Pet. ether: EtOAc=3:1, 30 min, 30 mL / min, dry loaded) to give ethyl (R)-4-(1-((1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl)piperidin-4-yl)butanoate. MS (ESI) [M+H]+: m / z 410.3.

[0296] Step C: Ethyl (R)-4-(1-((2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)butanoate (Int-A126)

[0297] To a solution of ethyl (R)-4-(1-((1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)butanoate (200 mg, 0.488 mmol) in CF3CH2OH (5 mL) was added Pd-C (52.0 mg, 0.488 mmol) at 25 °C under nitrogen atmosphere. The reaction mixture was degassed and purged with H2 for three times, and then stirred at 25 °C for 16 h under H2 balloon (15 psi). TLC (SiO2, DCM / MeOH=10 / 1) showed the staring material was consumed and new point (desired product) was formed. The mixture was filtered by Celite, the filtrate was concentrated in vacuum to ethyl (R)-4-(1-((2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)butanoate (Int-A126). MS (ESI) [M+H]+: m / z 320.1.

[0298] Intermediate A127: (R)-(1-((1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)methanol (Int-A127)

[0299] Step A: Tert-butyl 4-(((tert-butyldiphenylsilyl)oxy)methyl)piperidine-1-carboxylate

[0300] To a solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (5 g, 23.22 mmol) in DMF (50 mL) was added imidazole (1.739 g, 25.5 mmol) and TBDPSCl (6.56 mL, 25.5 mmol) at 25 °C. The mixture was stirred at 25 °C for 16 h. LCMS showed starting material was consumed and desired peak was formed. The mixture was quenched with saturated NH4Cl solution (10 mL), extracted with EtOAc (200 mL). The organic layer was washed with water (3 x 30 mL) and brine (30 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give the crude product. The crude145021.598160 (002000.PC) product was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 5% ethyl acetate in petroleum ether gradient @ 70 mL / min) to give tert-butyl 4-(((tert-butyldiphenylsilyl)oxy)methyl)piperidine-1-carboxylate. MS (ESI) [M+H]+: m / z 454.3.

[0301] Step B: 4-(((tert-butyldiphenylsilyl)oxy)methyl)piperidine, HCl salt

[0302] To a solution of tert-butyl 4-(((tert-butyldiphenylsilyl)oxy)methyl)piperidine-1- carboxylate (5 g, 11.02 mmol) in IPA (3 mL) was added HCl (10 mL, 40.0 mmol, 4 M in Dioxane) at 25 °C. The mixture was stirred at 25 °C for 2 h. LCMS showed starting material was consumed and desired peak was formed. The solvent was evaporated under reduced pressure to give the crude product 4-(((tert- butyldiphenylsilyl)oxy)methyl)piperidine, HCl salt. MS (ESI) [M+H]+: m / z 354.3.

[0303] Step C: (S)- ((benzyloxy)methyl)-2,2-difluorocyclopropyl)methylmethanesulfonate

[0304] To a solution of (R)-(1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methanol (0.5 g, 2.191 mmol) in DCM (5 mL) was added TEA (0.8 mL, 5.74 mmol) and MsCl (0.54 g, 0.367 mL, 4.71 mmol) at 0 °C under N2 atmosphere. The mixture was stirred at 0 °C for 1 h. LCMS showed starting material was consumed and a new peak was formed. The mixture was quenched with H2O (5 mL), extracted with DCM (10 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 17% ethyl acetate in petroleum ether gradient @ 30 mL / min) to give (S)-(1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl methanesulfonate.1H NMR (400 MHz, CDCl3) į 7.28-7.43 (m, 5H), 4.49-4.63 (m, 2H), 4.34-4.46 (m, 2H), 3.69 (dt, J=10.6, 2.5 Hz, 1H), 3.53 (d, J=10.6 Hz, 1H), 2.99 (s, 3H), 1.51-1.59 (m, 1H), 1.37-1.46 (m, 1H).

[0305] Step D: (R)-1-((1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl)-4-(((tert- butyldiphenylsilyl)oxy)methyl)piperidine

[0306] To a solution of (S)-(1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl methanesulfonate (500 mg, 1.632 mmol) in MeCN (10 mL) was added 4-(((tert- butyldiphenylsilyl)oxy)methyl)piperidine, HCl salt (643 mg, 1.649 mmol) and K2CO3 (1354 mg, 9.79 mmol) at 25 °C. The mixture was stirred at 80 °C for 16 h. The reaction was monitored by TLC that showed the reaction was completed. The mixture was cooled, filtered and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 12 g145021.598160 (002000.PC) SepaFlash® Silica Flash Column, Eluent of 45% ethyl acetate in petroleum ether gradient 30 mL / min) to give (R)-1-((1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl)-4- (((tert-butyldiphenylsilyl)oxy)methyl)piperidine. MS (ESI) [M+H]+: m / z 564.5.

[0307] Step E: (R)-(1-((1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl)piperidin- 4-yl)methanol (Int-A127)

[0308] To a solution of (R)-1-((1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl)-4- (((tert-butyldiphenylsilyl)oxy)methyl)piperidine (558 mg, 0.990 mmol) in THF (5.5 mL) was added TBAF (1.485 mL, 1.485 mmol, 1 M in THF) at 15 °C. The mixture was stirred at 15 °C for 2 h. TLC (SiO2; DCM: MeOH = 15:1) showed starting material was consumed and a new spot was observed. The solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 7% MeOH in DCM gradient @ 30 mL / min) to give (R)-(1-((1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl)piperidin- 4-yl)methanol (Int-A127). MS (ESI) [M+H]+: m / z 326.3.

[0309] Intermediate A128: (R)-2-(3-(1-((1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)cyclobutyl)acetic acid (Int-A128)

[0310] Step A: Benzyl 4-vinylpiperidine-1-carboxylate

[0311] To a solution of methyltriphenylphosphonium iodide (16.43 g, 40.6 mmol) in THF (120 mL) was added potassium tert-butoxide (37.9 mL, 37.9 mmol) at 0 °C under N2atmosphere. The mixture was stirred at 25 °C for 30 min, then benzyl 4-formylpiperidine- 1-carboxylate (6.7g, 27.1 mmol) in THF (30 mL) was added at 0 °C. The mixture was145021.598160 (002000.PC) allowed to warm to 25 °C and stirred for another 1 h. LCMS showed desired mass was observed. The mixture was quenched with NH4Cl solution (100 mL, in water) and extracted with EtOAc (500 mL x 3). The organic layer was dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®, 120 g Agela Flash Column, petroleum ether: ethyl acetate= 0~10%, 20 min, 40 mL / min, dry loaded) to afford benzyl 4-vinylpiperidine- 1-carboxylate. MS (ESI) [M+H]+: m / z 246.2.

[0312] Step B: Benzyl 4-(2,2-dichloro-3-oxocyclobutyl)piperidine-1-carboxylate

[0313] To a stirred solution of benzyl 4-vinylpiperidine-1-carboxylate (500 mg, 2.038 mmol) in Et2O (20 mL) was added zinc-copper couple (2628 mg, 20.38 mmol), POCl3(0.209 mL, 2.242 mmol) at 25 °C. Then trichloroacetyl chloride (1853 mg, 10.19 mmol) in Et2O (10.00 mL) was added, and the mixture was stirred at 25 °C for 16 h under N2 atmosphere. LCMS showed the starting material was consumed and desired MS was found. The mixture was poured into saturated aqueous NaHCO3 (20 mL) at 0 °C and extracted with EtOAc (50 mL * 3). The organic layer was dried over Na2SO4, filtered and concentrated in vacuum to afford crude benzyl 4-(2,2-dichloro-3-oxocyclobutyl)piperidine- 1-carboxylate. MS (ESI) [M+H]+: m / z 356.1.

[0314] Step C: Benzyl 4-(3-oxocyclobutyl)piperidine-1-carboxylate

[0315] To a stirred solution of benzyl 4-(2,2-dichloro-3-oxocyclobutyl)piperidine-1- carboxylate (726 mg, 2.038 mmol) in sat. NH4Cl dissolved in MeOH (20 mL) was added zinc powder (666 mg, 10.19 mmol), and the mixture was stirred at 25 °C for 16 h under N2atmosphere. LCMS showed the starting material was consumed and desired MS was found. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 12 g Agela Silica Flash Column, eluent of 0~30% ethyl acetate / Pet. ether gradient @ 30 mL / min) to give benzyl 4-(3- oxocyclobutyl)piperidine-1-carboxylate. MS (ESI) [M+H]+: m / z 288.1.

[0316] Step D: 4-(tert-butoxy)-8-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a yl)methoxy)-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine To a solution of ethyl 2-(diethoxyphosphoryl)acetate (546 mg, 2.436 mmol) in THF (5 mL) was added potassium tert-butoxide (2.192 mL, 2.192 mmol) at 0 °C, and the mixture was stirred at 25 °C for 30 min. Then a solution of benzyl 4-(3-oxocyclobutyl)piperidine-1- carboxylate (350 mg, 1.218 mmol) in THF (2 mL) was added to the reaction mixture at 0 °C. The mixture was stirred at 25 °C for 1 h. LCMS showed the starting material was consumed and desired MS was formed. The mixture was poured into saturated aqueous145021.598160 (002000.PC) NH4Cl (10 mL), and extracted with EtOAc (20 mL * 3). The organic layer was dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 12 g Agela Silica Flash Column, eluent of 0~30% ethyl acetate / Pet. ether gradient @ 30 mL / min) to give benzyl 4-(3-(2-ethoxy-2- oxoethylidene)cyclobutyl)piperidine-1-carboxylate. MS (ESI) [M+H]+: m / z 358.1.

[0318] Step E: Ethyl 2-(3-(piperidin-4-yl)cyclobutyl)acetate

[0319] To a solution of benzyl 4-(3-(2-ethoxy-2-oxoethylidene)cyclobutyl)piperidine-1- carboxylate (4.5 g, 12.59 mmol) in EtOH (50 mL) was added Pd-C (1.340 g, 1.259 mmol) (10% Wt) at 25 °C under nitrogen atmosphere, and then the mixture was degassed and purged with hydrogen for three times. The reaction was stirred at 25 °C for 40 h under 15 psi of H2 atmosphere (H2 balloon). LCMS showed the starting material was consumed and desired product was formed. The mixture was diluted with EtOH (20 mL). The mixture was filtered and the solvent was evaporated under reduced pressure to give the crude product ethyl 2-(3-(piperidin-4-yl)cyclobutyl)acetate. MS (ESI) [M+H]+: m / z 226.1.

[0320] Step F: Ethyl (R)-2-(3-(1-((1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)cyclobutyl)acetate

[0321] To a solution of ethyl 2-(3-(piperidin-4-yl)cyclobutyl)acetate (1.6 g, 7.10 mmol) in MeCN (8 mL) was added (S)-(1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl methanesulfonate (1.45g, 4.73 mmol) and DIEA (2.480 mL, 14.20 mmol) at 25 °C. The mixture was stirred at 80 °C for 16 h. LCMS showed starting material was consumed and new product was formed. The reaction mixture was treated with H2O (5 mL) and EtOAc (5 mL). The organic layer was separated and the aqueous layer was re-extracted with EtOAc (50 mL * 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by preparative TLC (SiO2, dichloromethane: methanol= 10: 1) to give ethyl (R)-2-(3-(1-((1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)cyclobutyl)acetate. MS (ESI) [M+H]+: m / z 436.6.

[0322] Step G: (R)-2-(3-(1-((1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)cyclobutyl)acetic acid (Int-A128)

[0323] To a solution of ethyl (R)-2-(3-(1-((1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)cyclobutyl)acetate (1.84 g, 4.22 mmol) in THF (10 mL), MeOH (10 mL) and Water (5 mL) was added Lithium hydroxide monohydrate (1.773 g, 42.2 mmol) at 25 °C. The mixture was stirred at 25 °C for 1 h. LCMS showed145021.598160 (002000.PC) starting material was consumed and desired MS was formed. The mixture was diluted with EtOAc (40 mL), acidified with aq. HCl solution (1 M) until pH 7. The organic phase was separated and dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give the crude product (R)-2-(3-(1-((1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)cyclobutyl)acetic acid (Int-A128). MS (ESI) [M+H]+: m / z 408.3. Synthesis of Core Intermediates

[0324] Intermediate C01: butyl (1S,5R)-3-(6,8-difluoro-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl) 1-yl)-2-(methylsulfonyl)quinazolin-4-yl)-1-methyl- 3,8-diazabicyclo octane-8-carboxylate (Int-C01)

[0325] Step A: 4-(tert-butoxy)-6,8-difluoro-7-(3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)quinazoline (Int-C01A)

[0326] To a stirred solution of 4-(tert-butoxy)-6,8-difluoro-2-(methylthio)quinazoline (6.26 g, 22.0 mmol) in THF (31 mL) was added TMP2Zn · MgCl2 · LiCl (0.2 M in THF, 127 mL, 25.3 mmol). The resulting mixture was stirred at RT for 1 h. Then, to a stirred solution of 3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (13.64 g, 26.4 mmol) and XPhos Pd G3 (2.79 g, 3.30 mmol) in dioxane (56 mL) was added the above aged solution via cannula. The resulting mixture was heated to 80 °C overnight, cooled to RT, diluted with EtOAc, and then quenched by addition of water. The resulting mixture was stirred, and then filtered. The organic layer was separated, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash145021.598160 (002000.PC) chromatography (silica gel, 0-100% DCM / hexanes) to give a first batch of racemic 4-(tert- butoxy)-6,8-difluoro-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1- yl)-2-(methylthio)quinazoline (9.22 g). A second batch of the racemic compound (1.83 g) was combined with the first batch. Stereoisomers were separated by chiral SFC (IC: 21x250mm / 5 um, 20% iPrOH in supercritical CO2(scCO2) with 0.1% NH4OH modifier) to give 4-(tert-butoxy)-6,8-difluoro-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen- 1-yl)-2-(methylthio)quinazoline, peak 1 (Int-C01A) (5.11 g). ESI-MS m / z calc’d for C36H45F2N2O3SSi [M+H]+: 651; found: 651.

[0327] Step B: 6,8-difluoro-7-(3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)quinazolin-4-ol (Int-C01B)

[0328] To a stirred solution of 4-(tert-butoxy)-6,8-difluoro-7-(3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)quinazoline, peak 1 (Int-C01A) (1.70 g, 2.61 mmol) in MeCN (20 mL) and water (5.22 mL) was added TFA (0.52 mL). The resulting mixture was stirred at RT for 2 h, diluted with EtOAc, and then quenched by addition of sat’d NaHCO3. The organic layer was separated, dried over MgSO4, filtered, and concentrated in vacuo to give 6,8-difluoro-7-(3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)quinazolin-4-ol (Int-C01B), which was used directly in the next step without further purification. ESI-MS m / z calc’d for C32H37F2N2O3SSi [M+H]+: 595; found: 595.

[0329] Step C: Tert-butyl (1S,5R)-3-(6,8-difluoro-7-(3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)quinazolin-4-yl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-C01C)

[0330] To a stirred solution of 6,8-difluoro-7-(3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)quinazolin-4-ol (Int-C01B) in MeCN (6.5 mL) were added DIPEA (1.14 mL, 6.53 mmol) and BOP (1.73 g, 3.92 mmol). The resulting mixture was stirred at RT for 5 min and then tert-butyl (1S,5R)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (709 mg, 3.13 mmol) in MeCN (6.5 mL) was added. The resulting mixture was heated to 70 °C for 2 h, cooled to RT, diluted with EtOAc, and then quenched by addition of sat’d NaHCO3. The organic layer was separated, washed with sat’d NaHCO3 (2x), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0-55% EtOAc / hexanes) to give tert-butyl (1S,5R)-3-(6,8-difluoro-7-(3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)quinazolin-4-yl)-1-methyl-3,8-145021.598160 (002000.PC) diazabicyclo[3.2.1]octane-8-carboxylate (Int-C01C) (0.86 g). ESI-MS m / z calc’d for C44H57F2N4O4SSi [M+H]+: 803; found: 803.

[0331] Step D: butyl (1S,5R)-3-(6,8-difluoro-7-(3-(methoxymethoxy)-8-( naphthalen-1-yl)-2-(methylsulfonyl)quinazolin-4-yl)-1-methyl- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-C01)

[0332] To a stirred solution of tert-butyl (1S,5R)-3-(6,8-difluoro-7-(3-(methoxymethoxy)- 8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)quinazolin-4-yl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-C01C) (860 mg, 1.07 mmol) in DCM (5.4 mL) at 0 °C was added mCPBA (70 wt%, 634 mg, 2.57 mmol). The resulting mixture was stirred at 0 °C for 1 h and then diluted with cold EtOAc. The organic layer was washed with cold 1:1 sat’d NaHCO3 / sat’d Na2S2O3, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0-90% EtOAc / hexanes) to give tert-butyl (1S,5R)-3-(6,8-difluoro-7-(3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)quinazolin-4-yl)-1-methyl- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-C01) (800 mg). ESI-MS m / z calc’d for C44H57F2N4O6SSi [M+H]+: 835; found: 835.1H NMR (400MHz, CD3OD) į 7.93 (dd, J = 1.0, 8.3 Hz, 1H), 7.71 (dd, J = 1.3, 10.0 Hz, 1H), 7.67 – 7.63 (m, 2H), 7.48 (dd, J = 7.4, 8.1 Hz, 1H), 7.23 (d, J = 2.5 Hz, 1H), 5.36 (s, 2H), 4.85 – 4.76 (m, 2H), 4.44 (br d, J = 7.0 Hz, 1H), 4.22 (br d, J = 12.4 Hz, 1H), 3.93 (br d, J = 12.0 Hz, 1H), 3.52 (s, 3H), 3.39 (s, 4H), 2.28 – 2.18 (m, 1H), 2.02 – 1.90 (m, 1H), 1.89 – 1.78 (m, 1H), 1.66 (s, 3H), 1.63 – 1.43 (m, 12H), 0.91 (d, J = 7.4 Hz, 9H), 0.85 (d, J = 7.5 Hz, 9H).

[0333] Compounds in the table below were synthesized via a similar route as described in the above synthesis of Int-C01 by making the appropriate substitutions that are available commercially, synthesized as described in the literature, synthesized using methods available to those skilled in the art, or synthesized as described herein. In Step A, alternatively, XPhos Pd G2 may be used. Also, if containing a mixture of isomers, this intermediate may be further separated by chiral SFC such as with AD or AS columns.145021.598160 (002000.PC)

[0334] A representative NMR spectrum is provided below.

[0335] Int-C07

[0336] 1H NMR (400 MHz, CD3OD) į 8.04 (s, 1H), 7.13 (d, J = 8.6 Hz, 4H), 6.83 (d, J = 8.6 Hz, 4H), 6.65 (s, 1H), 4.81 – 4.67 (m, 3H), 4.64 – 4.50 (m, 3H), 4.42 – 4.31 (m, 2H), 3.80 (br d, J = 12.2 Hz, 1H), 3.76 (s, 6H), 3.69 (br d, J = 12.3 Hz, 1H), 3.39 (s, 3H), 2.42 (d, J = 1.3 Hz, 3H), 1.94 – 1.75 (m, 3H), 1.74 – 1.64 (m, 1H), 1.53 (s, 9H).

[0337] Intermediate C02: Tert-butyl (1S,5R)-3-(2-chloro-7-(8-chloro-3- (methoxymethoxy)naphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-C02)145021.598160 (002000.PC)octane-

[0339] To a stirred solution of 2,4-dichloro-6,8-difluoroquinazoline (5.10 g, 21.7 mmol) in dioxane (100 mL) were added tert-butyl (1S,5R)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (4.91 g, 21.7 mmol) and DIPEA (11.4 mL, 65.1 mmol). The resulting mixture was heated to 80 °C for 1 h, cooled to RT, and then concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0-15% EtOAc / pet. ether) to give tert-butyl (1S,5R)-3-(2-chloro-6,8-difluoroquinazolin-4-yl)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-C02A) (9.20 g). ESI-MS m / z calc’d for C20H24ClF2N4O2 [M+H]+: 425; found: 425.1H NMR (400 MHz, CDCl3) į 7.30 – 7.21 (m, 2H), 4.43 – 4.28 (m, 2H), 4.18 (br d, J = 12.47 Hz, 1H), 3.56 (br d, J = 12.47 Hz, 2H), 2.01 – 1.82 (m, 2H), 1.81 – 1.70 (m, 1H), 1.58 (s, 4H), 1.51 (s, 9H).

[0340] Step B: Tert-butyl (1S,5R)-3-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-1- methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-C02B)

[0341] To a stirred solution of diisopropylamine (3.00 mL, 9.41 mmol) in THF (9 mL) at 0 °C was added n-BuLi (2.5 M in hexanes, 7.00 mL, 17.5 mmol). The resulting mixture was stirred at 0 °C for 30 min. Then, to a stirred solution of tert-butyl (1S,5R)-3-(2-chloro-6,8- difluoroquinazolin-4-yl)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-C02A) (4.00 g, 9.41 mmol) in THF (40 mL) at –75 °C was added the above aged solution. The resulting mixture was stirred at –75 °C for 1 h and quenched by addition of sat’d NH4Cl. The organic layer was separated, and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 17% EtOAc / pet. ether) to give tert-butyl (1S,5R)-3-(7-bromo-2-chloro-6,8-difluoroquinazolin-4- yl)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-C02B) (3.50 g). ESI-MS m / z calc’d for C20H2381BrClF2N4O2 [M+H]+: 505; found: 505.1H NMR (400MHz, CDCl3) į 7.39 (br dd, J = 2.0, 9.0 Hz, 1H), 4.47 – 4.31 (m, 2H), 4.20 (br d, J = 12.2 Hz, 1H), 3.60 (br d, J = 12.2 Hz, 2H), 2.03 – 1.74 (m, 4H), 1.60 (s, 3H), 1.53 (s, 9H).145021.598160 (002000.PC)

[0342] Step C: Tert-butyl (1S,5R)-3-(2-chloro-7-(8-chloro-3- (methoxymethoxy)naphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-C02)

[0343] To a stirred solution of tert-butyl (1S,5R)-3-(7-bromo-2-chloro-6,8- difluoroquinazolin-4-yl)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-C02B) (8.00 g, 15.9 mmol) in THF (80 mL) were added 2-(8-chloro-3- (methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.54 g, 15.9 mmol), K3PO4(10.1 g, 47.6 mmol), rac-BI-DIME (1.05 g, 3.18 mmol) and Pd(OAc)2(0.357 g, 1.59 mmol). The resulting mixture was heated to 80 °C for 16 h, cooled to RT, and then quenched by addition of brine. The organic layer was separated, and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0-20% EtOAc / pet. ether) to give racemic tert-butyl (1S,5R)-3- (2-chloro-7-(8-chloro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-1- methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5.40 g). The racemic compound was separated by chiral SFC (Cellulose-2: 50x250 mm / 10 um, 35% EtOH in scCO2 with 0.1% NH4OH modifier) to give tert-butyl (1S,5R)-3-(2-chloro-7-(8-chloro-3- (methoxymethoxy)naphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate, peak 1 (Int-C02) (2.20 g). ESI-MS m / z calc’d for C32H33Cl2F2N4O4[M+H]+: 645; found: 645.1H NMR (400 MHz, CDCl3) į 7.77 (dd, J = 1.6, 7.8 Hz, 1H), 7.57 (d, J = 2.7 Hz, 1H), 7.42 – 7.34 (m, 3H), 7.20 (d, J = 2.3 Hz, 1H), 5.32 (s, 2H), 4.45 (br d, J = 6.7 Hz, 1H), 4.38 – 4.29 (m, 2H), 3.69 – 3.55 (m, 2H), 3.53 (s, 3H), 2.04 – 1.95 (m, 2H), 1.87 – 1.77 (m, 1H), 1.71 – 1.66 (m, 1H), 1.64 (s, 3H), 1.54 (s, 9H).

[0344] The compound in the table below was synthesized via a similar route as described in the above synthesis of Int-C02 by making the appropriate substitutions that are available commercially, synthesized as described in the literature, synthesized using methods available to those skilled in the art, or synthesized as described herein. In Step B, Pd(dppf)Cl2 may be used as the catalyst and the chiral SFC may be skipped.145021.598160 (002000.PC)7.51 – 7.47 (m, 2H), 7.46 – 7.41 (m, 1H), 7.35 – 7.31 (m, 1H), 7.29 – 7.27 (m, 1H), 5.35 (s, 2H), 4.49 – 4.41 (m, 2H), 4.31 (br dd, J = 12.7, 15.9 Hz, 1H), 3.69 – 3.59 (m, 2H), 3.56 (s, 3H), 2.05 – 1.94 (m, 2H), 1.87 – 1.77 (m, 1H), 1.72 – 1.67 (m, 1H), 1.65 (d, J = 2.6 Hz, 3H), 1.55 (s, 9H).

[0348] Intermediate C05: 4-(tert-butoxy)-6,8-difluoro-7-(3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)quinazoline (Int-C05)

[0349] To a stirred solution of 4-(tert-butoxy)-6,8-difluoro-7-(3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)quinazoline, peak 1 (Int-C01A) (5.11 g, 7.85 mmol) in DCM (102 mL) at 0 °C was added mCPBA (70 wt%, 3.52 g, 15.7 mmol). The resulting mixture was stirred at 0 °C for 15 min, warmed to RT, and stirred at RT overnight. The resulting mixture was quenched by addition of sat’d NaHCO3. The organic layer was separated, dried over MgSO4, filtered, and concentrated in vacuo to give 4-(tert-butoxy)-6,8-difluoro-7-(3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)quinazoline (Int-C05) (5.19 g), which was used directly in subsequent step(s) without further purification. ESI-MS m / z calc’d for C36H44F2N2NaO5SSi [M+Na]+: 705; found: 705.145021.598160 (002000.PC)

[0350] Intermediate C08: Tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-8-fluoro-2-(methylsulfonyl)-6-(trifluoromethyl)quinazolin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-C08)

[0351] Step A: Tert-butyl 3-(7-bromo-8-fluoro-2-(methylthio)-6- (trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0352] To a stirred solution of 7-bromo-8-fluoro-2-(methylthio)-6- (trifluoromethyl)quinazolin-4-ol (20 g, 56.0 mmol) in MeCN (200 mL) were added BOP (37.2 g, 84.0 mmol) and DIPEA (27.8 mL, 168 mmol). The resulting mixture was stirred at RT for 10 min and then tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (17.8 g, 84.0 mmol) was added. The resulting mixture was heated to 50 °C for 8 h, cooled to RT, diluted with EtOAc, and then quenched by addition of water. The organic layer was separated, washed with water, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 10% EtOAc / pet ether) to give tert- butyl 3-(7-bromo-8-fluoro-2-(methylthio)-6-(trifluoromethyl)quinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-C08A) (27.7 g). ESI-MS m / z calc’d for C21H24BrF4N4O2S [M+H]+: 551; 553; found: 551, 553.1H NMR (400 MHz, CD3OD) į 8.06 (s, 1H), 4.48 (br d, J = 12.5 Hz, 2H), 4.35 (br s, 2H), 3.67 (br d, J = 12.5 Hz, 2H), 2.60 (s, 3H), 1.91 (br d, J = 4.8 Hz, 2H), 1.74 (br d, J = 7.2 Hz, 2H), 1.52 (s, 9H).

[0353] Step B: Tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-8-fluoro-2-(methylthio)-6-(trifluoromethyl)quinazolin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-C08B)

[0354] To a solution of tert-butyl 3-(7-bromo-8-fluoro-2-(methylthio)-6- (trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-C08A) (10.5 g, 19.0 mmol) in dioxane (25 mL) were added tert-butyl (3-cyano-4-(5,5-dimethyl- 1,3,2-dioxaborinan-2-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (10.0 g, 24.8 mmol), PdCl2(DPEPhos) (2.73 g, 3.81 mmol) and Cs2CO3 (27.9 g, 86.0 mmol). The reaction mixture was heated to 100 °C for 15 h, cooled to RT, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 19% EtOAc / pet. ether) to145021.598160 (002000.PC) give racemic tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-8-fluoro-2-(methylthio)-6-(trifluoromethyl)quinazolin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5.56 g). The racemic compound was separated by chiral SFC (IG, 50x250mm / 10 um, 30% iPrOH in scCO2with 0.1% NH4OH modifier) to give tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4- yl)-8-fluoro-2-(methylthio)-6-(trifluoromethyl)quinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate, peak 2 (Int-C08B) (2.19 g). ESI-MS m / z calc’d for C35H36F5N6O4S2[M+H]+: 763; found: 763.

[0355] Step C: Tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-8-fluoro-2-(methylsulfonyl)-6-(trifluoromethyl)quinazolin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-

[0356] To a stirred solution of tert-butyl 3-(7-(2-( amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-8-fluoro-2-(methylthio)-6-(trifluoromethyl)quinazolin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate, peak 2 (Int-C08B) from several batches (3.20 g, 4.19 mmol) in DCM (32 mL) was added mCPBA (85 wt%, 1.87 g, 9.23 mmol). The resulting mixture was stirred at RT for 1 h, diluted with DCM, and then quenched by addition of sat’d NaHCO3. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 34% EtOAc / pet. ether) to give tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-8-fluoro-2-(methylsulfonyl)-6-(trifluoromethyl)quinazolin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-C08) (2.8 g). ESI-MS m / z calc’d for C35H36F5N6O6S2[M+H]+: 795; found: 795.1H NMR (400 MHz, CD3OD) į 8.31 (s, 1H), 7.41 (dd, J = 8.3, 4.9 Hz, 1H), 7.25 (t, J = 8.9 Hz, 1H), 4.78 (br d, J = 12.5 Hz, 1H), 4.55 (br d, J = 11.0 Hz, 1H), 4.40 (br d, J = 12.8 Hz, 2H), 3.91 (br d, J = 12.2 Hz, 1H), 3.79 (br d, J = 11.2 Hz, 1H), 3.40 (s, 3H), 1.93 (br s, 2H), 1.81 – 1.66 (m, 2H), 1.55 (d, J = 10.1 Hz, 18H).

[0357] Intermediate C09: Tert-butyl 3-(6,8-difluoro-7-(6-methyl-1-(tetrahydro-2H-pyran- 2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)-2-(methylsulfonyl)quinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-C09)145021.598160 (002000.PC)

[0358] Step A: 4-(tert-butoxy)-6,8-difluoro-7-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-(methylthio)quinazoline (Int-

[0359] To 4-(tert-butoxy)-6,8-difluoro-2-(methylthio)quinazoline g, 6.33 mmol) was added TMP2Zn · MgCl2· LiCl (0.4 M in THF, 47.5 mL, 19.0 mmol). The resulting mixture was heated to 50 °C for 1 h and then cooled to RT. Then, a solution of 4-bromo-6-methyl-1- (tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazole (2.76 g, 7.60 mmol) and SPhos Pd G3 (494 mg, 0.633 mmol) in dioxane (48 mL) was added. The resulting mixture was heated to 50 °C for 12 h, cooled to RT, diluted with EtOAc, and then quenched by addition of sat’d NaHCO3. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0-10% EtOAc / pet. ether) to give 4-(tert-butoxy)-6,8-difluoro-7-(6-methyl-1-(tetrahydro-2H-pyran- 2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)-2-(methylthio)quinazoline (Int-C09A) (900 mg). ESI-MS m / z calc’d for C27H28F5N4O2S [M+H]+: 567; found: 567.

[0360] Step B: 6,8-difluoro-7-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)-2- (methylthio)quinazolin-4-ol (Int-C09B)145021.598160 (002000.PC)

[0361] To a solution of 4-(tert-butoxy)-6,8-difluoro-7-(6-methyl-1-(tetrahydro-2H-pyran-2- yl)-5-(trifluoromethyl)-1H-indazol-4-yl)-2-(methylthio)quinazoline (Int-C09A) (900 mg, 1.59 mmol) in DCM (10 mL) was added TFA (3.0 mL, 39 mmol). The resulting mixture was stirred at RT for 30 min, diluted with DCM, and then quenched by addition of sat’d NaHCO3. The organic layer was separated, and the aqueous layer was extracted with DCM (3x). The combined organic layers were dried over Na2CO3, filtered, and concentrated in vacuo to give 6,8-difluoro-7-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)-2- (methylthio)quinazolin-4-ol (Int-C09B), which was used directly in the next step without further purification. ESI-MS m / z calc’d for C18H12F5N4OS [M+H]+: 427; found: 427.

[0362] Step C: Tert-butyl 3-(6,8-difluoro-7-(6-methyl-5-(trifluoromethyl)-1H-indazol-4- yl)-2-(methylthio)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-C09C)

[0363] To a solution of 6,8-difluoro-7-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)-2- (methylthio)quinazolin-4-ol (Int-C09B) in MeCN (1 mL) was added BOP (1.37 g, 3.10 mmol). The resulting mixture was stirred at RT for 10 min. Then, a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (527 mg, 2.48 mmol) in MeCN (1 mL) and DIPEA (1.1 mL, 6.2 mmol) was added. The resulting mixture was heated to 60 °C for 1 h, cooled to RT, and concentrated in vacuo. The residue was purified by flash chromatography (0-30% EtOAc / pet. ether) to give racemic tert-butyl 3-(6,8-difluoro-7-(6-methyl-5- (trifluoromethyl)-1H-indazol-4-yl)-2-(methylthio)quinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (714 mg). The racemic compound was separated by chiral SFC (AD, 30x250 mm / 10 um, 30% EtOH in scCO2with 0.1% NH4OH modifier) to give tert-butyl 3-(6,8-difluoro-7-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)-2- (methylthio)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, peak 1 (Int- C09C) (280 mg). ESI-MS m / z calc’d for C29H30F5N6O2S [M+H]+: 621; found: 621.

[0364] Step D: Tert-butyl 3-(6,8-difluoro-7-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-(methylthio)quinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-C09D)

[0365] To a stirred solution of tert-butyl 3-(6,8-difluoro-7-(6-methyl-5-(trifluoromethyl)- 1H-indazol-4-yl)-2-(methylthio)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate, peak 1 (Int-C09C) (280 mg) in DCM (5 mL) were added pTsOH (14 mg, 0.084 mmol) and 3,4-dihydro-2H-pyran (115 μL, 1.26 mmol). The resulting mixture was stirred at RT for 15 min and then concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 50% EtOAc / pet. ether) to give tert-butyl 3-(6,8-difluoro-7-(6- methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)-2-145021.598160 (002000.PC) (methylthio)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-C09D) (270 mg). ESI-MS m / z calc’d for C34H38F5N6O3S [M+H]+: 705; found: 705.

[0366] Step E: Tert-butyl 3-(6,8-difluoro-7-(6-methyl-1-(tetrahydro-2H- 2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)-2-(methylsulfonyl)quinazolin-4-yl)-diazabicyclo[3.2.1]octane- (Int-C09)

[0367] To a stirred tert- 3-(6,8-difluoro-7-(6-methyl-1-(tetrahydro-2H- pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)-2-(methylthio)quinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-C09D) (236 mg, 0.335 mmol) in DCM (3 mL) at 0 °C was added mCPBA (85 wt%, 204 mg, 1.01 mmol). The resulting mixture was stirred at RT for 30 min and then quenched by addition of sat’d NH4Cl. The organic layer was separated, and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc / pet. ether) to give tert-butyl 3- (6,8-difluoro-7-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4- yl)-2-(methylsulfonyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int- C09) (183 mg). ESI-MS m / z calc’d for C34H38F5N6O5S [M+H]+: 737; found: 737.

[0368] Intermediate 12A8: Tert-butyl (4-(6-chloro-8-fluoro-4-hydroxy-2- (methylthio)quinazolin-7-yl)-3-cyano-5,7-difluorobenzo[b]thiophen-2-yl)carbamate (Int- 12A8)

[0369] Step 1: Methyl 2-amino-4-bromo-3-fluorobenzoate (Int-12A2)145021.598160 (002000.PC)

[0370] To a mixture of 2-amino-4-bromo-3-fluorobenzoic acid (Int-12A1) (325 g, 1.39 mol) in DMF (1.63 L) was added K2CO3 (384 g, 2.78 mol) at 25oC. Methyl iodide (237 g, 16.67 mol) was added to the reaction mixture and the resulting reaction mixture was stirred for 1 h at 0 °C and for 2 h at 25oC. The reaction mixture was cooled with an ice-water bath and slowly diluted with water (500 mL). The resulting mixture was stirred for 10 min and then filtered to collect a solid. The solid was dried by a continuous flow of nitrogen for 12 h to afford methyl 2-amino-4-bromo-3-fluorobenzoate (Int-12A2), which was used directly in the next step without further purification.

[0371] Step 2: Methyl 2-amino-3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzoate (Int-12A3)

[0372] To a mixture of methyl 2-amino-4-bromo-3-fluorobenzoate (Int-12A2) (318 g, 1.28 mol) in dioxane (2.22 L) at 25 °C was charged bis(pinacolato)diboron (488 g, 1.92 mol) and then CH3COOK (502 g, 5.12 mol) and the resulting mixture was stirred under a nitrogen atmosphere. Pd(dppf)Cl2was charged to the reaction mixture at 25 °C and then the reaction was heated at 100 °C for 1 h. The reaction mixture was cooled to RT, and then filtered to collect the organic phase. The organic phase was concentrated in vacuo to provide a residue. The residue was purified by silica gel column chromatography Petroleum ether / Ethyl acetate to provide methyl 2-amino-3-fluoro-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzoate (Int-12A3).

[0373] Step 3: Methyl 2-amino-4-(2-(((benzyloxy)carbonyl)amino)-3-cyano-5,7- difluorobenzo[b]thiophen-4-yl)-3-fluorobenzoate (Int-12A5)

[0374] A round-bottom flask equipped with a stirrer bar was charged with benzyl (4- bromo-3-cyano-5,7-difluorobenzo[b]thiophen-2-yl)carbamate (Int-12A4) (57 g, 146 mmol), methyl 2-amino-3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (Int- 12A3) (54.0 g, 183 mmol), cesium carbonate (119 g, 366 mmol), and dichloro[bis(2- (diphenylphosphino)phenyl)ether]palladium(II) (2.097 g, 2.93 mmol). The round-bottom flask was placed under a nitrogen atmosphere and 1,4-dioxane (340 ml) was added. The mixture was stirred and degassed. Water (34 ml) was added before the mixture was heated to 100 °C for 2 hours. Further batches of dichloro[bis(2- (diphenylphosphino)phenyl)ether]palladium(II) (1.045 g, 1.46 mmol) and Int-12A3 (5 g, 16.9 mmol) were added to the reaction. The reaction mixture continued stirring at 100 °C for 2 hours. The reaction mixture was diluted with water (450 mL) and to the hot stirring solution was added CELITE® (28.5 g). The mixture was stirred for 10 minutes before hot filtration into a round-bottom flask equipped with an overhead stirrer. The mixture was145021.598160 (002000.PC) heated to 70 °C. The filter cake was washed with 2:1 water:dioxane (100 mL). The reaction mixture was cooled to 40 °C which formed a suspension and then the solution was seeded with 6 g of compound Int-12A5. After 5 minutes, 500 mL of water was added slowly and the slurry was stirred for 2 hours. The mixture was then allowed to cool to room temperature and was stirred at room temperature overnight. The solids were collected by filtration and washed with 3.5:1 water:dioxane (80 mL) and then water (80 mL). The solids were dried under vacuum with a flow of nitrogen to provide methyl 2-amino-4-(2- (((benzyloxy)carbonyl)amino)-3-cyano-5,7-difluorobenzo[b]thiophen-4-yl)-3- fluorobenzoate (Int-12A5).

[0375] Step 4: Methyl 2-amino-4-(2-(((benzyloxy)carbonyl)amino)-3-cyano-5,7- difluorobenzo[b]thiophen-4-yl)-5-chloro-3-fluorobenzoate (Int-12A6)

[0376] A round-bottom flask equipped with a stirrer bar was charged with methyl 2-amino- 4-(2-(((benzyloxy)carbonyl)amino)-3-cyano-5,7-difluorobenzo[b]thiophen-4-yl)-3- fluorobenzoate (Int-12A5) (24.398 g, 46.0 mmol) and DMF (244 mL). NCS (6.14 g, 46.0 mmol) was added to the stirred reaction mixture and then the reaction was heated to 60 °C and stirred for 2 h. A further charge of NCS (307 mg, 2.3 mmol) was added and the solution was stirred for 2 h. A further charge of NCS (307 mg, 2.3 mmol) was added and the solution was stirred for 1 h. A further charge of NCS (307 mg, 2.3 mmol) was added and the solution was stirred for 16 h. A further charge of NCS (307 mg, 2.3 mmol) was added and the solution was stirred for 1 h. To the mixture at 60 °C was added water (40 mL) dropwise and then the reaction mixture was cooled to room temperature slowly. Additional water (80 mL) was added dropwise at room temperature. The slurry was filtered and the precipitate was washed with 1:1 water:DMF, followed by water. The solids were dried to yield methyl 2-amino-4-(2-(((benzyloxy)carbonyl)amino)-3-cyano-5,7- difluorobenzo[b]thiophen-4-yl)-5-chloro-3-fluorobenzoate (Int-12A6).

[0377] Step 5: Methyl 4-(2-(((benzyloxy)carbonyl)amino)-3-cyano-5,7- difluorobenzo[b]thiophen-4-yl)-5-chloro-2-(3-(ethoxycarbonyl)thioureido)-3- fluorobenzoate (Int-12A7)

[0378] A round-bottom flask equipped with a stirrer bar was charged with methyl 2-amino- 4-(2-(((benzyloxy)carbonyl)amino)-3-cyano-5,7-difluorobenzo[b]thiophen-4-yl)-5-chloro- 3-fluorobenzoate (Int-12A6) (26.139 g, 44.7 mmol) and MeCN (261 mL). The mixture was cooled to 0 °C and O-ethyl carbonisothiocyanatidate (7.90 ml, 67.0 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 18 h. MeOH (15 mL) was added to quench the reaction and it was stirred for 10 mins. The mixture was concentrated145021.598160 (002000.PC) to remove MeCN to afford methyl 4-(2-(((benzyloxy)carbonyl)amino)-3-cyano-5,7- difluorobenzo[b]thiophen-4-yl)-5-chloro-2-(3-(ethoxycarbonyl)thioureido)-3- fluorobenzoate (Int-12A7), which was used directly in the next step without further purification.

[0379] Step 6: Tert-butyl (4-(6-chloro-8-fluoro-4-hydroxy-2-(methylthio)quinazolin-7-yl)- 3-cyano-5,7-difluorobenzo[b]thiophen-2-yl)carbamate (Int-12A8)

[0380] A round-bottom flask equipped with a stirrer bar was charged with methyl 4-(2- (((benzyloxy)carbonyl)amino)-3-cyano-5,7-difluorobenzo[b]thiophen-4-yl)-5-chloro-2-(3- (ethoxycarbonyl)thioureido)-3-fluorobenzoate (Int-12A7) (29.986 g, 46.6 mmol) and methanol (300 mL). The slurry was stirred. In the glove box potassium tert-butoxide (KOtBu) (15.70 g, 140 mmol) was added to THF (100 mL). The KOtBu solution was removed from the glove box and added to the slurry which caused the suspension to turn into a dark solution. The flask was fitted with a reflux condenser and the mixture was heated to 70 °C for 30 mins. The reaction mixture was cooled to 0 °C and then methyl iodide (8.75 mL, 140 mmol) was added, and the reaction mixture was allowed to warm to room temperature and stirred. The reaction mixture was acidified to pH 3-4 and concentrated on the rotary evaporator. The residue was extracted with chloroform and washed with water. The organics were combined, dried over Mg2SO4, filtered, and concentrated to dryness. The crude reaction mixture was purified by flash column chromatography (eluting 0-65% EtOAc in hexanes) to give tert-butyl (4-(6-chloro-8-fluoro- 4-hydroxy-2-(methylthio)quinazolin-7-yl)-3-cyano-5,7-difluorobenzo[b]thiophen-2- yl)carbamate (Int-12A8).

[0381] The atropisomers of tert-butyl (4-(6-chloro-8-fluoro-4-hydroxy-2- (methylthio)quinazolin-7-yl)-3-cyano-5,7-difluorobenzo[b]thiophen-2-yl)carbamate (Int- 12A8) were separated by SFC (IZ column, 70 mL / min, 35% MeOH with 0.1% modifier).

[0382] Intermediate C12: Tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-5,7- difluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-2- quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-C12)145021.598160 (002000.PC)

[0383] Step A: Tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-5,7- difluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-2-(methylthio)quinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-C12A)

[0384] To a stirred solution of tert-butyl (4-(6-chloro-8-fluoro-4-hydroxy-2- (methylthio)quinazolin-7-yl)-3-cyano-5,7-difluorobenzo[b]thiophen-2-yl)carbamate (Int- 12A8) (185 mg, 0.335 mmol) in MeCN (1.7 mL) was added DIPEA (298 uL, 1.67 mmol). The resulting mixture was stirred at RT for 5 min and then BOP (222 mg, 0.502 mmol) was added. The resulting mixture was stirred at RT for 30 min and then tert-butyl (1R,5S)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (107 mg, 0.502 mmol) was added. The resulting mixture was heated to 70 °C for 1 h, cooled to RT, and then diluted with EtOAc. The organic layer was washed with sat’d NaCl (3x), dried over Na2SO4, filtered, and concentratedvacuo. The residue was purified by flash chromatography (silica gel, 0- 100% EtOAc / hexanes) to give tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-5,7- difluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-2-(methylthio)quinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-C12A). ESI-MS m / z calc’d for C34H35ClF3N6O4S2 [M+H]+: 747; found: 747.

[0385] Step B: Tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-5,7- difluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-2-(methylsulfonyl)quinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-C12)

[0386] To a stirred solution of tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano- 5,7-difluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-2-(methylthio)quinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-C12A) (190 mg, 0.25 mmol) in DCM (3.4 mL) was added mCPBA (105 mg, 0.61 mmol). The resulting mixture was stirred at RT for 1 h, diluted with DCM, washed with 1:110% NaHCO3 / 20% Na2S2O3, water, then brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 10% EtOAc / isohexane) to give tert-butyl 3-(7-(2-((tert- butoxycarbonyl)amino)-3-cyano-5,7-difluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-2- (methylsulfonyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-C12). ESI-MS m / z calc’d for C34H35ClF3N6O6S2 [M+H]+: 779; found: 779. Synthesis of Alkyl Iodide Intermediates145021.598160 (002000.PC)

[0387] Intermediate H02: (2S,4R)-4-hydroxy-1-((S)-2-(3-(3-iodopropoxy)propanamido)- 3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int- H02)

[0388] Step A: (2S,4R)-1-((S)-2-(3-(3-chloropropoxy)propanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Int-H01)

[0389] To a stirred solution of 3-(3-chloropropoxy)propanoic acid (250 mg, 1.50 mmol) in DCM (4 mL) at 0 °C were added DIPEA (0.79 mL, 4.5 mmol), HOBt (345 mg, 2.25 mmol) and EDC (432 mg, 2.25 mmol). The resulting mixture was stirred at 0 °C for 5 min and then (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (646 mg, 1.50 mmol) was added. The resulting mixture was stirred at 0 °C for 2 h and then concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 5% MeOH / DCM) to give (2S,4R)-1-((S)-2-(3-(3- chloropropoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Int-H01) (1.10 g). ESI-MS m / z calc’d for C28H40ClN4O5S [M+H]+: 579; found: 579.

[0390] Step B: (2S,4R)-4-hydroxy-1-((S)-2-(3-(3-iodopropoxy)propanamido)-3,3- dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-H02)

[0391] To a stirred solution of (2S,4R)-1-((S)-2-(3-(3-chloropropoxy)propanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Int-H01) (800 mg, 1.38 mmol) in acetone (30 mL) was added NaI (3.11 g, 20.7 mmol). The resulting mixture was heated to 60 °C for 18 h and then quenched by addition of water. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give (2S,4R)-4- hydroxy-1-((S)-2-(3-(3-iodopropoxy)propanamido)-3,3-dimethylbutanoyl)-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-H02) (1.00 g), which was used145021.598160 (002000.PC) directly in subsequent step(s) without further purification. ESI-MS m / z calc’d for671; found: 671.

[0392] Compounds in the table below were synthesized via a similar route as described in the above synthesis ofby making the appropriate substitutions for the corresponding acyl halides. Appropriate substitutions are available commercially, synthesized as described in the literature, synthesized using methods available to those skilled in the art, or synthesized as described herein. In Step B, alternatively, water may be added to the acetone solvent.145021.598160 (002000.PC)145021.598160 (002000.PC)

[0393] Intermediate CL001: Tert-butyl (1S,5R)-3-(2-(((R)-2,2-difluoro-1-(((7-methoxy-7- oxoheptyl)(methyl)amino)methyl)cyclopropyl)methoxy)-6,8-difluoro-7-(3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-1-methyl- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-CL001)

[0394] To a stirred solution of tert-butyl (1S,5R)-3-(6,8-difluoro-7-(3-(methoxymethoxy)- 8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)quinazolin-4-yl)-1-methyl- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-C01) (180 mg, 0.216 mmol) and methyl (R)-7-(((2,2-difluoro-1-(hydroxymethyl)cyclopropyl)methyl)(methyl)amino)heptanoate (Int-A001) (126 mg, 0.431 mmol) in THF (2.2 mL) at 0 °C was added NaH (60 wt%, 25.9 mg, 0.647 mmol). The resulting mixture was stirred at 0 °C for 3 h and then quenched by addition of water. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0-60% EtOAc / hexanes) to give tert-butyl (1S,5R)-3-(2-(((R)-2,2-difluoro-1-(((7-methoxy-7- oxoheptyl)(methyl)amino)methyl)cyclopropyl)methoxy)-6,8-difluoro-7-(3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-1-methyl- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-CL001) (168 mg). ESI-MS m / z calc’d for C57H78F4N5O7Si [M+H]+: 1049; found: 1049.

[0395] Compounds in the table below were synthesized via a similar route as described in the above synthesis of Int-CL001 by making the appropriate substitutions for the corresponding core such as using Int-C03, Int-C07, Int-C08, Int-C09, Int-C11, or Int- C12 and making the appropriate substitutions for the corresponding alcohol. Appropriate145021.598160 (002000.PC) substitutions are available commercially, synthesized as described in the literature, synthesized using methods available to those skilled in the art, or synthesized as described herein. Alternatively, LiHMDS may be used as the base. The final compound, if containing a mixture of isomers, may be further separated by chiral SFC such as with IG, (R,R)- WHELK-O1, AD, or Cellulose-2 columns.145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)

[0396] A representative NMR spectrum is provided below.

[0397] Int-096A

[0398] 1H NMR (400MHz, CDCl3) į 7.96 (d, J = 1.4 Hz, 1H), 7.88 (br s, 1H), 7.25 (br d, J = 4.9 Hz, 1H), 7.18 – 7.11 (m, 1H), 4.74 (br d, J = 11.2 Hz, 1H), 4.44 (br d, J = 11.0 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 2.98 (br dd, J = 4.1, 12.8 Hz, 1H), 2.41 – 2.27 (m, 3H), 2.23 – 2.19 (m, 5H), 1.78 (s, 9H), 1.61 (br s, 5H), 1.58 (s, 9H), 1.54 – 1.38 (m, 5H), 1.27 – 1.25 (m, 3H).

[0399] Intermediate CL005: Tert-butyl (1S,5R)-3-(7-(8-chloro-3- (methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-((1-(((5-methoxy-5- oxopentyl)(methyl)amino)methyl)cyclopropyl)methoxy)quinazolin-4-yl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-

[0400] To a stirred solution of tert-butyl (1S,5R)-3-(2-chloro-7-(8-chloro-3- (methoxymethoxy)naphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-C02) (300 mg, 0.465 mmol) and RuPhos Pd G2 (54 mg, 0.070 mmol) in dioxane (9.3 mL) was added methyl 5-(((1- (hydroxymethyl)cyclopropyl)methyl)(methyl)amino)pentanoate (Int-A005) (110 mg, 0.479 mmol), followed by Cs2CO3 (454 mg, 1.39 mmol). The resulting mixture was heated to 55 °C for 2 h, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica, 0-60% EtOAc / hexanes) to give tert-butyl (1S,5R)-3-(7-(8-chloro-3- (methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-((1-(((5-methoxy-5- oxopentyl)(methyl)amino)methyl)cyclopropyl)methoxy)quinazolin-4-yl)-1-methyl-3,8-145021.598160 (002000.PC) diazabicyclo[3.2.1]octane-8-carboxylate (Int-CL005) (150 mg). ESI-MS m / z calc’d for C44H55ClF2N5O7 [M+H]+: 838; found: 838.

[0401] Compounds in the table below were synthesized via a similar route as described in the above synthesis of Int-CL005 by making the appropriate substitutions for the corresponding alcohols. Appropriate substitutions are available commercially, synthesized as described in the literature, synthesized using methods available to those skilled in the art, or synthesized as described herein.145021.598160 (002000.PC)

[0402] Intermediate CL006: Tert-butyl (1S,5R)-3-(6,8-difluoro-2-((1-(((5-methoxy-5- oxopentyl)(methyl)amino)methyl)cyclopropyl)methoxy)-7-(3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-CL006)145021.598160 (002000.PC)

[0403] To a stirred solution of tert-butyl (1S,5R)-3-(7-(8-chloro-3- (methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-((1-(((5-methoxy-5- oxopentyl)(methyl)amino)methyl)cyclopropyl)methoxy)quinazolin-4-yl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-CL005) (150 mg, 0.179 mmol) and XPhos Pd G2 (42 mg, 0.054 mmol) in DMF (2.0 mL) were added (triisopropylsilyl)acetylene (401 μL, 1.79 mmol) and N-cyclohexyl-N-methylcyclohexanamine (192 μL, 0.895 mmol). The resulting mixture was heated to 80 °C overnight, cooled to RT, and purified by flash chromatography (silica gel, 0-40% EtoAc / hexanes) to give tert-butyl (1S,5R)-3-(6,8- difluoro-2-((1-(((5-methoxy-5-oxopentyl)(methyl)amino)methyl)cyclopropyl)methoxy)-7- (3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-1- methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-CL006) (139 mg). ESI-MS m / z calc’d for C55H76F2N5O7Si [M+H]+: 985; found: 985.

[0404] Compounds in the table below were synthesized via a similar route as described in the above synthesis of Int-CL006 by making the appropriate substitutions. Appropriate substitutions are available commercially, synthesized as described in the literature, synthesized using methods available to those skilled in the art, or synthesized as described herein. Alternatively, XPhos Pd G3 or XPhos Pd G4 may be used as the catalyst.145021.598160 (002000.PC)145021.598160 (002000.PC)

[0405] Intermediate CL024: Tert-butyl (1S,5R)-3-(6,8-difluoro-2-((1-(((8-methoxy-8- oxooctyl)(methyl)amino)methyl)cyclopropyl)methoxy)-7-(3-(methoxymethoxy)naphthalen- 1-yl)quinazolin-4-yl)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-CL024)

[0406] To a stirred solution of tert-butyl (1S,5R)-3-(2-chloro-6,8-difluoro-7-(3- (methoxymethoxy)naphthalen-1-yl)quinazolin-4-yl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-C04) (40.0 mg, 0.065 mmol), RuPhos Pd G4(5.6 mg, 0.066 mmol), and Cs2CO3(107 mg, 0.327 mmol) in dioxane (0.6 mL) was addedmethyl 8-(((1-(hydroxymethyl)cyclopropyl)methyl)(methyl)amino)octanoate (Int-A018) (35.5 mg, 0.131 mmol). The resulting mixture was heated to 110 °C overnight, cooled to RT, filtered, and concentrated in vacuo to give tert-butyl (1S,5R)-3-(6,8-difluoro-2-((1-(((8- methoxy-8-oxooctyl)(methyl)amino)methyl)cyclopropyl)methoxy)-7-(3- (methoxymethoxy)naphthalen-1-yl)quinazolin-4-yl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-CL024), which was used directly in the next step without further purification. ESI-MS m / z calc’d for C47H63F2N5O7[(M+2H) / 2]2+: 424; found: 424.

[0407] Compounds in the table below were synthesized via a similar route as described in the above synthesis of Int-CL024 by making the appropriate substitutions. Appropriate substitutions are available commercially, synthesized as described in the literature, synthesized using methods available to those skilled in the art, or synthesized as described herein.145021.598160 (002000.PC)

[0408] Intermediate CL035: Tert-butyl (1S,5R)-3-(6,8-difluoro-2-((1-(((6-methoxy-6- oxohexyl)(methyl)amino)methyl)cyclopropyl)methoxy)-7-(3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-CL035)145021.598160 (002000.PC)

[0409] Step A: Methyl 6-(((1-(((4-(tert-butoxy)-6,8-difluoro-7-(3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-2- yl)oxy)methyl)cyclopropyl)methyl)(methyl)amino)hexanoate (Int-035A)

[0410] To a stirred solution of 4-(tert-butoxy)-6,8-difluoro-7-(3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)quinazoline (Int-C05) (52.0 mg, 0.076 mmol) and methyl 6-(((1- (hydroxymethyl)cyclopropyl)methyl)(methyl)amino)hexanoate (Int-A025) (20.4 mg, 0.084 mmol) in THF (0.76 mL) at 0 °C was added NaH (60 wt%, 9.2 mg, 0.23 mmol). The resulting mixture was stirred at 0 °C for 3 h and then quenched by addition of water. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0-100% EtOAc / hexanes) to give methyl 6-(((1-(((4-(tert- butoxy)-6,8-difluoro-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1- yl)quinazolin-2-yl)oxy)methyl)cyclopropyl)methyl)(methyl)amino)hexanoate (Int-035A) (39.8 mg). ESI-MS m / z calc’d for C48H66F2N3O6Si [M+H]+: 846; found: 846.

[0411] Step B: Methyl 6-(((1-(((6,8-difluoro-4-hydroxy-7-(3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-2- yl)oxy)methyl)cyclopropyl)methyl)(methyl)amino)hexanoate (Int-035B)145021.598160 (002000.PC)

[0412] To a stirred solution of methyl 6-(((1-(((4-(tert-butoxy)-6,8-difluoro-7-(3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-2- yl)oxy)methyl)cyclopropyl)methyl)(methyl)amino)hexanoate (Int-035A) (55.0 mg, 0.062 mmol) in MeCN (0.62 mL) and water (0.16 mL) was added TFA (16 μL). The resulting mixture was stirred at RT for 4 h, diluted with EtOAc, and then quenched by addition of sat’d NaHCO3. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to give methyl 6-(((1-(((6,8-difluoro-4-hydroxy-7-(3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-2- yl)oxy)methyl)cyclopropyl)methyl)(methyl)amino)hexanoate (Int-035B) (46.2 mg), which was used directly in the next step without further purification. ESI-MS m / z calc’d for C44H58F2N3O6Si [M+H]+: 790; found: 790.

[0413] Step C: Tert-butyl (1S,5R)-3-(6,8-difluoro-2-((1-(((6-methoxy-6- oxohexyl)(methyl)amino)methyl)cyclopropyl)methoxy)-7-(3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-CL035)

[0414] To a stirred solution of methyl 6-(((1-(((6,8-difluoro-4-hydroxy-7-(3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-2- yl)oxy)methyl)cyclopropyl)methyl)(methyl)amino)hexanoate (Int-035B) (46.2 mg) in MeCN (0.59 mL) were added DIPEA (41 μL, 0.23 mmol) and BOP (51.7 mg, 0.117 mmol). The resulting mixture was stirred at RT for 5 min and then tert-butyl (1S,5R)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (19.9 mg, 0.088 mmol) was added. The resulting mixture was heated to 70 °C overnight, cooled to RT, diluted with EtOAc, and then quenched by addition of sat’d NaHCO3. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0-100% EtOAc / hexanes) to give tert-butyl (1S,5R)-3-(6,8- difluoro-2-((1-(((6-methoxy-6-oxohexyl)(methyl)amino)methyl)cyclopropyl)methoxy)-7- (3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-1- methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-CL035) (35.0 mg). ESI-MS m / z calc’d for C56H79F2N5O7Si [(M+2H) / 2]2+: 500; found: 500.

[0415] Int-CL039 was synthesized via a similar route as described in the above synthesis of Int-CL035 by making the appropriate substitutions for the corresponding amine such as using tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate. Appropriate substitutions are available commercially, synthesized as described in the literature,145021.598160 (002000.PC) synthesized using methods available to those skilled in the art, or synthesized as described herein. In Step A, alternatively, LiHMDS may be used as the base.

[0416] Intermediate CL061: Tert-butyl (1S,5R)-3-(6,8-difluoro-2-((1-(((4-methoxy-4- oxobutyl)(methyl)amino)methyl)cyclopropyl)methoxy)-7-(3-(methoxymethoxy)naphthalen- 1-yl)quinazolin-4-yl)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-CL061)

[0417] To a stirred mixture of tert-butyl (1S,5R)-3-(6,8-difluoro-7-(3- (methoxymethoxy)naphthalen-1-yl)-2-((1- ((methylamino)methyl)cyclopropyl)methoxy)quinazolin-4-yl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-009B) (40.0 mg, 0.058 mmol) in DCM (2 mL) were added methyl 4-oxobutanoate (10.1 mg, 0.087 mmol) and NaBH3CN (5.5 mg, 0.087 mmol). The resulting mixture was stirred at RT for 16 h, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (silica gel, 10% MeOH / DCM) to give tert-145021.598160 (002000.PC) butyl (1S,5R)-3-(6,8-difluoro-2-((1-(((4-methoxy-4- oxobutyl)(methyl)amino)methyl)cyclopropyl)methoxy)-7-(3-(methoxymethoxy)naphthalen- 1-yl)quinazolin-4-yl)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-CL061) (24.0 mg). ESI-MS m / z calc’d for C43H54F2N5O7[M+H]+: 790; found: 790.

[0418] Intermediate LE001: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-((1-(((R)- 2,2-difluoro-1-(hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)methoxy)isoxazol-5-yl)- 3-methylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-

[0419] Step A: 5-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazole

[0420] To a solution of 5-methylisoxazol-3-ol (5 g, 50.5 mmol) in DCM (50 mL) was added DHP (7 mL, 77 mmol) and PPTS (1.268 g, 5.05 mmol) at 20 °C, the mixture was stirred at 20 °C for 2 h. LCMS showed starting material was consumed and desired peak was formed. The mixture was diluted with DCM (50 mL), washed with H2O (20 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 30% ethyl acetate in petroleum ether gradient @ 60 mL / min) to give 5-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazole. MS (ESI) [M+H]+: m / z 183.8.145021.598160 (002000.PC)

[0421] Step B: 2-(3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazol-5-yl)acetic acid

[0422] To a solution of 5-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazole (9.3 g, 50.8 mmol) in THF (90 mL) was added dropwise KHMDS (76 mL, 76 mmol, 1 M in THF) at - 66 °C under nitrogen atmosphere, and the reaction mixture was stirred at -66 °C for 0.5 h. Then to the reaction mixture was then bubbled carbon dioxide at -66° C for 1 h., and the mixture was stirred at room temperature (10 °C) for 1 h. LCMS showed starting material was consumed and desired peak was formed. The reaction mixture was quenched by saturated ammonium chloride aqueous solution (120 mL) and extracted with ethyl acetate (100 mL) two times. The aqueous layer was adjusted by aqueous hydrochloric acid solution (1 M) until pH 3 at 0 °C, extracted with DCM / IPA (v / v = 5:1, 250 mL, six times). The combined oaganic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude product 2-(3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazol-5- yl)acetic acid. MS (ESI) [M+H]+: m / z 228.2.

[0423] Step C: Methyl 2-(3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazol-5-yl)acetate

[0424] To a solution of 2-(3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazol-5-yl)acetic acid (4 g, 17.60 mmol) in a mixture of EtOAc (40 mL) and MeOH (40 mL) was added (trimethylsilyl)diazomethane (44 mL, 88 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. TLC (SiO2; petroleum ether: ethyl acetate = 1:1) showed a new spot was observed. The mixture was quenched with saturated NH4Cl solution (30 mL), extracted with EtOAc (2 x 50 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 40% ethyl acetate in petroleum ether gradient @ 40 mL / min) to give methyl 2-(3-((tetrahydro-2H- pyran-2-yl)oxy)isoxazol-5-yl)acetate. MS (ESI) [M+H]+: m / z 242.2.

[0425] Step D: Methyl 3-methyl-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazol-5- yl)butanoate

[0426] To a solution of methyl 2-(3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazol-5-yl)acetate (3.6 g, 14.92 mmol) in DMF (40 mL) was added potassium tert-butoxide (1.842 g, 16.41 mmol) and 2-iodopropane (2.79 g, 16.41 mmol) at 0 °C under N2 atmosphere. The mixture was stirred at 10 °C for 3 h. LCMS showed starting material was consumed and desired peak was formed. The mixture was diluted with EtOAc (150 mL), washed with saturated NH4Cl solution (30 mL), H2O (2 x 30 mL) and brine (40 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give the crude product methyl 3-145021.598160 (002000.PC) methyl-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazol-5-yl)butanoate. MS (ESI) [M+H]+: m / z 284.2.

[0427] Step E: 3-methyl-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazol-5-yl)butanoic acid

[0428] To a solution of methyl 3-methyl-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazol-5- yl)butanoate (800 mg, 2.82 mmol) in MeOH (8 mL) and water (0.8 mL) was added lithium hydroxide monohydrate (592 mg, 14.12 mmol) at 10 °C. The mixture was stirred at 10 °C for 3 h. LCMS showed starting material was consumed and desired peak was formed. The mixture was acidified with aq. HCl (1 M) until pH 3, extracted with DCM / iPrOH (v / v=5:1, 3 x 20 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give the crude product 3-methyl-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazol- 5-yl)butanoic acid. MS (ESI) [M+H]+: m / z 270.2.

[0429] Step F: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(3-methyl-2-(3-((tetrahydro-2H- pyran-2-yl)oxy)isoxazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide

[0430] To a solution of 3-methyl-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazol-5- yl)butanoic acid (368 mg, 1.367 mmol) in DMF (4 mL) was added PyBOP (853 mg, 1.640 mmol), (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (708 mg, 1.640 mmol) and DIEA (0.716 mL, 4.10 mmol) at 11 °C. The mixture was stirred at 11 °C for 2 h. LCMS showed starting material was consumed and desired peak was formed. The mixture was diluted with EtOAc (30 mL), washed with water (2 x 7 mL) and brine (8 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 5% MeOH in DCM gradient @ 30 mL / min) to give (2S,4R)-4- ((tert-butyldimethylsilyl)oxy)-1-(3-methyl-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazol-5- yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. MS (ESI) [M+H]+: m / z 683.3.

[0431] Step G: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-hydroxyisoxazol-5-yl)-3- methylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0432] To a solution of (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(3-methyl-2-(3- ((tetrahydro-2H-pyran-2-yl)oxy)isoxazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (669 mg, 0.980 mmol) in MeOH (7 mL) was added PPTS (738 mg, 2.94 mmol) at 15 °C. The mixture was stirred at 50 °C for 15 h. LCMS showed starting material was consumed and desired peak was formed. The mixture was145021.598160 (002000.PC) cooled, and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 5% MeOH in DCM gradient @ 30 mL / min) to give (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-hydroxyisoxazol-5-yl)-3- methylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. MS (ESI) [M+H]+: m / z 599.3.

[0433] Step H: (2S,4R)-1-(2-(3-((1-(((R)-1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)methoxy)isoxazol-5-yl)-3-methylbutanoyl)-4- ((tert-butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide

[0434] To a mixture of (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-hydroxyisoxazol- 5-yl)-3-methylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (307 mg, 0.513 mmol), (R)-(1-((1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)methanol (Int-A127) (170 mg, 0.523 mmol) and triphenylphosphine (403 mg, 1.538 mmol) in THF (3 mL) was added DIAD (0.299 mL, 1.538 mmol) at 0 °C under N2 atmosphere, and the reaction mixture was stirred at 60 °C for 2 h. LCMS showed starting material was consumed and desired peak was formed. The mixture was cooled, diluted with EtOAc (20 mL), washed with H2O (5 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give the residue. The residue was purified by preparative TLC (SiO2, EtOAc: MeOH = 10:1) to give (2S,4R)- 1-(2-(3-((1-(((R)-1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl)piperidin-4- yl)methoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. MS (ESI) [M+H]+: m / z 906.3.

[0435] Step I: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-((1-(((R)-2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)methoxy)isoxazol-5-yl)-3- methylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int- LE001)

[0436] To a solution of (2S,4R)-1-(2-(3-((1-(((R)-1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)methoxy)isoxazol-5-yl)-3-methylbutanoyl)-4- ((tert-butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (288 mg, 0.318 mmol) in CH2Cl2 (3 mL) was added trichloroborane (3.18 mL, 3.18 mmol, 1 M in DCM) at -78 °C under N2 atmosphere. The mixture was stirred at -78 °C for 1 h. LCMS showed starting material was consumed and desired peak was formed. The mixture was quenched with a mixture of DIEA (2.22 mL) and MeOH (4.44 mL), the145021.598160 (002000.PC) mixture was diluted with DCM (25 mL), washed with H2O (2 x 5 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 5% MeOH in EtOAc gradient @ 30 mL / min) to give (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-((1-(((R)-2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)methoxy)isoxazol-5-yl)-3- methylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int- LE001). MS (ESI) [M / 2+H]+: m / z 409.0.

[0437] Intermediate LE002: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(2-(3-(1- (((R)-2,2-difluoro-1-(hydroxymethyl)cyclopropyl)methyl)piperidin-4- yl)cyclobutyl)acetamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Int-LE002-1 & 2)

[0438] Step A: (2S,4R)-1-((S)-2-(2-(3-(1-(((R)-1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)cyclobutyl)acetamido)-3,3-dimethylbutanoyl)-4- ((tert-butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide

[0439] To a solution of (R)-2-(3-(1-((1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)cyclobutyl)acetic acid (Int-A128) (0.5 g, 1.227 mmol) in DMF (10 mL) was added PyBOP (0.958 g, 1.840 mmol) and DIEA (0.857 mL, 4.91 mmol) at 25 °C. The mixture was stirred at 25 °C for 30 min. Then (2S,4R)-1-((S)-2- amino-3,3-dimethylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (1.003 g, 1.840 mmol) was added to the solution, and the mixture was stirred at 25 °C for 30 min. LCMS showed starting material was consumed and desired peak was formed. The mixture was diluted with EtOAc (20 mL), washed with H2O (2 mL x 3), dried over Na2SO4, filtered and the solvent was evaporated under reduced145021.598160 (002000.PC) pressure to give the crude product. The crude product was purified by silica gel chromatography (DCM: MeOH= 10: 1) to give (2S,4R)-1-((S)-2-(2-(3-(1-(((R)-1- ((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl)piperidin-4-yl)cyclobutyl)acetamido)- 3,3-dimethylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide. MS (ESI) [M+H]+: m / z 934.4.

[0440] Step B: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(2-(3-(1-(((R)-2,2- difluoro-1-(hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)cyclobutyl)acetamido)-3,3- dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0441] To a solution of (2S,4R)-1-((S)-2-(2-(3-(1-(((R)-1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)cyclobutyl)acetamido)-3,3-dimethylbutanoyl)-4- ((tert-butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (210 mg, 0.225 mmol) in DCM (2 mL) was added trichloroborane (2.248 mL, 2.248 mmol) at -78 °C. The mixture was stirred at -78 °C for 1 h. LCMS showed starting material was consumed and desired MS was formed. The mixture was quenched with (N- ethyl-N-isopropylpropan-2-amine (1.570 mL, 8.99 mmol) dissolved in MeOH (0.785 mL)). The mixture was extracted with DCM (5 mL). The organic phase was dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The residue was purified by preparative TLC (SiO2, DCM: MeOH= 10: 1) to give racemic (2S,4R)-4-((tert- butyldimethylsilyl)oxy)-1-((S)-2-(2-(3-(1-(((R)-2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)cyclobutyl)acetamido)-3,3- dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. MS (ESI) [M+H]+: m / z 844.5.

[0442] Step C: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(2-(3-(1-(((R)-2,2- difluoro-1-(hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)cyclobutyl)acetamido)-3,3- dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int- LE002-1 & 2)

[0443] The racemic (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(2-(3-(1-(((R)-2,2- difluoro-1-(hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)cyclobutyl)acetamido)-3,3- dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (180 mg, 0.213 mmol) was separated by preparative SFC (Column DAICEL CHIRALPAK IE (250 mm * 30 mm, 10 um) Condition CO2-EtOH (0.1% NH3H2O) Begin B 55% End B 55% Gradient Time (min) 40100% B Hold Time 40 Flow Rate (mL / min) 100) to give (2S,4R)- 4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(2-(3-(1-(((R)-2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)cyclobutyl)acetamido)-3,3-145021.598160 (002000.PC) dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int- LE002-1, the first eluting isomer) and (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(2- (3-(1-(((R)-2,2-difluoro-1-(hydroxymethyl)cyclopropyl)methyl)piperidin-4- yl)cyclobutyl)acetamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Int-LE002-2, the second eluting isomer). MS (ESI) [M+H]+: m / z 844.5. Synthesis of Examples

[0444] Example 1: (((7-(8-ethynyl-3-hydroxynaphthalen-1-yl)-6,8-difluoro-4-( - [3.2.1]octan-3-yl)quinazolin-2-yl)oxy)methyl)- methyl)(methyl)amino)heptanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Ex.1)145021.598160 (002000.PC)

[0445] Step A: 7-((((1R)-1-(((4-((1S,5R)-8-(tert-butoxycarbonyl)-1-methyl-3,8- diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-7-(3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)(methyl)amino)heptanoic acid (Int-001A)

[0446] To a stirred solution of tert-butyl (1S,5R)-3-(2-(((R)-2,2-difluoro-1-(((7-methoxy-7- oxoheptyl)(methyl)amino)methyl)cyclopropyl)methoxy)-6,8-difluoro-7-(3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-1-methyl- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-CL001) (162 mg, 0.155 mmol) in THF (2.2 mL), MeOH (0.8 mL), and water (2.2 mL) was added NaOH (2.0 M in water, 686 μL, 1.37 mmol). The resulting mixture was stirred at RT overnight and then quenched by addition of HCl (1 M in water) until pH < 4. The aqueous layer was extracted with EtOAc145021.598160 (002000.PC) (3x). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give 7-((((1R)-1-(((4-((1S,5R)-8-(tert-butoxycarbonyl)-1-methyl-3,8- diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-7-(3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)(methyl)amino)heptanoic acid (Int-001A), which was used directly in the next step without further purification. ESI-MS m / z calc’d for C56H76F4N5O7Si [M+H]+: 1035; found: 1035.

[0447] Step B: Tert-butyl (1S,5R)-3-(2-(((R)-2,2-difluoro-1-(((7-(((S)-1-((2S,4R)-4- hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)-7-oxoheptyl)(methyl)amino)methyl)cyclopropyl)methoxy)-6,8- difluoro-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin- 4-yl)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate 001B)

[0448] To a stirred solution of 7-((((1R)-1-(((4-((1S,5R)-8- -1-methyl- 3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-7-(3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)(methyl)amino)heptanoic acid (Int-001A), (2S,4R)-1-((S)-2- amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (80.0 mg, 0.186 mmol) in DMF (3.1 mL) were added HATU (88.0 mg, 0.232 mmol) and DIPEA (270 μL, 1.55 mmol). The resulting mixture was stirred at RT for 1 h and then purified by reverse-phase preparative HPLC (C18, MeCN / water with 0.05% TFA modifier) to give tert-butyl (1S,5R)-3-(2-(((R)-2,2-difluoro-1-(((7-(((S)-1-((2S,4R)-4- hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)-7-oxoheptyl)(methyl)amino)methyl)cyclopropyl)methoxy)-6,8- difluoro-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin- 4-yl)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-001B) (209 mg). ESI-MS m / z calc’d for C78H105F4N9O9SSi [(M+2H) / 2]2+: 724; found: 724.

[0449] Step C: Tert-butyl (1S,5R)-3-(2-(((R)-2,2-difluoro-1-(((7-(((S)-1-((2S,4R)-4- hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)-7-oxoheptyl)(methyl)amino)methyl)cyclopropyl)methoxy)-7-(8- ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-

[0450] To a stirred solution of tert-butyl - (((R)-2,2-difluoro-1-(((7-(((S)-1- ((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2-yl)amino)-7-145021.598160 (002000.PC) oxoheptyl)(methyl)amino)methyl)cyclopropyl)methoxy)-6,8-difluoro-7-(3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-1-methyl- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-001B) (209 mg, 0.134 mmol) in DMF (5.4 mL) was added CsF (71.2 mg, 0.469 mmol). The resulting mixture was stirred at RT for 18 h and then purified by reverse-phase preparative HPLC (C18, MeCN / water with 0.05% TFA modifier) to give tert-butyl (1S,5R)-3-(2-(((R)-2,2-difluoro-1-(((7-(((S)-1-((2S,4R)-4- hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)-7-oxoheptyl)(methyl)amino)methyl)cyclopropyl)methoxy)-7-(8- ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-001C) (188 mg). ESI-MS m / z calc’d for C69H84F4N9O9S [(M+H)]+: 1291; found: 1291.

[0451] Step D: -1-(((7-(8-ethynyl-3-hydroxynaphthalen-1-yl)-6,8-difluoro-4-( - [3.2.1]octan-3-yl)quinazolin-2- yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)(methyl)amino)heptanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Ex.1)

[0101] To a stirred solution of tert-butyl (1S,5R)-3-(2-(((R)-2,2-difluoro-1-(((7-(((S)-1- ((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2-yl)amino)-7- oxoheptyl)(methyl)amino)methyl)cyclopropyl)methoxy)-7-(8-ethynyl-3- (methoxymethoxy)naphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-001C) (188 mg, 0.134 mmol) in iPrOH (1.7 mL) was added HCl (4 M in dioxane, 1.67 mL, 6.69 mmol). The resulting mixture was stirred at RT for 4 h and then diluted with Et2O. The precipitate was collected by filtration and then solubilized with MeOH. The organic layer was concentrated in vacuo. The residue was purified by reverse-phase preparative HPLC (C18, MeCN / water with 0.05% TFA modifier) to give (2S,4R)-1-((2S)-2-(7-((((1R)-1-(((7-(8-ethynyl-3-hydroxynaphthalen-1-yl)- 6,8-difluoro-4-((1S,5R)-1-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)quinazolin-2- yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)(methyl)amino)heptanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Ex.1) (48.0 mg). A sample of this material was re-purified with a 10 mM NH4HCO3 modifier for characterization.1H NMR (400 MHz, CD3OD) į 8.92 – 8.84 (m, 1H), 8.63 (t, J = 5.7 Hz, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.76 (br d, J = 8.8 Hz, 1H), 7.61 (br d, J = 9.7 Hz, 1H), 7.51 (d, J = 6.9 Hz, 1H), 7.48 – 7.44 (m, 2H), 7.43 – 7.38 (m, 3H), 7.34145021.598160 (002000.PC) (d, J = 2.5 Hz, 1H), 7.07 (d, J = 2.6 Hz, 1H), 4.64 – 4.46 (m, 6H), 4.39 – 4.23 (m, 3H), 3.92 – 3.77 (m, 4H), 3.62 (br d, J = 14.2 Hz, 2H), 3.00 (d, J = 8.3 Hz, 4H), 2.50 – 2.43 (m, 3H), 2.42 – 1.72 (m, 14H), 1.66 – 1.51 (m, 5H), 1.42 – 1.27 (m, 5H), 1.01 (s, 9H). ESI-MS m / z calc’d for C62H72F4N9O6S [M+H]+: 1147; found: 1147.

[0452] Compounds in the table below were synthesized via a similar route as described in the above synthesis of Ex.1 by making the appropriate substitutions. Appropriate substitutions are available commercially, synthesized as described in the literature, synthesized using methods available to those skilled in the art, or synthesized as described herein. If the corresponding acid is obtained in an earlier step, Step A may be skipped. In Step B, alternatively, MeCN may be used as the solvent. In Step C, alternatively, TBAF may be used as the reagent. Alternatively, Step C and Step D may be reversed.145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)

[0453] Example 19: (2S,4R)-1-((2S)-2-(3-(3-((((1R)-1-(((7-(8-ethynyl-3- hydroxynaphthalen-1-yl)-6,8-difluoro-4-((1S,5R)-1-methyl-3,8-diazabicyclo[3.2.1]octan-3- yl)quinazolin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)(methyl)amino)propoxy)propanamido)-3,3-dimethylbutanoyl)- 4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Ex.19)

[0454] Step C: Tert-butyl (1S,5R)-3-(2-(((R)-2,2-difluoro-1- ((methylamino)methyl)cyclopropyl)methoxy)-6,8-difluoro-7-(3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-

[0455] To a stirred solution of tert-butyl - (((R)-1- ((((benzyloxy)carbonyl)(methyl)amino)methyl)-2,2-difluorocyclopropyl)methoxy)-6,8-145021.598160 (002000.PC) difluoro-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin- 4-yl)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-008B) (1.00 g, 0.961 mmol) in DCM (10 mL) were added triethylsilane (2.24 g, 19.2 mmol), NEt3 (0.41 mL, 2.9 mmol), and PdCl2(392 mg, 2.21 mmol). The resulting mixture was stirred at RT for 18 h and then filtered. The resulting mixture was diluted with MeOH, stirred for 20 min, and then quenched by addition of NEt3until pH = 7. The resulting mixture was diluted with water. The organic layer was separated, and the aqueous layer was extracted with DCM (3x). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (silica gel, 5% MeOH / DCM) to give tert-butyl (1S,5R)-3-(2-(((R)-2,2-difluoro-1-((methylamino)methyl)cyclopropyl)methoxy)- 6,8-difluoro-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1- yl)quinazolin-4-yl)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-008C) (400 mg). ESI-MS m / z calc’d for C49H64F4N5O5Si [M+H]+: 906; found: 906.

[0456] Step D: Tert-butyl (1S,5R)-3-(2-(((R)-2,2-difluoro-1-(((3-(3-(((S)-1-((2S,4R)-4- hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)-3-oxopropoxy)propyl)(methyl)amino)methyl)cyclopropyl)methoxy)- 6,8-difluoro-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1- yl)quinazolin-4-yl)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-001D)

[0457] To a stirred solution of tert-butyl (1S,5R)-3-(2-(((R)-2,2-difluoro-1- ((methylamino)methyl)cyclopropyl)methoxy)-6,8-difluoro-7-(3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-008C) (300 mg, 0.331 mmol) in MeCN (10 mL) were added (2S,4R)-4-hydroxy-1-((S)-2-(3-(3-iodopropoxy)propanamido)-3,3- dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-H02) (666 mg, 0.993 mmol) and K2CO3(137 mg, 0.993 mmol). The resulting mixture was heated to 90 °C for 18 h, cooled to RT, and then concentrated in vacuo. The residue was purified by preparative HPLC (C18, MeCN / water with 0.01% TFA modifier) to give tert-butyl (1S,5R)-3-(2-(((R)-2,2-difluoro-1-(((3-(3-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- yl)amino)-3-oxopropoxy)propyl)(methyl)amino)methyl)cyclopropyl)methoxy)-6,8- difluoro-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin- 4-yl)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-001D) (206 mg). ESI-MS m / z calc’d for C77H103F4N9O10SSi [(M+2H) / 2]2+: 725; found: 725.145021.598160 (002000.PC)

[0458] Step E: Tert-butyl (1S,5R)-3-(2-(((R)-2,2-difluoro-1-(((3-(3-(((S)-1-((2S,4R)-4- hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2-yl) -3-oxopropoxy)propyl)(methyl) methyl)cyclopropyl)methoxy)-7-(8-ethynyl- naphthalen-1-yl)- 4-yl)-1-methyl- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-

[0459] To a stirred solution of tert-butyl (1S,5R)- (R)-2,2-difluoro-1-(((3-(3-(((S)-1- ((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2-yl)amino)-3- oxopropoxy)propyl)(methyl)amino)methyl)cyclopropyl)methoxy)-6,8-difluoro-7-(3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-1-methyl- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-001D) (160 mg, 0.110 mmol) in DMF (4 mL) was added CsF (50.3 mg, 0.331 mmol). The resulting mixture was stirred at RT for 18 h and then quenched by addition of water. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine (3x), dried over Na2SO4, filtered, and concentrated in vacuo to give tert-butyl (1S,5R)-3-(2-(((R)-2,2-difluoro-1-(((3- (3-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1- yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3- oxopropoxy)propyl)(methyl)amino)methyl)cyclopropyl)methoxy)-7-(8-ethynyl-3- (methoxymethoxy)naphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-001E) (140 mg), which was used directly in the next step without further purification. ESI-MS m / z calc’d for C68H83F4N9O10S [(M+2H) / 2]2+: 647; found: 647.

[0460] Step F: -1-(((7-(8-ethynyl-3-hydroxynaphthalen-1-yl)-6,8- - [3.2.1]octan-3-yl)quinazolin-2-yl)oxy)methyl)- methyl)(methyl)amino)propoxy)propanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Ex.19)

[0461] To a stirred solution of tert-butyl (1S,5R)-3-(2-(((R)-2,2-difluoro-1-(((3-(3-(((S)-1- ((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2-yl)amino)-3- oxopropoxy)propyl)(methyl)amino)methyl)cyclopropyl)methoxy)-7-(8-ethynyl-3- (methoxymethoxy)naphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-001E) (130 mg, 0.082 mmol) in iPrOH (1 mL) was added HCl (4 M in dioxane, 1.00 mL, 4.00 mmol). The resulting mixture was145021.598160 (002000.PC) stirred at RT for 1 h and then quenched with sat’d NaHCO3. The organic layer was concentrated in vacuo. The residue was purified by reverse-phase preparative HPLC (C18, MeCN / water with 10 mM NH4HCO2 modifier) to give (2S,4R)-1-((2S)-2-(3-(3-((((1R)-1- (((7-(8-ethynyl-3-hydroxynaphthalen-1-yl)-6,8-difluoro-4-((1S,5R)-1-methyl-3,8- diazabicyclo[3.2.1]octan-3-yl)quinazolin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)(methyl)amino)propoxy)propanamido)-3,3-dimethylbutanoyl)- 4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Ex.19) (40 mg).1H NMR (500 MHz, CD3OD) į 8.86 (s, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.50 – 7.44 (m, 4H), 7.41 – 7.34 (m, 3H), 7.30 (d, J = 2.6 Hz, 1H), 7.07 (d, J = 2.6 Hz, 1H), 4.63 – 4.60 (m, 2H), 4.58 – 4.53 (m, 2H), 4.52 – 4.48 (m, 2H), 4.44 (br d, J = 13.4 Hz, 1H), 4.37 – 4.31 (m, 2H), 3.87 (br d, J = 10.8 Hz, 1H), 3.78 (br dd, J = 4.0, 11.1 Hz, 1H), 3.63 (br d, J = 6.9 Hz, 1H), 3.59 – 3.56 (m, 1H), 3.52 (br d, J = 11.9 Hz, 2H), 3.45 – 3.39 (m, 4H), 3.37 (br s, 2H), 3.00 – 2.96 (m, 1H), 2.86 (br d, J = 10.7 Hz, 1H), 2.48 (br d, J = 2.9 Hz, 1H), 2.46 (s, 5H), 2.39 – 2.34 (m, 1H), 2.24 – 2.17 (m, 4H), 2.09 – 2.03 (m, 1H), 1.98 (br d, J = 12.1 Hz, 1H), 1.93 – 1.83 (m, 2H), 1.71 (quin, J = 6.8 Hz, 2H), 1.63 (br s, 1H), 1.55 – 1.48 (m, 1H), 1.33 (s, 4H), 1.01 – 0.97 (m, 9H). ESI-MS m / z calc’d for C61H70F4N9O7S [M+H]+: 1149; found: 1149.

[0462] Example 20: -1-((2S)-2-(3-(3-(((1-(((6,8-difluoro-7-(3-hydroxynaphthalen-1-yl)-4-((1S,5R)-1- diazabicyclo[3.2.1]octan-3-yl)quinazolin-2- yl)oxy)methyl)cyclopropyl)methyl)(methyl)amino)propoxy)propanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Ex.20)145021.598160 (002000.PC)((((benzyloxy)carbonyl)(methyl)amino)methyl)cyclopropyl)methoxy)-6,8-difluoro-7-(3- (methoxymethoxy)naphthalen-1-yl)quinazolin-4-yl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-009A)

[0464] To a stirred solution of tert-butyl (1S,5R)-3-(2-chloro-6,8-difluoro-7-(3- (methoxymethoxy)naphthalen-1-yl)quinazolin-4-yl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-C04) (3.00 g, 4.91 mmol) in DMSO (50 mL) at 15 °C were added CsF (2.98 g, 19.6 mmol) and benzyl ((1- (hydroxymethyl)cyclopropyl)methyl)(methyl)carbamate (Int-A027) (1.22 g, 4.91 mmol). The resulting mixture was stirred at 15 °C for 2 min and then heated to 90 °C for 16 h. The resulting mixture was concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0-30% EtOAc / pet. ether) to give tert-butyl (1S,5R)-3-(2-((1- ((((benzyloxy)carbonyl)(methyl)amino)methyl)cyclopropyl)methoxy)-6,8-difluoro-7-(3- (methoxymethoxy)naphthalen-1-yl)quinazolin-4-yl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-009A) (3.00 g). ESI-MS m / z calc’d for C46H52F2N5O7 [M+H]+: 824; found: 824.145021.598160 (002000.PC)

[0465] Step B: Tert-butyl (1S,5R)-3-(6,8-difluoro-7-(3-(methoxymethoxy)naphthalen-1- yl)-2-((1-((methylamino)methyl)cyclopropyl)methoxy)quinazolin-4-yl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-009B)

[0466] To a stirred solution of tert-butyl (1S,5R)-3-(2-((1- ((((benzyloxy)carbonyl)(methyl)amino)methyl)cyclopropyl)methoxy)-6,8-difluoro-7-(3- (methoxymethoxy)naphthalen-1-yl)quinazolin-4-yl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-009A) (100 mg, 0.121 mmol) in DCM (2 mL) were added triethylsilane (282 mg, 2.43 mmol), NEt3(37.0 mg, 0.364 mmol), and PdCl2(4.3 mg, 0.024 mmol). The resulting mixture was stirred at RT for 1 h and then filtered. The resulting mixture was diluted with MeOH, stirred for 20 min and then concentrated in vacuo to give tert-butyl (1S,5R)-3-(6,8-difluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((1- ((methylamino)methyl)cyclopropyl)methoxy)quinazolin-4-yl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-009B) (84 mg). ESI-MS m / z calc’d for C38H46F2N5O5 [M+H]+: 690; found: 690.

[0467] Step C: Tert-butyl (1S,5R)-3-(6,8-difluoro-2-((1-(((3-(3-(((S)-1-((2S,4R)-4-hydroxy- 2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- yl)amino)-3-oxopropoxy)propyl)(methyl)amino)methyl)cyclopropyl)methoxy)-7-(3- (methoxymethoxy)naphthalen-1-yl)quinazolin-4-yl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-

[0468] To a stirred solution of tert-butyl - difluoro-7-(3- (methoxymethoxy)naphthalen-1-yl)-2-((1- ((methylamino)methyl)cyclopropyl)methoxy)quinazolin-4-yl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-009B) (84.0 mg, 0.122 mmol) in MeCN (2 mL) were added (2S,4R)-4-hydroxy-1-((S)-2-(3-(3-iodopropoxy)propanamido)-3,3- dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-H02) (110 mg, 0.164 mmol) and K2CO3 (68.0 mg, 0.492 mmol). The resulting mixture was heated to 90 °C for 15 h, cooled to RT, and then concentrated in vacuo. The residue was purified by preparative TLC (silica gel, 10% MeOH / DCM) to give tert-butyl (1S,5R)-3- (6,8-difluoro-2-((1-(((3-(3-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3- oxopropoxy)propyl)(methyl)amino)methyl)cyclopropyl)methoxy)-7-(3- (methoxymethoxy)naphthalen-1-yl)quinazolin-4-yl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-009C) (70.3 mg). ESI-MS m / z calc’d for C66H85F2N9O10S [(M+2H) / 2]2+: 617; found: 617.145021.598160 (002000.PC)

[0469] Step D: (2S,4R)-1-((2S)-2-(3-(3-(((1-(((6,8-difluoro-7-(3-hydroxynaphthalen-1-yl)- 4-((1S,5R)-1-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)quinazolin-2- yl)oxy)methyl)cyclopropyl)methyl)(methyl)amino)propoxy)propanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Ex.20)

[0470] To a stirred solution of tert-butyl (1S,5R)-3-(6,8-difluoro-2-((1-(((3-(3-(((S)-1- ((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2-yl)amino)-3- oxopropoxy)propyl)(methyl)amino)methyl)cyclopropyl)methoxy)-7-(3- (methoxymethoxy)naphthalen-1-yl)quinazolin-4-yl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-009C) (20 mg, 0.016 mmol) in iPrOH (0.2 mL) was added HCl (4 M in EtOAc, 0.30 mL, 1.2 mmol). The resulting mixture was stirred at RT for 1 h and then concentrated in vacuo. The residue was purified by preparative HPLC (C18, MeCN / water with 0.1% TFA modifier) to give (2S,4R)-1-((2S)-2-(3-(3-(((1- (((6,8-difluoro-7-(3-hydroxynaphthalen-1-yl)-4-((1S,5R)-1-methyl-3,8- diazabicyclo[3.2.1]octan-3-yl)quinazolin-2- yl)oxy)methyl)cyclopropyl)methyl)(methyl)amino)propoxy)propanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Ex.20) (16 mg). ESI-MS m / z calc’d for C59H73F2N9O7S [(M+2H) / 2]2+: 545; found: 545.

[0471] Compounds in the table below were synthesized via a similar route as described in the above synthesis of Ex.20 by making the appropriate substitutions. Appropriate substitutions are available commercially, synthesized as described in the literature, synthesized using methods available to those skilled in the art, or synthesized as described herein. In Step D, alternatively, TFA may be used as a deprotecting agent and DCM as the solvent. Steps A and B may be skipped if the intermediate is accessible through other means.145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)

[0472] Representative NMR spectra are provided below.145021.598160 (002000.PC)

[0473] Ex.21

[0474] 1H NMR (500 MHz, CD3OD) į 8.87 – 8.85 (m, 1H), 7.76 – 7.72 (m, 1H), 7.65 – 7.61 (m, 1H), 7.46 – 7.35 (m, 7H), 7.28 – 7.20 (m, 2H), 7.14 – 7.11 (m, 1H), 4.61 – 4.31 (m, 10H), 3.92 – 3.86 (m, 1H), 3.81 – 3.76 (m, 1H), 3.63 – 3.53 (m, 2H), 2.54 – 2.43 (m, 7H), 2.36 – 2.31 (m, 3H), 2.24 – 2.14 (m, 3H), 2.11 – 2.03 (m, 1H), 1.99 – 1.88 (m, 2H), 1.85 – 1.78 (m, 1H), 1.54 – 1.44 (m, 5H), 1.38 – 1.20 (m, 8H), 1.02 – 0.97 (m, 9H), 0.74 – 0.69 (m, 2H), 0.54 – 0.49 (m, 1H), 0.50 – 0.49 (m, 1H).

[0475] Ex.22

[0476] 1H NMR (400 MHz, CD3OD) į 8.90 (d, J = 3.1 Hz, 1H), 8.62 (s, 1H), 7.79 – 7.72 (m, 2H), 7.47 – 7.43 (m, 2H), 7.42 – 7.38 (m, 2H), 7.35 (br s, 1H), 7.30 (s, 1H), 7.24 (br d, J = 7.2 Hz, 1H), 7.12 (br s, 1H), 4.69 (br d, J = 12.4 Hz, 1H), 4.61 – 4.49 (m, 6H), 4.37 (s, 2H), 4.28 (br s, 1H), 3.87 (s, 1H), 3.82 – 3.68 (m, 3H), 3.50 – 3.44 (m, 1H), 3.19 (br s, 1H), 3.13 (t, J = 1.7 Hz, 2H), 2.97 (br s, 3H), 2.46 (s, 3H), 2.31 – 2.17 (m, 6H), 2.09 (br d, J = 8.1 Hz, 1H), 1.91 (br s, 1H), 1.77 (br s, 2H), 1.61 (s, 5H), 1.43 – 1.28 (m, 3H), 1.01 – 0.83 (m, 13H).

[0477] Ex.23

[0478] 1H NMR (400 MHz, CD3OD) į 8.92 – 8.85 (m, 1H), 7.76 (br d, J = 7.0 Hz, 1H), 7.62 (br d, J = 9.5 Hz, 1H), 7.48 – 7.36 (m, 5H), 7.36 – 7.31 (m, 2H), 7.07 (s, 1H), 4.64 – 4.44 (m, 8H), 4.43 – 4.32 (m, 2H), 4.25 (br s, 1H), 3.91 – 3.76 (m, 3H), 3.74 – 3.56 (m, 7H), 3.55 – 3.44 (m, 1H), 3.01 – 2.92 (m, 3H), 2.49 – 2.44 (m, 5H), 2.35 (br s, 1H), 2.30 – 1.99 (m, 7H), 1.91 (br s, 1H), 1.61 (s, 3H), 0.98 (br d, J = 6.2 Hz, 11H), 0.89 (br s, 2H).

[0479] Ex.27

[0480] 1H NMR (400 MHz, CD3OD) į 8.97 – 8.81 (m, 1H), 8.47 – 8.38 (m, 1H), 7.94 – 7.84 (m, 1H), 7.78 – 7.69 (m, 1H), 7.50 – 7.32 (m, 6H), 7.27 – 7.18 (m, 1H), 7.16 – 7.09 (m, 1H), 4.16 – 4.05 (m, 3H), 3.96 – 3.85 (m, 3H), 3.81 – 3.58 (m, 7H), 3.49 – 3.45 (m, 1H), 3.00 – 2.91 (m, 3H), 2.50 – 2.42 (m, 3H), 2.40 – 1.96 (m, 9H), 1.86 – 1.64 (m, 5H), 1.60 – 1.51 (m, 3H), 1.39 – 1.27 (m, 2H), 1.18 – 0.71 (m, 13H).

[0481] Ex.28145021.598160 (002000.PC)

[0482] 1H NMR (400MHz, CD3OD) į = 8.88 (d, J = 13.6 Hz, 1H), 7.75 – 7.63 (m, 4H), 7.48 – 7.45 (m, 2H), 7.44 – 7.38 (m, 4H), 7.29 – 7.23 (m, 2H), 7.17 (br d, J = 10.4 Hz, 1H), 7.10 (br d, J = 5.6 Hz, 1H), 6.87 – 6.77 (m, 2H), 4.65 – 4.53 (m, 5H), 4.49 (s, 2H), 4.34 (br d, J = 15.3 Hz, 1H), 4.25 – 4.18 (m, 2H), 4.09 – 3.98 (m, 2H), 3.95 – 3.87 (m, 2H), 3.77 – 3.62 (m, 1H), 3.50 – 3.39 (m, 1H), 3.06 (br s, 3H), 2.49 – 2.41 (m, 5H), 2.28 – 2.17 (m, 3H), 2.14 – 2.01 (m, 3H), 1.88 (br d, J = 10.0 Hz, 1H), 1.58 (s, 3H), 1.53 – 1.48 (m, 1H), 1.47 (s, 1H), 1.17 – 0.98 (m, 12H), 0.94 (br s, 2H).

[0483] Example 31: -1-(((7-(2-amino-3-cyano-7-fluorobenzo[b] - octan-3-yl)-6-chloro-8- fluoroquinazolin-2- methyl)-2,2-difluorocyclopropyl)methyl)-3-azaspiro[5.5] acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-145021.598160 (002000.PC)

[0484] Step A: 2-(3-(((1R)-1-(((4-(8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3- yl)-7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-8- fluoroquinazolin-2-yl) methyl)-2,2-difluorocyclopropyl)methyl)-3-azaspiro[5.5]undecan- acetic acid (Int-

[0485] To a stirred solution of tert-butyl (tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-6-chloro-2-(((R)-2,2-difluoro-1-((9-(2-methoxy-2-oxoethyl)- 3-azaspiro[5.5]undecan-3-yl)methyl)cyclopropyl)methoxy)-8-fluoroquinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-CL010) (90 mg, 0.088 mmol) in THF (1 mL), MeOH (0.5 mL), and water (0.5 mL) was added NaOH (1.0 M in water, 263 μL, 0.263 mmol). The resulting mixture was heated to 40 °C for 2 h, cooled to RT, and then the organic layer was concentrated in vacuo. The residue was diluted with water and quenched by addition of HCl (1 M in water) until pH < 4. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give 2-(3-(((1R)-1-(((4-(8-(tert-butoxycarbonyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)-7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoroquinazolin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)-3-azaspiro[5.5]undecan-9-yl)acetic acid (Int-010A), which was used directly in the next step without further purification. ESI-MS m / z calc’d for C50H59ClF4N7O7S [M+H]+: 1012; found: 1012.

[0486] Step B: Tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-6-chloro-2-(((R)-2,2-difluoro-1-((9-(2-(((S)-1-((2S,4R)-4- hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)-2-oxoethyl)-3-azaspiro[5.5]undecan-3- yl)methyl)cyclopropyl)methoxy)-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-

[0487] To a of 2-(3-(((1R)-1-(((4-(8-(tert-butoxycarbonyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)-7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoroquinazolin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)-3-azaspiro[5.5]undecan-9-yl)acetic acid (Int-010A) in MeCN (1.7 mL) was added HATU (66.7 mg, 0.175 mmol). After stirring for 10 min, to the resulting mixture was added (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N- (4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (75 mg, 0.175 mmol) and DIPEA (122 μL, 0.701 mmol). The resulting mixture was stirred at RT for 1 h and then purified by reverse-phase preparative HPLC (C18, MeCN / water with 0.05% TFA modifier)145021.598160 (002000.PC) to give tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen- 4-yl)-6-chloro-2-(((R)-2,2-difluoro-1-((9-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4- methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- yl)amino)-2-oxoethyl)-3-azaspiro[5.5]undecan-3-yl)methyl)cyclopropyl)methoxy)-8- fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-010B) (82 mg). ESI-MS m / z calc’d for C72H88ClF4N11O9S2[(M+2H) / 2]+: 713; found: 713.

[0488] Step C: (2S,4R)-1-((2S)-2-(2-(3-(((1R)-1-(((7-(2-amino-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8- fluoroquinazolin-2-yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)-3- azaspiro[5.5]undecan-9-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Ex.31)

[0489] To a stirred solution of tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-6-chloro-2-(((R)-2,2-difluoro-1-((9-(2-(((S)-1-((2S,4R)-4- hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)-2-oxoethyl)-3-azaspiro[5.5]undecan-3- yl)methyl)cyclopropyl)methoxy)-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-010B) (82 mg, 0.058 mmol) in DCM (0.50 mL) was added TFA (222 uL, 2.88 mmol). The resulting mixture was stirred at RT for 2 h and then concentrated in vacuo. The residue was purified by reverse-phase preparative HPLC (C18, MeCN / water with 0.05% TFA modifier) to give (2S,4R)-1-((2S)-2-(2-(3-(((1R)-1-(((7-(2-amino-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8- fluoroquinazolin-2-yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)-3- azaspiro[5.5]undecan-9-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Ex.31) (64.0 mg). ESI-MS m / z calc’d for C62H72ClF4N11O5S2[(M+2H) / 2]2+: 613; found: 613.

[0490] Compounds in the table below were synthesized via a similar route as described in the above synthesis of Ex.31 by making the appropriate substitutions. Appropriate substitutions are available commercially, synthesized as described in the literature, synthesized using methods available to those skilled in the art, or synthesized as described herein. In Step A, alternatively, LiOH (in water) or aluminum hydroxide hydrate may be used as the base and dioxane as the solvent. If the corresponding acid is obtained in an earlier step, Step A may be skipped. In Step B, alternatively, (2S,4R)-1-((S)-2-amino-3,3- dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-145021.598160 (002000.PC) carboxamide, (2S,4R)-1-((S)-2-amino-3-cyclobutylpropanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide, (2S,4R)-1-((S)-2-amino-2- cyclopentylacetyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide, (2S,4R)-1-((S)-2-amino-2-(tetrahydro-2H-pyran-4-yl)acetyl)-4-hydroxy-N-(4- (4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide, (2S,4R)-1-((S)-2-amino-3- cyclopropylpropanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide, (2S,4R)-1-(L-valyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2- hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide, or (2S,4R)-1-(L-valyl)-4-hydroxy-N- ((R)-2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide may be used as the amine, PyAOP or PyBOP may be used as a coupling agent, and DMF as the solvent. If containing a mixture of isomers, this intermediate may be further separated by chiral SFC. In Step C, alternatively, HCl may be used as a deprotecting agent and DCE as the solvent. The final compound, if containing a mixture of isomers, may be further separated by chiral SFC.145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)

[0491] Representative NMR spectra are provided below.145021.598160 (002000.PC)

[0492] Ex.45

[0493] 1H NMR (400 MHz, CD3OD) į 8.86 (s, 1H), 7.85 (s, 1H), 7.48 – 7.43 (m, 2H), 7.43 – 7.38 (m, 2H), 7.19 (dd, J = 5.01, 8.34 Hz, 1H), 7.02 (t, J = 8.94 Hz, 1H), 4.61 – 4.47 (m, 6H), 4.43 (br d, J = 11.80 Hz, 2H), 4.34 (d, J = 15.50 Hz, 1H), 3.90 – 3.84 (m, 1H), 3.81 – 3.75 (m, 1H), 3.68 – 3.56 (m, 4H), 3.43 – 3.36 (m, 2H), 3.28 (s, 2H), 2.79 (s, 2H), 2.46 (s, 3H), 2.36 – 2.16 (m, 6H), 2.07 (dt, J = 4.59, 8.85 Hz, 1H), 1.88 – 1.82 (m, 5H), 1.60 – 1.52 (m, 1H), 1.43 (br dd, J = 3.64, 12.34 Hz, 1H), 1.29 (s, 2H), 1.01 (s, 8H).

[0494] Ex.48

[0495] 1H NMR (400 MHz, CD3OD) į 8.95 – 8.82 (m, 1H), 7.81 – 7.68 (m, 2H), 7.13 (s, 8H), 4.69 – 4.16 (m, 11H), 3.48 (br s, 6H), 3.23 – 2.89 (m, 5H), 2.65 – 2.42 (m, 5H), 2.38 – 1.78 (m, 9H), 1.69 – 1.52 (m, 3H), 1.11 – 0.73 (m, 13H).

[0496] Ex.50

[0497] 1H NMR (400 MHz, CD3OD) į 8.86 (s, 1H), 8.11 (s, 1H), 7.49 – 7.37 (m, 4H), 7.21 (dd, J = 8.2, 4.8 Hz, 1H), 7.06 – 6.96 (m, 1H), 4.61 – 4.52 (m, 7H), 4.49 (br s, 1H), 4.42 (br d, J = 11.2 Hz, 1H), 4.34 (d, J = 15.4 Hz, 1H), 3.89 (br d, J = 11.4 Hz, 1H), 3.83 – 3.70 (m, 2H), 3.63 (br d, J = 11.6 Hz, 3H), 2.80 (br d, J = 13.1 Hz, 1H), 2.51 (br d, J = 12.4 Hz, 1H), 2.47 – 2.43 (m, 3H), 2.43 – 2.30 (m, 2H), 2.23 (s, 3H), 2.21 – 2.03 (m, 4H), 1.90 – 1.71 (m, 4H), 1.64 (br s, 1H), 1.51 – 1.39 (m, 4H), 1.31 – 1.20 (m, 4H), 1.00 (s, 9H).

[0498] Ex.53

[0499] 1H NMR (400MHz, CD3OD) į 8.88 (s, 1H), 7.87 (d, J = 1.19 Hz, 1H), 7.49 – 7.45 (m, 2H), 7.44 – 7.40 (m, 2H), 7.21 (dd, J = 5.13, 8.34 Hz, 1H), 7.07 – 7.00 (m, 1H), 4.62 – 4.55 (m, 4H), 4.54 – 4.49 (m, 2H), 4.46 – 4.41 (m, 2H), 4.36 (d, J = 15.50 Hz, 1H), 3.93 – 3.87 (m, 1H), 3.83 – 3.78 (m, 1H), 3.67 (br d, J = 12.76 Hz, 1H), 3.64 – 3.58 (m, 3H), 3.36 (s, 2H), 3.26 (s, 2H), 2.78 (s, 2H), 2.48 (s, 3H), 2.25 – 2.16 (m, 5H), 2.14 – 2.06 (m, 2H), 1.84 (br s, 4H), 1.72 (br dd, J = 7.93, 12.10 Hz, 2H), 1.67 – 1.61 (m, 2H), 1.60 – 1.53 (m, 1H), 1.48 – 1.39 (m, 1H), 1.03 (s, 9H).

[0500] Ex.56

[0501] 1H NMR (400 MHz, CD3OD) į 8.89 – 8.83 (m, 1H), 7.69 –7.60 (m, 3H), 7.50 – 7.37 (m, 4H), 4.64 – 4.47 (m, 9H), 4.34 (d, J = 15.50 Hz, 1H), 3.94 – 3.88 (m, 1H), 3.83 – 3.76 (m, 1H), 3.66 – 3.59 (m, 4H), 2.84 (br d, J = 13.11 Hz, 1H), 2.70 (br d, J = 1.55 Hz,145021.598160 (002000.PC) 3H), 2.50 – 2.44 (m, 4H), 2.42 – 2.29 (m, 2H), 2.23 (s, 3H), 2.21 – 2.04 (m, 4H), 1.86 (br s, 4H), 1.68 – 1.59 (m, 1H), 1.54 – 1.24 (m, 8H), 1.01 (s, 8H).

[0502] Ex.59

[0503] 1H NMR (400 MHz, CD3OD) į 8.88 (s, 1H), 7.87 (s, 1H), 7.46-7.50 (m, 2H), 7.44 – 7.41 (m, 2H), 7.23 (dd, J = 5.13, 8.34 Hz, 1H), 7.04 (t, J = 8.94 Hz, 1H), 4.68 – 4.62 (m, 2H), 4.60 – 4.53 (m, 4H), 4.51 (br s, 2H), 4.42 (br d, J = 12.76 Hz, 1H), 4.36 (d, J = 15.38 Hz, 1H), 3.92 – 3.88 (m, 1H), 3.84 – 3.78 (m, 1H), 3.67 (br d, J = 12.87 Hz, 1H), 3.62 (br d, J = 12.28 Hz, 3H), 2.97 (br t, J = 10.91 Hz, 2H), 2.84 (br d, J = 10.61 Hz, 1H), 2.48 (s, 4H), 2.37 – 2.28 (m, 1H), 2.27 – 2.19 (m, 1H), 2.10 (dt, J = 4.77, 8.76 Hz, 2H), 2.04 – 1.98 (m, 1H), 1.84 (br s, 3H), 1.76 (br s, 2H), 1.70 (br s, 3H), 1.36 (br s, 1H), 1.04 (s, 9H).

[0504] Ex.63

[0505] 1H NMR (500 MHz, CD3OD) į 7.88 (s, 1H), 7.54 (d, J = 1.9 Hz, 1H), 7.50 (d, J = 8.2 Hz, 2H), 7.45 – 7.42 (m, 2H), 7.22 (dd, J = 8.4, 5.1 Hz, 1H), 7.08 – 7.02 (m, 1H), 6.32 (d, J = 1.9 Hz, 1H), 5.05 (t, J = 6.0 Hz, 1H), 4.62 (q, J = 11.6, 9.9 Hz, 3H), 4.57 – 4.51 (m, 1H), 4.50 – 4.41 (m, 3H), 4.18 (q, J = 7.2 Hz, 2H), 3.94 (d, J = 11.1 Hz, 1H), 3.84 (d, J = 6.1 Hz, 2H), 3.78 (dd, J = 11.0, 4.0 Hz, 1H), 3.70 – 3.58 (m, 5H), 2.85 (d, J = 8.8 Hz, 1H), 2.65 – 2.53 (m, 2H), 2.51 – 2.40 (m, 2H), 2.31 – 2.20 (m, 2H), 2.17 (dd, J = 7.2, 2.5 Hz, 2H), 2.10 (dd, J = 14.5, 6.8 Hz, 2H), 2.00 (ddd, J = 13.2, 8.8, 4.6 Hz, 2H), 1.89 – 1.80 (m, 4H), 1.67 (d, J = 12.3 Hz, 2H), 1.60 – 1.51 (m, 3H), 1.45 – 1.34 (m, 7H), 1.03 (d, J = 6.7 Hz, 3H), 0.99 (d, J = 6.7 Hz, 3H), 0.13 – 0.10 (m, 1H).

[0506] Ex.64

[0507] 1H NMR (500 MHz, CD3OD) į 8.90 (s, 1H), 7.88 (d, J = 1.3 Hz, 1H), 7.50 – 7.44 (m, 4H), 7.22 (dd, J = 8.3, 5.1 Hz, 1H), 7.05 (dd, J = 9.4, 8.4 Hz, 1H), 5.04 (t, J = 6.1 Hz, 1H), 4.62 (q, J = 9.8, 8.8 Hz, 3H), 4.54 (d, J = 12.3 Hz, 1H), 4.45 (q, J = 9.4 Hz, 3H), 3.94 (d, J = 11.1 Hz, 1H), 3.83 (d, J = 6.2 Hz, 2H), 3.78 (dd, J = 10.9, 4.0 Hz, 1H), 3.70 – 3.58 (m, 5H),2.85 (d, J = 12.5 Hz, 1H), 2.58 (d, J = 22.9 Hz, 2H), 2.50 (s, 3H), 2.46 (d, J = 17.5 Hz, 2H), 2.32 – 2.20 (m, 2H), 2.19 – 2.07 (m, 4H), 2.00 (ddt, J = 16.0, 11.7, 5.9 Hz, 2H), 1.89 – 1.80 (m, 4H),1.67 (d, J = 11.9 Hz, 2H), 1.56 (d, J = 10.1 Hz, 3H), 1.47 – 1.29 (m, 5H), 1.03 (d, J = 6.7 Hz, 3H), 0.99 (d, J = 6.7 Hz, 3H), 0.13 – 0.10 (m, 1H).145021.598160 (002000.PC)

[0508] Example 66: -1-((2S)-2-(3-(4-((((1-(((6,8-difluoro-7-(3-hydroxynaphthalen-1-yl)-4-((1S,5R)-1- diazabicyclo[3.2.1]octan-3-yl)quinazolin-2- yl)oxy)methyl)cyclopropyl)methyl)(methyl)amino)methyl)phenyl)propanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Ex.66)

[0509] Step C: 3-(4-((((1-(((4-((1S,5R)-8-(tert-butoxycarbonyl)-1-methyl-3,8- diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-7-(3-(methoxymethoxy)naphthalen-1- yl)quinazolin-2-145021.598160 (002000.PC) yl)oxy)methyl)cyclopropyl)methyl)(methyl)amino)methyl)phenyl)propanoic acid (Int- 063C)

[0510] To a stirred solution of tert-butyl (1S,5R)-3-(6,8-difluoro-7-(3- (methoxymethoxy)naphthalen-1-yl)-2-((1- ((methylamino)methyl)cyclopropyl)methoxy)quinazolin-4-yl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-009B) (56 mg, 0.081 mmol) in DMF (1 mL) was added 3-(4-formylphenyl)propanoic acid (28.9 mg, 0.162 mmol). The resulting mixture was stirred at RT overnight and then a slurry of NaBH(OAc)3resin (0.5 M, 0.49 mL, 0.24 mmol) was added. The resulting mixture was stirred at RT for 4 h and then filtered, washing with MeOH. The filtrate was quenched by addition of water (adjusted to pH = 4), and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 1-10% EtOAc / hexanes) to afford 3-(4-((((1-(((4-((1S,5R)-8- (tert-butoxycarbonyl)-1-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-7-(3- (methoxymethoxy)naphthalen-1-yl)quinazolin-2- yl)oxy)methyl)cyclopropyl)methyl)(methyl)amino)methyl)phenyl)propanoic acid (Int- 063C) (65.5 mg). ESI-MS m / z calc’d for C48H56F2N5O7 [M+H]+: 852; found: 852.

[0511] Step D: Tert-butyl (1S,5R)-3-(6,8-difluoro-2-((1-(((4-(3-(((S)-1-((2S,4R)-4-hydroxy- 2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- yl)amino)-3-oxopropyl)benzyl)(methyl)amino)methyl)cyclopropyl)methoxy)-7-(3- (methoxymethoxy)naphthalen-1-yl)quinazolin-4-yl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-063D)

[0512] To a stirred solution of 3-(4-((((1-(((4-((1S,5R)-8-(tert-butoxycarbonyl)-1-methyl- 3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-7-(3-(methoxymethoxy)naphthalen-1- yl)quinazolin-2- yl)oxy)methyl)cyclopropyl)methyl)(methyl)amino)methyl)phenyl)propanoic acid (Int- 063C) (30.0 mg, 0.035 mmol) in DMF (0.3 mL) was added (2S,4R)-1-((S)-2-amino-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (22.7 mg, 0.053 mmol), NEt3 (20 uL, 0.14 mmol), and HATU (20.0 mg, 0.053 mmol). The resulting mixture was stirred at RT overnight and then quenched by addition of water. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 1-40% MeOH / DCM) to give tert-butyl (1S,5R)-3-(6,8-difluoro-2-((1-(((4-(3-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-145021.598160 (002000.PC) methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- yl)amino)-3-oxopropyl)benzyl)(methyl)amino)methyl)cyclopropyl)methoxy)-7-(3- (methoxymethoxy)naphthalen-1-yl)quinazolin-4-yl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-063D) (29.5 mg). ESI-MS m / z calc’d for C70H85F2N9O9S [(M+2H) / 2]2+: 633; found: 633.

[0513] Step E: (2S,4R)-1-((2S)-2-(3-(4-((((1-(((6,8-difluoro-7-(3-hydroxynaphthalen-1-yl)- 4-((1S,5R)-1-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)quinazolin-2- yl)oxy)methyl)cyclopropyl)methyl)(methyl)amino)methyl)phenyl)propanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl) pyrrolidine-2-carboxamide (Ex.66)

[0514] To a stirred solution of tert-butyl (1S,5R)-3-(6,8-difluoro-2-((1-(((4-(3-(((S)-1- ((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2-yl)amino)-3- oxopropyl)benzyl)(methyl)amino)methyl)cyclopropyl)methoxy)-7-(3- (methoxymethoxy)naphthalen-1-yl)quinazolin-4-yl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-063D) (29.5 mg) in DCM (0.2 mL) was added HCl (4 M in dioxane, 96 μL, 1.2 mmol). The resulting mixture was stirred at RT for 2 h, MeOH was added, and then the resulting mixture was concentrated in vacuo. The residue was purified by reverse-phase preparative HPLC (C18, MeCN / water) to give (2S,4R)-1- ((2S)-2-(3-(4-((((1-(((6,8-difluoro-7-(3-hydroxynaphthalen-1-yl)-4-((1S,5R)-1-methyl-3,8- diazabicyclo[3.2.1]octan-3-yl)quinazolin-2- yl)oxy)methyl)cyclopropyl)methyl)(methyl)amino)methyl)phenyl)propanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Ex.66) (14.1 mg). ESI-MS m / z calc’d for C63H72F2N9O6S [M+H]+: 1121; found: 1121.

[0515] Compounds in the table below were synthesized via a similar route as described in the above synthesis of Ex.66 by making the appropriate substitutions. Appropriate substitutions are available commercially, synthesized as described in the literature, synthesized using methods available to those skilled in the art, or synthesized as described herein.145021.598160 (002000.PC)

[0516] Example 67: (2S,4R)-1-((2S)-2-(7-((((1R)-1-(((7-(6-amino-4-methyl-3- (trifluoromethyl)pyridin-2-yl)-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8- fluoroquinazolin-2-yl) methyl)-2,2-difluorocyclopropyl) (methyl)amino)heptanamido)-3,3-dimethylbutanoyl)-4- hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Ex.67)145021.598160 (002000.PC)

[0517] Step B: Ethyl 7-((((1R)-1-(((7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)- 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8-fluoroquinazolin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)(methyl)amino)heptanoate (Int-069B)

[0518] To a stirred solution of tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3- (trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((R)-1-(((7-ethoxy-7- oxoheptyl)(methyl)amino)methyl)-2,2-difluorocyclopropyl)methoxy)-8-fluoroquinazolin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-069A) in DCM (1 mL) was added TFA (1 mL, 13 mmol). The resulting mixture was heated to 50 °C for 1 h, cooled to RT, and then concentrated in vacuo. The residue was re-dissolved in EtOAc and quenched by addition of sat’d NaHCO3 until pH = 8. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to give ethyl 7-((((1R)-1-(((7-(6-amino-4- methyl-3-(trifluoromethyl)pyridin-2-yl)-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8-145021.598160 (002000.PC) fluoroquinazolin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)(methyl)amino)heptanoate (Int-069B) (80 mg), which was used directly in the next step without further purification. ESI-MS m / z calc’d for C36H45ClF6N7O3[M+H]+: 772; found: 772.

[0519] Step C: Tert-butyl 3-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6- chloro-2-(((R)-1-(((7-ethoxy-7-oxoheptyl)(methyl)amino)methyl)-2,2- difluorocyclopropyl)methoxy)-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-069C)

[0520] To a stirred solution of ethyl 7-((((1R)-1-(((7-(6-amino-4-methyl-3- (trifluoromethyl)pyridin-2-yl)-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8- fluoroquinazolin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)(methyl)amino)heptanoate (Int-069B) (60 mg) in DCM (2 mL) was added NEt3 (39 mg, 0.39 mmol) and Boc2O (51 mg, 0.23 mmol). The resulting mixture was stirred at RT for 1 h, diluted with DCM, and then quenched by addition of water. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (silica gel, 10% MeOH / DCM) to give tert-butyl 3- (7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((R)-1-(((7-ethoxy-7- oxoheptyl)(methyl)amino)methyl)-2,2-difluorocyclopropyl)methoxy)-8-fluoroquinazolin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-069C) (42 mg). ESI-MS m / z calc’d for C41H53ClF6N7O5[M+H]+: 873; found: 873.

[0521] Step D: 7-((( -1-(((7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-4-(8-(tert- - diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8-fluoroquinazolin-2- yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)(methyl)amino)heptanoic acid (Int-069D)

[0522] To a stirred solution of tert-butyl 3-(7-(6-amino-4-methyl-3- (trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((R)-1-(((7-ethoxy-7- oxoheptyl)(methyl)amino)methyl)-2,2-difluorocyclopropyl)methoxy)-8-fluoroquinazolin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-069C) (40 mg, 0.046 mmol) in THF (0.5 mL) was added MeOH (0.5 mL), water (0.5 mL), and LiOH (3.3 mg, 0.14 mmol). The resulting mixture was stirred at RT for 2 h, diluted with EtOAc, and then quenched by addition of HCl (1 M in water) until pH = 6. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to give 7-((((1R)-1-(((7-(6-amino-4-methyl-3- (trifluoromethyl)pyridin-2-yl)-4-(8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3- yl)-6-chloro-8-fluoroquinazolin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)(methyl)amino)heptanoic acid (Int-069D), which was used in145021.598160 (002000.PC) the next step without further purification. ESI-MS m / z calc’d for C39H49ClF6N7O5 [M+H]+: 844; found: 844.

[0523] Step butyl 3-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(( - 1-(((7-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7- oxoheptyl)(methyl)amino)methyl)cyclopropyl)methoxy)-8-fluoroquinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-069E)

[0524] To a stirred solution of 7-((((1R)-1-(((7-(6-amino-4-methyl-3- (trifluoromethyl)pyridin-2-yl)-4-(8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3- yl)-6-chloro-8-fluoroquinazolin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)(methyl)amino)heptanoic acid (Int-069D) in DMF (1 mL) was added PyBOP (28 mg, 0.053 mmol) and DIPEA (19 uL, 0.11 mmol). The resulting mixture was stirred at RT for 1 h, and then (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4- hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (23 mg, 0.053 mmol) was added. The resulting mixture was stirred at RT for 1 h, diluted with EtOAc, and then quenched by addition of water. The organic layer was separated. The aqueous layer was extracted with EtOAc (2x). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (silica gel, 10% MeOH / DCM) to give tert-butyl 3-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2- yl)-6-chloro-2-(((R)-2,2-difluoro-1-(((7-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol- 5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7- oxoheptyl)(methyl)amino)methyl)cyclopropyl)methoxy)-8-fluoroquinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-069E) (30 mg). ESI-MS m / z calc’d for C61H77ClF6N11O7S [M+H]+: 1257; found: 1257.

[0525] Step F: -1-((2S)-2-(7-((((1R)-1-(((7-(6-amino-4-methyl-3-2-yl)-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8- fluoroquinazolin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)(methyl)amino)heptanamido)-3,3-dimethylbutanoyl)-4- hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Ex.67)

[0526] To a stirred solution of tert-butyl 3-(7-(6-amino-4-methyl-3- (trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((R)-2,2-difluoro-1-(((7-(((S)-1-((2S,4R)-4- hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)-7-oxoheptyl)(methyl)amino)methyl)cyclopropyl)methoxy)-8- fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-069E) (39 mg,145021.598160 (002000.PC) 0.031 mmol) from multiple batches in DCM (0.5 mL) was added TFA (0.10 mL, 1.3 mmol). The resulting mixture was stirred at RT for 1 h and then concentrated in vacuo. The residue was purified by preparative HPLC (C18, MeCN / water with 0.1% TFA modifier) to give (2S,4R)-1-((2S)-2-(7-((((1R)-1-(((7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2- yl)-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8-fluoroquinazolin-2-yl)oxy)methyl)- 2,2-difluorocyclopropyl)methyl)(methyl)amino)heptanamido)-3,3-dimethylbutanoyl)-4- hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Ex.67) (11 mg). ESI-MS m / z calc’d for C56H69ClF6N11O5S [M+H]+: 1156; found: 1156.1H NMR (400 MHz, CD3OD) į 8.93 (s, 1H), 7.95 – 7.90 (m, 1H), 7.47-7.51 (m, 2H), 7.45 – 7.42 (m, 2H), 6.66 (s, 1H), 4.84 (s, 1H), 4.65 – 4.62 (m, 2H), 4.59 – 4.56 (m, 2H), 4.55 – 4.51 (m, 2H), 4.41 – 4.36 (m, 1H), 4.26 (br s, 2H), 3.89 (br d, J = 6.32 Hz, 2H), 3.86 – 3.80 (m, 2H), 3.59 (br d, J = 6.20 Hz, 1H), 3.01 (s, 2H), 2.49 (s, 3H), 2.47 (br d, J = 0.95 Hz, 3H), 2.34 – 2.22 (m, 4H), 2.15 (br s, 3H), 2.13 –2.06 (m, 2H), 1.97 – 1.80 (m, 4H), 1.63 (br d, J = 5.72 Hz, 2H), 1.46 – 1.31 (m, 6H), 1.05 – 1.04 (m, 2H), 1.03 (s, 9H).

[0527] Ex.68 in the table below was synthesized via a similar route as described in the above synthesis of Ex.67 by making the appropriate substitutions. Appropriate substitutions are available commercially, synthesized as described in the literature, synthesized using methods available to those skilled in the art, or synthesized as described herein.145021.598160 (002000.PC)

[0528] The NMR spectrum is provided below.

[0529] Ex.68

[0530] 1H NMR (400 MHz, CD3OD) į 8.87 (s, 1H), 7.81 (s, 1H), 7.33-7.53 (m, 4H), 6.57 (s, 1H), 4.61 (s, 1H), 4.59 – 4.52 (m, 2H), 4.51 – 4.43 (m, 2H), 4.39 (br d, J = 10.8 Hz, 2H), 4.33 – 4.26 (m, 1H), 3.95 – 3.85 (m, 1H), 3.79 (dd, J = 10.9, 3.8 Hz, 1H), 3.66 – 3.55 (m, 4H), 2.56 – 2.49 (m, 1H), 2.49 – 2.45 (m, 3H), 2.45 – 2.35 (m, 6H), 2.27 (s, 3H), 2.24 – 2.13 (m, 3H), 2.13 – 2.03 (m, 1H), 1.88 – 1.72 (m, 4H), 1.57 –1.40 (m, 4H), 1.32 – 1.18 (m, 5H), 1.00 (s, 9H), 0.68 (br s, 2H), 0.48 (br s, 2H).

[0531] Example 69: (2S,4R)-1-((2S)-2-(7-((((1R)-1-(((7-(2-amino-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-6-chloro-4-(((1-(dimethylamino)cyclobutyl)methyl)amino)-8- fluoroquinazolin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)(methyl)amino)heptanamido)-3,3-dimethylbutanoyl)-4- hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Ex.69)145021.598160 (002000.PC)

[0532] To a stirred solution of (2S,4R)-1-((2S)-2-(7-((((1R)-1-(((7-(2-amino-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-4-hydroxyquinazolin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)(methyl)amino)heptanamido)-3,3-dimethylbutanoyl)-4- hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-096D, prepared from Int-096A) (100 mg) in MeCN (6.0 mL) was added DIPEA (49 μL, 0.28 mmol) and BOP (82.0 mg, 0.185 mmol). The resulting mixture was stirred at RT for 5 min and then 1-(aminomethyl)-N,N-dimethylcyclobutan-1-amine (14.3 mg, 0.111 mmol) was added. The resulting mixture was heated to 50 °C for 1 h and then diluted with EtOAc, quenched by addition of water, and then filtered. The organic layer was separated, and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (C18, MeCN / water with 10 mM NH4HCO3 modifier) to give (2S,4R)- 1-((2S)-2-(7-((((1R)-1-(((7-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-4- (((1-(dimethylamino)cyclobutyl)methyl)amino)-8-fluoroquinazolin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)(methyl)amino)heptanamido)-3,3-dimethylbutanoyl)-4- hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Ex.69) (34.8 mg). ESI-MS m / z calc’d for C59H71ClF4N11O5S2[M+H]+: 1188; found: 1188.1H NMR (400MHz, CD3OD) į 8.87 (s, 1H), 8.18 (d, J = 1.31 Hz, 1H), 7.50 – 7.46 (m, 2H), 7.42 – 7.39 (m, 2H), 7.21 (dd, J = 5.01, 8.34 Hz, 1H), 7.08 – 7.01 (m, 1H), 4.67 (br d, J = 11.32 Hz, 1H), 4.62 (s, 1H), 4.59 – 4.54 (m, 3H), 4.50 (br s, 1H), 4.36 (d, J = 15.62 Hz, 1H), 4.12 – 4.06 (m, 1H), 3.99 – 3.95 (m, 1H), 3.93 – 3.88 (m, 1H), 3.84 – 3.79 (m, 1H), 2.88 (br d, J = 13.35 Hz, 1H), 2.47 (s, 3H), 2.39 (s, 6H), 2.25 (s, 3H), 2.22 – 2.15 (m, 4H), 2.13 – 2.04145021.598160 (002000.PC) (m, 5H), 1.89 – 1.81 (m, 2H), 1.67 – 1.61 (m, 1H), 1.51 – 1.41 (m, 5H), 1.35 (br d, J = 4.29 Hz, 1H), 1.29 – 1.18 (m, 5H), 1.02 (s, 9H).

[0533] Example 70: (2S,4R)-1-((2S)-2-(4-((1-((-1-(((7-(2-amino-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8- fluoroquinazolin-2-yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)piperidin-4-yl)methyl)- 1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-

[0534] Step B: Tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-6-chloro-2-(((R)-2,2-difluoro-1-((4-(prop-2-yn-1-yl)piperidin- 1-yl)methyl)cyclopropyl)methoxy)-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (Int-124B)

[0535] To a stirred solution of tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-6-chloro-2-(((R)-2,2-difluoro-1-((4-(3-(triisopropylsilyl)prop- 2-yn-1-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoroquinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-124A) (137 mg, 0.127 mmol) in DMF (2.5 mL) was added TBAF (1 M in THF, 380 uL, 0.38 mmol). The resulting mixture was stirred145021.598160 (002000.PC) at RT overnight and then quenched by addition of water. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0-100% 3:1 EtOAc in EtOH / hexanes) to give tert-butyl 3-(7-(2-((tert- butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-2-(((R)-2,2- difluoro-1-((4-(prop-2-yn-1-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-8- fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-124B) (89 mg). ESI-MS m / z calc’d for C46H51ClF4N7O5S [M+H]+: 924; found: 924.

[0536] Step C: Tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo thiophen-4-yl)-6-chloro-2-(((R)-2,2-difluoro-1-((4-((1-((S)-1-((2S,4R)-4-hydroxy-2-( (4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)methyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)- 8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-124C)

[0537] To a stirred solution of tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-6-chloro-2-(((R)-2,2-difluoro-1-((4-(prop-2-yn-1-yl)piperidin- 1-yl)methyl)cyclopropyl)methoxy)-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (Int-124B) (89 mg, 0.096 mmol) and (2S,4R)-1-((S)-2-azido-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (132 mg, 0.289 mmol) in DMF (1.2 mL) was added a solution of copper(II) sulfate pentahydrate (144 mg, 0.578 mmol), (+)-sodium L-ascorbate (130 mg, 0.655 mmol), and tris(3-hydroxypropyltriazolylmethyl)amine (251 mg, 0.578 mmol) in water (1.2 mL). The resulting mixture was stirred at RT for 3 h. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by reverse-phase preparative HPLC (C18, MeCN / water with 0.05% TFA modifier) to give tert-butyl 3-(7-(2-((tert- butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-2-(((R)-2,2- difluoro-1-((4-((1-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4- yl)methyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoroquinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-124C) (78 mg). ESI-MS m / z calc’d for C68H79ClF4N13O8S2 [M+H]+: 1381; found: 1381.

[0538] Step D: (2S,4R)-1-((2S)-2-(4-((1-(((1R)-1-(((7-(2-amino-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8- fluoroquinazolin-2-yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)piperidin-4-yl)methyl)-145021.598160 (002000.PC) 1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Ex.70)

[0539] To a stirred solution of tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-6-chloro-2-(((R)-2,2-difluoro-1-((4-((1-((S)-1-((2S,4R)-4- hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)methyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)- 8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-124C) (78 mg) in DCM (800 μL) was added TFA (200 μL, 2.6 mmol). The resulting mixture was stirred at RT for 2 h, diluted with 3:1 CHCl3 / iPrOH, and then quenched by addition of sat’d NaHCO3. The organic layer was separated. The aqueous layer was extracted with 3:1 CHCl3 / iPrOH (5x). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (C18, MeCN / water with pH 10 NH4OH modifier) to give (2S,4R)-1-((2S)-2-(4-((1-(((1R)-1-(((7-(2-amino-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8- fluoroquinazolin-2-yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)piperidin-4-yl)methyl)- 1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Ex.70) (26 mg). ESI-MS m / z calc’d for C58H63ClF4N13O4S2 [M+H]+: 1180; found: 1180.1H NMR (500 MHz, CD3OD) į 8.89 (d, J = 5.0 Hz, 1H), 8.08 (s, 1H), 7.89 – 7.85 (m, 1H), 7.51 (d, J = 8.2 Hz, 2H), 7.47 – 7.43 (m, 2H), 7.22 (dd, J = 8.3, 5.1 Hz, 1H), 7.07 – 7.01 (m, 1H), 5.51 (s, 1H),4.66 – 4.50 (m, 6H), 4.39 (dd, J = 14.0, 6.0 Hz, 2H), 3.92 (dd, J = 11.0, 3.7 Hz, 1H), 3.78 (d, J = 11.1 Hz, 1H), 3.69 (d, J = 11.9 Hz, 1H), 3.66 – 3.55 (m, 3H), 2.98 – 2.79 (m, 3H), 2.57 (d, J = 6.8 Hz, 2H), 2.48 (s, 3H), 2.44 (d, J = 13.0 Hz, 1H), 2.25 (dd, J = 13.2, 7.6 Hz, 1H), 2.11 (ddt, J = 13.3, 9.4, 4.8 Hz, 1H), 2.00 (t, J = 10.7 Hz, 1H), 1.86 (ddt, J = 32.9, 18.8, 11.1 Hz, 5H), 1.68 – 1.51 (m, 4H), 1.39 – 1.30 (m, 2H), 1.20 (dq, J = 23.7, 11.8, 10.8 Hz, 2H), 1.06 (d, J = 9.5 Hz, 9H).

[0540] Compounds in the table below was synthesized via a similar route as described in the above synthesis of Ex.70 by making the appropriate substitutions for the corresponding alcohol such as using (R)-(1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methanol. Appropriate substitutions are available commercially, synthesized as described in the literature, synthesized using methods available to those skilled in the art, or synthesized as described herein. In Step C, alternatively, Cu(MeCN)4PF6 may be used as the catalyst and DIPEA may be used as the base.145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)

[0541] The NMR spectrum is provided below.

[0542] Ex.71

[0543] 1H NMR (400 MHz, CD3OD) į 8.91 – 8.80 (m, 1H), 7.85 (s, 1H), 7.81 – 7.70 (m, 1H), 7.50 – 7.40 (m, 4H), 7.16 (dd, J = 8.4, 5.1 Hz, 1H), 7.01 (t, J = 8.9 Hz, 1H), 5.24 (d, J = 10.4 Hz, 1H), 4.70 – 4.59 (m, 2H), 4.57 – 4.48 (m, 4H), 4.47 – 4.37 (m, 3H), 4.00 – 3.88 (m, 1H), 3.83 (br d, J = 11.0 Hz, 1H), 3.68 – 3.55 (m, 4H), 2.88 (br dd, J = 13.2, 3.5 Hz, 1H), 2.60 – 2.48 (m, 3H), 2.46 (s, 3H), 2.44 – 2.31 (m, 3H), 2.22 (s, 4H), 2.14 – 2.04 (m, 1H), 1.86 – 1.74 (m, 4H), 1.68 – 1.59 (m, 1H), 1.51 – 1.40 (m, 3H), 1.39 – 1.29 (m, 2H), 1.22 (br s, 3H), 1.10 (d, J = 6.7 Hz, 3H), 0.71 (d, J = 6.6 Hz, 3H).145021.598160 (002000.PC)

[0544] Example 113: (2S,4R)-1-(2-(3-((1-(((1R)-1-(((7-(2-amino-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8- fluoroquinazolin-2-yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)piperidin-4- yl)methoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Ex.113)

[0545] Step A: Tert-butyl (1R,5S)-3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-2-(((1R)-1-((4-(((5-(1-((2S,4R)-4-((tert- butyldimethylsilyl)oxy)-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3- methyl-1-oxobutan-2-yl)isoxazol-3-yl)oxy)methyl)piperidin-1-yl)methyl)-2,2- difluorocyclopropyl)methoxy)-6-chloro-8-fluoroquinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate145021.598160 (002000.PC)

[0546] To a solution of tert-butyl (1R,5S)-3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-2-(methylsulfonyl)quinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-C03) (100 mg, 0.131 mmol) and (2S,4R)-4- ((tert-butyldimethylsilyl)oxy)-1-(2-(3-((1-(((R)-2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)methoxy)isoxazol-5-yl)-3- methylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int- LE001) (107 mg, 0.131 mmol) in THF (1 mL) was added NaH (26.3 mg, 0.657 mmol, 60% Wt) at 10 °C under N2atmosphere. The mixture was stirred at 10 °C for 1 h. LCMS showed starting material was consumed and desired peak was formed. The mixture was quenched with saturated NH4Cl solution (2 mL), extracted with EtOAc (4 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give the crude product tert-butyl (1R,5S)-3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-2-(((1R)-1-((4-(((5-(1-((2S,4R)-4-((tert- butyldimethylsilyl)oxy)-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3- methyl-1-oxobutan-2-yl)isoxazol-3-yl)oxy)methyl)piperidin-1-yl)methyl)-2,2- difluorocyclopropyl)methoxy)-6-chloro-8-fluoroquinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate. MS (ESI) [M / 2+H]+: m / z 749.6.

[0547] Step B: Tert-butyl (1R,5S)-3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-2-(((1R)-1-((4-(((5-(1-((2S,4R)-4-((tert- butyldimethylsilyl)oxy)-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3- methyl-1-oxobutan-2-yl)isoxazol-3-yl)oxy)methyl)piperidin-1-yl)methyl)-2,2- difluorocyclopropyl)methoxy)-6-chloro-8-fluoroquinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

[0548] The racemic tert-butyl (1R,5S)-3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-2-(((1R)-1-((4-(((5-(1-((2S,4R)-4-((tert- butyldimethylsilyl)oxy)-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3- methyl-1-oxobutan-2-yl)isoxazol-3-yl)oxy)methyl)piperidin-1-yl)methyl)-2,2- difluorocyclopropyl)methoxy)-6-chloro-8-fluoroquinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.134 mmol) was separated by SFC (Column: DAICEL CHIRALPAK IH (250 mm * 30 mm, 10 um); Condition: n-Heptane- EtOH (0.1% NH3āH2O); Begin B--End B: 10%--10%; Gradient Time (min): 1; 100%B Hold Time (min): 2; FlowRate (mL / min): 80) to give tert-butyl (1R,5S)-3-(7-(2-((tert- butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-2-(((1R)-1-((4-(((5-(1- ((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-((4-(4-methylthiazol-5-145021.598160 (002000.PC) yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3- yl)oxy)methyl)piperidin-1-yl)methyl)-2,2-difluorocyclopropyl)methoxy)-6-chloro-8- fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (the first eluting isomer from SFC) and tert-butyl (1R,5S)-3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-2-(((1R)-1-((4-(((5-(1-((2S,4R)-4-((tert- butyldimethylsilyl)oxy)-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3- methyl-1-oxobutan-2-yl)isoxazol-3-yl)oxy)methyl)piperidin-1-yl)methyl)-2,2- difluorocyclopropyl)methoxy)-6-chloro-8-fluoroquinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (the second eluting isomer from SFC). MS (ESI) [M / 2+H]+: m / z 749.6.

[0549] Step C: (2S,4R)-1-(2-(3-((1-(((1R)-1-(((7-(2-amino-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8- fluoroquinazolin-2-yl)oxy)methyl)-2,2-difluorocyclopropyl) piperidin-4-yl)methoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy- 5- yl)benzyl)pyrrolidine-2-carboxamide (Ex.113)

[0550] A solution of tert-butyl (1R,5S)-3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-2-(((1R)-1-((4-(((5-(1-((2S,4R)-4-((tert- butyldimethylsilyl)oxy)-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3- methyl-1-oxobutan-2-yl)isoxazol-3-yl)oxy)methyl)piperidin-1-yl)methyl)-2,2- difluorocyclopropyl)methoxy)-6-chloro-8-fluoroquinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (60 mg, 0.040 mmol) (the first eluting isomer) in TFA (2 mL, 26.0 mmol) was stirred at 15 °C for 15 h. The reaction solution was evaporated under reduced pressure to give the residue. To the residue dissolved in MeOH (5 mL) was added sodium bicarbonate (100 mg, 1.19 mmol) at 15 °C, and the mixture was stirred at 15 °C for 3 h. The reaction solution separated and the filtrate was purified directly by reverse preparative HPLC (Column: Boston Prime C18150 * 30 mm * 5 um; Condition: water (0.04% NH3āH2O + 10 mM NH4HCO3)-ACN; Begin B--End B: 62--92; Gradient Time (min): 10; 100% B Hold Time (min): 2; FlowRate (mL / min): 25) to give the crude product (28 mg, 92.95% ee) as white solid. The crude product was separated by SFC (Column: DAICEL CHIRALPAK IH (250 mm * 30 mm, 10 um); Condition: n-Heptane-(i- PrOH / ACN= 2:1, 0.1% NH3āH2O); Begin B--End B: 25%--25%; Gradient Time (min): 1; 100%B Hold Time (min): 90; FlowRate (mL / min): 80) to give (2S,4R)-1-(2-(3-((1-(((1R)- 1-(((7-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8-fluoroquinazolin-2-yl)oxy)methyl)-2,2-145021.598160 (002000.PC) difluorocyclopropyl)methyl)piperidin-4-yl)methoxy)isoxazol-5-yl)-3-methylbutanoyl)-4- hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Ex.113). MS (ESI) [M+H]+: m / z 1182.4.1H NMR (400MHz, CD3OD) į 8.77-8.95 (m, 1H), 7.83 (s, 1H), 7.39-7.48 (m, 4H), 7.15-7.23 (m, 1H), 6.97-7.05 (m, 1H), 5.62-6.00 (m, 1H), 4.36-4.66 (m, 8H), 3.83-4.04 (m, 3H), 3.53-3.72 (m, 6H), 2.88-3.02 (m, 2H), 2.83 (br d, J=14.4 Hz, 1H), 2.47 (s, 3H), 2.33-2.45 (m, 2H), 2.16-2.26 (m, 1H), 1.88-2.16 (m, 4H), 1.84 (br s, 4H), 1.57-1.76 (m, 3H), 1.35 (br d, J=7.3 Hz, 3H), 1.03 (br d, J=6.4 Hz, 3H), 0.85-0.89 (m, 3H).

[0551] Example 114 & 115 : (2S,4R)-1-((2S)-2-(2-(3-(1-(((1R)-1-(((7-(2-amino-3-cyano- 7-fluorobenzo[b]thiophen-4-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8- fluoroquinazolin-2-yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)piperidin-4- yl)cyclobutyl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Ex.114 & 115)145021.598160 (002000.PC)

[0552] Step A: Tert-butyl (1R,5S)-3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-2-(((R)-1-((4-(3-(2-(((S)-1-((2S,4R)-4-((tert- butyldimethylsilyl) -2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1- yl)amino)-2-oxoethyl)cyclobutyl)piperidin-1-yl)methyl)-2,2- difluorocyclopropyl)methoxy)-6-chloro-8-fluoroquinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

[0553] To a solution of tert-butyl (1R,5S)-3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-2-(methylsulfonyl)quinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-C03) (35 mg, 0.046 mmol) and (2S,4R)-4- ((tert-butyldimethylsilyl)oxy)-1-((S)-2-(2-(3-(1-(((R)-2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)cyclobutyl)acetamido)-3,3- dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (32 mg, 0.038 mmol) (Int-LE002-1 & 2) in THF (1 mL) was added sodium hydride (9.19 mg, 0.230 mmol) (60% in mineral oil) at 25 °C under N2 atmosphere. The mixture was stirred at 25 °C for 1 h. LCMS showed desired product mass was observed. The mixture was quenched with aq. NH4Cl (5 mL), and then extracted with EtOAc (3 * 30 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to give the crude product tert-butyl (1R,5S)-3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-2-(((R)-1-((4-(3-(2-(((S)-1-((2S,4R)-4-((tert- butyldimethylsilyl)oxy)-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)cyclobutyl)piperidin-1-yl)methyl)-2,2- difluorocyclopropyl)methoxy)-6-chloro-8-fluoroquinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate. MS (ESI) [M / 2+H]+: m / z 763.8.

[0554] Step B: (2S,4R)-1-((2S)-2-(2-(3-(1-(((1R)-1-(((7-(2-amino-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8- fluoroquinazolin-2-yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)piperidin-4- yl)cyclobutyl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Ex.114 &

[0555] A solution of tert-butyl (1R,5S)-3-(7-(2-( butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-2-(((R)-1-((4-(3-(2-(((S)-1-((2S,4R)-4-((tert- butyldimethylsilyl)oxy)-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)cyclobutyl)piperidin-1-yl)methyl)-2,2- difluorocyclopropyl)methoxy)-6-chloro-8-fluoroquinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (44 mg, 0.029 mmol) in TFA (1 mL) was stirred at145021.598160 (002000.PC) 25 °C for 12 h. Most of the solvent was removed by nitrogen flow, and the residue was diluted with MeOH (1 mL), and sodium bicarbonate solution (400 mg, 4.76 mmol) was added to the mixture (adjust pH to 9). The mixture was stirred at 25 °C for 1 h. The mixture was filtered and the solvent was evaporated under reduced pressure. The residue was purified by reverse preparative HPLC (Column Boston Prime C18150 * 30 mm * 5 um Condition water (0.04% NH3H2O+10 mm NH4HCO3)-MeCN Begin B 65 End B 95 Gradient Time (min) 10100% B Hold Time 2 Flow Rate (ml / min) 25) to give (2S,4R)-1- ((2S)-2-(2-(3-(1-(((1R)-1-(((7-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-4- ((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8-fluoroquinazolin-2-yl)oxy)methyl)- 2,2-difluorocyclopropyl)methyl)piperidin-4-yl)cyclobutyl)acetamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Ex.114 or Ex.115).

[0556] Ex.114: MS (ESI) [M / 2+H]+: m / z 606.2.1H NMR (400MHz, CD3OD) į 8.90 (s, 1H), 7.87 (s, 1H), 7.36-7.61 (m, 4H), 7.22 (J=8.4, 5.1 Hz, 1H), 7.05 (t, J=8.9 Hz, 1H), 4.50- 4.68 (m, 7H), 4.32-4.46 (m, 2H), 3.74-3.99 (m, 2H), 3.58-3.69 (m, 4H), 2.91 (s, 2H), 2.81 (d, J=10.6 Hz, 1H), 2.39-2.53 (m, 5H), 2.08-2.37 (m, 6H), 1.73-2.00 (m, 7H), 1.60 (d, J=10.6 Hz, 3H), 1.37 (d, J=8.9 Hz, 4H), 0.98-1.08 (m, 11H).

[0557] Ex.115: MS (ESI) [M+H]+: m / z 606.2.1H NMR (400MHz, CD3OD) į 8.89 (s, 1H), 7.87 (s, 1H), 7.38-7.54 (m, 4H), 7.22 (J=8.3, 5.2 Hz, 1H), 7.05 (t, J=8.9 Hz, 1H), 4.47- 4.66 (m, 7H), 4.31-4.46 (m, 2H), 3.75-3.97 (m, 2H), 3.57-3.71 (m, 4H), 2.77-3.00 (m, 3H), 2.34-2.58 (m, 7H), 2.17-2.27 (m, 1H), 1.96-2.12 (m, 3H), 1.75-1.92 (m, 8H), 1.54-1.71 (m, 3H), 1.15-1.50 (m, 3H), 0.97-1.11 (m, 11H). Assays

[0558] HiBiT Potency Data

[0559] ASPC-1 KRASG12D-HiBiT protein degradation assay: A frozen vial of ASPC-1 KRASG12D N-terminal HiBiT tagged cell line was thawed and cultured in RPMI1640 media supplemented with 10% heat inactive fetal bovine serum, 2 mM GlutaMax, and 100U / mL Penicillin-Streptomycin for 7 days. Media was changed on day 4. On the day of the assay, cells were washed with 1x PBS and dissociated with 0.25mg / ml Trypsin / EDTA. Cells were resuspended in culture media and 20 μL of cell suspension were plated in 384 W culture plate at 10,000 cells per well. Cells were incubated in 37ºC, 5% CO2 with 95% relative humidity incubator for 16-24 h. Cells were treated with compounds and incubated for an additional 24145021.598160 (002000.PC) h. Equal volume of premixed HiBiT detection reagent containing HiBiT Lytic buffer, 1% of LgBiT Protein and 2% of HiBiT Lytic Substrate was added to the plate. Plates were shaken on a shaker setting 400 rpm for 20 min at room temperature with protection from light. Luminescence was read on EnVision® Multilabel Reader. The results of this assay are presented in the table below.145021.598160 (002000.PC)145021.598160 (002000.PC)145021.598160 (002000.PC)

Claims

145021.598160 (002000.PC) We claim:

1. A compound of the Formula (I)wherein:MLis selected from the group consisting of:Ring CLis selected from:(i) a 7- to 14-membered spiroheterocycloalkyl containing 0 to 2 additional heteroatoms independently selected from the group consisting of N, O, and S in addition to the illustrated N atom; and (ii) a 4- to 6-membered saturated monocyclic heterocycloalkyl containing 0 to 1 additional heteroatom selected from the group consisting of N, O, and S in addition to the illustrated N atom; wherein Ring CLis unsubstituted or substituted by 1 to 3 RCLsubstituents independentlyselected from the group consisting of halo, C1-C3alkyl, C1-C3fluoroalkyl, and C1-C3alkoxy;Lb is -CH2-, -O-, -CH2-O-, -CH2CH2-O-, -O-piperidinylene-, -(C3-C7cycloalkylene)-, orabsent;Lc is C1-C3alkyl;Ldis selected from the group consisting of:(i) -CH2-;145021.598160 (002000.PC) (ii) -CF2-;(iii) -O-; (iv) -phenylene-; (v) -O-phenylene-; and (vi) -piperidinylene-;Leis selected from the group consisting of:R5 is H or C1-C3alkyl;Xe, Xf, Xg, and Xhare independently selected from the group consisting of C(H), C(RLe),N, S, and O; wherein at least one of Xe, Xf, Xg, and Xhis C(H) or C(RLe); andeach RLesubstituent is independently selected from the group consisting of halo, C1-C3alkyl, C1-C3fluoroalkyl, and C1-C3alkoxy;R1 is C1-C6alkyl, -CH2-C1, C3-C7cycloalkyl, or C3-C7heterocycloalkyl containing 1 to 2heteroatoms selected from the group consisting of N, O, and S; wherein C1 is C3-C7cycloalkyl;each R2is H, C1-C6alkyl, or -CH2OH, or alternatively, two R2, together with the carbon atom to which both are attached, form a 3- to 7- membered saturated monocyclic ring;each R3 is independently H, fluoro, C1-C3alkyl, or C1-C3fluoroalkyl;each Rc is independently fluoro or C1-C3alkyl;Xa, Xb, Xc, Xd, and Xiare independently selected from the group consisting of C(H), C(R4),N, N(R4), S and O; wherein at least one of Xa, Xb, Xc, Xd, and Xiis C(H) or C(R4);R4 is halo, C1-C3alkyl or C1-C3fluoroalkyl;X1is N or C(H);Rx is halo, C1-C3alkyl or C1-C3fluoroalkyl;Ring Y is (i) phenyl or naphthyl; or145021.598160 (002000.PC) (ii) a 5- to 6-membered mono- or a 9- to 10-membered bicyclic heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; wherein Ring Y is unsubstituted or substituted by 1 to 4 RYsubstituents selected from the group consisting of halo, hydroxy, C1-C3alkyl, C2-C3alkynyl, C1-C3fluoroalkyl, C1-C3alkoxy, C1-C3fluoroalkoxy, C1-C3alkylthio, C1-C3fluoroalkylthio, amino, C1-C3alkylamino, C1-C3dialkylamino and cyano;A is selected from the group consisting of:Ring A is a saturated 8- to 10-membered N-containing bridged bicyclic ring which contains at least one further N atom in addition to the illustrated N atom;RA is selected from the group consisting of C1-C3alkyl,GC2-C4alkenyl, C1-C3alkoxy, C1-C3alkoxy(C1-C3)alkyl, halo, C1-C3fluoroalkyl, hydroxy, C1-C3hydroxyalkyl, CF3-C(H)(OH)-, C(H)(F2)-C(H)(OH)-, cyano, and C1-C3cyanoalkyl;each Ra* is independently C1-C3alkyl;subscript i is 0, 1, or 2; subscript j is 1, 2, or 3; subscript k is 0, 1, or 2; subscript m is 0, 1, or 2; subscript o is 0, 1, 2, 3, 4, or 5; subscript r is 0, 1, 2, or 3; subscript s is 0, 1, 2, or 3; subscript t is 1, 2, 3, 4, or 5; subscript u is 0 or 1; and subscript v is 0, 1, 2, or 3; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein MLis145021.598160 (002000.PC).

3. The compound of claim 2 or the pharmaceutically acceptable salt thereof, wherein, wherein: subscripts p and q are independently 1, 2, or 3; andring CL2is a 4- to 6-membered saturated ring containing 0 to 1 heteroatom selected from thegroup consisting of N, S, and O.

4. The compound of claim 2 or the pharmaceutically acceptable salt thereof, wherein MLis5. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein MLis.

6. The compound of claim 5 or the pharmaceutically acceptable salt thereof, wherein Lcis methyl. The compound of claim 5 or the pharmaceutically acceptable salt thereof, wherein Ldis -CH2-.145021.598160 (002000.PC) 8. The compound of any one of claims 2-7 or the pharmaceutically acceptable salt thereof, wherein9. The compound of claim 8 or the pharmaceutically acceptable salt thereof, wherein R5is H.

10. The compound of any one of claims 2-7 or the pharmaceutically acceptable salt thereof, wherein.

11. The compound of claim 10 or the pharmaceutically acceptable salt thereof, wherein Leis selected from the group consisting of:.

12. The compound of claim 11 or the pharmaceutically acceptable salt thereof, wherein subscript u is 0.

13. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein the.145021.598160 (002000.PC) 14. The compound of claim 13 or the pharmaceutically acceptable salt thereof, whereinthe moiety is selected from the group consisting of:145021.598160 (002000.PC)15. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein the moiety16. The compound of claim 15 or the pharmaceutically acceptable salt thereof, wherein the moietyselected from the group consisting of:145021.598160 (002000.PC)145021.598160 (002000.PC) 17. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein the18. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein Ring Y is selected from the group consisting of:wherein subscript y is 0, 1, 2 or 3.

19. The compound of claim 18 or the pharmaceutically acceptable salt thereof, wherein Ring Y is selected from the group consisting of:.145021.598160 (002000.PC) 20. The compound of claim 18 or the pharmaceutically acceptable salt thereof, wherein Ring Y is selected from the group consisting of:

21. The compound of claim 20 or the pharmaceutically acceptable salt thereof, wherein Ring Y is selected from the group consisting of:.

22. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein Ring A iswherein subscript v is 0, 1, or 2.

23. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein R1is t-butyl.145021.598160 (002000.PC) 24. The compound of claim 1 or the pharmaceutically acceptable salt thereof, whereineach R2is H.

25. The compound of claim 1 or the pharmaceutically acceptable salt thereof, whereinsubscript j is 1 and each R3<sub>is H.

26. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein<img src='' class="img-anchor img-center" img-id="IMGF000224_0001" / >.

27. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of Example Nos.1-115.

28. A compound of the Formula (II)<img src='' class="img-anchor img-center" img-id="IMGF000224_0002" / >wherein:MLis selected from the group consisting of:Ring CLis selected from:145021.598160 (002000.PC) (i) a 7- to 14-membered spiroheterocycloalkyl containing 0 to 2 additional heteroatoms independently selected from the group consisting of N, O, and S in addition to the illustrated N atom; and (ii) a 4- to 6-membered saturated monocyclic heterocycloalkyl containing 0 to 1 additional heteroatom selected from the group consisting of N, O, and S in addition to the illustrated N atom; wherein Ring CLis unsubstituted or substituted by 1 to 3 RCLsubstituents independentlyselected from the group consisting of halo, C1-C3alkyl, C1-C3fluoroalkyl, and C1-C3alkoxy;absent;Lc is C1-C3alkyl;Ldis selected from the group consisting of: (i) -CH2<sup>-;(ii) -CF2<sup>-;< / sup>(iii) -O-; (iv) -phenylene-; and (v) -O-phenylene-;Leis selected from the group consisting of:R5 is H or C1-C3alkyl;Xe, Xf, Xg, and Xhare independently selected from the group consisting of C(H), C(RLe),N, S, and O; wherein at least one of Xe, Xf, Xg, and Xhis C(H) or C(RLe); andeach RLesubstituent is independently selected from the group consisting of halo, C1-C3alkyl, C1-C3fluoroalkyl, and C1-C3alkoxy;R1 is C1-C6alkyl, -CH2-C1, C3-C7cycloalkyl, or C3-C7heterocycloalkyl containing 1 to 2heteroatoms selected from the group consisting of N, O, and S;145021.598160 (002000.PC) wherein C1 is C3-C7cycloalkyl;R2 is H, C1-C6alkyl, or -CH2OH;each R3is independently H, fluoro, C1-C3alkyl, or C1-C3fluoroalkyl;each Rc is independently fluoro or C1-C3alkyl;Xa, Xb, Xcand Xdare independently selected from the group consisting of C(H), C(R4), N,N(R4), S and O; wherein at least one of Xa, Xb, Xcand Xdis C(H) or C(R4);R4 is halo, C1-C3alkyl or C1-C3fluoroalkyl;X1is N or C(H);Rx is halo, C1-C3alkyl or C1-C3fluoroalkyl;Ring Y is (i) phenyl or naphthyl; or (ii) a 5- to 6-membered mono- or a 9- to 10-membered bicyclic heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; wherein Ring Y is unsubstituted or substituted bysubstituents selected from the group consisting of halo, hydroxy, C1-C3alkyl, C2-C3alkynyl, C1-C3fluoroalkyl, C1-C3alkoxy, C1-C3fluoroalkoxy, C1-C3alkylthio, C1-C3fluoroalkylthio, amino, C1-C3alkylamino, C1-C3dialkylamino and cyano;A is selected from the group consisting of:Ring A is a saturated 8- to 10-membered N-containing bridged bicyclic ring which contains at least one further N atom in addition to the illustrated N atom;RA is selected from the group consisting of C1-C3alkyl,GC2-C4alkenyl, C1-C3alkoxy, C1-C3alkoxy(C1-C3)alkyl, halo, C1-C3fluoroalkyl, hydroxy, C1-C3hydroxyalkyl, CF3-C(H)(OH)-, C(H)(F2)-C(H)(OH)-, cyano, and C1-C3cyanoalkyl;each Ra* is independently C1-C3alkyl;subscript i is 0, 1, or 2; subscript j is 1, 2, or 3; subscript k is 0, 1, or 2; subscript m is 0, 1, or 2;145021.598160 (002000.PC) subscript o is 0, 1, 2, 3, 4, or 5; subscript r is 0, 1, 2, or 3; subscript s is 0, 1, 2, or 3; subscript t is 1, 2, 3, 4, or 5; subscript u is 0 or 1; and subscript v is 0, 1, 2, or 3; or a pharmaceutically acceptable salt thereof.

29. A pharmaceutical composition comprising the compound of any one of claims 1-28 or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

30. A pharmaceutical composition comprising the compound of any one of claims 1-28 or the pharmaceutically acceptable salt thereof, an additional anti-cancer agent, and a pharmaceutically acceptable carrier.

31. A method of degrading KRAS G12D protein in a cell, comprising administering the compound of any one of claims 1-28 or the pharmaceutically acceptable salt thereof, resulting in degradation of the KRAS G12D protein in the cell.

32. A method of treating cancer comprising administering a therapeutically effective amount of the compound of any one of claims 1-28 or the pharmaceutically acceptable salt thereof, to a subject in need of such treatment.

33. The method of claim 32, further comprising administering an additional active agent to the subject.

34. The compound of any one of claims 1-28 or the pharmaceutically acceptable salt thereof, for use in therapy, or use of the compound of any one of claims 1-28 or the pharmaceutically acceptable salt thereof, in therapy.

35. The compound of any one of claims 1-28 or the pharmaceutically acceptable salt thereof, for use in treating cancer, or use of a compound of any one of claims 1-28 or the pharmaceutically acceptable salt thereof, for treating cancer.145021.598160 (002000.PC) 36. The compound of any one of claims 1-28 or the pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of cancer, or use of the compound of any one of claims 1-28 or the pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of cancer.

37. The compound of any one of claims 1-28 or the pharmaceutically acceptable salt thereof, and an additional anti-cancer agent, for use in the treatment of cancer, or use of the compound of any one of claims 1-28 or the pharmaceutically acceptable salt thereof, and the additional anti-cancer agent for treating cancer.

38. The compound of any one of claims 1-28 or the pharmaceutically acceptable salt thereof, and an additional anti-cancer agent, for the preparation of a medicament for the treatment of cancer, or use of the compound of any one of claims 1-28 or the pharmaceutically acceptable salt thereof, and the additional anti-cancer agent, for the preparation of a medicament for the treatment of cancer.

39. A pharmaceutical composition comprising the compound of any one of claims 1-28 or the pharmaceutically acceptable salt thereof, for use in the treatment of cancer, or use of the pharmaceutical composition comprising the compound of any one of claims 1-28 or the pharmaceutically acceptable salt thereof, for treating cancer.

40. A pharmaceutical composition comprising the compound of any one of claims 1-28 or the pharmaceutically acceptable salt thereof, and an additional anti-cancer agent, for use in the treatment of cancer, or use of the pharmaceutical composition comprising the compound of any one of claims 1-28, or the pharmaceutically acceptable salt thereof, and the additional anti-cancer agent, for treating cancer.

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