WO2025240740A1 - Small molecule protein degraders of kras g12d mutant - Google Patents

Abstract

Compounds 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

SMALL MOLECULE PROTEIN DEGRADERS OF KRAS G12D MUTANT

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U.S. Provisional Application No 63/647,988, filed May 15, 2024, 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, and 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 heterobifiinctional 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 the 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: _M ^L _{is selected from the group consisting of: Ring C} ^L _{is selected from:} (i) a 7- to 14-membered spirocyclic heterocyclylene 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 or a 7- to 10-membered bridged bicyclic heterocyclylene 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 C^L is unsubstituted or substituted by 1 to 3 R^CL substituents independently selected from the group consisting of halo, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, and C₁- C₃ alkoxy; Ring C^y is a 3- to 6-membered monocyclic or a 5- to 8-membered bridged bicyclic cycloalkylene; wherein Ring C^y is unsubstituted or substituted by 1 to 2 R^Cy substituents independently selected from the group consisting of halo, C₁-C₃ alkyl, and C₁-C₃ fluoroalkyl, each of L^b1, L^b2, L^b3, and L^b4 is independently -CH₂-, -O-, C₄-C₆ cycloalkylene, or absent; L^c is C₁-C₃ alkyl or H; L^e is selected from the group consisting of: R⁵ is H or C₁-C₃ alkyl; X^e, X^f, X^g, and X^h are independently selected from the group consisting of C, C(H), C(R^Le), N, O, and S; wherein at least one of X^e, X^f, X^g, and X^h is C, C(H), or C(R^Le); Xⁱ is C or N; each R^Le substituent is independently selected from the group consisting of halo, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, and C₁-C₃ alkoxy; R¹ is C₁-C₆ alkyl, -CH₂-C1, C₃-C₇ cycloalkyl, or C₃-C₇ heterocycloalkyl containing 1 to 2 heteroatoms selected from the group consisting of N, O, and S; wherein C¹ is C₃-C₇ cycloalkyl; R² is H, C₁-C₆ alkyl, -CH₂OH, or -CH₂OP(=O)(OH)₂; each R^c is independently fluoro or C₁-C₃ alkyl; each R³ is independently H, fluoro, C₁-C₃ alkyl, or C₁-C₃ fluoroalkyl; X^a, X^b, X^c and X^d are independently selected from the group consisting of C(H), C(R⁴), N, N(R⁴), S, and O; wherein at least one of X^a, X^b, X^c and X^d is C(H) or C(R⁴); R⁴ is halo, C₁-C₃ alkyl, or C₁-C₃ fluoroalkyl; W^A is S, O, or N(R^W1); R^W1 is selected from the group consisting of C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₃-C₆ cycloalkyl, and C₃-C₆ fluorocycloalkyl; Ring A is a saturated 5- to 8-membered N-containing monocyclic heterocyclyl or a saturated 8- to 10-membered N-containing bridged bicyclic heterocyclyl, wherein the saturated 8- to 10-membered N-containing bridged bicyclic heterocyclyl contains at least one further N atom in addition to the illustrated N atom; R^A is selected from the group consisting of C₁-C₃ alkyl, C₂-C₄ alkenyl, C₁-C₃ alkoxy, C₁- C₃ alkoxy(C₁-C₃)alkyl, halo, C₁-C₃ fluoroalkyl, hydroxy, C₁-C₃ hydroxyalkyl, CF₃- C(H)(OH)-, C(H)(F₂)-C(H)(OH)-, cyano, and C₁-C₃ cyanoalkyl; Y is (i) 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; (ii) a 12- to 14-membered tricyclic heterocyclyl, where at least 2 of the rings of the 12- to 14-membered tricyclic heterocyclyl are aromatic, the third ring is unsaturated or aromatic, wherein the 12- to 14-membered tricyclic heterocyclyl contains 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S; or (iii) phenyl or naphthyl; wherein Y is unsubstituted or substituted by 1 to 4 R^Y substituents independently selected from the group consisting of halo, hydroxy, C₁-C₃ alkyl, C₂-C₄ alkynyl, C₁-C₃ fluoroalkyl, C₃-C₆ cycloalkyl, C₃-C₆ fluorocycloalkyl, C₂- C₃ acyl, C₁-C₃ alkoxy, C₁-C₃ fluoroalkoxy, C₁-C₃ alkylthio, C₁-C₃ fluoroalkylthio, amino, C₁-C₃ alkylamino, C₁-C₃ dialkylamino, and cyano; or alternatively, 2 R^Y substituents, together with the carbon atom to which both are attached, form a 3- to 5-membered saturated carbocyclic ring; subscript i is 0, 1, or 2; subscript m is 0, 1, or 2; subscript n is 0, 1, 2, or 3; subscript o1 is 0 or 1; subscript o2 is 0 or 1; subscript o3 is 0 or 1; subscript o4 is 0 or 1; subscript o5 is 1, 2, 3, 4, or 5; and subscript u is 0 or 1. [0010] In an embodiment, the moiety selected from the group consisting of: _{[0011] In an embodiment, M} ^L _is [0012] In an embodiment, M^L is selected from the group consisting of:

[0013] In an embodiment, M^L is [0014] In an embodiment, M^L is selected from the group consisting of: [0015] In an embodiment, M^L is [0016] In an embodiment, M^L is [0017] In an embodiment, L^e is [0018] In an embodiment, W^A is S. [0019] In an embodiment, Ring A is and subscript n is 0, 1, or 2. [0020] In an embodiment, Y is unsubstituted or substituted phenyl, naphthyl, pyridyl, indazolyl, benzothienyl, benzoxazolyl, benzothiazolyl, or isoquinolinyl. [0021] In an embodiment, Y is naphthyl or indazolyl, wherein Y is substituted by 1 to 3 R^Y substituents independently selected from the group consisting of halo, hydroxy, amino, C₁- C₃ alkyl, C₁-C₃ fluoroalkyl, C₃-C₆ cycloalkyl, C₃-C₆ fluorocycloalkyl, C₂-C₄ alkynyl, and cyano. [0022] In an embodiment, Y is selected from the group consisting of: and subscript s is 0, 1, 2, 3, or 4. [0023] In an embodiment, Y is and subscript s is 0, 1, 2, or 3. [0024] In an embodiment, Y is selected from the group consisting of: and subscript s is 0, 1, 2, or 3. [0025] In an embodiment, Y is selected from the group consisting of: [0026] In an embodiment, R¹ is tert-butyl or isopropyl. [0027] In an embodiment, R² is H or methyl. [0028] In an embodiment, each R³ is H. [0029] In an embodiment, the moiety [0030] In specific embodiments, the present disclosure provides a compound as described in any one of Examples 1-71 as set forth below, or a pharmaceutically acceptable salt thereof. [0031] In one embodiment, the present disclosure provides a compound having structural Formula (I), or a pharmaceutically acceptable salt thereof, as shown above, wherein: M^L is selected from the group consisting of: _{Ring C} ^L _{is selected from:} (i) a 7- to 14-membered spirocyclic heterocyclylene 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 or a 7- to 10-membered bridged bicyclic heterocyclylene 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 C^L is unsubstituted or substituted by 1 to 3 R^CL substituents independently selected from the group consisting of halo, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, and C₁- C₃ alkoxy; Ring C^y is a 3- to 6-membered monocyclic or a 5- to 8-membered bridged bicyclic cycloalkylene; wherein Ring C^y is unsubstituted or substituted by 1 to 2 R^Cy substituents independently selected from the group consisting of halo, C₁-C₃ alkyl, and C₁-C₃ fluoroalkyl, each of L^b1, L^b2, L^b3, and L^b4 is independently -CH₂-, -O-, C₄-C₆ cycloalkylene, or absent; Lc is C₁-C₃ alkyl or H; L^e is selected from the group consisting of: R⁵ is H or C₁-C₃ alkyl; X^e, X^f, X^g, and X^h are independently selected from the group consisting of C, C(H), C(R^Le), N, O, and S; wherein at least one of X^e, X^f, X^g, and X^h is C, C(H), or C(R^Le); Xⁱ is C or N; each R^Le substituent is independently selected from the group consisting of halo, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, and C₁-C₃ alkoxy; R¹ is C₁-C₆ alkyl, -CH₂-C1, C₃-C₇ cycloalkyl, or C₃-C₇ heterocycloalkyl containing 1 to 2 heteroatoms selected from the group consisting of N, O, and S; wherein C¹ is C₃-C₇ cycloalkyl; R² is H, C₁-C₆ alkyl, or -CH₂OH; each R^c is independently fluoro or C₁-C₃ alkyl; each R³ is independently H, fluoro, C₁-C₃ alkyl, or C₁-C₃ fluoroalkyl; X^a, X^b, X^c and X^d are independently selected from the group consisting of C(H), C(R⁴), N, N(R⁴), S, and O; wherein at least one of X^a, X^b, X^c and X^d is C(H) or C(R⁴); R⁴ is halo, C₁-C₃ alkyl, or C₁-C₃ fluoroalkyl; W^A is S, O, or N(R^W1); R^W1 is selected from the group consisting of C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₃-C₆ cycloalkyl, and C₃-C₆ fluorocycloalkyl; Ring A is a saturated 5- to 8-membered N-containing monocyclic heterocyclyl or a saturated 8- to 10-membered N-containing bridged bicyclic heterocyclyl, wherein the saturated 8- to 10-membered N-containing bridged bicyclic heterocyclyl contains at least one further N atom in addition to the illustrated N atom; R^A is selected from the group consisting of C₁-C₃ alkyl, C₂-C₄ alkenyl, C₁-C_{3 alkoxy,} C₁- C₃ alkoxy(C₁-C₃)alkyl, halo, C₁-C₃ fluoroalkyl, hydroxy, C₁-C₃ hydroxyalkyl, CF₃- C(H)(OH)-, C(H)(F₂)-C(H)(OH)-, cyano, and C₁-C₃ cyanoalkyl; Y is (i) 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; (ii) a 12- to 14-membered tricyclic heterocyclyl, where at least 2 of the rings of the 12- to 14-membered tricyclic heterocyclyl are aromatic, the third ring is unsaturated or aromatic, wherein the 12- to 14-membered tricyclic heterocyclyl contains 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S; or (iii) phenyl or naphthyl; wherein Y is unsubstituted or substituted by 1 to 4 R^Y substituents independently selected from the group consisting of halo, hydroxy, C₁-C₃ alkyl, C₂-C₄ alkynyl, C₁-C₃ fluoroalkyl, C₃-C₆ cycloalkyl, C₃-C₆ fluorocycloalkyl, C₂- C₃ acyl, C₁-C₃ alkoxy, C₁-C₃ fluoroalkoxy, C₁-C₃ alkylthio, C₁-C₃ fluoroalkylthio, amino, C₁-C₃ alkylamino, C₁-C₃ dialkylamino, and cyano; or alternatively, 2 R^Y substituents, together with the carbon atom to which both are attached, form a 3- to 5-membered saturated carbocyclic ring; subscript i is 0, 1, or 2; subscript m is 0, 1, or 2; subscript n is 0, 1, 2, or 3; subscript o1 is 0 or 1; subscript o2 is 0 or 1; subscript o3 is 0 or 1; subscript o4 is 0 or 1; subscript o5 is 1, 2, 3, 4, or 5; and subscript u is 0 or 1. [0032] 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 [0033] 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. [0034] As used throughout this disclosure, “compound(s) of Formula (I)”, “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). The compounds of Formula (I) 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)) herein is understood to include reference to salts thereof, unless otherwise indicated. [0035] “Acyl” refers to a moiety derived by the removal of one or more hydroxyl groups from an oxoacid. An acyl group contains a central carbon atom, a double-bonded oxygen atom to the central carbon atom, and a single-bonded alkyl group to the central carbon atom. In some embodiments, for example, the acyl group can be a C₂ acyl, i.e., acetyl or a C₃ acyl, i.e., proprionyl. [0036] “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. [0037] “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. [0038] “Alkylamino” means one or two alkyl groups linked to an amino group. The bond to the parent moiety is through a nitrogen atom of the amino component. [0039] “Alkylthio” means an alkyl group linked to a sulfur. The bond to the parent group is through the sulfur atom of the group. “Fluoroalkylthio” means an alkylthio that is mono- or multiple-fluoro-substituted. [0040] “Alkoxy” and “alkyl-O-” are used interchangeably and refer to an alkyl group linked to oxygen. The bond to the parent group is through the oxygen atom of the group. [0041] “Alkoxyalkyl” means an alkoxy group linked to an alkyl group. The bond to the parent moiety is through a carbon atom of the alkyl component. [0042] “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. [0043] “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. [0044] “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. [0045] “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. [0046] “Cyano” means a N≡C- group. The bond to the parent group is through the carbon atom. [0047] “Cyanoalkyl” means an -alkyl-CN group in which the alkyl is as previously defined. The bond to the parent moiety is through a carbon atom of the alkyl component. Non- limiting examples of suitable cyanoalkyl groups include cyanomethyl and 3-cyanopropyl. [0048] “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. “Fluorocycloalkyl” means a saturated cyclic hydrocarbon radical that is mono- or multiple-fluoro-substituted, e.g., doubly fluoro-substituted cyclopentyl. [0049] “Cycloalkylene” means a divalent saturated monocyclic, bicyclic, tricyclic or tetracyclic hydrocarbon radical ring system. In contrast to cycloalkyl, two single bonds exist and each single bond attaches to a different parent group. 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. [0050] “Dialkylamino” means an alkylamino as previously defined, wherein the amino atom is substituted by two alkyl substituents, which substitutions can be the same or different, e.g., -N(CH₃)₂ or -N(CH₃)(CH₂CH₃). [0051] “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. “Fluoroalkoxy” includes mono- substituted as well as multiple fluoro-substituted “alkoxy” groups as previously defined. [0052] “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). [0053] “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. [0054] “Heterocyclyl” or “heterocyclic ring” means a partially aromatic, non-aromatic, or 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. The heterocyclyl or heterocyclic ring can be saturated or unsaturated. There are no adjacent oxygen and/or sulfur atoms present in the ring system. In some embodiments, heterocyclyls 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 heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. For instance, in some embodiments, the heterocyclyl can contain N, S, S(O), S(O)₂ and/or O (which are referred to herein as “heteroatom groups”). Non-limiting examples of suitable monocyclic heterocyclyls include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4- dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, phosphorinane, phosphinane, 1- oxophosphinan-1-ium, pyrrolinyl, dihydropyranyl, and the like. 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. For example, “spirocyclic heterocyclyl” means a heterocyclyl having at least two rings sharing only a single atom. [0055] “Heterocyclylene” means a divalent hydrocarbon group radical derived from a heterocyclyl or heterocyclic ring. In contrast to heterocyclyl or heterocyclic ring, two single bonds exist and each single bond attaches to a different parent group. Non-limiting examples of a heterocyclylene include azetidinylene, pyrrolidinylene, and piperidinylene. 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. For example, “bridged bicyclic heterocyclylene” means a heterocyclylene having at least two rings sharing only a single atom. [0056] “Heterocycloalkyl” means a saturated heterocyclyl or heterocyclic ring. The bond to the parent group is through a carbon atom. 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. For example, “spiroheterocycloalkyl” means a heterocycloalkyl having at least two rings sharing only a single atom. “Fused bicyclic heterocycloalkyl” means a heterocycloalkyl having at least two rings sharing two adjacent atoms. “Bridged bicyclic heterocycloalkyl” means a heterocycloalkyl having at least two rings sharing three or more atoms with two bridgehead atoms being connected by a bridge containing at least one atom. [0057] “Hydroxy” means a HO- group in which the bond to the parent moiety is through the oxygen atom. [0058] “Hydroxyalkyl” means a HO-alkyl- group in which alkyl is as previously defined. The bond to the parent moiety is through a carbon atom of the alkyl group. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl. [0059] “Trialkylsilyl” means a silicon radical having three alkyl groups covalently bonded to the silicon atom. [0060] When any variable (e.g., R^x) occurs more than one time in any constituent or in Formula (I) 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., R^x, 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). [0061] 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. [0062] Unless expressly depicted or described otherwise, variables depicted in a structural formula with a “floating” bond, such as R^X, 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 any embodiment thereof, it means that Formula (I) 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. [0063] The wavy line , as used herein, indicates a point of attachment to the rest of the compound. [0064] The compounds of Formula (I) 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) can all independently of one another have S configuration or R configuration. The compounds of Formula (I) 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). 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) 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. [0065] The compounds of Formula (I) 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) may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known absolute configuration.

[0066] 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 be 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.

[0067] The compounds of Formula (I) which contain olefinic double bonds, unless specified otherwise, they are meant to include both E and Z geometric isomers.

[0068] 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).

[0069] Some of the compounds of Formula (I) 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) 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. [0070] In the compounds of Formula (I), 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) 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. [0071] The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When a compound of Formula (I) is acidic, its corresponding salt can be conveniently prepared from pharmaceutically 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 be formed 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. [0072] When a compound of Formula (I) 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) 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) 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) 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.

[0073] Furthermore, the compounds of Formula (I) 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), including the Examples, are intended to be included within the scope of the present disclosure. In addition, some of the compounds of Formula (I) may form solvates with water (z. 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.

[0074] Any pharmaceutically acceptable pro-drug modification of a compound of Formula (I) which results in conversion in vivo to a compound within the scope of this disclosure is also within the scope of this disclosure.

[0075] 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.

[0076] 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) 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) 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) 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) [0077] The dosage regimen utilizing a compound of Formula (I) 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 be 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. [0078] While individual needs vary, determination of optimal ranges of effective amounts of the compounds of Formula (I) 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) 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

[0079] The compounds of Formula (I) 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 existing 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.

[0080] 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.

[0081] Furthermore, the present disclosure provides pharmaceutical compositions which comprise as active component an effective dose of at least one compound of Formula (I) 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.

[0082] 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) 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.

[0083] 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.

[0084] 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. [0085] 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 amount of active compound of a compound of Formula (I) 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) 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) 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.

[0086] 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) 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.

[0087] 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)

[0088] The present application provides a method of modulating RAS-mediated cell signaling comprising contacting a cell with a compound of Formula (I) or a pharmaceutically acceptable salt thereof. Modulation of RAS-mediated signal transduction 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 binding affinity or an increase in GDP binding affinity; (c) an increase in K_off of GTP or a decrease in K_off of GDP; (d) a decrease in the levels of signaling transduction molecules downstream 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.

[0089] 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.

[0090] 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. [0091] 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.

[0092] 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. [0093] 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 determined 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.

[0094] 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).

[0095] 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. [0096] 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 wildtype human KRAS are known in the art.

[0097] 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, 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.

[0098] 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. [0099] 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.

[00100] 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 cell tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary, midline tract carcinoma, mouth cancer; multiple endocrine neoplasia syndromes, multiple myeloma/plasma cell neoplasm, mycosis fungoides, 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)). [00101] 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 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) may provide therapeutic benefit for include, but are not limited to, glandular tumors, carcinoid tumors and undifferentiated carcinomas.

[00102] 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 or 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

[00103] One or more additional pharmacologically active agents may be administered in combination with a compound of Formula (I) (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). 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) 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 pharmaceutically acceptable salts thereof) can be administered in combination with radiation therapy, hormone therapy, surgery or immunotherapy.

[00104] 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 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) 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. In another embodiment, such therapy includes radiation treatment to provide a synergistic or additive therapeutic effect.

[00105] 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 anticancer agents can be classified within one or more of these groups. While certain anticancer 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.

[00106] 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”.

[00107] 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, a matrix-metalloproteinase (MMP) inhibitor, a hepatocyte growth factor inhibitor, a TOR inhibitor, a KDR inhibitor, a VEGF inhibitor, a HIF-1α inhibitor, a HIF-2α 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. [00108] 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. [00109] 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. [00110] 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. [00111] 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; broxuridine; cladribine; cyclophosphamide; cytarabine; emitefur; hydroxyurea; mercaptopurine; nelarabine; pemetrexed; pentostatin; tegafur; and troxacitabine. [00112] Non-limiting examples of platinum analogs include carboplatin, cisplatin, dicycloplatin, heptaplatin, lobaplatin, nedaplatin, oxaliplatin, satraplatin, and triplatin tetranitrate. [00113] Non-limiting examples of enzymes include asparaginase and pegaspargase. [0114] 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. [0115] Non-limiting examples of retinoids include alitretinoin, bexarotene, fenretinide, isotretinoin, liarozole, RII retinamide, and tretinoin. [0116] Non-limiting examples of aziridines include benzodopa, carboquone, meturedopa, and uredopa. [0117] 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. [0118] 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; lanreotide; LDI 200 (Milkhaus); letrozole; leuprorelin; mifepristone; nafarelin; nafoxidine; osaterone; prednisone; thyrotropin alfa; and triptorelin. [0119] 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. [0120] 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. [0121] 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). [0122] 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. [0123] 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. [0124] 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. [0125] 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. [0126] 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. [0127] 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. [0128] 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 (Y ang, 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.

[0129] Non-limiting examples of histone deacetylase (HD AC) inhibitors include belinostat, panobinostat, romidepsin, and vorinostat.

[0130] Non-limiting examples of proteasome inhibitors include bortezomib, carfilzomib, ixazomib, marizomib (salinosporamide a), and oprozomib.

[0131] Non-limiting examples of cell-cycle inhibitors, including CDK inhibitors, include abemaciclib, alvocidib, palbociclib, and ribociclib.

[0132] 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-la inhibitors such as PX 478; HIF-2a inhibitors such as belzutifan and the HIF-2a 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-Angl 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.

[0133] 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).

[0134] Non-limiting examples of VEGF and VEGFR inhibitory agents include bevacizumab, cediranib, CEP 7055, CP 547632, KRN 633, orantinib, pazopanib, pegaptanib, pegaptanib octasodium, semaxanib, sorafenib, sunitinib, VEGF antagonist (Borean, Denmark), and VEGF-TRAP™.

[0135] 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 (IV AX, 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, 0X14503, 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. [0136] 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. [0137] Non-limiting examples of RAF inhibitors include dabrafenib, encorafenib, regorafenib, sorafenib, and vemurafenib. [0138] Non-limiting examples of MEK inhibitors include binimetinib, CI-1040, cobimetinib, PD318088, PD325901, PD334581, PD98059, refametinib, selumetinib, and trametinib. [0139] Non-limiting examples of ERK inhibitors include LY3214996, LTT462, MK-8353, SCH772984, ravoxertinib, ulixertinib, and an ERKi as described in WO 2017/068412. [0140] 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. [0141] 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. [0142] 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, WO 95/16691, WO 96/41807, WO 96/41807 and US 5,256,790; and phosphorus-containing rapamycin derivatives (e.g., WO 05/016252). [0143] Non-limiting examples of MCL-1 inhibitors include AMG-176, MIK665, and S63845. [0144] Non-limiting examples of SHP2 inhibitors include SHP2 inhibitors described in WO 2019/167000 and WO 2020/022323. [0145] 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. [0146] The present disclosure further provides a method for using the compounds of Formula (I) 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) in this combination therapy can be determined as described herein.

[0147] 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, 1-131, 1 -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 1-125, 1 -131, Yb-169, Ir-192 as a solid source, 1-125 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 1-125 or 1-131, 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. [0148] 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 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) with chemotherapeutic agents, immunotherapeutic agents, hormonal therapy agents, therapeutic antibodies, targeted therapy agents, and radiation treatment, to provide a synergistic or additive therapeutic effect.

[0149] 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, 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) 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) 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) 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) and any of the agents described above are administered a few minutes apart, or a few hours apart, or a few days apart.

[0150] 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), 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.

[0151] The present disclosure also provides for the compound of Formula (I), or the pharmaceutically acceptable salt thereof, for use in therapy, or use of the compound of Formula (I), or the pharmaceutically acceptable salt thereof, in therapy. The present disclosure also provides for the compound of Formula (I), or the pharmaceutically acceptable salt thereof, for use in treating cancer, or use of a compound of Formula (I), or the pharmaceutically acceptable salt thereof, for treating cancer. The present disclosure also provides for the compound of Formula (I), or the pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of cancer, or use of the compound of Formula (I), 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 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 the pharmaceutically acceptable salt thereof, and the additional anti -cancer agent for treating cancer. The disclosure also provides the compound of Formula (I), 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 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 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 the pharmaceutically acceptable salt thereof, for treating cancer. The present disclosure also provides for a pharmaceutical composition comprising the compound of Formula (I), 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 the pharmaceutically acceptable salt thereof, and the additional anti -cancer agent, for treating cancer.

Methods of Preparing the Compounds of the Disclosure

[0152] 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-." [0153] 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; 2- MeTHF = 2-methyltetrahydrofuran; Ac = acetyl; AcO = acetate; Am = amyl; t-AmOH = t- amyl alcohol; aq. = aqueous; atm = atmosphere; BBA = tetrahydroxydiboron; BH₃·DMS = borane dimethyl sulfide complex; Bn = benzyl; Boc = tert-butyloxycarbonyl; BOP = ((1H- benzo[d][1,2,3]triazol-1-yl)oxy)tris(dimethylamino)phosphonium hexafluorophosphate(V); B(pin) = (pinacolato)boron; B₂pin₂ = bis(pinacolato)diboron; Bu = butyl; tBu = tert-butyl; tBuO = tert-butoxide; cataCXium A Pd G2 = chloro[(di(1-adamantyl)-N-butylphosphine)- 2-(2-aminobiphenyl)]palladium(II); cataCXium A Pd G3 = mesylate[(di(1-adamantyl)-n- butylphosphine)-2-(2′-amino-1,1′-biphenyl)]palladium(II); Cbz = benzyloxycarbonyl; CbzCl = benzyl chloroformate; CMBP = cyanomethylenetributylphosphorane; conc. = concentrated; CSA = (1R)-(-)-camphor-10-sulfonic acid; DAST = (diethylamino)sulfur trifluoride; Davis reagent = Davis oxaziridine = 3-phenyl-2-(phenylsulfonyl)-1,2- oxaziridine; DCE = 1,2-dichloroethane; DCM = dichloromethane; DHP = 3,4-dihydro-2H- pyran; DIAD = diisopropyl azodicarboxylate; DIEA = DIPEA = N,N- diisopropylethylamine; DMA = N,N-dimethylacetamide; DMAP = 4- (dimethylamino)pyridine = N,N-dimethylpyridin-4-amine; DMF = N,N-dimethylformamide; DMP = dimethyl phthalate; DMS = dimethyl sulfide; DMSO = dimethylsulfoxide; DPEPhos PdCl₂ = dichloro[bis(2-(diphenylphosphino)phenyl)ether]palladium(II); dppf = 1,1'-bis(diphenylphosphino)ferrocene; EDC = N-(3-dimethylaminopropyl)-N′- ethylcarbodiimide; equiv, eq. = equivalent(s); Et = ethyl; EtOAc = ethyl acetate; EtOH = ethanol; GDP = guanosine diphosphate; GTP = guanosine triphosphate; h = hour; HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate=2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; Hex = hex = hexanes; HMDS = hexamethydisilazane; HOBt = 1- hydroxybenzotriazole = 1H-benzo[d][1,2,3]triazol-1-ol; HPLC = high pressure liquid chromatography; IBX = 2-iodoxybenzoic acid; Int = intermediate; i-Pr = = iPr = isopropyl; IPA = i-PrOH = isopropyl alcohol; KHMDS = potassium bis(trimethylsilyl)amide; LAH = lithium aluminum hydride; LCMS = liquid chromatography-mass spectrometry; min = minute; LDA = lithium diisopropylamide; LiHMDS = lithium bis(trimethylsilyl)amide; M = Molar; mCPBA = 3-chlorobenzoperoxoic acid = m-chloroperoxybenzoic acid; Me = methyl; MeCN, ACN = acetonitrile; MeOH = methanol; MO = methoxy; MS = mass spectrometry; Ms = methanesulfonyl; MsCl = methanesulfonyl chloride; Ms₂O = methanesulfonic anhydride; MTBE = tert-butyl methyl ether; N = Normal; NBS = N- bromosuccinimide; NCS = N-chlorosuccinimide; NMR = nuclear magnetic resonance; Pd/C = palladium on carbon; Pd(dppf)Cl₂ = [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pd(OH)₂/C = palladium hydroxide on carbon; Pet. ether = petroleum ether; Ph = phenyl; pin = pinacolato; PPTS = pyridinium p-toluenesulfonate; PyAOP = (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate; PyBOP = (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate; rac = racemic; RP-HPLC = reverse phase HPLC; RPLC = reverse phase liquid chromatography; r.t. = room temperature; SEM = (2- methoxyethyl)trimethylsilane; SEMCl = (2-(chloromethoxy)ethyl)trimethylsilane; SFC = supercritical fluid chromatography; SOS = Son of Sevenless; SPE = solid phase extraction; SPhos Pd G3 = (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl)[2-(2′-amino-1,1′- biphenyl)]palladium(II) methanesulfonate; TBAF = tetra-n-butylammonium fluoride; TBDMS = tert-butyldimethylsilyl; TBDPS = tert-butyldiphenylsilyl; TBDPSCl = tert- butylchlorodiphenylsilyl; TBS = tert-butyl dimethyl silyl; TBSOTf₂ = tert- butyldimethylsilyl trifluoromethanesulfonate; tBu₃P Pd G2 = chloro[(tri-tert- butylphosphine)-2-(2-aminobiphenyl)]palladium(II); TEA = Et₃N = triethylamine; Tf = trifluoromethanesulfonyl; TfO = trifluoromethanesulfonate; Tf₂O = trifluoromethanesulfonic anhydride; TFA = trifluoroacetic acid; THF = tetrahydrofuran; TIPS = triisopropypsilyl; TLC = thin layer chromatography; TMP = trimethyl phosphate; TMS = trimethylsilyl; TMSCN = Trimethylsilyl cyanide; TsOH = p-toluenesulfonic acid = 4-methylbenzenesulfonic acid; UPLC = ultra-performance liquid chromatography; VCD = vibrational circular dichroism; v, v/v = volume, volume to volume; w, w/w = weight, weight to weight; XPhos Pd G2 = chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′- biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II); XPhos Pd G4 = (SP-4-3)- [dicyclohexyl[2′,4′,6′-tris(1-methylethyl)[1,1′-biphenyl]-2-yl]phosphine](methanesulfonato- κO)[2′-(methylamino-κN)[1,1′-biphenyl]-2-yl-κC]palladium; μm = micrometer. EXAMPLES [0154] Concentration refers to the removal of the volatile components at reduced pressure (e.g., by rotary evaporation) unless otherwise noted. All temperatures are in degrees Celsius unless otherwise noted. Mass spectra (MS) were measured by electrospray ion- mass spectroscopy (ESI) in positive ion detection mode and m/z refers to the [M+H]+ ion unless otherwise noted.1H NMR spectra were recorded at 400-600 MHz at ambient temperature unless otherwise noted. Protons reported as 0.5 H are due to rotameric signals. RP-HPLC refers to reverse-phase HPLC on C18-functionalized preparative or semi- preparative columns with gradient elution using acetonitrile and water modified with trifluoroacetic acid or ammonium hydroxide as eluents and fractions were lyophilized or concentrated by rotary evaporation unless otherwise noted. Purification by column chromatography on silica gel was accomplished using a flash silica gel chromatography system (e.g., ISCO® or Biotage®) and commercial pre-packed silica gel columns with elution using the stated solvent systems. Compounds described herein were synthesized as the racemates unless otherwise noted in the experimental procedures and compound tables. Certain products/intermediates in the examples include indication of “Peak 1” and/or “Peak 2”, which refer to the order of elution of the indicated product/intermediate from the chromatography column (e.g., an SFC column) used to isolate the compound under the specified conditions. Thus, for example, Peak 1 refers to the first eluting compound, e.g., first eluting stereoisomer, under the specified conditions. Intermediate Syntheses: [0155] Intermediate 1: (5-(difluoromethyl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-4-yl)boronic acid (Int-1)

[0156] Step A: 2-bromo-6-fluoro-3-iodo-4-methylbenzaldehyde (Int-1A) [0157] To a solution of diisopropylamine (15 mL, 106 mmol) in THF (45 ml) was added n- butyllithium (40 mL, 100 mmol, 2.5 M in hexanes) at -78 °C, and the mixture was stirred at -78 °C for 30 min to give LDA. To a solution of 1-bromo-5-fluoro-2-iodo-3-methylbenzene (24 g, 76 mmol) in THF (45 mL) was added LDA (91 mL, 91 mmol, 1 M in THF) at -78 °C under N₂ atmosphere. The mixture was stirred at -78 °C for 0.5 h, charged with ethyl formate (6.21 g, 84 mmol), and the resulting mixture was stirred at -78 °C for 15 min. The mixture was slowly poured into sat. aq. NH₄Cl (200 mL) and extracted with EtOAc (3 x 400 mL). The organic layer was dried over sodium sulfate, filtered, and the solvent was concentrated in vacuo. The residue was purified by silica gel chromatography (5% EtOAc in petroleum ether) to give 2-bromo-6-fluoro-3-iodo-4-methylbenzaldehyde (Int-1A).¹H NMR (400MHz, CDCl₃) δ 10.16 - 10.02 (m, 1H), 7.05 (d, J=11.0 Hz, 1H), 2.56 (s, 3H). [0158] Step B: 4-bromo-5-iodo-6-methyl-1H-indazole (Int-1B) [0159] To a solution of 2-bromo-6-fluoro-3-iodo-4-methylbenzaldehyde (Int-1A) (18.7 g, 54.5 mmol) in DMSO (200 mL) was added hydrazine (19.84 mL, 327 mmol, 85% aqueous solution) at 20 °C under N₂ atmosphere. The reaction mixture was stirred at 120 °C for 12 h. The reaction mixture was poured into ice water (50 mL) and extracted with EtOAc (3 x 400 mL). The organic layer was washed with sat. aq. NaCl (2 x 50 mL), dried over sodium sulfate, filtered, and the solvent was concentrated in vacuo to give 4-bromo-5-iodo-6- methyl-1H-indazole (Int-1B), which was used directly in the next step without further purification. MS (ESI): m/z (M+H)⁺ 337, 339. [0160] Step C: 4-bromo-5-iodo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Int- 1C) [0161] To a solution of 4-bromo-5-iodo-6-methyl-1H-indazole (Int-5B) (15.5 g, 46.0 mmol) in THF (200 mL) was added 4-methylbenzenesulfonic acid (1.584 g, 9.20 mmol) and DHP (8.41 mL, 92 mmol) at 20 °C, and the mixture was stirred at 50 °C for 12 h. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel chromatography (0 to 15% EtOAc in petroleum ether). The collected solid was diluted with MeOH (50 mL), and the resulting mixture was stirred for 5 min and then filtered. The solid was collected and dried in vacuum to afford 4-bromo-5-iodo-6-methyl-1-(tetrahydro-2H- pyran-2-yl)-1H-indazole (Int-1C). MS (ESI): m/z (M+H)⁺ 421, 423.¹H NMR (400MHz, CDCl₃) δ 7.84 (s, 1H), 7.44 - 7.35 (m, 1H), 5.58 (dd, J=2.7, 9.1 Hz, 1H), 4.00 - 3.85 (m, 1H), 3.73 - 3.59 (m, 1H), 2.67 - 2.58 (m, 3H), 2.52 - 2.36 (m, 1H), 2.16 - 1.93 (m, 2H), 1.76 - 1.51 (m, 3H). [0162] Step D: 4-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-vinyl-1H-indazole (Int- 1D) [0163] To a solution of 4-bromo-5-iodo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H- indazole (Int-1C) (6 g, 14.25 mmol) in t-amyl alcohol (60 ml) and water (20 mL) was added potassium vinyltrifluoroborate (2.481 g, 18.52 mmol), Cs₂CO₃ (13.93 g, 42.7 mmol), and Pd(PPh₃)₄ (0.823 g, 0.712 mmol) at 25 °C. The mixture was stirred at 100 °C for 16 h under N₂. The reaction mixture was quenched with H₂O (20 mL) and extracted with EtOAc (200 x 3 mL). The organic layer was dried over Na₂SO₄, filtered, and the solvent was concentrated in vacuo. The residue was purified by silica gel chromatography (0 to 15% EtOAc in petroleum ether) to give 4-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-vinyl- 1H-indazole (Int-1D). MS (ESI): m/z (M+H)⁺ 321, 323. [0164] Step E: 4-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5- carbaldehyde (Int-1E) [0165] To a solution of 4-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-vinyl-1H- indazole (Int-1D) (4.5 g, 12.89 mmol) in THF (50 mL) and water (50 mL) was added sodium periodate (11.03 g, 51.6 mmol), 2,6-lutidine (2.76 g, 25.8 mmol), and potassium osmate(VI) dihydrate (0.475 g, 1.289 mmol) at 25 °C, and the mixture was stirred at 50 °C for 2 h. The reaction mixture was quenched with sat. aq. Na₂SO₃ (20 mL), and the mixture was extracted with EtOAc (3x 200 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/EtOAc = 5/1) to give 4-bromo- 6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carbaldehyde (Int-1E). MS (ESI): m/z (M+H)⁺ 323, 325.¹H NMR (400MHz, CDCl₃) δ 10.62 - 10.44 (m, 1H), 8.09 (s, 1H), 7.30 (s, 1H), 5.62 (dd, J=2.8, 9.1 Hz, 1H), 4.02 - 3.85 (m, 1H), 3.69 (ddd, J=3.0, 10.0, 11.6 Hz, 1H), 2.66 (d, J=0.7 Hz, 3H), 2.51 - 2.34 (m, 1H), 2.17 - 1.92 (m, 2H), 1.78 - 1.56 (m, 3H). [0166] Step F: 4-bromo-5-(difluoromethyl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H- indazole (Int-1F) [0167] To a solution of 4-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5- carbaldehyde (Int-1E) (3 g, 9.28 mmol) in DCM (30 mL) was added DAST (6.13 mL, 46.4 mmol) at -78 °C under N₂ atmosphere, and the mixture was stirred at 25 °C for 12 h. The reaction mixture was added dropwise to aq. NaHCO₃ (50 mL), and the mixture was extracted with EtOAc (3 x 120 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/EtOAc = 5/1) to give 4-bromo-5-(difluoromethyl)-6- methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Int-1F). MS (ESI): m/z (M+H)⁺ 345, 347.¹H NMR (400MHz, CDCl₃) δ 7.96 (s, 1H), 7.45 - 7.06 (m, 2H), 5.61 (dd, J=2.8, 9.1 Hz, 1H), 3.97 - 3.88 (m, 1H), 3.72 - 3.60 (m, 1H), 2.62 (s, 3H), 2.51 - 2.38 (m, 1H), 2.14 - 1.95 (m, 2H), 1.77 - 1.54 (m, 3H). [0168] Step G: (5-(difluoromethyl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4- yl)boronic acid (Int-1) [0169] To a solution of 4-bromo-5-(difluoromethyl)-6-methyl-1-(tetrahydro-2H-pyran-2- yl)-1H-indazole (Int-1F) (0.308 g, 0.892 mmol) in THF (8 mL) was added n-butyllithium (1.6 M in hexanes, 0.725 mL, 1.160 mmol) at -78 °C. The resulting mixture was stirred at this temperature for 30 min. Then, triisopropyl borate (618 μL, 2.68 mmol) was added via syringe. The mixture was stirred at -78 °C for 10 min. The mixture was quenched with sat. aq. NH₄Cl (2 mL) and extracted with EtOAc (3 x 20 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. (5-(difluoromethyl)-6-methyl-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)boronic acid (Int-1) was obtained and used directly in subsequent step(s) without further purification. MS (ESI): [M+H]⁺ m/z: 311. [0170] Intermediate 2: (6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H- indazol-4-yl)boronic acid (Int-2)

[0171] Step A: 1-bromo-5-fluoro-2-iodo-3-methylbenzene (Int-2A) [0172] 2-bromo-4-fluoro-6-methylaniline (200 g, 0.983 mol) was dissolved in MeCN (800 mL). The resulting mixture was cooled down to 0 °C. Concentrated HCl (12 M, 245 mL) was added into the reaction mixture while maintaining the reaction temperature at 0 °C. A solution of NaNO₂ (81.1 g, 1.18 mol eq.) in water (400 mL) was added dropwise into the reaction mixture maintaining the reaction temperature at 0 °C. The resulting mixture was stirred for 0.5 h at 0 °C. Then a solution of KI (195 g, 1.18 mol) in water (400 mL) was added dropwise into the reaction mixture at 0 °C. The resulting mixture was warmed up to room temperature and stirred for 12 h at 20 °C. This reaction was repeated in one additional batch using the above conditions. The two batches of reactions were combined. The product mixture was adjusted to pH 8-9 by aq. NaOH and the aqueous phase was extracted with EtOAc (2.00 L × 2). The organic phase was dried over Na₂SO₄, filtered, and concentrated. The residue obtained was purified by column chromatography (SiO₂, Petroleum ether : Ethyl acetate = 1 : 0 to 0 : 1) to afford 1-bromo-5-fluoro-2-iodo-3-methylbenzene (Int-2A). ¹H NMR (400 MHz, CDCl₃) δ 7.27 - 7.22 (m, 1H), 6.95 (dd, J = 2.4, 8.8 Hz, 1H), 2.56 (s, 3H). [0173] Step B: 1-bromo-5-fluoro-3-methyl-2-(trifluoromethyl)benzene (Int-2B) [0174] 1-bromo-5-fluoro-2-iodo-3-methylbenzene (Int-2A) (100 g, 0.317 mol) was dissolved in DMF (1.50 L). To this mixture were added CuI (514 g, 2.70 mol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (518 g, 2.70 mol) at 25 °C. The reaction mixture was heated and stirred for 12 h at 60 °C. This reaction was repeated in 3 additional batches using the above conditions. The four batches of reactions were combined and quenched with water (24 L). The mixture was extracted with petroleum ether (8.00 L × 2). The combined organic layers were washed with brine (4 L × 2) and dried over Na₂SO₄. The dried solution was filtered and the filtrate was concentrated in vacuo to afford a crude material containing 1-bromo-5-fluoro-3-methyl-2-(trifluoromethyl)benzene (Int-2B), which was used directly in the next step without further purification. [0175] Step C: 2-bromo-6-fluoro-4-methyl-3-(trifluoromethyl)benzaldehyde (Int-2C) [0176] 1-bromo-5-fluoro-3-methyl-2-(trifluoromethyl)benzene (Int-2B) (100 g, 0.382 mol) was dissolved in 2-MeTHF (500 mL). The reaction mixture was cooled down to -65 °C. A 2 M solution of LDA (213 mL, 426 mmol) was added into the mixture at -65 °C. The reaction mixture was stirred for 0.5 h at -65 °C. To this mixture was added dropwise DMF (31.2 g, 0.420 mol) at -65 °C. The reaction mixture was stirred for 2 h at -65 °C. This reaction was repeated in 2 additional batches using the above conditions. The three batches of reactions were combined. The reaction mixture pH was adjusted to 3-4 by using 1 M HCl and the aqueous phase was extracted with 2-MeTHF (500 mL × 2). The organic phase was dried over Na₂SO₄, filtered, and concentrated to obtain 2-bromo-6-fluoro-4-methyl-3- (trifluoromethyl)benzaldehyde (Int-2C), which was used directly in the next step without further purification. [0177] Step D: 4-bromo-6-methyl-5-(trifluoromethyl)-1H-indazole (Int-2D) [0178] 2-bromo-6-fluoro-4-methyl-3-(trifluoromethyl)benzaldehyde (Int-2C) (100 g, 0.351 mol) was dissolved in 2-MeTHF (800 mL). To this mixture was added N₂H₄·H₂O (53.7 g, 1.05 mol) at 25 °C. The mixture was heated and stirred for 2 h at 60 °C. The product mixture was quenched with water (400 mL) and extracted with EtOAc (200 mL × 2). The combined organic layers were washed with brine (200 mL) and dried over Na₂SO₄. The dried solution was filtered and the filtrate was concentrated in vacuo to give the residue. This reaction was repeated in 2 additional batches using the above conditions. The three batches of reactions were combined. The residue obtained was triturated with DCM (100 mL) at 15 °C for 2 h. The solid was collected by filtration to afford 4-bromo-6-methyl-5- (trifluoromethyl)-1H-indazole (Int-2D). ¹H NMR (400 MHz, CDCl₃) δ 10.61 - 10.20 (m, 1H), 8.20 (d, J = 0.8 Hz, 1H), 7.34 (d, J = 0.6 Hz, 1H), 2.67 - 2.63 (m, 3H). [0179] Step E: 4-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H- indazole (Int-2E) [0180] 4-bromo-6-methyl-5-(trifluoromethyl)-1H-indazole (Int-2D) (60.0 g, 0.215 mol) was dissolved in DCM (240 mL) and MeCN (240 mL). DHP (21.7 g, 0.258 mol) and TsOH·H₂O (8.18 g, 0.043 mol) were added to the mixture at 20 °C. The reaction mixture was stirred for 12 h at 25 °C. Water (200 mL) was added to the product mixture. The resulting mixture was extracted with DCM (200 mL × 2). The combined organic layers were washed with brine (200 mL) and dried over Na₂SO₄. The dried solution was filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by column chromatography (SiO₂, Petroleum ether: Ethyl acetate = 1:0 to 0:1) to afford 4- bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazole (Int-2E). ¹H NMR (400 MHz, CDCl₃- d) δ 8.12 (s, 1H), 7.44 (s, 1H), 5.69 (dd, J = 3, 9 Hz, 1H), 4.09 - 3.94 (m, 1H), 3.81 - 3.69 (m, 1H), 2.69 - 2.63 (m, 3H), 2.56 - 2.43 (m, 1H), 2.19 - 2.14 (m, 1H), 2.12 - 2.04 (m, 1H), 1.87 - 1.73 (m, 2H), 1.71 - 1.63 (m, 1H). [0181] Step F: (6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4- yl)boronic acid (Int-2) [0182] To a solution of 4-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazole (Int-2E) (1.2 g, 3.30 mmol) in MeOH (15 mL) was added tetrahydroxydiboron (1.185 g, 13.22 mmol), TEA (1.382 mL, 9.91 mmol), and cataCXium A Pd G2 (0.110 g, 0.165 mmol). The mixture was stirred at r.t. for 16 h under N₂ atmosphere. The mixture was concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-20% EE (EtOAc:EtOH=3:1) / petroleum ether) to give (6- methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)boronic acid (Int-2). MS (ESI) [M+H]⁺: m/z 329. [0183] Intermediate 3: (5-((triisopropylsilyl)ethynyl)-2-((2- (trimethylsilyl)ethoxy)methyl)-2H-thieno[3,2-f]indazol-4-yl)boronic acid (Int-3)

[0184] Step A: Ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate (Int- 3A) [0185] To a solution of ethyl 1H-pyrazole-4-carboxylate (13.75 g, 98 mmol) in DCM (100 mL) at 0 °C was added N,N-diisopropylethylamine (25.4 g, 196 mmol). The mixture was stirred for 15 min, then (2-(chloromethoxy)ethyl)trimethylsilane (24.54 g, 147 mmol) was added slowly. The mixture was warmed to room temperature and stirred for 16 h. The mixture was quenched with water (50 mL) and extracted with DCM (3 x 200 mL). The combined organic layer was dried over Na₂SO₄, filtered, and the filtrate was evaporated under reduced pressure. The crude product was purified by flash silica gel chromatography (0 to 35% EtOAc in petroleum ether) to give ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazole-4-carboxylate (Int-3A). MS (ESI) [M+H]⁺: m/z 271. [0186] Step B: N-methoxy-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4- carboxamide (Int-3B) [0187] To a mixture of ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4- carboxylate (Int-3A) (20 g, 74.0 mmol) and N,O-dimethylhydroxylamine hydrochloride (10.82 g, 111 mmol) in dry THF (350 mL) was added iPrMgBr (77 mL, 222 mmol, 2.9M in 2-methyltetrahydrofuran) at 0 °C. The mixture was warmed to 25 °C and stirred for 16 h. The mixture was quenched with sat. aq. NH₄Cl (100 mL) and extracted with EtOAc (3 x 300 mL). The organic layer was dried over Na₂SO₄, filtered, and the filtrate was evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (0 to 50% EtOAc in petroleum ether) to give N-methoxy-N- methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide (Int-3B). MS (ESI) [M+H]⁺: m/z 286. [0188] Step C: 3,4-dibromothiophene-2-carbaldehyde (Int-3C) [0189] To the solution of 3,4-dibromothiophene (12.38 g, 51.2 mmol) in THF (120 mL) was added LDA (102 mL, 102 mmol, 1 M in THF) at -78 °C and the reaction mixture was stirred at -78 °C for 2 h. N,N-dimethylformamide (4.73 mL, 61.4 mmol) was added dropwise to the reaction mixture, warmed to 25 °C, and stirred for 1 h. The mixture was quenched with aqueous NH₄Cl (100 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layer was washed with brine (2 x 50 mL), dried over Na₂SO₄, filtered, and evaporated under reduced pressure. The crude product was purified by flash silica gel chromatography (0 to 50% EtOAc in petroleum ether) to give 3,4-dibromothiophene-2- carbaldehyde (Int-3C).¹H NMR (400 MHz, CDCl₃) δ: 9.96 (d, J=1.4 Hz, 1H), 7.76 (d, J=1.3 Hz, 1H). [0190] Step D: 5-((3,4-dibromothiophen-2-yl)(hydroxy)methyl)-N-methoxy-N-methyl-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide (Int-3D) [0191] To a stirred solution of N-methoxy-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazole-4-carboxamide (Int-3B) (6.20 g, 21.7 mmol) in THF (150 mL) was added lithium diisopropylamide (22.81 mL, 22.81 mmol, 1 M in THF) at -78 °C under N₂ atmosphere and the reaction was stirred at -78 °C for 0.5 h.3,4-dibromothiophene-2- carbaldehyde (Int-3C) (8.80 g, 32.6 mmol) in THF (10 mL) was added at -78 °C and the reaction was warmed 25 °C and stirred for 16 h. The mixture was quenched with sat. aq. NH₄Cl (40 mL) and extracted with EtOAc (3 x 200 mL). The organic layers were washed with brine (2 x 50 mL), dried over Na₂SO₄, filtered, and the solvent was evaporated under reduced pressure to give the crude product. The residue was purified by flash silica gel chromatography (0 to 50% EtOAc in petroleum ether) to give 5-((3,4-dibromothiophen-2- yl)(hydroxy)methyl)-N-methoxy-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazole-4-carboxamide (Int-3D).¹H NMR (400 MHz, CDCl₃) δ: 8.04 (s, 1H), 7.28 (s, 1H), 6.39 (s, 1H), 5.56 (d, J=8.1 Hz, 2H), 3.70 (s, 3H), 3.39-3.55 (m, 2H), 3.37 (s, 3H), 0.60-0.92 (m, 2H), -0.05 (s, 9H). [0192] Step E: 5-((3,4-dibromothiophen-2-yl)methyl)-N-methoxy-N-methyl-1H-pyrazole- 4-carboxamide (Int-3E) [0193] To a solution of 5-((3,4-dibromothiophen-2-yl)(hydroxy)methyl)-N-methoxy-N- methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide (Int-3D) (7.38 g, 13.29 mmol) in DCM (18 mL) was added triethylsilane (36.5 mL, 229 mmol) and TFA (18.25 mL, 237 mmol) at 25 °C. The mixture was warmed to 60 °C and stirred for 5 h. After 5 h, the reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with DCM (50 mL) and adjusted to pH ~8 with sat. aq. NaHCO₃. The layers were separated and the organic layer was washed with brine (2 x 30 mL), dried with Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0 to 100% EtOAc in petroleum ether) to give 5-((3,4-dibromothiophen-2- yl)methyl)-N-methoxy-N-methyl-1H-pyrazole-4-carboxamide (Int-3E).¹H NMR (400 MHz, CDCl₃) δ: 8.07 (s, 1H), 7.25 (s, 1H), 4.63 (s, 2H), 3.69 (s, 3H), 3.36 (s, 3H). [0194] Step F: 3-((3,4-dibromothiophen-2-yl)methyl)-N-methoxy-N-methyl-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide (Int-3F) [0195] To a solution of 5-((3,4-dibromothiophen-2-yl)methyl)-N-methoxy-N-methyl-1H- pyrazole-4-carboxamide (Int-3E) (4.85 g, 11.9 mmol) in DCM (50 mL) was added N,N- diisopropylethylamine (3.06 g, 23.7 mmol), and the mixture was stirred at 0 °C for 15 min. (2-(chloromethoxy)ethyl)trimethylsilane (2.96 g, 17.78 mmol) was added slowly at 0 °C. The mixture was warmed to 25 °C and stirred for 2 h. The mixture was quenched with H₂O (10 mL) and extracted with DCM (3 x 50 mL). The combined organic layer was dried over Na₂SO₄, filtered, and the filtrate was evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (0 to 100% EtOAc in petroleum ether) to give 3-((3,4-dibromothiophen-2-yl)methyl)-N-methoxy-N- methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide (Int-3F). MS (ESI) [M+H]⁺: m/z 538. [0196] Step G: 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-thieno[3,2-f]indazol-4-ol (Int-3G) [0197] To a stirred solution of 3-((3,4-dibromothiophen-2-yl)methyl)-N-methoxy-N- methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide (Int-3F) (2 g, 3.71 mmol) in THF (20 mL) was added dropwise isopropylmagnesium chloride lithium chloride complex (5.70 mL, 7.42 mmol, 1.3 M in THF) at 0 °C. The reaction was warmed to 25 °C and stirred for 16 h under N₂ atmosphere. The mixture was quenched with sat. aq. NH₄Cl (15 mL) and extracted with EtOAc (3 x 50 mL). The organic layer was dried over Na₂SO₄, filtered, and the filtrate was evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (0 to 35% EtOAc in petroleum ether) to give 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H- thieno[3,2-f]indazol-4-ol (Int-3G). MS (ESI) [M+H]⁺: m/z 399. [0198] Step H: 5-((triisopropylsilyl)ethynyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H- thieno[3,2-f]indazol-4-ol (Int-3H) [0199] To a solution of 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-thieno[3,2- f]indazol-4-ol (Int-3G) (620 mg, 1.552 mmol) in triethylamine (15 mL) was added ethynyltriisopropylsilane (425 mg, 2.329 mmol), copper(I) iodide (29.6 mg, 0.155 mmol), triphenylphosphine (40.7 mg, 0.155 mmol), and bis(triphenylphosphine)palladium(II) dichloride (54.5 mg, 0.078 mmol) at 25 °C under N₂ atmosphere. The mixture was heated to 80 °C and stirred for 2 h. The reaction mixture was cooled and evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (0 to 10% EtOAc in petroleum ether) to give 5-((triisopropylsilyl)ethynyl)- 2-((2-(trimethylsilyl)ethoxy)methyl)-2H-thieno[3,2-f]indazol-4-ol (Int-3H). MS (ESI) [M+H]⁺: m/z 501. [0200] Step I: 5-((triisopropylsilyl)ethynyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H- thieno[3,2-f]indazol-4-yl trifluoromethanesulfonate (Int-3I) [0201] To a solution of 5-((triisopropylsilyl)ethynyl)-2-((2-(trimethylsilyl)ethoxy)methyl)- 2H-thieno[3,2-f]indazol-4-ol (Int-3H) (442 mg, 0.883 mmol) in DCM (8 mL) under N₂ atmosphere was added N,N-diisopropylethylamine (0.462 mL, 2.65 mmol) at 0 °C and the mixture was stirred at 0 °C for 10 min. Trifluoromethanesulfonic anhydride (0.224 mL, 1.324 mmol) was added to the above mixture. The reaction was stirred at 0 °C for 1 h under N₂ atmosphere. The reaction mixture was warmed to room temperature and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (petroleum ether/EtOAc = 10/1) to give 5-((triisopropylsilyl)ethynyl)-2-((2- (trimethylsilyl)ethoxy)methyl)-2H-thieno[3,2-f]indazol-4-yl trifluoromethanesulfonate (Int- 3I). MS (ESI) [M+H]⁺: m/z 633. [0202] Step J: (5-((triisopropylsilyl)ethynyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H- thieno[3,2-f]indazol-4-yl)boronic acid (Int-3) [0203] To a solution of 5-((triisopropylsilyl)ethynyl)-2-((2-(trimethylsilyl)ethoxy)methyl)- 2H-thieno[3,2-f]indazol-4-yl trifluoromethanesulfonate (Int-3I) (424 mg, 0.670 mmol) in MeOH/THF (5 mL, 3:1 v/v) was added hypodiboric acid (360 mg, 4.02 mmol) and cataCXium A Pd G2 (44.8 mg, 0.067 mmol) and TEA (339 mg, 3.35 mmol), and the mixture was stirred at 25 °C for 2 h. The mixture was diluted with water (3 mL) and extracted with EtOAc (3 x 10 mL). The organic layer was dried over Na₂SO₄, filtered, and the filtrate was evaporated under reduced pressure. The crude product was purified by flash silica gel chromatography (0 to 35% EtOAc in petroleum ether) to give (5- ((triisopropylsilyl)ethynyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-thieno[3,2-f]indazol-4- yl)boronic acid (Int-3). MS (ESI) [M+H]⁺: m/z 529. [0204] Intermediate 4: 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-6,7- dihydrocyclopenta[f]indazol-5(1H)-one (Int-4) [0205] Step A: 7-bromo-5-fluoro-2,3-dihydrospiro[indene-1,2'-[1,3]dioxolane] (Int-4A) [0206] Five reactions of the following were performed in parallel.7-bromo-5-fluoro-2,3- dihydro-1H-inden-1-one (60.0 g, 262 mmol) was dissolved in toluene (2.58 L) at room temperature. Then, ethylene glycol (325 g, 5.24 mol) and TsOH•H₂O (9.97 g, 52.4 mmol) were added to the mixture at room temperature. A Dean-Stark trap was added to the reactor and the reaction was heated to 140 °C for 19 h. The five reactions were cooled to room temperature, combined, and partitioned between EtOAc (3 x 2.50 L) and sat. aq. NaHCO₃ (3.00 L). The organic phase was washed with water (3 x 2.50 L) and brine, dried over Na₂SO₄, filtered, and concentrated. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc = 50/1 to 1/1) to provide 7-bromo-5-fluoro-2,3- dihydrospiro[indene-1,2'-[1,3]dioxolane] (Int-4A).¹H NMR (400MHz, CDCl₃) δ 7.18 (dd, J = 8.4, 2.0 Hz, 1H), 6.89 (dd, J = 8.4, 1.2 Hz, 1H), 4.32-4.36 (m, 2H), 4.09-4.11 (m, 2H), 2.90 (t, J = 7.2 Hz, 2H), 2.32 (t, J = 7.2 Hz, 2H). [0207] Step B: 7-bromo-5-fluoro-2,3-dihydrospiro[indene-1,2'-[1,3]dioxolane]-6- carbaldehyde (Int-4B) [0208] Two reactions of the following were performed in parallel.7-bromo-5-fluoro-2,3- dihydrospiro[indene-1,2'-[1,3]dioxolane] (Int-4A) (80.0 g, 293 mmol) was dissolved in THF (1.60 L) at room temperature. The reaction was cooled to -78 °C and LDA (220 mL, 440 mmol, 2 M in THF) was added. The reaction was stirred at -78 °C for 1 h. Then, DMF (85.7 g, 1.17 mol) was added to the mixture and the reaction was stirred at -78 °C for 0.5 h. The two reactions were combined and quenched with sat. aq. NH₄Cl (3.00 L). The reaction mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (1.00 L), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue. The crude residue was triturated with MTBE (500 mL) for 30 min to provide 7-bromo-5-fluoro-2,3-dihydrospiro[indene-1,2'-[1,3]dioxolane]-6- carbaldehyde (Int-4B).¹H NMR (400MHz, CDCl₃) δ 10.43 (s, 1H), 7.01 (d, J = 10.0 Hz, 1H), 4.34-4.36 (m, 2H), 4.10-4.14 (m, 2H), 2.95 (t, J = 7.2 Hz, 2H), 2.34 (t, J = 7.2 Hz, 2H). [0209] Step C: 4-bromo-6,7-dihydro-1H-spiro[cyclopenta[f]indazole-5,2'-[1,3]dioxolane] (Int-4C) [0210] Two reactions of the following were performed in parallel.7-bromo-5-fluoro-2,3- dihydrospiro[indene-1,2'-[1,3]dioxolane]-6-carbaldehyde (Int-4B) (80.0 g, 266 mmol) was dissolved in DMSO (133 mL) and N₂H₄•H₂O (204 g, 3.99 mol) was added to the mixture at room temperature. The reaction was heated to 120 °C for 1.5 h. The two reaction mixtures were combined and quenched with water (1.0 L). The reaction mixture was extracted with EtOAc (2 x 500 mL) and the combined organic layers were washed with brine (500 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc = 50/1 to 0/1) to afford 4-bromo-6,7-dihydro-1H-spiro[cyclopenta[f]indazole-5,2'-[1,3]dioxolane] (Int-4C).¹H NMR (400MHz, DMSO-d₆) δ 13.25 (s, 1H), 8.02 (s, 1H), 7.37 (s, 1H), 4.24 (t, J = 3.6 Hz, 2H), 4.03 (t, J = 3.6 Hz, 2H), 2.93 (t, J = 6.4 Hz, 2H), 2.24 (t, J = 7.2 Hz, 2H). [0211] Step D: 4-bromo-6,7-dihydrocyclopenta[f]indazol-5(1H)-one (Int-4D) [0212] 4-bromo-6,7-dihydro-1H-spiro[cyclopenta[f]indazole-5,2'-[1,3]dioxolane] (Int-4C) (100 g, 339 mmol) was dissolved in acetone (1.00 L) and H₂O (200 mL) at room temperature. Then, HCl (200 mL, 6 M in H₂O) was added to the mixture at room temperature. The reaction was heated to 60 °C for 0.5 h. After 0.5 h, the reaction was cooled to room temperature and the pH was adjusted to ~7-8 with sat. aq. NaHCO₃. The precipitated solid was collected by filtration, washed with water, and dried to afford 4- bromo-6,7-dihydrocyclopenta[f]indazol-5(1H)-one (Int-4D).¹H NMR (400 MHz, DMSO- d₆) δ 13.56 (s, 1H), 8.23 (s, 1H), 7.58 (s, 1H), 3.15 (t, J = 6.8 Hz, 2H), 2.74 (t, J = 6.8 Hz, 2H). [0213] Step E: 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-6,7-dihydrocyclopenta[f]indazol- 5(1H)-one (Int-4) [0214] 4-bromo-6,7-dihydrocyclopenta[f]indazol-5(1H)-one (Int-4D) (75.0 g, 299 mmol) was dissolved in toluene (1350 mL) at 20 ºC and 3,4-dihydro-2H-pyran (100 g, 1.19 mol) and CSA (6.94 g, 29.9 mmol) was added to the mixture at room temperature. The reaction mixture was heated to 100 ºC and stirred for 3 h. The reaction was quenched with sat. aq. NH₄Cl (2.0 L) and the organic layer was separated. The aqueous phase was extracted with DCM (2 x 0.5 L) and the combined organic layers were washed with brine (0.5 L), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude residue was triturated with a mixture of MTBE and petroleum ether (3:2, 500 mL) at 25 ºC for 30 mins to afford 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-6,7- dihydrocyclopenta[f]indazol-5(1H)-one (Int-4).1H NMR (400MHz, CDCl₃) δ 8.20 (s, 1H), 7.53 (s, 1H), 5.72 (dd, J = 9.2, 3.2 Hz, 1H), 4.00-4.03 (m, 1H), 3.76-3.77 (m, 1H), 3.20-3.23 (m, 2H), 2.81-2.85 (m, 2H), 2.49-2.53 (m, 1H), 2.08-2.18 (m, 2H), 1.70-1.78 (m, 3H). [0215] Intermediate 5: (5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7- tetrahydrocyclopenta[f]indazol-4-yl)boronic acid (Int-5) [0216] Step A: 4-bromo-5-methylene-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7- tetrahydrocyclopenta[f]indazole (Int-5A) [0217] To a solution of methyltriphenylphosphonium bromide (6.39 g, 17.90 mmol) in THF (59.7 ml) was added potassium tert-butoxide (17.90 mL, 17.90 mmol, 1 M) at 25 °C and was stirred for 30 min.4-bromo-1-(tetrahydro-2H-pyran-2-yl)-6,7- dihydrocyclopenta[f]indazol-5(1H)-one (Int-4) (3 g, 8.95 mmol) was added as a mixture in THF (5 mL) at 0 °C and was stirred at 25 °C for 1 h. The mixture was quenched with sat. NaHCO₃ (50 mL, aq.), and extracted with EtOAc (50 mL x 3). The organic layer was dried over Na₂SO₄, filtered, and the filtrate was concentrated in vacuum. The residue was purified by silica gel column chromatography (0-15% EtOAc in hex) to afford 4-bromo-5- methylene-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7-tetrahydrocyclopenta[f]indazole (Int-5A). [M+H]⁺ Found: 333, 335. [0218] Step B: 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7- tetrahydrocyclopenta[f]indazole (Int-5B) [0219] 4-bromo-5-methylene-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7- tetrahydrocyclopenta[f]indazole (2.5 g, 7.50 mmol) was dissolved in EtOAc (50.0 ml) and rhodium (3.09 g, 1.500 mmol) was added. Mixture was bubbled through with H₂ for 10 minutes and heated at 50 °C under H₂ balloon for 1 h. The reaction was cooled, degassed with bubbling N₂, and filtered through a pad of CELITE®. The filtrate was concentrated and purified by silica gel column chromatography (0-50% EtOAc in hexane) to afford 4- bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7-tetrahydrocyclopenta[f]indazole (Int-5B). [M+H]⁺ Found: 335, 337. [0220] Step C: 4-bromo-5-methyl-1,5,6,7-tetrahydrocyclopenta[f]indazole (Int-5C) [0221] 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7- tetrahydrocyclopenta[f]indazole (Int-5B) (2.46 g, 7.34 mmol) was taken up in 2-propanol (24.46 mL) and 4 N HCl in 1,4-dioxane (12.23 mL) was added. Reaction was stirred at 45 °C overnight, then quenched with sat. NaHCO₃, extracted with DCM (3x), dried over Na₂SO₄ and concentrated under reduced pressure. The reaction mixture was purified using SFC chromatography (OD-H 21x150 mm, 1:1 MeOH:MeCN) to afford 4-bromo-5-methyl- 1,5,6,7-tetrahydrocyclopenta[f]indazole (peak 1; R_t = 3 minutes) and 4-bromo-5-methyl- 1,5,6,7-tetrahydrocyclopenta[f]indazole (peak 2; R_t = 4 minutes) (Int-5C). [M+H]⁺ Found: 251, 253. [0222] Step D: 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7- tetrahydrocyclopenta[f]indazole (Int-5D) [0223] 4-bromo-5-methyl-1,5,6,7-tetrahydrocyclopenta[f]indazole (Int-5C) (570 mg, 2.270 mmol) and p-toluenesulfonic acid monohydrate (130 mg, 0.681 mmol) were taken up in THF (7566 μL).3,4-dihydro-2H-pyran (828 μL, 9.08 mmol) was added and the reaction was stirred at 25 °C overnight. The mixture was quenched with NaHCO₃, extracted with DCM, concentrated under reduced pressure, then purified by silica gel column chromatography (0-100% EtOAc in hexane) to afford 4-bromo-5-methyl-1-(tetrahydro-2H- pyran-2-yl)-1,5,6,7-tetrahydrocyclopenta[f]indazole (Int-5D). [M+H]⁺ Found: 335, 337. [0224] Step E: (5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7- tetrahydrocyclopenta[f]indazol-4-yl)boronic acid (Int-5) [0225] To a solution of 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7- tetrahydrocyclopenta[f]indazole (Int-5D) (1.19 g, 3.55 mmol) in MeOH (17.75 ml) was added triethylamine (1.979 mL, 14.20 mmol), tetrahydroxydiboron (0.477 g, 5.32 mmol) and chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (0.237 g, 0.355 mmol) at 20 °C under N₂ atmosphere, the mixture was stirred at 50 °C for 1 h. The reaction mixture was concentrated under reduced pressure and the residue purified directly by silica gel column chromatography (0-50% 3:1 EtOAc:EtOH in hex) to give (5-methyl-1- (tetrahydro-2H-pyran-2-yl)-1,5,6,7-tetrahydrocyclopenta[f]indazol-4-yl)boronic acid (Int- 5). [M+H]⁺ Found: 301. [0226] Intermediate 6: 4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-6-fluoro-1- ((trifluoromethyl)sulfonyl)-5-((triisopropylsilyl)ethynyl)-1H-benzo[f]indazole (Int-6) [0227] Step A: 5-((2-bromo-4-fluorophenyl)(hydroxy)methyl)-N-methoxy-N-methyl-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide (Int-6A) [0228] To a stirred solution of N-methoxy-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazole-4-carboxamide (Int-3B) (24.7 g, 87.0 mmol) in THF (50 mL) was added lithium diisopropylamide (95 mL, 95 mmol, 1 M in THF) at -78 °C under N₂, and the reaction was stirred at -78 °C for 1 h. Then 2-bromo-4-fluorobenzaldehyde (16 g, 79 mmol) was added at -78 °C and the reaction was stirred at -78 °C for 1 h. The mixture was warmed to room temperature and concentrated in vacuum. The mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 500 mL). The organic layers were washed with sat. brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by flash silica gel chromatography (0 to 25% EtOAc in petroleum ether) to give 5-((2-bromo-4-fluorophenyl)(hydroxy)methyl)-N-methoxy-N-methyl-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide (Int-6A). MS (ESI) [M+H]⁺: m/z 488, 490. [0229] Step B: 5-(2-bromo-4-fluorobenzyl)-N-methoxy-N-methyl-1H-pyrazole-4- carboxamide (Int-6B) [0230] To a solution of 5-((2-bromo-4-fluorophenyl)(hydroxy)methyl)-N-methoxy-N- methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide (Int-6A) (20.0 g, 40.9 mmol) in DCM (56 mL) was added triethylsilane (118 mL, 737 mmol) and TFA (56.8 mL, 737 mmol), and the mixture was stirred at 60 °C for 3 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc (400 mL). The reaction mixture was basified with sat. aq. NaHCO₃ to pH~8. The organic layer was washed with brine (2 x 30 mL), dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0 to 15% ethyl acetate in petroleum ether) to give 5-(2-bromo-4-fluorobenzyl)-N-methoxy-N-methyl-1H-pyrazole-4- carboxamide (Int-6B). MS (ESI) [M+H]⁺: m/z 342, 344. [0231] Step C: 5-(2-bromo-4-fluorobenzyl)-N-methoxy-N-methyl-1-(tetrahydro-2H-pyran- 2-yl)-1H-pyrazole-4-carboxamide (Int-6C) [0232] To a solution of 5-(2-bromo-4-fluorobenzyl)-N-methoxy-N-methyl-1H-pyrazole-4- carboxamide (Int-6B) (7.50 g, 21.9 mmol) in THF (80 mL) was added 4- methylbenzenesulfonic acid (0.377 g, 2.19 mmol) and DHP (4.01 mL, 43.8 mmol) at 25 °C, and the mixture was stirred for 2 h. The mixture was concentrated in vacuo and the residue was purified by flash silica gel chromatography (petroleum ether/EtOAc = 2/1) to give 5-(2- bromo-4-fluorobenzyl)-N-methoxy-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4- carboxamide (Int-6C). MS (ESI) [M+H]⁺: m/z 426, 428. [0233] Step D: 6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1,9-dihydro-4H-benzo[f]indazol-4- one (Int-6D) [0234] To a stirred solution of 5-(2-bromo-4-fluorobenzyl)-N-methoxy-N-methyl-1- (tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxamide (Int-6C) (22 g, 51.6 mmol) in THF (220 mL) was added nBuLi (31 mL, 77 mmol, 2.5 M in hexane) dropwise over 30 min at - 78 °C under N₂. The mixture was stirred at -78 °C for 0.5 h. The reaction mixture was poured into sat. aq. NH₄Cl (200 mL) and diluted with EtOAc (200 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash silica gel chromatography (0 to 22% THF in petroleum ether) to give 6-fluoro-1-(tetrahydro-2H- pyran-2-yl)-1,9-dihydro-4H-benzo[f]indazol-4-one (Int-6D). MS (ESI) [M+H]⁺: m/z 287. [0235] Step E: 6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5-((triisopropylsilyl)ethynyl)-1,9- dihydro-4H-benzo[f]indazol-4-one (Int-6E) [0236] To a solution of 6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1,9-dihydro-4H- benzo[f]indazol-4-one (Int-6D) (6.50 g, 22.7 mmol) in dioxane (120 mL) was added (bromoethynyl)triisopropylsilane (17.8 g, 68.1 mmol), potassium acetate (7.8 g, 79 mmol), and dichloro(p-cymene)ruthenium(II) dimer (6.95 g, 11.4 mmol) at 25 °C under N₂. The mixture was stirred at 100 °C for 3 h. The mixture was cooled, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (2% ethyl acetate in DCM) to give 6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5- ((triisopropylsilyl)ethynyl)-1,9-dihydro-4H-benzo[f]indazol-4-one (Int-6E). MS (ESI) [M+H]⁺: m/z 467. [0237] Step F: 6-fluoro-1-((trifluoromethyl)sulfonyl)-5-((triisopropylsilyl)ethynyl)-1H- benzo[f]indazol-4-yl trifluoromethanesulfonate (Int-6F) [0238] A solution of 6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5-((triisopropylsilyl)ethynyl)- 1,9-dihydro-4H-benzo[f]indazol-4-one (Int-6E) (5.50 g, 11.8 mmol) and N,N- diisopropylethylamine (12.4 mL, 70.7 mmol) in DCM (60 mL) was added Tf₂O (5.97 mL, 35.4 mmol) at -40 °C, and the reaction mixture was stirred for 15 min. The reaction mixture was concentrated in vacuo at 30 °C and the residue was purified by flash silica gel chromatography (petroleum ether/EtOAc = 20/1) to give 6-fluoro-1- ((trifluoromethyl)sulfonyl)-5-((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl trifluoromethanesulfonate (Int-6F).¹H NMR (400 MHz, CDCl₃) δ 8.71 (s, 1H), 8.50 (s, 1H), 8.04 (dd, J = 5.36, 9.18 Hz, 1H), 7.55 (t, J = 8.64 Hz, 1H), 1.17-1.24 (m, 21H). [0239] Step G: 4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-6-fluoro-1- ((trifluoromethyl)sulfonyl)-5-((triisopropylsilyl)ethynyl)-1H-benzo[f]indazole (Int-6) [0240] A solution of 5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) (3.14 g, 13.9 mmol), potassium acetate (1.37 g, 13.9 mmol), 6-fluoro-1-((trifluoromethyl)sulfonyl)-5- ((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl trifluoromethanesulfonate (Int-6F) (3.00 g, 4.64 mmol), dichlorobis(triphenylphosphine)palladium(II) (326 mg, 464 μmol) in dioxane (30 mL) was stirred for 10 min at 25 °C. Then, dichlorobis(triphenylphosphine)palladium(II) (0.760 g, 1.08 mmol) was added at 25°C and the mixture was stirred at 80 °C for 24 h under N₂ atmosphere. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with MeCN (70 mL), filtered, and the solid was dried under reduced pressure to give 4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-6-fluoro-1- ((trifluoromethyl)sulfonyl)-5-((triisopropylsilyl)ethynyl)-1H-benzo[f]indazole (Int-6). MS (ESI): m/z (M+H)⁺ 611.¹H NMR (CDCl₃, 400 MHz) δ 8.64 (s, 1H), 8.33 (s, 1H), 7.92 (dd, 1H, J=5.7, 9.2 Hz), 7.37 (t, 1H, J=8.7 Hz), 3.86 (s, 4H), 1.14 (s, 21H), 1.07 (s, 6H). [0241] Intermediate 7: (5-(1-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-6- (trifluoromethyl)-1H-indazol-4-yl)boronic acid (Int-7) [0242] Step A: 5-nitro-6-(trifluoromethyl)-1H-indazole (Int-7A) [0243] To a solution of 6-(trifluoromethyl)-1H-indazole (7.4 g, 40 mmol) in H₂SO₄ (100 mL, conc. aq.) at 0 °C, was slowly added KNO₃ (4.5 g, 44 mmol). The reaction mixture was warmed up to room temperature. After stirring for 3 h at room temperature, it was poured into crushed ice. The precipitated solid was collected by filtration and washed with water to afford 5-nitro-6-(trifluoromethyl)-1H-indazole (Int-7A). MS (ESI) [M+H]⁺: m/z 232. [0244] Step B: 6-(trifluoromethyl)-1H-indazol-5-amine (Int-7B) [0245] A mixture of 5-nitro-6-(trifluoromethyl)-1H-indazole (Int-7A) (8.91 g, 38.5 mmol), iron (10.8 g, 193 mmol), and NH₄Cl (10.3 g, 193 mmol) in EtOH (120 mL) and water (20 mL) was vigorously stirred at 70 °C for 1 h. The mixture was diluted with EtOAc (200 mL), filtered by glass fiber membrane filter, and washed with EtOAc. The filtrate was concentrated under reduced pressure and sat. aq. NaHCO₃ and EtOAc were added. The layers were separated, and the organic phase was washed with brine, dried over Na₂SO₄, filtered, and concentrated to give 6-(trifluoromethyl)-1H-indazol-5-amine (Int-7B). MS (ESI) [M+H]⁺: m/z 202. [0246] Step C: 4-chloro-6-(trifluoromethyl)-1H-indazol-5-amine (Int-7C) [0247] To a solution of 6-(trifluoromethyl)-1H-indazol-5-amine (Int-7B) (616 mg, 3.06 mmol) in THF (15 mL) was added 1,3-dimethylimidazolium chloride (40 mg, 0.30 mmol) and NCS (430 mg, 3.22 mmol). After stirring overnight at room temperature, sat. aq. NaHCO₃ and EtOAc were added to the reaction mixture. The layers were separated, and the organic phase was washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel chromatography (0 to 100% EtOAc in hexanes) to give 4- chloro-6-(trifluoromethyl)-1H-indazol-5-amine (Int-7C). MS (ESI) [M+H]⁺: m/z 236. [0248] Step D: 4-chloro-5-iodo-6-(trifluoromethyl)-1H-indazole (Int-7D) [0249] To a solution of 4-chloro-6-(trifluoromethyl)-1H-indazol-5-amine (Int-7C) (634 mg, 2.69 mmol) in MeCN (20 mL) was added nitrosyl tetrafluoroborate (380 mg, 3.25 mmol) at 0 °C. The mixture was stirred at 0 °C for 10 min before a solution of KI (5.0 g, 30 mmol) in water (10 mL) was added with vigorous stirring. After stirring for 10 min, EtOAc and water were added and the layers were separated. The organic phase was washed with the mixture of sat. aq. NaHCO₃ and Na₂S₂O₃ solution, dried over Na₂SO₄, and concentrated to give 4-chloro-5-iodo-6-(trifluoromethyl)-1H-indazole (Int-7D). MS (ESI) [M+H]⁺: m/z 347. [0250] Step E: 4-chloro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H- indazole (Int-7E) [0251] A mixture of 4-chloro-5-iodo-6-(trifluoromethyl)-1H-indazole (Int-7D) (920 mg), (1R)-(-)-camphor-10-sulfonic acid (60 mg, 0.26 mmol), and 3,4-dihydro-2H-pyran (0.72 mL, 8.0 mmol) in toluene (20 mL) was stirred at 100 °C for 2.5 h. The reaction mixture was cooled to room temperature, and sat. aq. NaHCO₃ was added. The layers were separated, and the organic phase was washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel chromatography (0 to 100% EtOAc in hexanes) to give 4-chloro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H-indazole (Int- 7E). MS (ESI) [M+H]⁺: m/z 431. [0252] Step F: 1-(4-chloro-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H-indazol- 5-yl)cyclopropan-1-ol (Int-7F) [0253] KOH (1.25 mL, 2.50 mmol, 2 N in H₂O) was added to a solution of (4-chloro-5- iodo-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H-indazole (Int-7E) (430 mg, 0.999 mmol), 2,2'-cyclopropylidenebis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) (740 mg, 2.52 mmol), and chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (100 mg, 0.195 mmol) in 1,4-dioxane (10 mL). The mixture was stirred at 50 °C for 3 h. The mixture was cooled to 0 °C, and MeOH (1 mL) and NaOH (5 mL, 2 N in H₂O) were added. H₂O₂ (1.2 mL, 30 wt% in H₂O) was added slowly at 0 °C and stirred for 10 min. After 10 min, MeOH (2 mL) was added and stirred at 0 °C for 30 min. The reaction was quenched with H₃PO₄ (10% aq.) and CHCl₃ and the layers were separated. The organic phase was washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel chromatography (0 to 100% EtOAc in hexanes) to afford 1-(4-chloro-1- (tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H-indazol-5-yl)cyclopropan-1-ol (Int-7F). MS (ESI) [M+H]⁺: m/z 361. [0254] Step G: 4-chloro-5-(1-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-6- (trifluoromethyl)-1H-indazole (Int-7G) [0255] Diethylaminosulfur trifluoride (0.035 mL, 0.265 mmol) was added to a solution of 1-(4-chloro-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H-indazol-5-yl)cyclopropan- 1-ol (Int-7F) (43 mg, 0.12 mmol) in DCM (3 mL) at -78 °C. After stirring at -78 °C for 30 min, sat. aq. NaHCO₃ and EtOAc were added to the reaction mixture. The layers were separated and the organic phase was washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel chromatography (0 to 100% EtOAc in hexanes) to give 4-chloro-5-(1-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-6- (trifluoromethyl)-1H-indazole (Int-7G). MS (ESI) [M+H]⁺: m/z 363. [0256] Step H: (5-(1-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)- 1H-indazol-4-yl)boronic acid (Int-7) [0257] The mixture of 4-chloro-5-(1-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-6- (trifluoromethyl)-1H-indazole (Int-7G) (34 mg, 0.094 mmol), tetrahydroxydiboron (40 mg, 0.45 mmol), cataCXium A Pd G3 (6.0 mg, 0.0082 mmol) and Et₃N (0.080 mL, 0.57 mmol) in MeOH (1 mL) was stirred at room temperature for 60 h. EtOAc (30 mL), CHCl₃ (1 mL), and H₃PO₄ (10% aq.) were added to the reaction mixture. The layers were separated and the organic phase was washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel chromatography (0 to 100% EtOAc in hexanes) to give (5- (1-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H-indazol-4- yl)boronic acid (Int-7). MS (ESI) [M+H]⁺: m/z 373. [0258] Intermediate 8: (6-chloro-5-(1-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazol-4-yl)boronic acid (Int-8)

[0259] Step A: 4-chloro-2-fluoro-5-nitrobenzaldehyde (Int-8A) [0260] To a solution of 4-chloro-2-fluorobenzaldehyde (58 g, 370 mmol) in conc. H₂SO₄ (500 mL) was added potassium nitrate (47 g, 470 mmol) at 0 °C. Then the reaction was stirred at 25 °C for 1 h. The reaction mixture was quenched with ice water (2 L), filtered, and the solid was washed with water (2 x 500 mL), dried in vacuo to give 4-chloro-2- fluoro-5-nitrobenzaldehyde (Int-8A). ¹H NMR (400 MHz, CDCl₃) δ 10.32 (s, 1H), 8.47 (d, J=6.6 Hz, 1H), 7.48 (d, J=9.2 Hz, 1H). [0261] Step B: 6-chloro-5-nitro-1H-indazole (Int-8B) [0262] To a solution of 4-chloro-2-fluoro-5-nitrobenzaldehyde (Int-8A) (67.0 g, 329 mmol) in DMF (1.00 L) was added hydrazine hydrate (161 mL, 2.82 mol) at 25 °C under N₂ atmosphere. The reaction mixture was stirred at 100 °C for 15 h. The reaction mixture was cooled and quenched with ice water (2 L). The mixture was filtered and the filtered cake was washed with water (2 x 300 mL), dried in vacuum to give 6-chloro-5-nitro-1H-indazole (Int-8B). MS (ESI) [M+H]+: m/z 198. 1H NMR (400 MHz, DMSO-d₆) δ 8.44 (s, 1H), 8.25 (s, 1H), 7.70 (s, 1H). [0263] Step C: 6-chloro-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Int-8C) [0264] To a solution of 6-chloro-5-nitro-1H-indazole (Int-8B) (92 g, 0.47 mol) in THF (1.0 L) were added 3,4-dihydro-2H-pyran (85 mL, 0.93 mol) and p-toluenesulfonic acid (8.0 g, 47 mmol) at 25 °C under N₂ atmosphere. The reaction mixture was stirred at 70 °C for 5 h. The reaction mixture was cooled and evaporated under reduced pressure to give a crude product. The crude product was purified by flash silica gel chromatography (20 % EtOAc in petroleum ether) to give 6-chloro-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Int- 8C). MS (ESI) [M+H]⁺: m/z 282.¹H NMR (400 MHz, CDCl₃) δ 8.38 (s, 1H), 8.16 (s, 1H), 7.81 (s, 1H), 5.73 (dd, J=8.9, 2.5 Hz, 1H), 3.99-4.04 (m, 1H), 3.76-3.81 (m, 1H), 2.46-2.50 (m, 1H), 2.10-2.18 (m, 2H), 1.71-1.77 (m, 3H). [0265] Step D: 6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (Int-8D) [0266] To a solution of 6-chloro-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Int- 8C) (38.6 g, 137 mmol) in EtOH (1.00 L) and water (200 mL) were added ammonium chloride (22.0 g, 411 mmol) and iron dust (38.3 g, 685 mmol) while stirring at 25 °C under N₂ atmosphere. The reaction mixture was stirred at 70 °C for 15 h. The reaction mixture was cooled, diluted with EtOAc (200 mL), filtered, and the solvent was concentrated in vacuo. The residue was then dissolved in EtOAc (3 x 300 mL), washed with brine (100 mL), dried over Na₂SO₄, filtered, and the solvent was evaporated under reduced pressure to give a crude product. The crude product was purified by flash silica gel chromatography (15% EtOAc in petroleum ether) to give 6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol- 5-amine (Int-8D). MS (ESI) [M+H]⁺: m/z 252.¹H NMR (400 MHz, CDCl₃) δ 7.82 (d, J=0.8 Hz, 1H), 7.60 (s, 1H), 7.04 (s, 1H), 5.61 (dd, J=9.4, 2.7 Hz, 1H), 4.02-4.07 (m, 1H), 3.89-4.01 (m, 2H), 3.71-3.77 (m, 1H), 2.49-2.56 (m, 1H), 2.06-2.17 (m, 2H), 1.68-1.79 (m, 3H). [0267] Step E: 4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (Int- 8E) [0268] To a solution of 6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (Int- 8D) (66.6 g, 265 mmol) in MeCN (660 mL) was added NBS (56.5 g, 318 mmol) at 20 °C under N₂ atmosphere. The reaction mixture was stirred at 20 °C for 3 h. The reaction mixture was quenched with water (200 mL), diluted with EtOAc (200 mL), filtered, and concentrated. The residue was extracted with EtOAc (2 x 200 mL), washed with brine (100 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 (10% EtOAc in petroleum ether) to give 4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazol-5-amine (Int-8E). MS (ESI) [M+H]⁺: m/z 330, 332.¹H NMR (400 MHz, CDCl₃) δ 7.84 (s, 1H), 7.59 (s, 1H), 5.61 (dd, J=9.0, 2.7 Hz, 1H), 3.97-4.01 (m, 1H), 3.70- 3.76 (m, 1H), 2.44-2.52 (m, 1H), 2.05-2.16 (m, 2H), 1.66-1.77 (m, 3H). [0269] Step F: 4-bromo-6-chloro-1H-indazol-5-amine (Int-8F) [0270] To a solution of 4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- amine (Int-7E) (30 g, 90 mmol) was added 4 N HCl in MeOH (300 mL). The reaction was stirred at 50 °C for 2 h. The reaction mixture was cooled and evaporated under reduced pressure to give 4-bromo-6-chloro-1H-indazol-5-amine (Int-8F) isolated as an HCl salt. MS (ESI) [M+H]⁺: m/z 246, 248. [0271] Step G: 4-bromo-6-chloro-5-iodo-1H-indazole (Int-8G) [0272] To a solution of 4-bromo-6-chloro-1H-indazol-5-amine (Int-8F), HCl (10 g, 35 mmol) in 6 M aq. HCl (100 mL) was added a solution of sodium nitrite (2.9 g, 42 mmol) in water (20 mL) dropwise at -5 °C and stirred for 5 min. Then a solution of KI (23 g, 140 mmol) in water (100 mL) was added dropwise to the reaction mixture at -5 °C. The reaction mixture was stirred at 90 °C for 1 h. The reaction was cooled, quenched with ice water (150 mL) and sat. aq. Na₂SO₃ (100 mL), and then basified with sat. aq. NaHCO₃ (200 mL) to pH 8. The aqueous layer was extracted with EtOAc (2 x 200 mL), and the organic layer was dried over Na₂SO₄, filtered, and the solvent was evaporated under reduced pressure to give 4-bromo-6-chloro-5-iodo-1H-indazole (Int-8G). MS (ESI) [M+H]⁺: m/z 357, 359. ¹H NMR (400 MHz, DMSO-d₆) δ 13.62 (br s, 1H), 8.00 (s, 1H), 7.88 (d, J=0.8 Hz, 1H). [0273] Step H: 4-bromo-6-chloro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Int- 8H) [0274] To a solution of 4-bromo-6-chloro-5-iodo-1H-indazole (Int-8G) (32 g, 90 mmol) in THF (300 mL) were added 4-methylbenzenesulfonic acid (1.5 g, 9.0 mmol) and 3,4- dihydro-2H-pyran (16 mL, 180 mmol) at 20 °C under N₂ atmosphere. The reaction mixture was stirred at 70 °C for 3 h. The mixture was cooled, evaporated under reduced pressure to give a crude product. The crude product was purified by flash silica gel chromatography (10% THF in petroleum ether) to give 4-bromo-6-chloro-5-iodo-1-(tetrahydro-2H-pyran-2- yl)-1H-indazole (Int-8H). MS (ESI) [M+H]⁺: m/z 441, 443.¹H NMR (400 MHz, CDCl₃) δ 7.93 (s, 1H), 7.79 (d, J=0.7 Hz, 1H), 5.65 (dd, J=8.8, 2.7 Hz, 1H), 3.96-4.00 (m, 1H), 3.71- 3.77 (m, 1H), 2.42-2.50 (m, 1H), 2.07-2.16 (m, 2H), 1.69-1.79 (m, 3H). [0275] Step I: 1-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)cyclopropan-1-ol (Int-8I) [0276] 4-bromo-6-chloro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Int-8H) (0.2019 g, 0.457 mmol) was added to a vial with a stir bar and the headspace was swept with N₂.2-methyltetrahydrofuran (880 μL) was added to the vial via syringe and the reaction was cooled to 0 °C. Isopropylmagnesium chloride lithium chloride complex (0.343 mL, 0.686 mmol, 2 M in THF) was added dropwise via syringe. The reaction was stirred at 0 °C for 30 min. A separate 50 mL round bottom flask with a stir bar was charged with 1- (phenylsulfonyl)cyclopropan-1-ol (80 mg, 0.387 mmol) and placed under N₂.2-MeTHF (880 μL) was added and the solution was cooled to -78 °C. Methylmagnesium chloride (123 μL, 0.368 mmol, 3 M in THF) was added to the reaction followed by the contents of the first reaction flask containing 4-bromo-6-chloro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H- indazole (Int-8H), both dropwise via syringe. The reaction was allowed to warm to room temperature overnight. Sat. aq. Na₂CO₃ (50 mL), H₂O (500 mL), brine (25 mL), and EtOAc (100 mL) were added and the layers were separated. The aqueous phase was extracted with EtOAc (2 x 150 mL) and the combined organic layers were washed with brine (100 mL), dried over MgSO₄, filtered, and concentrated. The crude residue was purified via silica gel chromatography (0 to 40% EtOAc in hexanes) to provide 1-(4-bromo-6-chloro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropan-1-ol (Int-8I). MS (ESI): [M+H]⁺ m/z 371. [0277] Step J: 4-bromo-6-chloro-5-(1-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazole (Int-8J) [0278] Diethylaminosulfur trifluoride (90 μL, 0.681 mmol) was added to a solution of 1-(4- bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropan-1-ol (Int-8I) (111.6 mg, 0.300 mmol) in DCM (2.5 mL) at -78 °C. The mixture was stirred at -78 °C for 50 min. The mixture was quenched with sat. aq. NaHCO₃ and extracted with DCM (3x). The combined organic layers were washed with brine, dried over MgSO₄, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (0 to 40% EtOAc in hexane) to afford 4-bromo-6-chloro-5-(1-fluorocyclopropyl)-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazole (Int-8J). MS (ESI): [M+H]⁺ m/z 373, 375. [0279] Step K: (6-chloro-5-(1-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-4-yl)boronic acid (Int-8) [0280] CataCXium A Pd G2 (24 mg, 0.036 mmol), hypodiboric acid (56.4 mg, 0.629 mmol), and Et₃N (110 μL, 0.789 mmol) in MeOH (2000 μl) were added to a vial containing 4-bromo-6-chloro-5-(1-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Int- 8J) (78.4 mg, 0.210 mmol). The mixture was evacuated and backfilled with N₂ (3x). The mixture was stirred at 50 °C for 2 h. The mixture was diluted with water and extracted with EtOAc (3x) and the combined organic layers were washed with brine, dried over MgSO₄, filtered, and concentrated in vacuo to afford (6-chloro-5-(1-fluorocyclopropyl)-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)boronic acid (Int-8). MS (ESI): [M+H]⁺ m/z 339. [0281] Intermediate 9: (5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)- 1H-indazol-4-yl)boronic acid (Int-9) [0282] Step A: 4-bromo-6-(trifluoromethyl)-1H-indazol-5-amine (Int-9A) [0283] NBS (880 mg, 5.0 mmol) was added to a stirred solution of 6-(trifluoromethyl)-1H- indazol-5-amine (Int-7B) (1.0 g, 5.0 mmol) in MeCN (25 mL) at room temperature. After 10 min, the mixture was partitioned between EtOAc and sat. aq. NaHCO₃. The organic phase was washed with brine, dried over Na₂SO₄, and concentrated. The crude residue was purified via silica gel chromatography (0 to 20% EtOAc in hexane) to give 4-bromo-6- (trifluoromethyl)-1H-indazol-5-amine (Int-9A). MS (ESI) [M+H]⁺: m/z 280. [0284] Step B: 4-bromo-5-iodo-6-(trifluoromethyl)-1H-indazole (Int-9B) [0285] Copper iodide (612 mg, 3.21 mmol) and tert-butyl nitrite (0.395 mL, 3.32 mmol) were added to a stirred solution of 4-bromo-6-(trifluoromethyl)-1H-indazol-5-amine (Int- 9A) (300 mg, 1.07 mmol) in MeCN (25 mL) at room temperature. The mixture was warmed to 70°C and stirred for 30 min. After cooling, the mixture was partitioned between EtOAc and sat. aq. NaHCO₃. The organic phase was washed with brine, dried over Na₂SO₄, and concentrated. The crude residue was purified via silica gel chromatography (0 to 20% EtOAc in hexane) to give 4-bromo-5-iodo-6-(trifluoromethyl)-1H-indazole (Int-9B). MS (ESI) [M+H]⁺: m/z 391. [0286] Step C: 4-bromo-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H- indazole (Int-9C) [0287] A mixture of 4-bromo-5-iodo-6-(trifluoromethyl)-1H-indazole (Int-9B) (320 mg, 0.81 mmol), 3,4-dihydro-2H-pyran (0.15 mL, 1.61 mmol), (1R)-(-)-camphor-10-sulfonic acid (24 mg, 0.11 mmol) in THF (10 mL) was stirred at 70 °C for 3 h. After cooling to room temperature, the mixture was partitioned between EtOAc and aqueous sat. aq. NaHCO₃. The organic phase was washed with brine, dried over Na₂SO₄, filtered, and concentrated. The crude residue was purified via silica gel chromatography (0 to 10% EtOAc in hexane) to give 4-bromo-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H-indazole (Int- 9C). MS (ESI) [M+H]⁺: m/z 475. [0288] Step D: 4-bromo-5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)- 1H-indazole (Int-9D) [0289] A mixture of 4-bromo-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H- indazole (Int-9C) (170 mg, 0.358 mmol), cyclopropylboronic acid (31 mg, 0.36 mmol), [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (52 mg, 0.071 mmol), sodium carbonate (1.07 mL, 1.07 mmol, 1 M in H₂O) in 2-methyltetrahydrofuran (3.6 mL) was evacuated and backfilled with N₂ (3x). The mixture was stirred at 100 °C under N₂ for 8 h. Additional cyclopropylboronic acid (15 mg, 0.18 mmol) and [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (26 mg, 0.036 mmol) were added to the mixture and stirred at 100 °C for 2 h. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The organic phase was washed with brine, dried over Na₂SO₄, filtered, and concentrated. The crude residue was purified via silica gel chromatography (0 to 10% EtOAc in hexane) to give 4-bromo-5-cyclopropyl-1-(tetrahydro- 2H-pyran-2-yl)-6-(trifluoromethyl)-1H-indazole (Int-9D). MS (ESI) [M+H]⁺: m/z 389. [0290] Step E: (5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H- indazol-4-yl)boronic acid (Int-9) [0291] CataCXium A Pd G3 (12 mg, 0.017 mmol) was added to a stirred mixture of 4- bromo-5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H-indazole (Int- 9D) (66 mg, 0.17 mmol), triethylamine (0.095 mL, 0.68 mmol), and tetrahydroxydiboron (31 mg, 0.34 mmol) in MeOH (3.4 mL) at room temperature. The reaction was stirred at room temperature for 1 h. The mixture was filtered through a pad of CELITE®, washed with MeOH and the filtrate was concentrated. The residue was purified via silica gel chromatography (10 to 50% EtOAc in hexanes) to give (5-cyclopropyl-1-(tetrahydro-2H- pyran-2-yl)-6-(trifluoromethyl)-1H-indazol-4-yl)boronic acid (Int-9). MS (ESI) [M+H]⁺: m/z 355. [0292] Intermediate 10: ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (Int-10) [0293] To a solution of 7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (15 g, 28.1 mmol) in dioxane (150 mL) was added bis(pinacolato)diboron (13.32 g, 52.5 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.053 g, 2.81 mmol), and potassium acetate (6.88 g, 70.1 mmol). The reaction was stirred at 110 °C under N₂ for 15 h. The mixture was concentrated and the residue was purified by flash silica gel chromatography (petroleum ether) to give ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (Int-10). ¹H NMR (400MHz, CDCl₃) δ 7.69 - 7.64 (m, 1H), 7.51 (d, J=2.5 Hz, 1H), 7.38 (d, J=2.6 Hz, 1H), 7.23 (t, J=8.8 Hz, 1H), 5.29 - 5.26 (m, 2H), 3.51 (s, 3H), 1.44 (s, 12H), 1.18 - 1.14 (m, 21H). [0294] Intermediate 11J, 11K, 11L: Tert-butyl 3-(8-chloro-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-11J), tert-butyl 3-(8-chloro-2-(methylsulfinyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-11K) & tert-butyl 3-(8- chloro-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-11L)

[0295] Step A: Methyl 2-chloro-3-fluoroisonicotinate (Int-11A) [0296] Eight reactors were set up in parallel. To each reactor was charged MeOH (4.0 L) at 25 °C, 2-chloro-3-fluoroisonicotinic acid (400 g, 2.3 mol), and conc. H₂SO₄ (45.0 g, 0.40 mol). The mixture was heated to 75 °C and stirred for 12 h. The contents of the eight reactors were combined and concentrated to remove the volatiles. The pH of the resulting residue was adjusted to ~7 using aq. Na₂CO₃ and the mixture was extracted with EtOAc (20 L × 2). The combined organic layers were dried with Na₂SO₄ and concentrated under reduced pressure to give methyl 2-chloro-3-fluoroisonicotinate (Int-11A), which was used directly in the next step without further purification. [0297] Step B: (2-chloro-3-fluoropyridin-4-yl)methanol (Int-11B) [0298] Twelve reactors were set up in parallel. To each reactor was charged EtOH (2.3 L), methyl 2-chloro-3-fluoroisonicotinate (Int-11A) (235 g, 1.2 mol), and CaCl₂ (206 g, 1.8 mol). The reactor was degassed and purged with N₂ three times and cooled to 0~10 ℃. NaBH₄ (93.0 g, 2.4 mol) was added at 0~10 ºC and stirred for 1 h. The mixture was warmed to 20~25 ℃ and stirred for 12 h. The contents of the twelve reactors were combined and the mixture was slowly poured into ice water (5.0 V) under N₂ atmosphere. The mixture was filtered, and the filter cake was washed with EtOAc (5.0 V). The filtrate was concentrated under reduced pressure to give (2-chloro-3-fluoropyridin-4-yl)methanol (Int-11B).¹H NMR (400 MHz, CDCl₃) δ 2.91 (s, 1 H), 4.85 (s, 2H), 7.45 - 7.46 (t, J = 4.0 Hz, 1 H), 8.17 - 8.18 (d, J = 4.0 Hz, 1H). [0299] Step C: 4-(bromomethyl)-2-chloro-3-fluoropyridine (Int-11C) [0300] Twelve reactors were set up in parallel. To each reactor was charged DCM (2.0 L) and (2-chloro-3-fluoropyridin-4-yl)methanol (Int-11B) (200 g, 1.2 mol). PBr₃ (402 g, 1.5 mol) was charged into the reactor vessel at 0 ℃. The vessel was warmed to 25 ℃ and stirred for 12 h. The contents of the twelve reactors were combined for workup and poured into 10% aq. NaHCO₃ (1.0 L) slowly. The reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with DCM (20 L) and the organic phase was separate. The aqueous solution was extracted with DCM (2 x 20 L). The combined organic layers were dried with Na₂SO₄, filtered, and concentrated under reduce pressure to give 4- (bromomethyl)-2-chloro-3-fluoropyridine (Int-11C). MS (ESI) [M+H]⁺: m/z 224. [0301] Step D: 2-(2-chloro-3-fluoropyridin-4-yl)acetonitrile (Int-11D) [0302] Eight reactors were set up in parallel. To each reactor was charged MeCN (2.3 L), 4-(bromomethyl)-2-chloro-3-fluoropyridine (Int-19C) (230 g, 1.0 mol), TMSCN (1.01 kg, 10 mol), and LiOH (51 g, 1.2 mol). The mixture was stirred at 0 ℃ for 4 h and then warmed to room temperature and stirred for 8 h. The contents of the eight reactors were combined and concentrated to remove the volatiles. The mixture was diluted with EtOAc (25 L) and H₂O (10 L) and the layers were separated. The aqueous phase was extracted with EtOAc (2 x 10 L) and the combined organic layers were dried with Na₂SO₄, filtered, and concentrated in vacuo to give 2-(2-chloro-3-fluoropyridin-4-yl)acetonitrile (Int-11D). MS (ESI) [M+H]⁺: m/z 171. [0303] Step E: 2-amino-7-chlorothieno[2,3-c]pyridine-3-carbonitrile (Int-11E) [0304] Twelve reactors were set up in parallel. To each reactor was charged DMSO (1.7 L) and 2-(2-chloro-3-fluoropyridin-4-yl)acetonitrile (Int-11D) (170 g, 1.00 mol). The reactor was degassed and purged with N₂ three times. Potassium tert-butoxide (123 g, 1.1 mol) was added in batches at 25 ℃ over 30 min. The mixture was stirred at 25 ℃ for 30 min. After 30 min, ethoxycarbonyl isothiocyanate (143 g, 1.1 mol) was added at 25 ℃. The mixture was stirred at 25 ℃ for 30 min. The reactor was warmed to 100 ℃ and stirred at 100 ℃ for 1 h. NaOH (1 L, 5.00 mol, 5 M in H₂O) was added and the mixture was stirred at 100 ℃ for 10 h. The reaction was cooled to room temperature and the contents of the 12 reactors were combined for workup. The reaction was poured into ice water (10 V) and stirred at 0 ℃ for 30 min. The resulting solid was filtered, washed with H₂O (5.0 L), and oven-dried at 50 ℃ for 12 h to obtain 2-amino-7-chlorothieno[2,3-c]pyridine-3-carbonitrile (Int-11E). MS (ESI) [M+H]⁺: m/z 210. [0305] Step F: 2-amino-7-chlorothieno[2,3-c]pyridine-3-carboxamide (Int-11F) [0306] Six reactors were set up in parallel. To each reactor was charged DMSO (2.1 L), 2- amino-7-chlorothieno[2,3-c]pyridine-3-carbonitrile (Int-11E) (70.0 g, 0.3 mol), and K₂CO₃ (92.0 g, 0.60 mol). H₂O₂ (615 g, 5.4 mol, 30 wt%) was added slowly into the reactor in portions over 4 h. The reaction mixture was stirred at 25 ℃ for 6 h. The contents of the six reactors were combined, and the resulting mixture was poured into 10% aq. Na₂SO₃ at 15- 25 ℃. The mixture was stirred at 0 ℃ for 0.5 h. The reaction mixture was filtered, and the filter cake was washed with H₂O (5.0 L). The resulting solid was dried in an oven at 50 ℃ for 12 h to give 2-amino-7-chlorothieno[2,3-c]pyridine-3-carboxamide (Int-11F). MS (ESI) [M+H]⁺: m/z 228.¹H NMR (400 MHz, DMSO-d₆) δ 7.19 - 7.20 (d, J = 4.0 Hz, 1 H), 8.10 - 8.11 (d, J = 4.0 Hz, 1H). [0307] Step G: 8-chloro-2-mercaptopyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-ol (Int-11G) [0308] Five reactors were set up in parallel. To each reactor was charged EtOH (0.5 L) and KOH (52.0 g, 0.90 mol), and the mixture was stirred at 25 ℃ for 0.5 h. CS₂ (70.0 g, 0.9 mol) was added at 25 ℃ and the mixture was stirred at 25 ℃ for 0.5 h. H₂O (0.5 L) was added followed by 2-amino-7-chlorothieno[2,3-c]pyridine-3-carboxamide (Int-11F) (70.0 g, 0.3 mol). The mixture was heated to 110 ℃ and stirred for 12 h. The contents of the five reactors were combined. The volatiles were removed under reduced pressure and the pH was adjusted to ~3 with aq. HCl. The mixture was stirred at 0 ℃ for 1 h, filtered, and washed with H₂O (5.0 L). The resulting solid was triturated with EtOH (10 V) at 25 ℃ for 8 h and dried in an oven at 40 ℃ for 12 h to give 8-chloro-2- mercaptopyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-ol (Int-11G). MS (ESI) [M+H]⁺: m/z 270. [0309] Step H: 8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-ol (Int- 11H) [0310] Two reactors were set up in parallel. To each reactor was charged EtOH (1.0 L), H₂O (1.0 L), 8-chloro-2-mercaptopyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-ol (Int-11G) (135 g, 0.50 mol), and KOH (56.0 g, 1.0 mol). The mixture was stirred at 0 ℃ for 0.5 h. MeI (85.0 g, 0.60 mol) was added at 0 ℃ and the mixture was stirred for 1.5 h. The contents of the two reactors were combined. The volatiles were removed under reduced pressure and the pH was adjusted to ~3 with aq. HCl. The mixture was stirred at 0 ℃ for 1 h, filtered, and washed with H₂O (5.0 L). The resulting solid was triturated with EtOH (10 V) at 25 ℃ for 8 h and then dried in an oven at 40 ℃ for 12 h to give 8-chloro-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-ol (Int-11H). MS (ESI) [M+H]⁺: m/z 284.¹H NMR (400 MHz, DMSO-d₆) δ 2.62 (s, 3H), 8.16 - 8.17 (d, J = 4.0 Hz, 1H), 8.44 - 8.45 (d, J = 4.0 Hz, 1H), 13.4 (s, 1H). [0311] Step I: 4,8-dichloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidine (Int- 11I) [0312] Three reactors were set up in parallel. To each reactor was charged POCl₃ (2.02 kg, 13 mol) and 8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-ol (Int-11H) (55.0 g, 0.20 mol). The reaction mixture was stirred at 120 ℃ for 5 h. The contents of the three reactors were combined. The resulting mixture was concentrated under reduced pressure and the residue was triturated with EtOH (10 V) at 25 ℃ for 8 h. The resulting solid was dried in an oven at 40 ℃ for 12 h to give 4,8-dichloro-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidine (Int-11I). MS (ESI) [M+H]⁺: m/z 302. ¹H NMR (400 MHz, DMSO-d₆) δ 2.67 (s, 3H), 8.48 - 8.49 (d, J = 4.0 Hz, 1H), 8.65 - 8.66 (d, J = 4.0 Hz, 1H). [0313] Step J: Tert-butyl 3-(8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-11J) [0314] To a stirred mixture of 4,8-dichloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3- d]pyrimidine (Int-11I) (170 mg, 0.56 mmol) and N,N-diisopropylethylamine (300 μL, 1.69 mmol) in DMF (5 mL) was added tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (119 mg, 0.56 mmol) at 0 °C. The mixture was warmed to room temperature and stirred for 1 h. The mixture was diluted with EtOAc and water and the layers were separated. The organic phase was washed with water and brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified via silica gel chromatography (30 to 50% EtOAc in hexane) to give tert-butyl 3-(8-chloro-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-11J). MS (ESI) [M+H]+: m/z 478. 1H NMR (400 MHz, CDCl₃) δ = 8.43 (d, J = 5.5 Hz, 1H), 7.47 (d, J = 5.5 Hz, 1H), 4.48 - 4.21 (m, 3H), 4.18 - 3.99 (m, 1H), 3.84 - 3.38 (m, 2H), 2.65 (s, 3H), 1.96 - 1.84 (m, 2H), 1.82 - 1.63 (m, 2H), 1.55 (s, 9H). [0315] Step K: Tert-butyl 3-(8-chloro-2-(methylsulfinyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-11K) [0316] To a stirring solution of tert-butyl 3-(8-chloro-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-11J) (200 mg, 2.52 mmol) in DCM (2.5 mL) was added m- chloroperoxybenzoic acid (580 mg, 2.52 mmol, 75 wt%) at 0 °C. The mixture was quenched with sat. aq. NaHCO₃ and the mixture was extracted with CHCl₃. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated. The crude residue was purified via silica gel chromatography (60 to 100% EtOAc in hexane) to give tert-butyl 3-(8-chloro-2-(methylsulfinyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-11K). MS (ESI) [M+H]⁺: m/z 494.¹H NMR (400 MHz, CDCl₃) δ = 8.52 (d, J = 5.6 Hz, 1H), 7.58 (d, J = 5.5 Hz, 1H), 4.62 - 4.28 (m, 3H), 4.23 - 4.02 (m, 1H), 3.93 - 3.47 (m, 2H), 3.01 (s, 3H), 1.96 - 1.87 (m, 2H), 1.83 - 1.61 (m, 2H), 1.56 (s, 9H) [0317] Step L: Tert-butyl 3-(8-chloro-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-11L) [0318] Tert-butyl 3-(8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-11J) (500 mg, 1.046 mmol) was dissolved in DCM (10 mL). The solution was cooled to zero degree. To above solution was added mCPBA (469 mg, 2.092 mmol) at 0 °C. The reaction was stirred at zero degree for 1 h. Cold DCM was added to the reaction mixture, followed by washing with sat aqueous NaHCO₃ (5 mL). The organic layer was dried over Na₂SO₄, filtered and concentrated under vacuum. The crude was purified by flash silica gel chromatography (ISCO®, 40 g), eluted with 0- 100% EtOAc/Hex to give tert-butyl 3-(8-chloro-2- (methylsulfonyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-11L) (430mg, 0.843 mmol, 81 % yield) as white solid. ESI-MS m/z calc’d for C₂₁H₂₄ClN₅O₄S₂: 510.0, found [M+H]⁺: 510.3. [0319] Intermediate 12: Tert-butyl 3-(8-(3-(methoxymethoxy)naphthalen-1-yl)-2- (methylsulfonyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-12)

[0320] Step A: Tert-butyl 3-(8-(3-(methoxymethoxy)naphthalen-1-yl)-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-12A) [0321] To a stirred solution of tert-butyl 3-(8-chloro-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-11J) (254 mg, 0.531 mmol), 2-(3-(methoxymethoxy)naphthalen-1-yl)- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (184 mg, 0.584 mmol), XPhos Pd G4 (46 mg, 0.053 mmol) in dioxane (4 mL) was added K₃PO₄ (2 M in water, 0.797 mL, 1.59 mmol) and the biphasic mixture was heated to 110 °C overnight, cooled to r.t., and then diluted with EtOAc, and quenched by addition of sat. NaHCO₃. The organic layer was separated, and the aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over MgSO₄, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (silica gel, 0-25% EtOAc/DCM) to give tert-butyl 3-(8-(3- (methoxymethoxy)naphthalen-1-yl)-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin- 4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-12A). ESI-MS m/z calc’d for C₃₃H₃₆N₅O₄S₂ [M+H]⁺: 630; found: 630. [0322] Step B: butyl 3-(8-(3-(methoxymethoxy)naphthalen-1-yl)-2- (methylsulfonyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-12) [0323] To a stirred solution of tert-butyl 3-(8-(3-(methoxymethoxy)naphthalen-1-yl)-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-12A) (206 mg, 0.328 mmol) in DCM (5 mL) was added mCPBA (70 wt%, 170 mg, 0.690 mmol). The resulting mixture was stirred at r.t. for 1 h, diluted with DCM, and quenched by addition of 1:1 Na₂S₂O₃ (1 N in water)/sat’d NaHCO₃. The organic layer was separated, and the aqueous layer was extracted with DCM twice. The combined organic layers were dried over MgSO₄, filtered, and concentrated in vacuo to give tert-butyl 3-(8-(3- (methoxymethoxy)naphthalen-1-yl)-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-12), which was used directly in subsequent step(s) without further purification. ESI m/z calc’d for C₃₃H₃₆N₅O₆S₂ [M+H]⁺: 662; found: 662. [0324] Intermediate 13: Tert-butyl 3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-(methylsulfinyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-13) [0325] Step A: Tert-butyl 3-(8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-13A) [0326] To a solution of 4,8-dichloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidine (Int-11I) (2 g, 6.62 mmol) in isopropyl alcohol (10 mL) was added tert-butyl 3,8- diazabicyclo[3.2.1]octane-8-carboxylate (1.475 g, 6.95 mmol) and K₂CO₃ (1.829 g, 13.24 mmol). The reaction was stirred at 80 °C for 5 h. LCMS showed the reaction was finished. The reaction was cooled to room temperature and poured into ice water (30 mL). Yellow solid was precipitated. The mixture was filtered. The filtered cake was washed with H₂O (30 mL), IPA (30 mL) and EtOAc (30 mL). The filtered cake was collected and concentrated in vacuo to afford tert-butyl 3-(8-chloro-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-13A). MS (ESI) [M+H]⁺: m/z 478.2. [0327] Step B: Tert-butyl 3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-13B) [0328] To a solution of tert-butyl 3-(8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-13A) (0.5 g, 1.046 mmol) in toluene (10 mL) was added (6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)boronic acid (Int-2) (0.515 g, 1.569 mmol), SPhos Pd G3 (0.408 g, 0.523 mmol) and K₂CO₃ (1.569 mL, 3.14 mmol) (2 M in H₂O) in the glove box. The reaction was stirred at 80 °C for 16 h. LCMS showed the reaction was completed. The mixture was quenched with water (20 mL) and extracted with EtOAc (3 * 20 mL), dried over Na₂SO₄, filtered and the solvent was evaporated under reduced pressure to give crude product. The crude was purified by flash silica gel chromatography (ISCO®; 12 g Agela® Silica Flash Column, Eluent of 0~35% THF/Pet. ether gradient @ 40 mL/min, dry loaded) to give tert-butyl 3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H- indazol-4-yl)-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-13B). MS (ESI) [M+H]⁺: m/z 726.3. [0329] Step C: Tert-butyl 3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-(methylsulfinyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-13) [0330] Tert-butyl 3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H- indazol-4-yl)-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (1.2 g, 1.653 mmol) was taken up in CHCl₃ (16.5 ml) and 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (0.48 g, 1.82 mmol) was added. The reaction was stirred at 25 °C. The reaction was concentrated in vacuo and purified by silica gel column chromatography (0 to 100% (3:1 EtOAc :EtOH) in hexane) to afford tert-butyl 3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)-2- (methylsulfinyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (Int-13). MS (ESI) [M+H]⁺: m/z 742.¹H NMR (499 MHz, DMSO) δ 8.83 (t, J = 5.1 Hz, 1H), 8.05 (d, J = 4.5 Hz, 1H), 8.00 (d, J = 5.6 Hz, 1H), 7.56 (s, 1H), 5.97 (d, J = 9.7 Hz, 1H), 4.45 – 4.34 (m, 1H), 4.28 (d, J = 22.5 Hz, 2H), 4.21 – 4.12 (m, 1H), 3.97 – 3.89 (m, 1H), 3.86 – 3.77 (m, 2H), 3.73 – 3.64 (m, 1H), 2.94 – 2.88 (m, 3H), 2.72 (s, 3H), 2.44 – 2.33 (m, 1H), 2.07 – 2.01 (m, 2H), 1.81 – 1.70 (m, 3H), 1.70 – 1.63 (m, 1H), 1.63 – 1.57 (m, 2H), 1.54 – 1.51 (m, 1H), 1.50 (s, 9H). [0331] Intermediate 14: Tert-butyl 3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-14)

[0332] Step A: Tert-butyl 3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-14) [0333] To a solution of tert-butyl 3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-13B) (450 mg, 0.620 mmol) in DCM (6 mL) was added mCPBA (378 mg, 1.860 mmol), and the reaction was stirred at 25 °C for 1 h. LCMS showed that the reaction was completed. The mixture was diluted with DCM (10 mL), quenched with sat. Na₂SO₃ (aq., 5 mL), sat. NaHCO₃ (aq., 5 mL) and stirred for 30 min. The mixture was extracted with DCM (10 mL x 3). The combined organic layer was washed with sat. NaHCO₃ (5 mL) and brine (5 mL). The organic layer was dried over Na₂SO₄, filtered and the filtrate was concentrated in vacuo to give the crude product. The crude was purified by flash silica gel chromatography (ISCO®; 4 g Agela® Silica Flash Column, Eluent of 0~35% THF/Pet. ether gradient @ 40 mL/min, dry loaded) to give tert- butyl 3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)-2- (methylsulfonyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-14). MS (ESI) [M+H]⁺: m/z 758.2. [0334] Intermediate 15: Tert-butyl 3-(2-(methylsulfonyl)-8-(5-((triisopropylsilyl)ethynyl)- 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-15)

[0335] Step A: Tert-butyl 3-(2-(methylthio)-8-(5-((triisopropylsilyl)ethynyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-15A) [0336] To a solution of tert-butyl 3-(8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-11J) (160 mg, 0.335 mmol) in toluene (2.5 mL) was added (5-((triisopropylsilyl)ethynyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4-yl)boronic acid (Int-3) (212 mg, 0.402 mmol), potassium carbonate (0.502 mL, 1.004 mmol, 2 M in water) and SPhos Pd G3 (131 mg, 0.167 mmol) at 25 °C. The mixture was stirred at 50 °C for 16 h under N₂ atmosphere. LCMS showed the reaction was finished. The mixture was extracted with ethyl acetate (10 mL x 3). The organic layer was dried over Na₂SO₄, filtered and the filtrate was evaporated under reduced pressure. The residue was purified by preparative TLC (SiO₂, petroleum ether : ethyl acetate = 2 : 1) to give tert-butyl 3-(2-(methylthio)-8-(5- ((triisopropylsilyl)ethynyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-15A). MS (ESI) [M+H]⁺: m/z 926.3. [0337] Step B: Tert-butyl 3-(2-(methylsulfonyl)-8-(5-((triisopropylsilyl)ethynyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-15) [0338] To a solution of tert-butyl 3-(2-(methylthio)-8-(5-((triisopropylsilyl)ethynyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-15A) (300 mg, 0.324 mmol) in DCM (5 mL) was added mCPBA (145 mg, 0.712 mmol, 85%) at 0 °C under N₂ atmosphere. The mixture was stirred at 0 °C for 1 h. LCMS showed the starting material was consumed and desired MS was found. The reaction was filtered and the filtered cake was washed with DCM (3 mL), the filtrate was quenched with Na₂SO₃ (aq., 5 mL) and NaHCO₃ (5 mL). The mixture was stirred for 20 min, and extracted with DCM (20 mL x 3). The combined organic layer was washed with NaHCO₃ (2 mL), brine (3 mL), dried over Na₂SO₄, filtered and the filtrate was evaporated under reduced pressure give the crude product. The residue was purified by preparative TLC (SiO₂, petroleum ether : ethyl acetate =1 : 1) to give tert-butyl 3-(2-(methylsulfonyl)-8-(5-((triisopropylsilyl)ethynyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-15). MS (ESI) [M+H]⁺: m/z 958.3. [0339] Intermediate 16: Tert-butyl 3-(2-(methylsulfinyl)-8-(5-((triisopropylsilyl)ethynyl)- 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-16) [0340] Step A: tert-butyl 3-(2-(methylsulfinyl)-8-(5-((triisopropylsilyl)ethynyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-16) [0341] To a solution of tert-butyl 3-(2-(methylthio)-8-(5-((triisopropylsilyl)ethynyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-15A) (641 mg, 0.692 mmol) in DCM (7 mL) was added 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (651 mg, 2.491 mmol) at 20 °C under N₂ atmosphere. The mixture was stirred at 20 °C for 2 h. TLC (SiO₂; petroleum ether:ethyl acetate = 1:2) showed the reaction was complete. The mixture was evaporated under reduced pressure. The crude product was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~30% EtOAc/Pet. ether gradient @ 40 mL/min) to give tert-butyl 3-(2-(methylsulfinyl)-8-(5- ((triisopropylsilyl)ethynyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-16). MS (ESI) [M+H]⁺: m/z 942.5. [0342] Intermediate 17: Tert-butyl 3-(8-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5- ((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)-2- (methylsulfinyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (Int-17) [0343] Step A: Tert-butyl 3-(8-(6-fluoro-1-((trifluoromethyl)sulfonyl)-5- ((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-17A) [0344] To a mixture of tert-butyl 3-(8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4.8 g, 10.04 mmol) and 4- (5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-6-fluoro-1-((trifluoromethyl)sulfonyl)-5- ((triisopropylsilyl)ethynyl)-1H-benzo[f]indazole (Int-6) (7.97 g, 13.05 mmol), (2- dicyclohexylphosphino-2',6'-dimethoxybiphenyl) [2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (3.92 g, 5.02 mmol) in toluene (120 mL) was added K₂CO₃ (20.08 mL, 40.2 mmol) (2 M in H₂O) at 25 °C, and the mixture was stirred at 50 °C for 2 h under N₂ atmosphere. LCMS showed the starting material was consumed and the desired MS was found. The mixture was diluted with EtOAc (200 mL), and the mixture was washed with H₂O (15 mL) and brine (10 mL). The organic phase was dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 20% THF in petroleum ether gradient @ 40 mL/min) to give tert-butyl 3-(8-(6-fluoro-1- ((trifluoromethyl)sulfonyl)-5-((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-17A). MS (ESI) [M+H]⁺: m/z 940.2. [0345] Step B: Tert-butyl 3-(8-(6-fluoro-5-((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol- 4-yl)-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-17B) [0346] To a mixture of tert-butyl 3-(8-(6-fluoro-1-((trifluoromethyl)sulfonyl)-5- ((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-17A) (3 g, 3.19 mmol) in DCM (10 mL) was added ammonia (25 mL, 175 mmol) (7 M in MeOH) at 25 °C, and the mixture was stirred at 25 °C for 2 h. The reaction was monitored by LCMS that showed the starting material was consumed and desired MS was found. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 20% THF in petroleum ether gradient @ 40 mL/min) to give tert-butyl 3-(8-(6-fluoro-5-((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-17B). MS (ESI) [M+H]⁺: m/z 808.3. [0347] Step C: Tert-butyl 3-(8-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5- ((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-17C) [0348] To a mixture of tert-butyl 3-(8-(6-fluoro-5-((triisopropylsilyl)ethynyl)-1H- benzo[f]indazol-4-yl)-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (2.4 g, 2.97 mmol) in DCM (30 mL) was added 4- methylbenzenesulfonic acid (0.153 g, 0.891 mmol) and DHP (0.815 mL, 8.91 mmol) at 25 °C, and the mixture was stirred at 25 °C for 16 h. LCMS showed the starting material was consumed and desired MS was found. The mixture was concentrated in vacuum, the residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 20% ethyl acetate in petroleum ether gradient @ 40 mL/min) to give tert-butyl 3-(8-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5-((triisopropylsilyl)ethynyl)- 1H-benzo[f]indazol-4-yl)-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-17C). MS (ESI) [M+H]⁺: m/z 892.6. [0349] Step D: Tert-butyl 3-(8-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5- ((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)-2- (methylsulfinyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (Int-17) [0350] To a solution of tert-butyl 3-(8-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5- ((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-17C) (1.8 g, 2.017 mmol) in DCM (30 mL) was added 3-phenyl-2- (phenylsulfonyl)-1,2-oxaziridine (1.318 g, 5.04 mmol) at 25 °C, and the mixture was stirred at 25 °C for 2 h. LCMS showed the starting material was consumed and desired MS was found. The reaction mixture was concentrated in vacuo at 35 °C, and the residue was purified by silica gel chromatography (glass column, 40 g silica gel (100-200Å), Pet. ether/THF=1/1, dry loading) to give tert-butyl 3-(8-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)- 5-((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)-2- (methylsulfinyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (Int-17). MS (ESI) [M+H]⁺: m/z 908.5. ¹H NMR (400MHz, CD₃OD) δ 8.83 – 8.80 (m, 1H), 8.52 (d, J=3.8 Hz, 1H), 8.37 - 8.24 (m, 1H), 8.07 (br t, J=6.0 Hz, 1H), 7.54 - 7.14 (m, 2H), 6.01 (br t, J=8.9 Hz, 1H), 5.18 - 4.97 (m, 1H), 4.45 (br s, 1H), 4.39 - 4.28 (m, 1H), 4.22 (br t, J=12.3 Hz, 1H), 4.15 - 3.96 (m, 2H), 3.96 - 3.84 (m, 1H), 3.56 (br d, J=12.5 Hz, 1H), 3.10 - 2.94 (m, 3H), 2.61 - 2.31 (m, 1H), 2.22 - 1.67 (m, 9H), 1.62 - 1.54 (m, 9H), 0.86 (br d, J=6.9 Hz, 9H), 0.75 - 0.56 (m, 12H). [0351] Intermediate 18: Tert-butyl 3-(8-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5- ((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)-2- (methylsulfonyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-18)

[0352] Step A: Tert-butyl 3-(8-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5- ((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)-2- (methylsulfonyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-18) [0353] To a solution of tert-butyl 3-(8-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5- ((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-17C) (85 mg, 0.095 mmol) in DCM (3 mL) was added mCPBA (58.0 mg, 0.286 mmol) (85% w/w) at 0 °C, and the mixture was stirred at 25 °C for 30 min. LCMS showed the starting material was consumed and desired MS was found. The reaction mixture was directly purified by preparative TLC plate (SiO₂, Pet. ether/EtOAc=1/1) to give tert-butyl 3-(8-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5-((triisopropylsilyl)ethynyl)-1H- benzo[f]indazol-4-yl)-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-18). MS (ESI) [M+H]⁺: m/z 924.6. [0354] Intermediate 19: Tert-butyl 3-(8-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-19) [0355] Step A: Tert-butyl 3-(8-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-19A) [0356] To a solution of tert-butyl 3-(8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-11J) (200 mg, 0.418 mmol) in toluene (2 mL) was added ((8-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-fluoro-6- (methoxymethoxy)naphthalen-1-yl)ethynyl)triisopropylsilane (209 mg, 0.418 mmol), (2- dicyclohexylphosphino-2',6'-dimethoxybiphenyl) [2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (98 mg, 0.126 mmol) and K₂CO₃ (1.046 mL, 2.092 mmol) (2 M in water) under N₂ atmosphere. The reaction mixture was stirred at 60 °C for 16 h. LCMS showed the starting material was consumed and desired MS was found. 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®; 4 g SepaFlash® Silica Flash Column, Eluent of 19% ethyl acetate in petroleum ether gradient @ 20 mL/min) to give tert-butyl 3-(8-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-19A). MS (ESI) [M+H]⁺: m/z 828.4. [0357] Step B: Tert-butyl 3-(8-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-19) [0358] To a solution of tert-butyl 3-(8-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-19A) (141 mg, 0.126 mmol) in CH₂Cl₂ (2 mL) was added mCPBA (61.4 mg, 0.302 mmol, wt 85 %) at 0 °C under N₂ atmosphere. The mixture was stirred at 25 °C for 1 h. LCMS showed the starting material was consumed and the desired MS was found. The mixture was quenched with sat. aq. Na₂SO₃ (2 mL) and sat. aq. NaHCO₃ (2 mL), extracted with CH₂Cl₂ (3 x 2 mL), dried over Na₂SO₄, filtered and the solvent was evaporated under reduced pressure to give the crude tert-butyl 3-(8-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-19). MS (ESI) [M+H]⁺: m/z 860.4. [0359] Intermediate 20: Tert-butyl 3-(8-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7- tetrahydrocyclopenta[f]indazol-4-yl)-2-(methylsulfinyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-20) [0360] Step A: Tert-butyl 3-(8-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7- tetrahydrocyclopenta[f]indazol-4-yl)-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin- 4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-20A) [0361] Tert-butyl 3-(8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-11J) (69 mg, 0.144 mmol), (5-methyl-1- (tetrahydro-2H-pyran-2-yl)-1,5,6,7-tetrahydrocyclopenta[f]indazol-4-yl)boronic acid (Int-5) (60.7 mg, 0.202 mmol), SPhos Pd G3 (17 mg, 0.022 mmol) and potassium phosphate tribasic (92 mg, 0.433 mmol) were added to a vial. THF (1299 μL) and water (144 μL) were added through the septum and the resulting mixture was degassed and backfilled with nitrogen (3x) and was stirred at 60 °C overnight. The reaction mixture was diluted with DCM and water and was extracted with DCM (2x). The combined organic fractions were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-100% EtOAc in hexane) to afford tert-butyl 3-(8-(5-methyl-1- (tetrahydro-2H-pyran-2-yl)-1,5,6,7-tetrahydrocyclopenta[f]indazol-4-yl)-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-20A). [M+H]+ Found: 698. [0362] Step B: Tert-butyl 3-(8-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7- tetrahydrocyclopenta[f]indazol-4-yl)-2-(methylsulfinyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-20) [0363] Tert-butyl 3-(8-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7- tetrahydrocyclopenta[f]indazol-4-yl)-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin- 4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-20A) (88.5 mg, 0.127 mmol) was taken up in CHCl₃ (1268 μL) and 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (39.8 mg, 0.152 mmol) was added. Reaction was stirred at 25 °C for 4 h and was directly purified by silica gel column chromatography (0-100% 3:1 EtOAc:EtOH in hex) to afford tert-butyl 3- (8-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7-tetrahydrocyclopenta[f]indazol-4-yl)-2- (methylsulfinyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (Int-20). [M+H]⁺ Found: 714. [0364] Intermediate 21: Tert-butyl 3-(2-(((S)-2,2-difluoro-1- (((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran- 2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-21) [0365] Step A: Tert-butyl 3-(2-hydroxy-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-21A) [0366] A solution of tert-butyl 3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-(methylsulfinyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-13) (498 mg, 0.671 mmol) in THF (6.7 ml) was cooled to 0 °C and then treated with 1 N NaOH (3356 μL, 3.36 mmol). After ~30-45 min the reaction was complete. The crude reaction was then partitioned between EtOAc and water and the organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to obtain crude tert-butyl 3-(2-hydroxy-8- (6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-21A), which was used directly in the next step without further purification. MS (ESI) m/z 696 [M+H]⁺. [0367] Step B: Tert-butyl 3-(2-(((S)-1-(((tert-butyldimethylsilyl)oxy)methyl)-2,2- difluorocyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-21B) [0368] A solution of tert-butyl 3-(2-hydroxy-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-21A) (474 mg, 0.68 mmol) and (R)-(1-(((tert- butyldimethylsilyl)oxy)methyl)-2,2-difluorocyclopropyl)methyl 4-nitrobenzenesulfonate (447 mg, 1.022 mmol) in acetonitrile (6813 μL) was treated with Cs₂CO₃ (444 mg, 1.36 mmol) at 50 °C. After ~3.5 h the reaction was cooled, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 24 g Redisep Gold Flash Column, eluent of 20-100% EtOAc/Hexanes gradient) to give tert-butyl 3-(2-(((S)-1-(((tert- butyldimethylsilyl)oxy)methyl)-2,2-difluorocyclopropyl)methoxy)-8-(6-methyl-1- (tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-21B). MS (ESI) m/z 930 [M+H]⁺. [0369] Step C: Tert-butyl 3-(2-(((R)-2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-21C) [0370] A solution of tert-butyl 3-(2-(((S)-1-(((tert-butyldimethylsilyl)oxy)methyl)-2,2- difluorocyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-21B) (495 mg, 0.53 mmol) in THF (3.5 ml) and treated wtih TBAF (2.1 ml, 2.1 mmol) at RT. After ~30min the reaction was partitioned between EtOAc and sat. ammonium chloride. The organic layer was washed with water, brine and then dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 24 g Redisep Gold Flash Column, eluent of 20-100% [3:1 EtOAc/EtOH]/Hexanes gradient) to give tert-butyl 3-(2- (((R)-2,2-difluoro-1-(hydroxymethyl)cyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H- pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-21C). MS (ESI) m/z 816 [M+H]⁺. [0371] Step D. Tert-butyl 3-(2-(((S)-2,2-difluoro-1- (((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran- 2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-21) [0372] A solution of tert-butyl 3-(2-(((R)-2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-21C) (338 mg, 0.414 mmol), and triethylamine (87 μL, 0.621 mmol) in DCM (4143 μl) was cooled to 0 °C and then treated with a solution of MsCl (40.4 μL, 0.518 mmol) in DCM (75 μL). The reaction was allowed to stir at 0 °C and was deemed complete in 10 minutes. The reaction was partitioned between DCM and sat. sodium bicarbonate solution, the organic layer was then washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 40 g Redisep Gold Flash Column, eluent of 10-100% [3:1 EtOAc/EtOH]/Hexanes gradient) to give tert-butyl 3-(2-(((S)-2,2- difluoro-1-(((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro- 2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-21). MS (ESI) m/z 894 [M+H]⁺. [0373] Intermediate 22: Tert-butyl 3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-((3-methylpiperidin-3- yl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-22)

[0374] Step A: Benzyl 3-(hydroxymethyl)-3-methylpiperidine-1-carboxylate (Int-22A) [0375] In a 100 mL round bottom flask, 3-(hydroxymethyl)-3-methylpiperidin-1-ium chloride (1500 mg, 9.05 mmol) was dissolved in DCM (22.6 ml). To above solution was added TEA (5048 μL, 36.2 mmol, 4 eq.), followed by CbzCl (4527 μL, 13.58 mmol, 1.5 eq.). The reaction was stirred at r.t. for 1h, quenched with water (5 mL), extracted with DCM (20 mL x 3). The organic layer was dried over MgSO₄, filtered and concentrated. The crude was purified by flash silica gel chromatography (ISCO®, 120 g column, eluted with 0-100% EtOAc/Hexane in 30 min). Fractions containing desired product were combined and concentrated to give benzyl 3-(hydroxymethyl)-3-methylpiperidine-1-carboxylate (Int- 22A). ESI-MS m/z calc’d for C₁₅H₂₁NO₃: 263.337, found [M+Na]⁺: 286.3. [0376] Step B: Tert-butyl 3-(2-((1-((benzyloxy)carbonyl)-3-methylpiperidin-3- yl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-22B) [0377] In a 40 ml vial, tert-butyl 3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-14) (200 mg, 0.264 mmol) and benzyl 3-(hydroxymethyl)-3-methylpiperidine-1-carboxylate (Int-22A) (141 mg, 0.528 mmol, 2 eq.) were dissolved in THF (2639 μL). The solution was cooled to zero degree, and was added NaH (63.3 mg, 1.583 mmol). The reaction was let stirred at zero degree for 1.5 h, quenched with NaHCO₃ (1 mL), extracted with DCM (5 mL x 3). The organic layer was dried over MgSO₄, filtered and concentrated. The crude was purified by flash silica gel chromatography (ISCO®, 24 g gold column, eluted with 0-20% MeOH/DCM). Fractions containing desired product were combined and concentrated to give tert-butyl 3-(2-((1-((benzyloxy)carbonyl)-3-methylpiperidin-3-yl)methoxy)-8-(6- methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-22B). ESI-MS m/z calc’d for C₄₉H₅₅F₃N₈O₆S: 941.084, found [M+H]⁺: 942.8. [0378] Step C: Tert-butyl 3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-((3-methylpiperidin-3- yl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-22) [0379] Tert-butyl 3-(2-((1-((benzyloxy)carbonyl)-3-methylpiperidin-3-yl)methoxy)-8-(6- methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-22B) (124 mg, 0.132 mmol) was dissolved in DCM (22 ml). To above solution was added TEA (55.1 μL, 0.395 mmol), triethylsilane (421 μL, 2.64 mmol) and palladium(II) chloride (35.0 mg, 0.198 mmol). The reaction was stirred under N₂ for 16 h, then quenched with addition of MeOH (5 mL) and stirred at room temperature for 10 min. To above solution was added TEA (1 mL). The crude was filtered and concentrated, purified by flash silica gel chromatography (ISCO®, 24 g gold column, eluted with 0-20% MeOH/DCM) to give tert-butyl 3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-((3-methylpiperidin-3- yl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-22). ESI-MS m/z calc’d for C₄₁H₄₉F₃N₈O₄S: 806.950, found [M+H]⁺: 807.4. [0380] Intermediate 23: Tert-butyl 3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-((3-methylazetidin-3- yl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-23)

[0381] Step A: Tert-butyl 3-(2-((1-((benzyloxy)carbonyl)-3-methylazetidin-3-yl)methoxy)- 8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-23A) [0382] In a 40 mL vial, tert-butyl 3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-14) (200 mg, 0.264 mmol) and benzyl 3-(hydroxymethyl)-3-methylazetidine-1-carboxylate (124 mg, 0.528 mmol, 2 eq.) were dissolved in THF (2639 μL). The solution was cooled to zero degree, and was added NaH (63.3 mg, 1.583 mmol). The reaction was let stirred at zero degree for 1.5 h, quenched with NaHCO₃ (1 mL), and extracted with DCM (5 mL x 3). The organic layer was dried over MgSO₄, filtered and concentrated. The crude was purified by flash silica gel chromatography (ISCO®, 24 g gold column, eluted with 0-20% MeOH/DCM). Fractions containing desired product were combined and concentrated to give tert-butyl 3- (2-((1-((benzyloxy)carbonyl)-3-methylazetidin-3-yl)methoxy)-8-(6-methyl-1-(tetrahydro- 2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-23A). ESI-MS m/z calc’d for C₄₇H₅₁F₃N₈O₆S: 913.03, found [M+H]⁺: 913.4. [0383] Step B: Tert-butyl 3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-((3-methylazetidin-3- yl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-23) [0384] Tert-butyl 3-(2-((1-((benzyloxy)carbonyl)-3-methylazetidin-3-yl)methoxy)-8-(6- methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-23A) (240 mg) was dissolved in CH₂Cl₂ (2629 μL). To the above solution was added TEA (110 μL, 0.789 mmol), triethylsilane (630 μL, 3.94 mmol) and palladium(II) chloride (55.9 mg, 0.315 mmol). The mixture was stirred under N₂ for 2 h. UPLC-MS indicated formation of the desired product. To the above mixture was added MeOH (5 ml) and stirred at r.t. for 10 min, then was added TEA (1 mL), and was filtered and concentrated. The crude was purified by flash silica gel chromatography (ISCO®, 24 g gold column, eluted with 0-20% MeOH/DCM). Fractions containing desired product were combined and concentrated to give tert-butyl 3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)- 5-(trifluoromethyl)-1H-indazol-4-yl)-2-((3-methylazetidin-3- yl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-23). ESI-MS m/z calc’d for C₃₉H₄₅F₃N₈O₄S: 778.896, found [M+H]⁺: 779.5. [0385] Intermediate 24: Tert-butyl 3-(2-hydroxy-8-(5-((triisopropylsilyl)ethynyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-24) [0386] Step A: Tert-butyl 3-(2-hydroxy-8-(5-((triisopropylsilyl)ethynyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-24) [0387] LiOH solution (1.6 mL, 1 M, aq.) was added to tert-butyl 3-(2-(methylsulfinyl)-8- (5-((triisopropylsilyl)ethynyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol- 4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-16) (300 mg, 0.32 mmol) in THF (1.6mL) dropwise. The mixture was stirred at 25ºC for overnight. The mixture was neutralized with 0.5 N HCl to pH7, and extracted with EtOAc (3x10mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to generate product tert-butyl 3-(2-hydroxy-8- (5-((triisopropylsilyl)ethynyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol- 4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-24). ESI-MS m/z calc’d for C₄₆H₆₁N₇O₄S₂Si₂ [M+H]⁺: 897; found: 897. [0388] Intermediate 25: (2S,4R)-1-(L-valyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5- yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide (Int-25) [0389] Step A: Tert-butyl (R)-(1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2- hydroxyethyl)carbamate (Int-25A) [0390] 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 r.t., filtered through a pad of MgSO₄/silica gel (rinsing with EtOAc), and concentrated in vacuo. The residue was purified by flash chromatography (silical gel, 0-100% EtOAc/hexanes) to give tert-butyl (R)-(1-(4-(1-ethyl- 1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)carbamate (Int-25A). ESI-MS m/z calc’d for C₁₈H₂₆N₃O₃ [M+H]⁺: 332; found: 332. [0391] Step B: (R)-2-amino-2-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)ethan-1-ol (Int-25B) [0392] To a stirred solution of tert-butyl (R)-(1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2- hydroxyethyl)carbamate (Int-25A) (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 r.t. 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 (Int-25B), which was used directly in the next step without further purification. ESI-MS m/z calc’d for C₁₃H₁₈N₃O [M+H]⁺: 232; found: 232. [0393] 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 (Int-25C) [0394] To a stirred solution of (R)-2-amino-2-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)ethan-1- ol (Int-25B) (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 r.t. for 15 min, and was quenched by addition of sat. 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 (Int-25C). ESI-MS m/z calc’d for C₂₈H₄₂N₅O₆ [M+H]⁺: 544; found: 544. [0395] Step D: (2S,4R)-1-(L-valyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2- hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide (Int-25) [0396] 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 (Int-25C) (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 r.t. 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 (Int-25). ESI-MS m/z calc’d for C₂₃H₃₄N₅O₄ [M+H]⁺: 444; found: 444.¹H NMR (500 MHz, DMSO-d₆) δ 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), 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). [0397] Compound in the table below was synthesized via a similar route as described in the above synthesis of Int-25 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. [0398] Int-26: ¹H NMR (500 MHz, DMSO-d6) δ 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). [0399] Intermediate 27: (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-((tert- butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int- 27) [0400] Step A: (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-((tert- butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int- 27) [0401] To a solution of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (1.7 g, 3.95 mmol) in DCM (20 mL) was added 1H-imidazole (0.403 g, 5.92 mmol) and tert-butylchlorodimethylsilane (0.893 g, 5.92 mmol) at 25 °C. The mixture was stirred at 25 °C for 12 h. LCMS showed the starting material was consumed and the desired MS was found. The mixture was diluted with water (5 mL) and extracted with DCM (40 mL * 3). The 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®, 40 g Agela Flash Column, DCM:MeOH=10:1, 30 min, 30 mL/min, dry loaded) to give (2S,4R)-1-((S)-2-amino-3,3- dimethylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Int-27). MS (ESI) [M+H]⁺: m/z 545.4. [0402] Intermediate 28: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Int-28) [0403] Step A: 4-(4-methylthiazol-5-yl)benzonitrile (Int-28A) [0404] To a solution of 4-bromobenzonitrile (20 g, 110 mmol) in DMA (280 mL) was added 4-methylthiazole (21.79 g, 220 mmol), Pd(OAc)₂ (0.247 g, 1.099 mmol) and potassium carbonate (21.57 g, 220 mmol) at 25 °C under N₂ atmosphere. The mixture was stirred at 149 °C for 2 h. LCMS showed the starting material was consumed and desired peak was formed. The mixture was cooled, diluted with EtOAc (500 mL), washed with H₂O (60 mL x 3), 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®; 120 g SepaFlash® Silica Flash Column, Eluent of 30% ethyl acetate in petroleum ether gradient @ 75 mL/min) to give 4-(4-methylthiazol-5- yl)benzonitrile (Int-28A). MS (ESI) [M+H]⁺: m/z 200.9. [0405] Step B: (4-(4-methylthiazol-5-yl)phenyl)methanamine (Int-28B) [0406] To a solution of 4-(4-methylthiazol-5-yl)benzonitrile (8.5 g, 42.4 mmol) and cobalt(II) chloride (8.27 g, 63.7 mmol) in MeOH (90 mL) was added sodium tetrahydroborate (9.76 g, 424 mmol) portionwise (~0.5 h) and the mixture was stirred at 0 °C for 1 h. LCMS showed the starting material was consumed and desired MS was found. The reaction was quenched with acetone (100 mL) and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (ISCO®; 120 g Agela® Silica Flash Column (basified by TEA), Eluent of 0~5% DCM/MeOH gradient @ 70 mL/min, dry loaded) to give (4-(4-methylthiazol-5-yl)phenyl)methanamine (Int-28B). MS (ESI) [M+H]⁺: m/z 205.1. [0407] Step C: Tert-butyl (2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidine-1-carboxylate (Int-28C) [0408] To a stirred solution of (4-(4-methylthiazol-5-yl)phenyl)methanamine (2.4 g, 11.75 mmol) and (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (2.99 g, 12.92 mmol) in DMF (35 mL) was added 1H-benzo[d][1,2,3]triazol-1-ol (1.905 g, 14.10 mmol), DIEA (6.16 mL, 35.2 mmol) and EDC (3.38 g, 17.62 mmol), and the mixture was stirred at 30 °C for 2 h. LCMS showed the starting material was consumed and desired MS was found. The reaction mixture was extracted with EtOAc (60 mL * 3). The combined organic layer was washed with H₂O (30 mL * 3), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give crude product. The residue was purified by flash silica gel chromatography (ISCO®, 20 g Agela Flash Column, Pet. ether/THF=1/2) to give tert-butyl (2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidine-1-carboxylate (Int-28C). ¹H NMR (400 MHz, CDCl₃) δ 8.70 (s, 1H), 7.41 - 7.31 (m, 4H), 4.48 (br s, 3H), 3.56 - 3.45 (m, 2H), 3.37 - 3.15 (m, 2H), 3.01 - 2.86 (m, 1H), 2.50 (s, 3H), 2.23 - 2.03 (m, 1H), 1.51 - 1.29 (m, 9H). [0409] Step D: (2S,4R)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Int-28D) [0410] The compound of tert-butyl (2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidine-1-carboxylate (Int-28C) (8 g, 19.16 mmol) was added to HCl (4.79 mL, 19.16 mmol) (4 M in dioxane) at 25 °C. The mixture was stirred at 25 °C for 30 min. LCMS showed the starting material was consumed and desired MS was found. The mixture was concentrated in vacuum and the residue underwent azeotropy with toluene (40 mL * 2) to give (2S,4R)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Int-28D). MS (ESI) [M+H]⁺: m/z 318.5. [0411] Step E: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Int-28) [0412] To a solution of (2S,4R)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide (Int-28D) (6 g, 18.90 mmol) in DCM (60 mL) was added 2,6-lutidine (33.0 mL, 284 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (30.0 g, 113 mmol) at 25 °C under N₂ atmosphere. The mixture was stirred at 25 °C for 30 min. LCMS showed the starting material was consumed and the desired MS was found. The mixture was concentrated under reduced pressure, purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0%-50% of EE (EtOAc:EtOH=3:1): petroleum ether gradient @ 70 mL/min) to (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-N-(4- (4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-28). MS (ESI) [M+H]⁺: m/z 432.2. [0413] Intermediate 29-a & 29-b: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3- hydroxyisoxazol-5-yl)-3-methylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Int-29-a & Int-29-b) [0414] Step A: 5-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazole (Int-29A) [0415] 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 (Int- 29A). MS (ESI) [M+H]⁺: m/z 183.8. [0416] Step B: 2-(3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazol-5-yl)acetic acid (Int-29B) [0417] 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 organic 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 (Int-29B). MS (ESI) [M+H]⁺: m/z 228.2. [0418] Step C: Methyl 2-(3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazol-5-yl)acetate (Int- 29C) [0419] To a solution of 2-(3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazol-5-yl)acetic acid (Int- 29B) (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 (Int-29C). MS (ESI) [M+H]⁺: m/z 242.2. [0420] Step D: Methyl 3-methyl-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazol-5- yl)butanoate (Int-29D) [0421] To a solution of methyl 2-(3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazol-5-yl)acetate (Int-29C) (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-methyl-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazol-5-yl)butanoate (Int-29D). MS (ESI) [M+H]⁺: m/z 284.2. [0422] Step E: 3-methyl-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)isoxazol-5-yl)butanoic acid (Int-29E) [0423] 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 (Int-29E). MS (ESI) [M+H]⁺: m/z 270.2. [0424] 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 (Int-29F) [0425] 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 (Int-28) (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 (Int-29F). MS (ESI) [M+H]⁺: m/z 683.3. [0426] 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 (Int-29G) [0427] 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 (Int-29F) (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 was 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 racemic (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-hydroxyisoxazol-5-yl)-3- methylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-29G). MS (ESI) [M+H]⁺: m/z 599.3. [0428] Step H: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-hydroxyisoxazol-5-yl)-3- methylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-29-a & Int-29-b) [0429] The racemic (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-hydroxyisoxazol-5- yl)-3-methylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int- 29G) (280 mg, 0.468 mmol) was separated by SFC (Column: Daicel Chiralcel OD (250 mm * 30 mm, 10 um); Condition: CO₂- MeOH (0.1% NH₃·H₂O); Begin B--End B: 20--20; Gradient Time (min): 10; 100% B Hold Time (min): 10; FlowRate (mL/min): 70) 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 (Int-29-a, the first eluting isomer from SFC) and (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-hydroxyisoxazol-5- yl)-3-methylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int- 29-b, the second eluting isomer from SFC). MS (ESI) [M+H]+: m/z 599.2. [0430] Intermediate 30: (2S,4R)-1-(L-valyl)-4-((tert-butyldimethylsilyl)oxy)-N-((S)-2- ((tert-butyldimethylsilyl)oxy)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide (Int-30)

[0431] At 0 °C, to a solution of (2S,4R)-1-(L-valyl)-N-((S)-1-(4-(1-ethyl-1H-pyrazol-5- yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide (15 mg, 1 eq.) and imidazole (9.2 mg, 4 eq.) in DCM (0.4 mL) was added TBS-Cl(15.3 mg, 3 eq.), and the resulting mixture was allowed to stir at ambient temperature for 48 h. The reaction mixture was diluted with DCM and washed twice with water and once with brine. The combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica eluted with Hex/(EtOAc/EtOH 3:1) 10-100, to give desired product (2S,4R)-1-(L-valyl)-4-((tert- butyldimethylsilyl)oxy)-N-((S)-2-((tert-butyldimethylsilyl)oxy)-1-(4-(1-ethyl-1H-pyrazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Int-30). ESI-MS m/z calc’d for C₃₅H₆₁N₅O₄Si₂ [M+H]+: 672; found: 672. [0432] Intermediate 31: (2S,4R)-1-((S)-2-azido-3,3-dimethylbutanoyl)-4-hydroxy-N-(4- (4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-31) [0433] Step A: (2S,4R)-1-((S)-2-azido-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-31) [0434] To a mixture of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (2 g, 4.28 mmol) in DMF (40 mL) were added 1H-imidazole-1-sulfonyl azide hydrochloride (1.077 g, 5.14 mmol) and potassium bicarbonate (3 M in water) (7.14 mL, 21.41 mmol) at 0 °C. The mixture was stirred at room temperature for 2 h. The mixture was diluted with ethyl acetate (400 mL) and washed with water (300 mL × 2), brine (300 mL × 2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Combi-flash with the following: Column: AQ-C18 Column, 220 g, 60 Å, 40-60 μm; Mobile Phase A: water, Mobile Phase B: MeCN; Flow rate: 80 mL / min; 0% B to 100% B in 25 min; Detector: UV 254 / 210 nm. The product-containing fractions were combined, roto-evaporated in vacuo to give (2S,4R)-1-((S)-2-azido-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Int-31). MS ESI calculated for C₂₂H₂₈N₆O₃S [M + H]+ 457.19 found 457.10. ¹H NMR (300 MHz, CD₃OD) δ 8.88 (s, 1H), 7.57 - 7.29 (m, 4H), 4.73 - 4.56 (m, 1H), 4.56 - 4.25 (m, 3H), 4.03 (s, 1H), 3.86 - 3.62 (m, 2H), 2.48 (s, 3H), 2.33 - 2.16 (m, 1H), 2.16 - 2.05 (m, 1H), 1.12 - 0.96 (m, 9H). [0435] Intermediate 32: (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4-hydroxy-N-((R)-2- hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Int-32) [0436] Step A: Methyl (2S,4R)-1-((tert-butoxycarbonyl)-L-valyl)-4-hydroxypyrrolidine-2- carboxylate (Int-32A) [0437] To a stirred mixture of (tert-butoxycarbonyl)-L-valine (2 g, 9.21 mmol) in DMF (20 mL) were added HATU (3.85 g, 10.13 mmol), methyl (2S,4R)-4-hydroxypyrrolidine-2- carboxylate (1.336 g, 9.21 mmol) and DIEA (6.43 mL, 36.8 mmol) at 0 °C. The resulting mixture was warmed to room temperature and stirred for 2 h. The reaction progress was monitored by LCMS. The reaction mixture was quenched by water (50 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic fractions were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by Combi-Flash with the following conditions: Column: AQ-C18 Column (220 g); Mobile Phase: MeCN and water (Gradient: 0% - 100% within 50 min); Flow rate: 80 mL/min; Detector: UV 254 / 210 nm. The collected fractions were combined and concentrated under reduced pressure to give methyl (2S,4R)-1-((tert-butoxycarbonyl)- L-valyl)-4-hydroxypyrrolidine-2-carboxylate (Int-32A) (3 g, 8.71 mmol, 95% yield) as a white solid. MS ESI calculated for C₁₆H₂₈N₂O₆ [M - C₄H₈ + H]+ 289.19, found 289.05. ¹H NMR: (400 MHz, CDCl₃) δ 5.33 - 5.14 (m, 1H), 4.75 - 4.61 (m, 1H), 4.52 (s, 1H), 4.20 - 3.94 (m, 2H), 3.72 (s, 4H), 2.79 (s, 1H), 2.43 - 2.26 (m, 1H), 2.04 - 1.93 (m, 2H), 1.41 (s, 9H), 1.05 - 0.89 (m, 6H). [0438] Step B: Methyl (2S,4R)-1-(L-valyl)-4-hydroxypyrrolidine-2-carboxylate (Int-32B) [0439] To a stirred mixture of methyl (2S,4R)-1-((tert-butoxycarbonyl)-L-valyl)-4- hydroxypyrrolidine-2-carboxylate (Int-32A) (3 g, 8.71 mmol) in dichloromethane (14 mL) was added hydrochloride in 1,4-dioxane (30 mL, 4 M, 120 mmol) at room temperature. The resulting mixture was stirred for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was washed by hexane to afford methyl (2S,4R)-1-(L-valyl)-4- hydroxypyrrolidine-2-carboxylate hydrochloride (Int-32B) (3 g, 10.69 mmol, 99% yield) a white solid. MS ESI calculated for C₁₁H₂₀N₂O₄ [M + H]+ 245.14, found 245.10. [0440] Step C: Methyl (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4-hydroxypyrrolidine-2- carboxylate (Int-32C) [0441] To a stirred mixture of methyl (2S,4R)-1-(L-valyl)-4-hydroxypyrrolidine-2- carboxylate (Int-32B) (3 g, 12.28 mmol) in DMF (30 mL) were added 1H-imidazole-1- sulfonyl azide hydrochloride (3.09 g, 14.74 mmol) and aqueous potassium bicarbonate (3 M, 20.47 mL, 61.4 mmol) at room temperature. The resulting mixture was stirred for 2 h. The reaction progress was monitored by LCMS. The reaction mixture was quenched by water (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic fractions were washed with brine (100 mL × 3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by Combi-Flash with the following conditions: Column: AQ-C18 Column (220 g); Mobile Phase: MeCN and water (Gradient: 0% - 100% within 50 min); Flow rate: 80 mL/min; Detector: UV 254 / 210 nm. The collected fractions were combined and concentrated under reduced pressure to give methyl (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4- hydroxypyrrolidine-2-carboxylate (Int-32C) (1.45 g, 5.36 mmol, 43.7% yield) as a white solid. MS ESI calculated for C₁₆H₂₈N₂O₆ [M + H]+ 271.13, found 271.05. ¹H NMR: (300 MHz, DMSO-d₆) δ 5.24 (s, 1H), 4.46 - 4.27 (m, 2H), 3.81 (d, J = 8.1 Hz, 1H), 3.62 (s, 3H), 3.60 - 3.55 (m, 2H), 2.26 - 1.97 (m, 2H), 1.96 - 1.83 (m, 1H), 1.07 - 0.91 (m, 6H). [0442] Step D: (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4-hydroxypyrrolidine-2- carboxylic acid (Int-32D) [0443] To a stirred mixture of methyl (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4- hydroxypyrrolidine-2-carboxylate (Int-32C) (1.45 g, 5.36 mmol) in methanol (27 mL) was added LiOH (6.71 mL, 26.8 mmol) at room temperature. The resulting mixture was stirred for 2 h. The reaction mixture was quenched by aq. HCl (1 M, 20 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic fractions were washed with brine (50 mL × 3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4-hydroxypyrrolidine- 2-carboxylic acid (Int-32D) (900 mg, 3.51 mmol, 65.5% yield) as a white solid. MS ESI calculated for C₁₀H₁₆N₄O₄ [M + H]+ 257.12, found 257.10. ¹H NMR: (400 MHz, DMSO- d₆) δ 5.21 (d, J = 3.6 Hz, 1H), 4.39 - 4.25 (m, 2H), 3.79 (d, J = 8.0 Hz, 1H), 3.63 - 3.50 (m, 2H), 3.34 (s, 1H), 2.21 - 2.02 (m, 2H), 1.95 - 1.84 (m, 1H), 1.06 - 0.92 (m, 6H). [0444] Step E: (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy-1- (4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Int-32) [0445] To a stirred mixture of (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4- hydroxypyrrolidine-2-carboxylic acid (Int-32D) (700 mg, 2.73 mmol) in DMF (8 mL) were added HATU (1428 mg, 3.76 mmol), (R)-2-amino-2-(4-(4-methylthiazol-5-yl)phenyl)ethan- 1-ol (800 mg, 3.41 mmol) and DIEA (2.385 mL, 13.66 mmol) at 0 °C. The resulting mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was quenched by water (50 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic fractions were washed with brine (100 mL × 3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by Combi-Flash with the following conditions: Column: AQ-C18 Column (120 g); Mobile Phase: MeCN and water (Gradient: 0% - 100% within 50 min); Flow rate: 80 mL/min; Detector: UV 254 / 210 nm. The collected fractions were combined and concentrated under reduced pressure to give (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4- hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide (Int-32) (1.1 g, 2.328 mmol, 68.2% yield) as a white solid. MS ESI calculated for C₂₂H₂₈N₆O₄S [M + H]+ 473.19, found 473.00. ¹H NMR: (300 MHz, CD₃OD) δ 8.88 (s, 1H), 7.57 - 7.28 (m, 4H), 5.02 (t, J = 6.0 Hz, 1H), 4.67 (t, J = 8.4 Hz, 1H), 4.55 - 4.39 (m, 1H), 3.82 (d, J = 6.0 Hz, 2H), 3.76 - 3.64 (m, 3H), 2.48 (s, 3H), 2.31 - 2.13 (m, 2H), 2.03 - 1.88 (m, 1H), 1.19 - 0.91 (m, 6H). [0446] Intermediate 33: (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl- 1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide (Int-33) [0447] Step A: (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H- pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide (Int-33) [0448] To a stirred mixture of (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4- hydroxypyrrolidine-2-carboxylic acid (Int-32D) (950 mg, 3.71 mmol) in DMF (9.5 mL) were added HATU (1551 mg, 4.08 mmol), (R)-2-amino-2-(4-(1-ethyl-1H-pyrazol-5- yl)phenyl)ethan-1-ol (Int-25B) (857 mg, 3.71 mmol) and DIEA (2.59 mL, 14.83 mmol) at 0 °C. The resulting mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was quenched by water (50 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic fractions were washed with brine (100 mL × 3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by Combi-Flash with the following conditions: Column: AQ-C¹⁸ Column (120 g); Mobile Phase: MeCN and water (Gradient: 0% - 100% within 50 min); Flow rate: 80 mL/min; Detector: UV 254 / 210 nm. The collected fractions were combined and concentrated under reduced pressure to give (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)- N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2- carboxamide (Int-33) (1 g, 2.130 mmol, 57.4% yield) as a white solid. MS ESI calculated for C₂₃H₃₁N₇O₄ [M + H]⁺ 470.24 found 470.00. ¹H NMR: (400 MHz, CD₃OD) δ 7.61 - 7.30 (m, 5H), 6.31 (m, 1H), 5.13 - 4.97 (m, 1H), 4.76 - 4.60 (m, 1H), 4.51 - 4.37 (m, 1H), 4.29 - 4.06 (m, 2H), 3.83 (m, 2H), 3.78 - 3.63 (m, 3H), 2.33 - 2.13 (m, 2H), 2.02 - 1.90 (m, 1H), 1.44 - 1.26 (m, 3H), 1.16 - 0.92 (m, 6H). [0449] Intermediate 34: (2S,4R)-1-((S)-2-azido-3,3-dimethylbutanoyl)-4-((tert- butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int- 34) [0450] Step A: (2S,4R)-1-((S)-2-azido-3,3-dimethylbutanoyl)-4-((tert- butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int- 34) [0451] To a solution of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-((tert- butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int- 27) (6.0 g, 11.01 mmol) in acetonitrile (60 mL) and water (30 mL) was added 1H- imidazole-1-sulfonyl azide hydrochloride (2.77 g, 13.22 mmol), copper(II) sulfate pentahydrate (0.275 g, 1.101 mmol) and TEA (4.60 mL, 33.0 mmol) at 25 °C under N₂ atmosphere. The mixture was stirred at 25 °C for 16 h. LCMS showed the starting material was consumed and desired MS was found. The mixture was extracted with EtOAc (100 mL * 2). The 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®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~5% MeOH in DCM gradient @ 30 mL/min) to give (2S,4R)-1-((S)-2-azido-3,3-dimethylbutanoyl)-4- ((tert-butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Int-34). MS (ESI) [M+H]⁺: m/z 571.4. [0452] Intermediate 35: (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4-((tert- butyldimethylsilyl)oxy)-N-((S)-2-((tert-butyldimethylsilyl)oxy)-1-(4-(1-ethyl-1H-pyrazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Int-35) [0453] Step A: (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)- N-((S)-2-((tert-butyldimethylsilyl)oxy)-1-(4-(1-ethyl-1H-pyrazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Int-35) [0454] At 0 °C, to a solution of (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-N-((S)-1-(4-(1- ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide (50 mg, 0.1 mmol) and 1H-imidazole (29 mg, 0.43 mmol) in DCM (1.06 mL) was added TBSCl (48.1 mg, 0.319 mmol) and the resulting mixture was allowed to stir for 48 h at 25 ºC. The reaction mixture was diluted with DCM and washed twice with water and once with brine. The combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (eluted with Hex/(EtOAc/EtOH 3:1) (0-100%) to obtain titled product (2S,4R)-1- ((S)-2-azido-3-methylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)-N-((S)-2-((tert- butyldimethylsilyl)oxy)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide (Int-35). ESI-MS m/z calc’d for C₃₅H₅₉N₇O₄Si₂ [M+H]+: 698; found: 698. [0455] Compound in the table below was synthesized via a similar route as described in the above synthesis of Int-35 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. [0456] Intermediate 37: Ethyl (R)-7-(((2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)(methyl)amino)heptanoate (Int-37) [0457] Step A, B: (R)-1-(1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)-N- methylmethanamine (Int-37B) [0458] To a solution of (R)-(1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methanol (5 g, 21.91 mmol) in DCM (50 mL) was added TEA (6.11 mL, 43.8 mmol) and MsCl (3.04 mL, 39 mmol) at 0 °C under N₂ atmosphere. The mixture was stirred at 25 °C for 1 h under N₂ atmosphere. TLC (Pet. ether: EtOAc = 5: 1) showed the starting material was consumed and new spot was formed. [0459] MeNH₂ (26.3 mL, 168 mmol) (30% in EtOH) was added to the above mixture and the resulting 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 reaction mixture was concentrated in vacuum, and the residue was purified by flash silica gel chromatography (ISCO®; 80 g Agela® Silica Flash Column, Eluent of 0~5% MeOH / DCM (contained 0.1% TEA) gradient @ 60 mL/min, dry loaded) to give (R)-1-(1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)-N-methylmethanamine (Int-37B). MS (ESI) [M+H]⁺: m/z 241.9. [0460] Step C: Ethyl (R)-7-(((1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)(methyl)amino)heptanoate (Int-37C) [0461] To a solution of (R)-1-(1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)-N- methylmethanamine (Int-37B) (2.6 g, 10.78 mmol) in MeCN (30 mL) was added K₂CO₃ (4.47 g, 32.3 mmol) and ethyl 7-bromoheptanoate (10.22 g, 43.1 mmol), and the reaction was stirred at 50 °C for 16 h. LCMS showed the starting material was consumed and desired MS was found. The mixture was filtrated, and the filtrate was concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 80 g Agela® Silica Flash Column, Eluent of 0~15% EtOAc / Pet. ether (contained 0.1% TEA) gradient @ 60 mL/min, dry loaded) to give ethyl (R)-7-(((1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)(methyl)amino)heptanoate (Int-37C). MS (ESI) [M+H]⁺: m/z 398.5. [0462] Step D: Ethyl (R)-7-(((2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)(methyl)amino)heptanoate (Int-37) [0463] To a solution of ethyl (R)-7-(((1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)(methyl)amino)heptanoate (Int-37C) (2.17 g, 5.46 mmol) in CF₃CH₂OH (20 mL) was added Pd/C (1.5 g, 14.10 mmol) under nitrogen atmosphere. The 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 (EtOAc) showed the starting material was consumed and new spot was formed. The mixture was filtered, and the filtrate was concentrated in vacuum to give crude ethyl (R)-7-(((2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)(methyl)amino)heptanoate (Int-37). ¹H NMR (400MHz, CDCl₃) δ 4.02-4.10 (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), 2.43-2.53 (m, 2H), 2.35-2.42 (m, 1H), 2.30 (s, 3H), 2.23 (t, J=7.45 Hz, 2H), 1.45-1.68 (m, 4H), 1.22-1.37 (m, 5H), 1.19 (t, J=7.15 Hz, 3H), 0.96-1.05 (m, 1H). [0464] Compound in the table below was synthesized via a similar route as described in the above synthesis of Int-37 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. [0465] Intermediate 39: Methyl 2-((S)-9-(((R)-2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)-1-oxa-9-azaspiro[5.5]undecan-3-yl)acetate (Int-39) [0466] Step A: Methyl 2-((S)-9-(((R)-1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)-1-oxa-9-azaspiro[5.5]undecan-3-yl)acetate (Int-39A) [0467] To a solution of (S)-(1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl methanesulfonate (Int-55A) (200 mg, 0.653 mmol) in MeCN (6 mL) was added K₂CO₃ (180 mg, 1.306 mmol) and methyl (S)-2-(1-oxa-9-azaspiro[5.5]undecan-3-yl)acetate (223 mg, 0.979 mmol) at 25 °C. The mixture was stirred at 75 °C for 16 h. LCMS showed the reaction was finished. The mixture was filtered and the filtrate was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 10% ethyl acetate in petroleum ether gradient @ 30 mL/min) to give methyl 2-((S)-9-(((R)-1- ((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl)-1-oxa-9-azaspiro[5.5]undecan-3- yl)acetate (Int-39A). MS (ESI) [M+H]⁺: m/z 438.2. [0468] Step B: Methyl 2-((S)-9-(((R)-2,2-difluoro-1-(hydroxymethyl)cyclopropyl)methyl)- 1-oxa-9-azaspiro[5.5]undecan-3-yl)acetate (Int-39) [0469] To a solution of methyl 2-((S)-9-(((R)-1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)-1-oxa-9-azaspiro[5.5]undecan-3-yl)acetate (Int-39A) (230 mg, 0.526 mmol) in CF₃CH₂OH (30 mL) was added Pd/C (55.9 mg, 0.053 mmol) under N₂ atmosphere. The mixture was degassed and purged with H₂ for three times, and then stirred at 25 °C for 16 h under H₂ atmosphere (15 psi, H₂ balloon). LCMS showed that the material was consumed and desired MS was formed. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give methyl 2-((S)-9-(((R)-2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)-1-oxa-9-azaspiro[5.5]undecan-3-yl)acetate (Int-39). MS (ESI) [M+H]⁺: m/z 348.3. [0470] Compounds in the table below were synthesized via a similar route as described in the above synthesis of Int-39 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. [0471] Intermediate 43: Tert-butyl 2-(prop-2-yn-1-yl)-7-azaspiro[3.5]nonane-7- carboxylate (Int-43) [0472] Step A: Tert-butyl 2-(2-hydroxyethyl)-7-azaspiro[3.5]nonane-7-carboxylate (Int- 43A) [0473] To a stirred mixture of 2-(7-(tert-butoxycarbonyl)-7-azaspiro[3.5]nonan-2-yl)acetic acid (4.8 g, 16.94 mmol) in THF (48 mL) was added BH₃ · THF (169 mL, 169 mmol) at 0 °C under argon atmosphere. The resulting mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was quenched by water (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic fractions were washed with brine (50 mL × 3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1 - 80% ethyl acetate in petroleum ether to afford tert-butyl 2-(2-hydroxyethyl)-7- azaspiro[3.5]nonane-7-carboxylate (Int-43A). MS ESI calculated for C₁₅H₂₇NO₃ [M – C₄H₈ + H]⁺ 214.20, found 214.20. ¹H NMR: (300 MHz, CDCl₃) δ 3.63 - 3.54 (m, 2H), 3.37 - 3.30 (m, 2H), 3.28 - 3.21 (m, 2H), 2.42 - 2.27 (m, 1H), 2.04 - 1.91 (m, 2H), 1.74 - 1.62 (m, 2H), 1.59 - 1.50 (m, 2H), 1.46 (s, 1H), 1.44 (s, 9H), 1.43 - 1.36 (m, 2H), 1.32 (s, 1H). [0474] Step B: Tert-butyl 2-(2-oxoethyl)-7-azaspiro[3.5]nonane-7-carboxylate (Int-43B) [0475] To a stirred mixture of tert-butyl 2-(2-hydroxyethyl)-7-azaspiro[3.5]nonane-7- carboxylate (Int-43A) (4.5 g, 16.70 mmol) in DMSO (20 mL) was added IBX (7.02 g, 25.06 mmol) at room temperature under argon atmosphere. The resulting mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was quenched by water (200 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic fractions were washed with brine (200 mL × 3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1 - 80% ethyl acetate in petroleum ether to afford tert-butyl 2-(2-oxoethyl)-7-azaspiro[3.5]nonane-7-carboxylate (Int-43B). MS ESI calculated for C₁₅H₂₅NO₃ [M – C₄H₈ + H]⁺ 212.18 found 212.05. ¹H NMR: (400 MHz, CDCl₃) δ 9.72 - 9.68 (m, 1H), 3.37 - 3.32 (m, 2H), 3.27 - 3.22 (m, 2H), 2.76 - 2.66 (m, 1H), 2.60 - 2.54 (m, 2H), 2.12 - 2.03 (m, 2H), 1.61 - 1.56 (m, 2H), 1.51 - 1.45 (m, 4H), 1.44 (s, 9H). [0476] Step C: Tert-butyl 2-(prop-2-yn-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (Int-43) [0477] To a stirred mixture of tert-butyl 2-(2-oxoethyl)-7-azaspiro[3.5]nonane-7- carboxylate (Int-43B) (3.9 g, 14.59 mmol) in MeOH (40 mL) were added dimethyl (1- diazo-2-oxopropyl)phosphonate (2.80 g, 14.59 mmol) and potassium carbonate (2.016 g, 14.59 mmol) at 0 °C under argon atmosphere. The mixture was stirred at room temperature for 16 h. The resulting mixture was stirred for 3 h. The reaction progress was monitored by LCMS. The reaction mixture was quenched by water (200 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic fractions were washed with brine (100 mL× 3). The collected fractions were combined and concentrated under reduced pressure. The filtrate was concentrated under reduced pressure and the residue was purified by Combi- Flash with the following conditions: Column: AQ-C¹⁸ Column (120 g); Mobile Phase: MeCN and water (Gradient: 0% - 100% within 50 min); Flow rate: 80 mL/min; Detector: UV 254 / 210 nm. The collected fractions were combined and concentrated under reduced pressure to afford tert-butyl 2-(prop-2-yn-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (Int- 43). MS ESI calculated for C₁₆H₂₅NO₂ [M – C₄H₈ + MeCN + H]⁺ 249.19 found 249.15. ¹H NMR: (400 MHz, CDCl₃) δ3.40 - 3.20 (m, 4H), 2.53 - 2.39 (m, 1H), 2.30 - 2.22 (m, 2H), 2.01 - 1.91 (m, 3H), 1.62 - 1.52 (m, 4H), 1.49 - 1.39 (m, 11H). [0478] Intermediate 44: (R)-(2,2-difluoro-1-((4-(4-(triisopropylsilyl)but-3-yn-1- yl)piperidin-1-yl)methyl)cyclopropyl)methanol (Int-44) [0479] Step A: Tert-butyl 4-(4-(triisopropylsilyl)but-3-yn-1-yl)piperidine-1-carboxylate (Int-44A) [0480] To tert-butyl 4-(but-3-yn-1-yl)piperidine-1-carboxylate (1000 mg, 4.21 mmol) in THF (2.81E+04 μL) cooled to -78 °C was added 2.5 M nBuLi in hexanes (2528 μL, 6.32 mmol) dropwise via a syringe. The resulting mixture was stirred at the same temperature for 30 min before TIPS-Cl (1785 μL, 8.43 mmol) was added. The reaction mixture was warmed to r.t. and stirred overnight before it was quenched with sat. aq. NH₄Cl and water. The mixture was extracted with EtOAc (2x, 50.0 mL), and the combined organic layers were dried over MgSO₄, filtered and concentrated under vacuum. The crude was purified by silica gel chromatography (0-30% EtOAc/hexanes) to give tert-butyl 4-(4- (triisopropylsilyl)but-3-yn-1-yl)piperidine-1-carboxylate (Int-44A).¹H NMR (500 MHz, CDCl₃) δ 4.11 (d, J = 13.4 Hz, 2H), 2.69 (td, J = 13.1, 2.4 Hz, 2H), 2.32 (t, J = 7.1 Hz, 2H), 1.75 – 1.65 (m, 3H), 1.48 (s, 12H),1.20 (d, J = 7.4 Hz, 5H), 1.08 (d, J = 5.5 Hz, 38H). [0481] Step B: 4-(4-(triisopropylsilyl)but-3-yn-1-yl)piperidine 2,2,2-trifluoroacetate (Int- 44B) [0482] To tert-butyl 4-(4-(triisopropylsilyl)but-3-yn-1-yl)piperidine-1-carboxylate (Int- 44A) (1659 mg, 4.21 mmol) in DCM (8428 μL) was added 4.0 M HCl in dioxane (7375 μL, 29.5 mmol). The reaction mixture was stirred at r.t. for 1 h before being concentrated under vacuum. The residue was purified by reverse-phase silica gel chromatography (C18, MeCN/water with 0.05% TFA modifier) and lyophilized to give 4-(4-(triisopropylsilyl)but- 3-yn-1-yl)piperidine 2,2,2-trifluoroacetate (Int-44B). ESI-MS m/z calc’d for C₁₈H₃₅NSi [M+2H]²⁺: 295; found: 295.¹H NMR (500 MHz, CD₃OD) δ 3.41 (d, J = 12.7 Hz, 2H), 2.95 (td, J = 13.0, 3.1 Hz, 2H), 2.39 (t, J = 7.2 Hz, 2H), 2.02 (d, J = 14.1 Hz, 2H),1.84 (dtq, J = 14.8, 7.0, 3.5 Hz, 1H), 1.58 (q, J = 7.1 Hz, 2H), 1.46 – 1.36 (m, 2H), 1.13 – 1.01 (m, 21H). [0483] Step C: (R)-1-((1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl)-4-(4- (triisopropylsilyl)but-3-yn-1-yl)piperidine (Int-44C) [0484] (S)-(1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl methanesulfonate (Int- 55A) (738 mg, 2.409 mmol) in acetonitrile (1.61E+04 μL) was added 4-(4- (triisopropylsilyl)but-3-yn-1-yl)piperidine 2,2,2-trifluoroacetate (Int-44B) (1277 mg, 3.13 mmol) followed by K₂CO₃ (1332 mg, 9.64 mmol). The reaction mixture was heated and stirred at 90 °C overnight before being cooled to rt and filtered. The filtrate was then concentrated under vacuum, and the crude residue was purified by silica gel chromatography (0-50% EtOAc/hexanes) to give (R)-1-((1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)-4-(4-(triisopropylsilyl)but-3-yn-1-yl)piperidine (Int-44C). ESI-MS m/z calc’d for C₃₀H₄₇F₂NOSi [M+2H]²⁺: 505; found: 505. [0485] Step D: (R)-(2,2-difluoro-1-((4-(4-(triisopropylsilyl)but-3-yn-1-yl)piperidin-1- yl)methyl)cyclopropyl)methanol (Int-44) [0486] To (R)-1-((1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl)-4-(4- (triisopropylsilyl)but-3-yn-1-yl)piperidine (Int-44C) (1072 mg, 2.128 mmol) in DCM (1.42E+04 μL) at -78 °C was added 1.0 M boron trichloride in DCM (8511 μL, 8.51 mmol) dropwise via a syringe. The reaction mixture was stirred at the same temperature for 2 h, warmed to 0 °C and quenched with methanol. The resulting mixture was concentrated under vacuum, and the residue was redissolved in MeOH (3000 μL) and 1.5 N aqueous HCl (3000 μL). The resulting mixture was stirred at 50 °C for 30 min. After being cooled to r.t., MeOH was evaporated under vacuum. The aqueous layer was basified with sat. aq. NaHCO₃, and extracted with EtOAc (3x, 40.0 mL). The combined organic layers were dried over MgSO₄, filtered and concentrated under vacuum. The crude was purified by silica gel chromatography (0-70% 3 : 1 EtOAc : EtOH mixture/hexanes) to give (R)-(2,2-difluoro-1- ((4-(4-(triisopropylsilyl)but-3-yn-1-yl)piperidin-1-yl)methyl)cyclopropyl)methanol (Int- 44). ESI-MS m/z calc’d for C₂₃H₄₁F₂NOSi [M+H]⁺: 414; found: 414. [0487] Compounds in the table below were synthesized via a similar route as described in the above synthesis of Int-44 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.

[0488] Intermediate 49: (R)-(2,2-difluoro-1-((4-(5-(triisopropylsilyl)pent-4-yn-1- yl)piperidin-1-yl)methyl)cyclopropyl)methanol (Int-49) [0489] Step A: Tert-butyl 4-(4-oxobutyl)piperidine-1-carboxylate (Int-49A) [0490] To tert-butyl 4-(4-hydroxybutyl)piperidine-1-carboxylate (1500 mg, 5.83 mmol) in DCM (2.91E+04 μL) cooled to 0 °C was added DMP (4944 mg, 11.66 mmol) in one portion. The reaction mixture was warmed to r.t. and stirred for 2 h before being quenched with water (20.0 mL). The two layers were separated, and the aqueous layer was extracted with DCM (1x, 30.0 mL). The combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated under vacuum. The crude was purified by silica gel chromatography (0-50% EtOAc/hexanes). Since there was a significant amount DMP byproduct coeluted with the product on the column, the mixed residues were triturated with 10% Et₂O/hexanes mixture. The white solid was filtered off, and the filtrate was concentrated under vacuum to give tert-butyl 4-(4-oxobutyl)piperidine-1-carboxylate (Int- 49A). MS m/z calc’d for C₁₄H₂₇NO₃ [M+²³Na]⁺: 278; found: 278.¹H NMR (500 MHz, CD₃Cl) δ 9.79 (s, 1H), 4.10 (d, J = 13.3 Hz, 2H), 2.69 (td, J = 13.1, 2.2 Hz, 2H), 2.46 (t, J = 7.3 Hz, 2H), 1.72 – 1.63 (m, 4H), 1.48 (s, 9H),1.40 (ddq, J = 14.6, 7.0, 4.0, 3.6 Hz, 1H), 1.33 – 1.25 (m, 2H), 1.11 (qd, J = 12.6, 4.2 Hz, 2H). [0491] Step B: Tert-butyl 4-(pent-4-yn-1-yl)piperidine-1-carboxylate (Int-49B) [0492] Dimethyl (1-diazo-2-oxopropyl)phosphonate (1763 μL, 11.75 mmol) in MeOH (10 mL) was added dropwise to a stirred mixture of tert-butyl 4-(4-oxobutyl)piperidine-1- carboxylate (Int-49A) (1500 mg, 5.87 mmol) and K₂CO₃ (1380 mg, 9.99 mmol) in MeOH (20.0 mL) at r.t. The resulting mixture was stirred at r.t. overnight. The solvent was evaporated under vacuum, dissolved in Et₂O and washed with sat. aq. NaHCO₃. The aqueous layer was extracted with Et₂O (2x, 20.0 mL), and the combined organic layers were dried over Na₂SO₄, filtered and concentrated under vacuum. The crude was purified by silica gel chromatography (0-30% EtOAc/hexanes) to give tert-butyl 4-(pent-4-yn-1- yl)piperidine-1-carboxylate (Int-49B). MS m/z calc’d for C₁₅H₂₅NO₂ [M+²³Na]⁺: 274; found: 274.¹H NMR (500 MHz, CD₃Cl) δ 4.14 – 4.05 (m, 2H), 2.69 (td, J = 13.1, 2.7 Hz, 2H), 2.21 (td, J = 7.1, 2.6 Hz, 2H), 1.97 (t, J = 2.6 Hz, 1H), 1.70 – 1.65 (m, 2H),1.57 (dt, J = 14.8, 7.2 Hz, 2H), 1.48 (s, 9H), 1.46 – 1.34 (m, 3H), 1.16 – 1.06 (m, 2H). [0493] Step C: Tert-butyl 4-(5-(triisopropylsilyl)pent-4-yn-1-yl)piperidine-1-carboxylate (Int-49C) [0494] To tert-butyl 4-(pent-4-yn-1-yl)piperidine-1-carboxylate (Int-49B) (1002 mg, 3.99 mmol) in THF (1.33E+04 μL) cooled to -78 °C was added 2.5 M nBuLi in hexanes (2392 μL, 5.98 mmol) dropwise via a syringe. The resulting mixture was stirred at the same temperature for 30 min before TIPS-Cl (1689 μL, 7.97 mmol) was added. The reaction mixture was warmed to r.t. and stirred overnight before it was quenched with sat. aq. NH₄Cl and water. The mixture was extracted with EtOAc (2x, 50.0 mL), and the combined organic layers were dried over MgSO₄, filtered and concentrated under vacuum. The crude was purified by silica gel chromatography (0-20% EtOAc/hexanes) to give tert-butyl 4-(5- (triisopropylsilyl)pent-4-yn-1-yl)piperidine-1-carboxylate (Int-49C).¹H NMR (500 MHz, CD₃Cl) δ 4.09 (d, J = 13.2 Hz, 2H), 3.70 (t, J = 6.6 Hz, 1H), 2.70 (td, J = 13.1, 2.7 Hz, 2H), 2.27 (t, J = 6.9 Hz, 2H), 1.67 (d, J = 12.2 Hz, 2H),1.61 – 1.53 (m, 3H), 1.48 (s, 9H), 1.43 – 1.37 (m, 3H), 1.08 (d, J = 5.3 Hz, 38H), 0.98 – 0.90 (m, 2H). [0495] Step D: 4-(5-(triisopropylsilyl)pent-4-yn-1-yl)piperidine hydrochloride (Int-49D) [0496] To tert-butyl 4-(5-(triisopropylsilyl)pent-4-yn-1-yl)piperidine-1-carboxylate (Int- 49C) (1625 mg, 3.99 mmol) in DCM (7971 μL) was added 4.0 M HCl in dioxane (6975 μL, 27.9 mmol). The reaction mixture was stirred at r.t. for 1 h before being concentrated under vacuum. The residue was triturated with hexanes to form white precipitates, which were vacuum-filtered to give 4-(5-(triisopropylsilyl)pent-4-yn-1-yl)piperidine hydrochloride (Int- 49D).¹H NMR (500 MHz, CD₃OD) δ 3.39 (d, J = 12.8 Hz, 2H), 2.99 (td, J = 12.9, 2.8 Hz, 2H), 2.33 (t, J = 6.7 Hz, 2H), 1.97 (d, J = 13.9 Hz, 2H), 1.71 – 1.57 (m, 3H),1.55 – 1.46 (m, 2H), 1.44 – 1.33 (m, 2H), 1.14 – 0.98 (m, 21H). [0497] Step E: (R)-1-((1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl)-4-(5- (triisopropylsilyl)pent-4-yn-1-yl)piperidine (Int-49E) [0498] (S)-(1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl methanesulfonate (Int- 55A) (354 mg, 1.156 mmol) in acetonitrile (7704 μL) was added 4-(5- (triisopropylsilyl)pent-4-yn-1-yl)piperidine hydrochloride (Int-49D) (716 mg, 2.080 mmol) followed by K₂CO₃ (639 mg, 4.62 mmol). The reaction mixture was heated and stirred at 90 °C overnight before being cooled to r.t. and filtered. The filtrate was then concentrated under vacuum, and the crude residue was purified by silica gel chromatography (0-30% EtOAc/hexanes) to give (R)-1-((1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl)-4- (5-(triisopropylsilyl)pent-4-yn-1-yl)piperidine (Int-49E). MS m/z calc’d for C₃₁H₄₉F₂NOSi [M+H]⁺: 519; found: 519. [0499] Step F: (R)-(2,2-difluoro-1-((4-(5-(triisopropylsilyl)pent-4-yn-1-yl)piperidin-1- yl)methyl)cyclopropyl)methanol (Int-49) [0500] (R)-1-((1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl)-4-(5- (triisopropylsilyl)pent-4-yn-1-yl)piperidine (Int-49E) (374 mg, 0.722 mmol) in DCM (7223 μL) at -78 °C was added 1.0 M boron trichloride in DCM (3611 μL, 3.61 mmol) dropwise via a syringe. The reaction mixture was stirred at the same temperature for 2 h, warmed to 0 °C and quenched with methanol (3 drops). The resulting mixture was concentrated under vacuum, and the residue was redissolved in MeOH (1000 μL) and 1.5 N aqueous HCl (1000 μL). The resulting mixture was stirred at 50 °C for 30 min. After being cooled to r.t., MeOH was evaporated under vacuum. The aqueous layer was basified with sat. aq. NaHCO₃, and extracted with EtOAc (3x, 20.0 mL). The combined organic layers were dried over MgSO₄, filtered and concentrated under vacuum. The crude was purified by silica gel chromatography (0-100% 3 : 1 EtOAc : EtOH mixture/hexanes) to give (R)-(2,2-difluoro-1- ((4-(5-(triisopropylsilyl)pent-4-yn-1-yl)piperidin-1-yl)methyl)cyclopropyl)methanol (Int- 49). MS m/z calc’d for C₂₄H₄₃F₂NOSi [M+H]⁺: 429; found: 429. [0501] Intermediate 50: (3-ethynylbicyclo[1.1.1]pentan-1-yl)methanol (Int-50)

[0502] Step A: Methyl 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate (Int-50A) [0503] To a solution of 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (23 g, 135 mmol) in THF (230 mL) was added BH₃·DMS (20.27 mL, 203 mmol, 10 M) at 0 °C under N₂ atmosphere. The mixture was stirred at 25 °C for 16 h. TLC (SiO₂, Pet. ether:EtOAc=2:1) showed the starting material was consumed and a new spot was formed. The reaction mixture was quenched with MeOH (58 mL) at 0 °C. Then the mixture was concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®, 220 g Agela Flash Column, Pet. ether/EtOAc=1/1) to give methyl 3- (hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate (Int-50A). ¹H NMR (400MHz, CDCl₃) δ 3.61 (s, 3H), 3.57 (br s, 2H), 1.93 (s, 6H). [0504] Step B: Methyl 3-formylbicyclo[1.1.1]pentane-1-carboxylate (Int-50B) [0505] A solution of oxalyl chloride (14.79 mL, 175 mmol) in DCM (400 mL) was cooled to -78 °C, and a solution of DMSO (24.81 mL, 350 mmol) in DCM (100 mL) was added dropwise. The mixture was stirred at -78 °C for 15 min. Then a solution of methyl 3- (hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate (Int-50A) (21g, 134 mmol) in DCM (80 mL) was added dropwise. The reaction mixture was stirred at -78 °C for 30 min. Then Et₃N (94 mL, 672 mmol) was added dropwise, and the mixture was stirred at -78 °C for another 30 min. TLC (SiO₂, Pet. ether/EtOAc = 1/1) showed the starting material was consumed and a new spot was formed. The mixture was warmed to room temperature, then H₂O (100 mL) was added. The organic phase was separated, and the aqueous phase was extracted with CH₂Cl₂ (400 mL). The combined organic layer was washed with NaHCO₃ (1 M aq.200 mL), and saturated aq. NaCl (200 mL), dried with Na₂SO₄, filtered, and concentrated under reduced pressure to give methyl 3-formylbicyclo[1.1.1]pentane-1- carboxylate (Int-50B). ¹H NMR (400 MHz, CDCl₃) δ 9.42-9.64 (m, 1H), 3.64 (s, 3H), 2.25 (s, 6H). [0506] Step C: Methyl 3-ethynylbicyclo[1.1.1]pentane-1-carboxylate (Int-50C) [0507] To a solution of methyl 3-formylbicyclo[1.1.1]pentane-1-carboxylate (Int-50B) (17.6 g, 114 mmol) in MeOH (360 mL) was added K₂CO₃ (47.3 g, 342 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (32.9 g, 171 mmol) at 25 °C The mixture was stirred at 25 °C for 16 h. TLC (SiO₂, Pet. ether/EtOAc = 1/1) showed the starting material was consumed and a new spot was formed. The solvent was evaporated under reduced pressure, and the residue was diluted with water (30 mL), and then extracted with EtOAc (3 * 500 mL). 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 SepaFlash® Silica Flash Column, Eluent of 0~10% EtOAc/Pet. ether gradient @ 60 mL/min) to give methyl 3-ethynylbicyclo[1.1.1]pentane-1- carboxylate (Int-50C). ¹H NMR (400 MHz, CDCl₃) 3.60 (s, 3H), 2.26 (s, 6H), 1.98 (s, 1H). [0508] Step D: (3-ethynylbicyclo[1.1.1]pentan-1-yl)methanol (Int-50) [0509] To a solution of methyl 3-ethynylbicyclo[1.1.1]pentane-1-carboxylate (Int-50C) (7.6 g, 50.6 mmol) in THF (80 mL) was added LiAlH₄ (20.24 mL, 50.6 mmol) (2.5 M in THF) at 0 °C, and the mixture was stirred at 0 °C for 1 h. TLC (SiO₂, Pet. ether/EtOAc = 5/1) showed the starting material was consumed and a new spot was formed. The reaction mixture was quenched with Na₂SO₄·10H₂O (60 g) and water (8 mL), and the resulting mixture was diluted with EtOAc (500 mL). Then the mixture was 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 0~30% EtOAc/Pet. ether gradient @ 60 mL/min) to give (3- ethynylbicyclo[1.1.1]pentan-1-yl)methanol (Int-50). ¹H NMR (400 MHz, CDCl₃) δ 3.61 (br d, J=4.65 Hz, 2H), 2.14 (s, 1H), 2.04 (s, 6H). [0510] Intermediate 51: (R)-(1-((1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)methanol (Int-51) [0511] Step A: Tert-butyl 4-(((tert-butyldiphenylsilyl)oxy)methyl)piperidine-1-carboxylate (Int-51A) [0512] 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 crude 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 (Int-51A). MS (ESI) [M+H]⁺: m/z 454.3. [0513] Step B: 4-(((tert-butyldiphenylsilyl)oxy)methyl)piperidine, HCl salt (Int-51B) [0514] To a solution of tert-butyl 4-(((tert-butyldiphenylsilyl)oxy)methyl)piperidine-1- carboxylate (Int-51A) (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 (Int-51B). MS (ESI) [M+H]⁺: m/z 354.3. [0515] Step C: (R)-1-((1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl)-4-(((tert- butyldiphenylsilyl)oxy)methyl)piperidine (Int-51C) [0516] To a solution of (S)-(1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl methanesulfonate (Int-55A) (500 mg, 1.632 mmol) in MeCN (10 mL) was added 4-(((tert- butyldiphenylsilyl)oxy)methyl)piperidine, HCl salt (Int-51B) (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 g 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 (Int-51C). MS (ESI) [M+H]⁺: m/z 564.5. [0517] Step D: (R)-(1-((1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl)piperidin- 4-yl)methanol (Int-51) [0518] To a solution of (R)-1-((1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl)-4- (((tert-butyldiphenylsilyl)oxy)methyl)piperidine (Int-51C) (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-51). MS (ESI) [M+H]⁺: m/z 326.3. [0519] Intermediate 52: (R)-7-((1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl)- 2-(prop-2-yn-1-yl)-7-azaspiro[3.5]nonane (Int-52) [0520] Step A: 2-(prop-2-yn-1-yl)-7-azaspiro[3.5]nonan-7-ium chloride (Int-52A) [0521] Tert-butyl 2-(prop-2-yn-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (Int-43) (300 mg, 1.139 mmol) was dissolved in 4 M HCl/dioxane (4 mL). The reaction was stirred at room temperature for 2 h. UPLC-MS indicated formation of desired product. The reaction was concentrated. The crude 2-(prop-2-yn-1-yl)-7-azaspiro[3.5]nonan-7-ium chloride (Int- 52A) was used directly in the next step without purification. ESI-MS m/z calc’d for C11H18ClN: 199.722, found [M+Na]⁺: 212.3. [0522] Step B: (R)-7-((1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl)-2-(prop-2- yn-1-yl)-7-azaspiro[3.5]nonane (Int-52) [0523] In a 40 mL vial was added crude 2-(prop-2-yn-1-yl)-7-azaspiro[3.5]nonan-7-ium chloride (Int-52A) (310 mg, 1.012 mmol), (S)-(1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl methanesulfonate (Int-55A) (227 mg, 1.137 mmol) and K₃PO₄ (644 mg.3.04 mmol). To above mixture was added acetonitrile (1.01E+04 μL). The reaction was stirred at 80 °C for 16 h, diluted with DCM, filtered and concentrated. The crude was purified by flash silica gel chromatography (ISCO®, 24 g gold column, eluted with 0-50% ETOAc/EtOH 3/1 in 15 min). Fractions containing product were combined and concentrated to give (R)-7-((1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl)-2- (prop-2-yn-1-yl)-7-azaspiro[3.5]nonane (Int-52). ESI-MS m/z calc’d for C₂₃H₂₉F₂NO: 373.488, found [M+H]⁺: 374.4. [0524] Compound in the table below was synthesized via a similar route as described in the above synthesis of Int-52 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. [0525] Intermediate 54: Methyl 2-((S)-9-(((R)-2,2-difluoro-1-((((4- nitrophenyl)sulfonyl)oxy)methyl)cyclopropyl)methyl)-1-oxa-9-azaspiro[5.5]undecan-3- yl)acetate (Int-54) [0526] Step A: Methyl 2-((S)-9-(((R)-2,2-difluoro-1-((((4- nitrophenyl)sulfonyl)oxy)methyl)cyclopropyl)methyl)-1-oxa-9-azaspiro[5.5]undecan-3- yl)acetate (Int-54) [0527] A solution of methyl 2-((S)-9-(((R)-2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)-1-oxa-9-azaspiro[5.5]undecan-3-yl)acetate (Int-39) (22 mg, 1 eq., 62.8 μmol), triethylamine (10.2 mg, 14 μL, 1.6 eq., 100 μmol) and N,N- dimethylpyridin-4-amine (12.3 mg, 1.6 eq., 100 μmol) in acetonitrile (0.50 mL) was cooled to 0 °C into which a solution of 4-nitrobenzenesulfonyl chloride (19.5 mg, 1.4 eq., 87.9 μmol) in acetonitrile (0.5 mL) was added. The reaction was then allowed to warm to r.t. The reaction was complete by LCMS in 30 min. The reaction was then concentrated and purified by flash silica gel chromatography (ISCO®, 12 g Gold column, eluted with 0-00% EtOAc in hexane in 12 min) to obtain product methyl 2-((S)-9-(((R)-2,2-difluoro-1-((((4- nitrophenyl)sulfonyl)oxy)methyl)cyclopropyl)methyl)-1-oxa-9-azaspiro[5.5]undecan-3- yl)acetate (Int-54). ESI-MS m/z calc’d for C₂₃H₃₀F₂N₂O₈S 532.56, found [M+H]+: 533.2. [0528] Intermediate 55: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(2-(3-(((R)-2,2- difluoro-1-(hydroxymethyl)cyclopropyl)methyl)-3-azaspiro[5.5]undecan-9-yl)acetamido)- 3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int- 55) [0529] Step A: (S)-(1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl methanesulfonate (Int-55A) [0530] A solution of (R)-(1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methanol (750 mg, 3.29 mmol) in DCM (11.000 mL) and TEA (1.374 mL, 9.86 mmol) was chilled to 0 °C under a stream of nitrogen. MsCl (0.384 mL, 4.93 mmol) was added dropwise and the resulting mixture was allowed to stir for 30 min at room temperature. Reaction was checked by TLC to show a new spot and complete consumption of starting material. The reaction mixture was quenched with water and extracted 3 times with DCM. The combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0-100% EtOAc/hexane). The desired fractions were pooled and concentrated under reduced pressure to afford (S)-(1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl methanesulfonate (Int-55A).¹H NMR (499 MHz, CDCl₃) δ 7.42 – 7.31 (m, 5H), 4.57 (q, J = 11.9 Hz, 2H), 4.43 (q, 2H), 3.71 (d, J = 10.6 Hz, 1H), 3.55 (d, J = 10.6 Hz, 1H), 3.01 (s, 3H), 1.56 (q, J = 8.2 Hz, 1H), 1.43 (q, J = 8.5 Hz, 1H). [0531] Step B: Methyl (R)-2-(3-((1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl)- 3-azaspiro[5.5]undecan-9-yl)acetate (Int-55B) [0532] A solution of (S)-(1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl methanesulfonate (Int-55A) (934 mg, 3.05 mmol) in acetonitrile (15.200 mL) was added to a vial containing methyl 2-(3-azaspiro[5.5]undecan-9-yl)acetate, HCl (958 mg, 3.66 mmol) and potassium carbonate (1686 mg, 12.20 mmol). The resulting mixture was allowed to stir overnight at 80 °C. The reaction was cooled to room temperature. The reaction mixture was filtered, and the residue was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica (0-50% EtOAc/hexane). The desired fractions were pooled and concentrated under reduced pressure to afford methyl (R)-2-(3-((1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)-3-azaspiro[5.5]undecan-9-yl)acetate as a clear oil (Int-55B). MS (ESI) [M+H]+: m/z 436. [0533] Step C: (R)-2-(3-((1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl)-3- azaspiro[5.5]undecan-9-yl)acetic acid (Int-55C) [0534] 2 M LiOH (aq.) (1.988 mL, 3.98 mmol) was added to a solution of methyl (R)-2-(3- ((1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl)-3-azaspiro[5.5]undecan-9- yl)acetate (Int-55B) (866 mg, 1.988 mmol) in THF (11.000 mL) and MeOH (5.50 mL). The resulting mixture was allowed to stir for 24 h at room temperature. The reaction mixture was concentrated to remove the organic solvent, diluted with water, and then the pH was adjusted to pH 3 with 2 M HCl. The aqueous solution was extracted 3x with DCM and the combined organic fraction was dried over sodium sulfate, filtered and concentrated to afford (R)-2-(3-((1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl)-3-azaspiro[5.5]undecan- 9-yl)acetic acid (Int-55C) as a white solid. MS (ESI) [M+H]+: m/z 422. [0535] Step D: (R)-2-(3-((2,2-difluoro-1-(hydroxymethyl)cyclopropyl)methyl)-3- azaspiro[5.5]undecan-9-yl)acetic acid (Int-55D) [0536] Palladium hydroxide on carbon (140 mg, 0.200 mmol) was added to a vial containing a solution of (R)-2-(3-((1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl)- 3-azaspiro[5.5]undecan-9-yl)acetic acid (Int-55C) (842 mg, 1.997 mmol) in trifluoroethanol (9987 μL). The vial was sealed and its contents were placed under an atmosphere of hydrogen by performing 10 vacuum / hydrogen cycles. The resulting mixture was allowed to stir overnight at room temperature. The reaction mixture was filtered through a pad of CELITE®, and the residue was washed with methanol. The filtrate was concentrated under reduced pressure to afford (R)-2-(3-((2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)-3-azaspiro[5.5]undecan-9-yl)acetic acid (Int-55D) as a white solid. MS (ESI) [M+H]+: m/z 332. [0537] Step E: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(2-(3-(((R)-2,2-difluoro- 1-(hydroxymethyl)cyclopropyl)methyl)-3-azaspiro[5.5]undecan-9-yl)acetamido)-3,3- dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-55) [0538] (R)-2-(3-((2,2-difluoro-1-(hydroxymethyl)cyclopropyl)methyl)-3- azaspiro[5.5]undecan-9-yl)acetic acid (Int-55D) (670 mg, 2.022 mmol), (2S,4R)-1-((S)-2- amino-3,3-dimethylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Int-27) (1157 mg, 2.123 mmol), HATU (846 mg, 2.224 mmol), DMF (13.500 mL), and DIEA (1.059 mL, 6.07 mmol) were added to a vial. The mixture was allowed to stir for 4 h at room temperature. The reaction mixture was added to water to form a precipitate. The solids were collected by vacuum filtration and dried to afford a white solid. The residue was purified by column chromatography on silica (0-10% DCM/Methanol). The desired fractions were pooled and concentrated under reduced pressure to afford (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(2-(3-(((R)-2,2- difluoro-1-(hydroxymethyl)cyclopropyl)methyl)-3-azaspiro[5.5]undecan-9-yl)acetamido)- 3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int- 55) as a white solid. MS (ESI) [M+H]+: m/z 858. [0539] Intermediate 56: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(2-(7-(((R)-2,2- difluoro-1-(hydroxymethyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)acetamido)-3,3- dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-56)

[0540] Step A: (R)-2-(7-((2,2-difluoro-1-(hydroxymethyl)cyclopropyl)methyl)-7- azaspiro[3.5]nonan-2-yl)acetic acid (Int-56A) [0541] To a solution of methyl (R)-2-(7-((2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)acetate (Int-41) (226 mg, 0.712 mmol) in MeOH (2 mL) was added water (0.1 mL) and lithium hydroxide monohydrate (51.2 mg, 2.136 mmol) at 25 °C. The mixture was stirred at 25 °C for 15 h. LCMS showed starting material was consumed and desired MS was formed. The mixture was acidified with aq. HCl (1 M) until pH 5, extracted with CH₂Cl₂/iPrOH (v/v=5:1, 5 x 2 mL), dried over Na₂SO₄, filtered and the solvent was evaporated under reduced pressure to give the crude product (R)-2-(7-((2,2-difluoro-1-(hydroxymethyl)cyclopropyl)methyl)-7- azaspiro[3.5]nonan-2-yl)acetic acid (Int-56A). MS (ESI) [M+H]⁺: m/z 303.9. [0542] Step B: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(2-(7-(((R)-2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)acetamido)-3,3- dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-56) [0543] To a solution of (R)-2-(7-((2,2-difluoro-1-(hydroxymethyl)cyclopropyl)methyl)-7- azaspiro[3.5]nonan-2-yl)acetic acid (Int-56A) (216 mg, 0.712 mmol) in DMF (5 mL) was added PyBOP (556 mg, 1.068 mmol), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4- ((tert-butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Int-27) (310 mg, 0.570 mmol) and DIEA (0.373 mL, 2.136 mmol) at 20 °C. The mixture was stirred at 20 °C for 1 h. LCMS showed starting material was consumed and desired peak was formed. 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 15% MeOH in CH₂Cl₂ gradient @ 30 mL/min) to give (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(2-(7-(((R)-2,2- difluoro-1-(hydroxymethyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)acetamido)-3,3- dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-56). MS (ESI) [M+H]⁺: m/z 830.4. [0544] Intermediate 57-a & 57-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 (Int-57-a & Int-57-b) [0545] Step A: Benzyl 4-vinylpiperidine-1-carboxylate (Int-57A) [0546] 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 N₂ atmosphere. 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 was 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 (Int-57A). MS (ESI) [M+H]⁺: m/z 246.2. [0547] Step B: Benzyl 4-(2,2-dichloro-3-oxocyclobutyl)piperidine-1-carboxylate (Int-57B) [0548] To a stirred solution of benzyl 4-vinylpiperidine-1-carboxylate (Int-57A) (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 (Int-57B). MS (ESI) [M+H]⁺: m/z 356.1. [0549] Step C: Benzyl 4-(3-oxocyclobutyl)piperidine-1-carboxylate (Int-57C) [0550] To a stirred solution of benzyl 4-(2,2-dichloro-3-oxocyclobutyl)piperidine-1- carboxylate (Int-57B) (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 N₂ atmosphere. 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 (Int-57C). MS (ESI) [M+H]⁺: m/z 288.1. [0551] Step D: Benzyl 4-(3-(2-ethoxy-2-oxoethylidene)cyclobutyl)piperidine-1- carboxylate (Int-57D) [0552] 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 (Int-57C) (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 aqueous 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 (Int-57D). MS (ESI) [M+H]⁺: m/z 358.1. [0553] Step E: Ethyl 2-(3-(piperidin-4-yl)cyclobutyl)acetate (Int-57E) [0554] To a solution of benzyl 4-(3-(2-ethoxy-2-oxoethylidene)cyclobutyl)piperidine-1- carboxylate (Int-57D) (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 (Int-57E). MS (ESI) [M+H]⁺: m/z 226.1. [0555] Step F: Ethyl (R)-2-(3-(1-((1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)cyclobutyl)acetate (Int-57F) [0556] To a solution of ethyl 2-(3-(piperidin-4-yl)cyclobutyl)acetate (Int-57E) (1.6 g, 7.10 mmol) in MeCN (8 mL) was added (S)-(1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl methanesulfonate (Int-55A) (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 (Int-57F). MS (ESI) [M+H]⁺: m/z 436.6. [0557] Step G: (R)-2-(3-(1-((1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)cyclobutyl)acetic acid (Int-57G) [0558] To a solution of ethyl (R)-2-(3-(1-((1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)cyclobutyl)acetate (Int-57F) (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 showed 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-57G). MS (ESI) [M+H]⁺: m/z 408.3. [0559] Step H: (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 (Int-57H) [0560] To a solution of (R)-2-(3-(1-((1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)cyclobutyl)acetic acid (Int-57G) (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 (Int-27) (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 reduced 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 (Int-57H). MS (ESI) [M+H]⁺: m/z 934.4. [0561] Step I: (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-57I) [0562] 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 (Int-57H) (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 (Int-57I). MS (ESI) [M+H]⁺: m/z 844.5. [0563] Step J: (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-57-a & Int-57-b) [0564] 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 (Int-57I) (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- dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-57-a, 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-57-b, the second eluting isomer). MS (ESI) [M+H]⁺: m/z 844.5. [0565] Intermediate 58: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(2-((S)-9-(((R)- 2,2-difluoro-1-(hydroxymethyl)cyclopropyl)methyl)-1-oxa-9-azaspiro[5.5]undecan-3- yl)acetamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Int-58)

[0566] Step A: 2-((S)-9-(((R)-2,2-difluoro-1-(hydroxymethyl)cyclopropyl)methyl)-1-oxa- 9-azaspiro[5.5]undecan-3-yl)acetic acid (Int-58A) [0567] To a solution of methyl 2-((S)-9-(((R)-2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)-1-oxa-9-azaspiro[5.5]undecan-3-yl)acetate (Int-39) (870 mg, 2.504 mmol) in MeOH (3 mL) was added water (0.3 mL) and LiOH·H₂O (315 mg, 7.51 mmol) at 25 °C. The mixture was stirred at 25 °C for 15 h. LCMS showed the starting material was consumed and desired MS was formed. The mixture was acidified with aq. HCl (4 M in dioxane) until pH 5, and the solvent was evaporated under reduced pressure to give the crude product 2-((S)-9-(((R)-2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)-1-oxa-9-azaspiro[5.5]undecan-3-yl)acetic acid (Int- 58A). MS (ESI) [M+H]⁺: m/z 334.0. [0568] Step B: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(2-((S)-9-(((R)-2,2- difluoro-1-(hydroxymethyl)cyclopropyl)methyl)-1-oxa-9-azaspiro[5.5]undecan-3- yl)acetamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Int-58) [0569] To a solution of 2-((S)-9-(((R)-2,2-difluoro-1-(hydroxymethyl)cyclopropyl)methyl)- 1-oxa-9-azaspiro[5.5]undecan-3-yl)acetic acid (Int-58A) (294 mg, 0.881 mmol) in DMF (8.0 mL) was added PyBOP (1146 mg, 2.203 mmol) and stirred at 25 °C for 10 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 (Int-27) (400 mg, 0.734 mmol) and DIEA (0.641 mL, 3.67 mmol) was added to the above reaction mixture at 25 °C. The mixture was stirred at 25 °C for 4 h. LCMS showed starting material was consumed and desired peak was formed. 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 15% MeOH in DCM gradient @ 30 mL/min) to give (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(2-((S)-9-(((R)-2,2- difluoro-1-(hydroxymethyl)cyclopropyl)methyl)-1-oxa-9-azaspiro[5.5]undecan-3- yl)acetamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Int-58). MS (ESI) [M+H]⁺: m/z 860.2. [0570] Intermediate 59: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(4-(3-(((((R)- 2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)(methyl)amino)methyl)bicyclo[1.1.1]pentan-1-yl)-1H- 1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Int-59) [0571] Step A: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(4-(3- (hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)- N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-59A) [0572] To a solution of (3-ethynylbicyclo[1.1.1]pentan-1-yl)methanol (Int-50) (600 mg, 4.91 mmol) in DCM (6 mL) was added tetrakis(acetonitrile)copper(I) tetrafluoroborate (2008 mg, 6.38 mmol), (2S,4R)-1-((S)-2-azido-3,3-dimethylbutanoyl)-4-((tert- butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int- 34) (2804 mg, 4.91 mmol) and DIEA (5.58 mL, 31.9 mmol) at 25 °C under N₂ atmosphere. The mixture was stirred at 40 °C for 16 h. LCMS showed the starting material was consumed and the desired MS was found. The solvent was removed under reduced pressure and the crude was purified by flash silica gel chromatography (ISCO®, 40 g Agela Flash Colum, Pet. ether/EtOAc, 30 min, 40 mL/min, dry loaded) to give (2S,4R)-4-((tert- butyldimethylsilyl)oxy)-1-((S)-2-(4-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-1H- 1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Int-59A). MS (ESI) [M+H]⁺: m/z 693.3. [0573] Step B: (3-(1-((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)-1H- 1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-yl)methyl methanesulfonate (Int-59B) [0574] To a solution of (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(4-(3- (hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)- N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-59A) (2.10 g, 3.03 mmol) in DCM (20 mL) was added DIEA (0.794 mL, 4.55 mmol) and methanesulfonic anhydride (0.581 g, 3.33 mmol) at 0 °C in portions. The mixture was stirred at 25 °C for 30 min. LCMS showed the starting material was consumed and the desired MS was found. The solvent was removed under reduced pressure. The crude was purified by flash silica gel chromatography (ISCO®, 40 g Agela Flash Colum, Pet. ether /THF, 30 min, 40 mL/min, dry loaded) to give (3-(1-((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)-1H- 1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-yl)methyl methanesulfonate (Int-59B). MS (ESI) [M+H]⁺: m/z 771.3. [0575] Step C: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-3,3-dimethyl-2-(4-(3- ((methylamino)methyl)bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-59C) [0576] To a solution of (3-(1-((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)-1H- 1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-yl)methyl methanesulfonate (Int-59B) (700 mg, 0.908 mmol) in EtOH (7 mL) was added methylamine (4.54 mL, 9.08 mmol) (30 % in EtOH) at 25 °C. The mixture was stirred at 50 °C for 2 h. LCMS showed the starting material was consumed and the desired MS was found. The solvent was removed under reduced pressure and the residue was diluted with EtOAc (50 mL), then washed with water (15 mL * 2). The 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®, 12 g Agela Flash Colum, Pet. ether/THF, 30 min, 35 mL/min, dry loaded) to give (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-3,3-dimethyl-2-(4-(3- ((methylamino)methyl)bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-59C). MS (ESI) [M+H]⁺: m/z 706.3. [0577] Step D: (2S,4R)-1-((S)-2-(4-(3-(((((R)-1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)(methyl)amino)methyl)bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3- triazol-1-yl)-3,3-dimethylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol- 5-yl)benzyl)pyrrolidine-2-carboxamide (Int-59D) [0578] To a solution of (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-3,3-dimethyl-2-(4- (3-((methylamino)methyl)bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-(4- (4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-59C) (650 mg, 0.921 mmol) in DMF (6 mL) was added (S)-(1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl methanesulfonate (Int-55A) (310 mg, 1.013 mmol), K₂CO₃ (509 mg, 3.68 mmol) and sodium iodide (138 mg, 0.921 mmol) at 25 °C. The mixture was stirred at 80 °C for 12 h. LCMS showed the starting material was consumed and the desired MS was found. The solvent was removed under reduced pressure. The crude was purified by flash silica gel chromatography (ISCO®, 12 g Agela Flash Colum, DCM/MeOH, 30 min, 35 mL/min, dry loaded) to give (2S,4R)-1-((S)-2-(4-(3-(((((R)-1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)(methyl)amino)methyl)bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3- triazol-1-yl)-3,3-dimethylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol- 5-yl)benzyl)pyrrolidine-2-carboxamide (Int-59D). MS (ESI) [M+H]⁺: m/z 916.4. [0579] Step E: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(4-(3-(((((R)-2,2-difluoro- 1-(hydroxymethyl)cyclopropyl)methyl)(methyl)amino)methyl)bicyclo[1.1.1]pentan-1-yl)- 1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Int-59) [0580] To a solution of (2S,4R)-1-((S)-2-(4-(3-(((((R)-1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)(methyl)amino)methyl)bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3- triazol-1-yl)-3,3-dimethylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol- 5-yl)benzyl)pyrrolidine-2-carboxamide (Int-59D) (512 mg, 0.559 mmol) in CH₂Cl₂ (5 mL) was added boron trichloride solution (5.59 mL, 5.59 mmol) (1 M in DCM) at -78 °C under N₂ atmosphere. The reaction was stirred at -78 °C for 30 min. LCMS showed the starting material was consumed and the desired MS was found. The mixture was quenched with DIEA/MeOH (3.9 mL of DIEA dissolved in 2 mL of MeOH) at -78 °C. Then the mixture was diluted with DCM (20 mL), and washed with water (2 mL * 2). The 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®, 12 g Agela Flash Column, DCM/MeOH, 30 min, 40 mL/min, dry loaded) to give (2S,4R)-4-((tert- butyldimethylsilyl)oxy)-1-((S)-2-(4-(3-(((((R)-2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)(methyl)amino)methyl)bicyclo[1.1.1]pentan-1-yl)-1H- 1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Int-59). MS (ESI) [M+H]⁺: m/z 826.3. [0581] Intermediate 60: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((2S)-2-(4-(3-((3- (hydroxymethyl)-3-methylpiperidin-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3- triazol-1-yl)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Int-60) [0582] Step A: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((2S)-2-(4-(3-((3- (hydroxymethyl)-3-methylpiperidin-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3- triazol-1-yl)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Int-60) [0583] To a solution of (3-(1-((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)-1H- 1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-yl)methyl methanesulfonate (Int-59B) (300 mg, 0.389 mmol) in DMF (5 mL) was added (3-methylpiperidin-3-yl)methanol hydrochloride (97 mg, 0.584 mmol), sodium iodide (58.3 mg, 0.389 mmol) and K₂CO₃ (269 mg, 1.945 mmol) at 30 °C. The mixture was stirred at 80 °C for 3 h. LCMS showed the starting material was consumed and desired MS was found. The mixture was diluted with water (2 mL), extracted with EtOAc (3 x 20 mL), dried over Na₂SO₄, filtered and the solvent was evaporated under reduced pressure to give the crude product. The residue was purified by flash silica gel chromatography (ISCO®; 4 g Agela® Silica Flash Column, Eluent of 40% EtOAc/Pet. ether @ 30 mL/min) to give (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((2S)-2- (4-(3-((3-(hydroxymethyl)-3-methylpiperidin-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)-1H- 1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Int-60). MS (ESI) [M+H]⁺: m/z 804.3. [0584] Intermediate 61: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(4-(2-(1-(((R)- 2,2-difluoro-1-(hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol- 1-yl)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-61) [0585] Step A: Tert-butyl 4-(2-(1-((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)-1H- 1,2,3-triazol-4-yl)ethyl)piperidine-1-carboxylate (Int-61A) [0586] To a solution of tert-butyl 4-(but-3-yn-1-yl)piperidine-1-carboxylate (350 mg, 1.475 mmol) in DCM (5 mL) was added Cu(CH₃CN)₄PF₆ (603 mg, 1.917 mmol), (2S,4R)-1-((S)- 2-azido-3,3-dimethylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Int-34) (842 mg, 1.475 mmol) and DIEA (1.674 mL, 9.59 mmol) at 25 °C under N₂ atmosphere. The mixture was stirred at 40 °C for 2 h. LCMS showed the starting material was consumed and the desired MS was found. The mixture was diluted with water (20 mL) and extracted with DCM (50 mL x 3). The organic layer was dried over Na₂SO₄, the mixture was filtered and the filtrate was evaporated under reduced pressure give the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~30% EtOAc/Pet. ether gradient @ 30 mL/min) to give tert-butyl 4-(2-(1-((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)-1H-1,2,3-triazol-4-yl)ethyl)piperidine-1-carboxylate (Int-61A). MS (ESI) [M+H]⁺: m/z 808.1. [0587] Step B: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-3,3-dimethyl-2-(4-(2- (piperidin-4-yl)ethyl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Int-61B) [0588] To a solution of tert-butyl 4-(2-(1-((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)-1H-1,2,3-triazol-4-yl)ethyl)piperidine-1-carboxylate (Int-61A) (1.2 g, 1.485 mmol) in DCM (10 mL) was added 2,6-lutidine (0.955 g, 8.91 mmol) and trimethylsilyl trifluoromethanesulfonate (1.320 g, 5.94 mmol) at 25 ºC. The resulting mixture was stirred at 100 °C for 16 h. LCMS showed some starting material was remained and the desired MS was found. The mixture was diluted with water (20 mL) and extracted with DCM (50 mL x 3). The organic layer was dried over Na₂SO₄, the mixture was filtered and the filtrate was evaporated under reduced pressure give the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~30% MeOH/DCM gradient @ 40 mL/min) to give (2S,4R)-4-((tert- butyldimethylsilyl)oxy)-1-((S)-3,3-dimethyl-2-(4-(2-(piperidin-4-yl)ethyl)-1H-1,2,3-triazol- 1-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-61B). MS (ESI) [M+H]⁺: m/z 708.3. [0589] Step C: (2S,4R)-1-((S)-2-(4-(2-(1-(((R)-1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-1-yl)-3,3- dimethylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Int-61C) [0590] To a solution of (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-3,3-dimethyl-2-(4- (2-(piperidin-4-yl)ethyl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Int-61B) (1 g, 1.412 mmol) in DMF (10 mL) was added (S)-(1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl methanesulfonate (Int- 55A) (0.433 g, 1.412 mmol), NaI (0.212 g, 1.412 mmol) and K₂CO₃ (0.586 g, 4.24 mmol) at 25 °C. The mixture was stirred at 80 °C for 16 h. LCMS showed the starting material was consumed and desired MS was found. The mixture was diluted with water (10 mL) and extracted with EtOAc (30 mL x 3). The organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The crude product was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~15% MeOH/DCM gradient @ 30 mL/min) to give (2S,4R)-1-((S)-2-(4-(2-(1-(((R)-1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-1-yl)-3,3- dimethylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Int-61C). MS (ESI) [M+H]⁺: m/z 918.4. [0591] Step D: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(4-(2-(1-(((R)-2,2- difluoro-1-(hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-1-yl)- 3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int- 61) [0592] To a solution of (2S,4R)-1-((S)-2-(4-(2-(1-(((R)-1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-1-yl)-3,3- dimethylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Int-61C) (877 mg, 0.955 mmol) in DCM (9 mL) was added BCl₃ (9.55 mL, 9.55 mmol, 1 M in DCM) at -78 °C under N₂ atmosphere. The mixture was stirred at -78 °C for 2 h. LCMS showed the starting material was consumed and desired MS was found. The reaction mixture was quenched with DIEA: MeOH= 2: 1 (9.7 mL), the mixture was diluted with DCM (50 mL), and washed with H₂O (10 mL x 2). The organic layer was dried with Na₂SO₄, filtered and the solvent was removed 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 0~15% MeOH/DCM gradient @ 30 mL/min) to give (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1- ((S)-2-(4-(2-(1-(((R)-2,2-difluoro-1-(hydroxymethyl)cyclopropyl)methyl)piperidin-4- yl)ethyl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Int-61). MS (ESI) [M+H]⁺: m/z 828.1. [0593] Intermediate 62: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(4-(2-(1-((1- (hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-1-yl)-3,3- dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-62) [0594] Step A: (1-((benzyloxy)methyl)cyclopropyl)methyl methanesulfonate (Int-62A) [0595] To a solution of (1-((benzyloxy)methyl)cyclopropyl)methanol (500 mg, 2.60 mmol) in CH₂Cl₂ (5 mL) was added DIEA (2.73 mL, 15.60 mmol) and Ms₂O (1359 mg, 7.80 mmol) at 0 °C under N₂ atmosphere. The mixture was stirred at 25 °C for 0.5 h. LCMS showed the starting material was consumed and the desired MS was found. The solvent was evaporated under reduced pressure. The crude product was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~30% EtOAc/Pet. ether gradient @ 20 mL/min) to give (1- ((benzyloxy)methyl)cyclopropyl)methyl methanesulfonate (Int-62A). MS (ESI) [M+H]⁺: m/z 271.3. [0596] Step B: (2S,4R)-1-((S)-2-(4-(2-(1-((1- ((benzyloxy)methyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-1-yl)-3,3- dimethylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Int-62B) [0597] To a solution of (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-3,3-dimethyl-2-(4- (2-(piperidin-4-yl)ethyl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Int-61B) (600 mg, 0.847 mmol) in DMF (6 mL) was added (1-((benzyloxy)methyl)cyclopropyl)methyl methanesulfonate (Int-62A) (275 mg, 1.017 mmol), KI (155 mg, 0.932 mmol) and K₂CO₃ (351 mg, 2.54 mmol) at 25 °C under N₂ atmosphere. The mixture was stirred at 80 °C for 3 h. LCMS showed the starting material was consumed and desired MS was found. The mixture was diluted with water (6 mL) and extracted with EtOAc (6 mL x 3). The organic layer was washed with brine (6 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 0~30% EtOAc/Pet. ether gradient @ 30 mL/min) to give (2S,4R)-1-((S)-2-(4-(2-(1-((1- ((benzyloxy)methyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-1-yl)-3,3- dimethylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Int-62B). MS (ESI) [M+H]⁺: m/z 882.7. [0598] Step C: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(4-(2-(1-((1- (hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-1-yl)-3,3- dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-62) [0599] To a solution of (2S,4R)-1-((S)-2-(4-(2-(1-((1- ((benzyloxy)methyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-1-yl)-3,3- dimethylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Int-62B) (229 mg, 0.260 mmol)) in CH₂Cl₂ (0.4 mL) was added boron trichloride solution (2.60 mL, 2.60 mmol, 1 M in CH₂Cl₂) at -78 °C under N₂ atmosphere. 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 MeOH (0.5 mL), basified with DIEA until pH to 7, and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by preparative TLC (SiO₂, CH₂Cl₂/MeOH= 10:1) to give (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(4- (2-(1-((1-(hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-1-yl)- 3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int- 62). MS (ESI) [M+H]⁺: m/z 792.4. [0600] Intermediate 63: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(4-((7-(((R)-2,2- difluoro-1-(hydroxymethyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)methyl)-1H- 1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Int-63)

[0601] Step A: (2S,4R)-1-((S)-2-(4-((7-(((R)-1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)methyl)-1H-1,2,3-triazol-1-yl)-3,3- dimethylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Int-63A) [0602] (R)-7-((1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl)-2-(prop-2-yn-1-yl)- 7-azaspiro[3.5]nonane (Int-52) (10 mg, 0.011 mmol) and (2S,4R)-1-((S)-2-azido-3,3- dimethylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Int-34) (7.72 mg, 0.017 mmol) were dissolved in CH₂Cl₂ (376 μL). To above solution was added tetrakis(acetonitrile)copper(I) hexafluorophosphate (8.40 mg, 0.023 mmol) and DIEA (11.81 μL, 0.068 mmol). The reaction was stirred at room temperature for 18 h. The reaction was concentrated and dissolved in DMF (1 ml), purified by RPLC (ISCO® C18 Gold column 15 g, eluted with 0- 100% ACN/water with 0.05% TFA). The fractions containing desired product were combined and lyophilized to give (2S,4R)-1-((S)-2-(4-((7-(((R)-1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)methyl)-1H-1,2,3-triazol-1-yl)-3,3- dimethylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Int-63A). ESI-MS m/z calc’d for C₅₁H₇₁F₂N₇O₄SSi: 944.36, found [M+H]⁺: 944.8. [0603] Step B: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(4-((7-(((R)-2,2-difluoro- 1-(hydroxymethyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)methyl)-1H-1,2,3- triazol-1-yl)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Int-63) [0604] (2S,4R)-1-((S)-2-(4-((7-(((R)-1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)methyl)-1H-1,2,3-triazol-1-yl)-3,3- dimethylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Int-63A) (180 mg, 0.191 mmol) was dissolved in CH₂Cl₂ (3812 μL), cooled to -78 °C. To above solution was added boron trichloride (1525 μL, 1.525 mmol) (cold) dropwise under N₂. The reaction was stirred at -78 °C for 2 h, then quenched with DIEA/MeOH (1/1, 0.5 mL). The mixture was diluted with DCM, washed with NaHCO₃ (2 mL), extracted with DCM (10 mL x3). The organic layer was dried over MgSO₄, filtered and concentrated. The crude was purified by flash silica gel chromatography (ISCO®, 24 g Gold column, eluted with 0-100% EtOAc/EtOH (3/1) in hexane 19 min. Fractions containing desired product were combined and concentrated to give (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(4-((7-(((R)-2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)methyl)-1H-1,2,3-triazol- 1-yl)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-63). ESI-MS m/z calc’d for C₄₄H₆₅F₂N₇O₄SSi: 854.91, found [M+H]⁺: 854.5. [0605] Intermediate 64: (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-64) [0606] Step A: (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 (Int-64A) [0607] 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 (Int-29) (307 mg, 0.513 mmol), (R)-(1-((1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)methanol (Int-51) (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 (Int-64A). MS (ESI) [M+H]⁺: m/z 906.3. [0608] Step B: (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-64) [0609] 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 (Int-64A) (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), the 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-64). MS (ESI) [M/2+H]⁺: m/z 409.0. [0610] Intermediate 65-a & 65-b: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(1-(2-(1- (((R)-2,2-difluoro-1-(hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3- triazol-4-yl)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Int-65-a & Int-65-b) [0611] Step A: Tert-butyl 4-(2-((methylsulfonyl)oxy)ethyl)piperidine-1-carboxylate (Int- 65A) [0612] To a solution of tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (5 g, 21.80 mmol), TEA (9.12 mL, 65.4 mmol) in DCM (50 mL) was added methanesulfonic anhydride (7.60 g, 43.6 mmol). The mixture was stirred at 25 °C for 16 h. LCMS showed the starting material was consumed and desired peak was formed. The mixture was diluted with DCM (90 mL), washed with H₂O (10 mL x 3), dried over Na₂SO₄, filtered and the solvent was evaporated under reduced pressure to give the crude product. The residue was purified by flash silica gel chromatography (ISCO®, 80 g Agela Flash Column, Eluent of 0~10% EtOAc/Pet. ether gradient @ 40 mL/min) to give tert-butyl 4-(2- ((methylsulfonyl)oxy)ethyl)piperidine-1-carboxylate (Int-65A). MS (ESI) [M+H-Boc]⁺: m/z 207.9. [0613] Step B: Tert-butyl 4-(2-azidoethyl)piperidine-1-carboxylate (Int-65B) [0614] To a solution of tert-butyl 4-(2-((methylsulfonyl)oxy)ethyl)piperidine-1-carboxylate (Int-65A) (3 g, 9.76 mmol) in DMF (30 mL) was added sodium azide (0.952 g, 14.64 mmol) at 25 °C. The mixture was stirred at 60 °C for 16 h under N₂. TLC showed the starting material was consumed and new spot was formed. The reaction was allowed to cool to room temperature, adjusted pH to 9 with NaHCO₃ (aq., 20 mL). The reaction was poured into water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layer was washed with brine (20 mL x 5), dried over Na₂SO₄ and filtered. The filtrate was concentrated in vacuum and the residue was purified by flash silica gel chromatography (ISCO®, 40 g Agela Flash Column, Eluent of 0~10% EtOAc/Pet. ether gradient) to give tert-butyl 4-(2-azidoethyl)piperidine-1-carboxylate (Int-65B). ¹H NMR (400 MHz, CDCl₃) δ 4.19 - 4.00 (m, 2H), 3.32 (t, J = 6.7 Hz, 2H), 2.68 (br t, J = 11.4 Hz, 2H), 1.66 (m, J = 12.6 Hz, 2H), 1.58 - 1.51 (m, 3H), 1.45 (s, 9H), 1.17 - 1.05 (m, 2H). [0615] Step C: 4-(2-azidoethyl)piperidine (Int-65C) [0616] The compound of tert-butyl 4-(2-azidoethyl)piperidine-1-carboxylate (Int-65B) (2 g, 7.86 mmol) was added to HCl (4.79 mL, 19.16 mmol) (4 M in dioxane) at 25 °C. The mixture was stirred at 25 °C for 16 h. LCMS showed the starting material was consumed and desired MS was formed. The solvent was evaporated under reduced pressure to give 4- (2-azidoethyl)piperidine (Int-65C). MS (ESI) [M+H]⁺: m/z 154.9. [0617] Step D: (R)-4-(2-azidoethyl)-1-((1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidine (Int-65D) [0618] To a solution of (S)-(1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl methanesulfonate (Int-55A) (2.409 g, 7.87 mmol) in MeCN (20 mL) was added K₂CO₃ (5.44 g, 39.3 mmol) and 4-(2-azidoethyl)piperidine (Int-65C) (1.213 g, 7.87 mmol) at 25 °C. The mixture was stirred at 60 °C for 16 h. LCMS showed the starting material was consumed and desired MS was formed. The reaction mixture was diluted with water (10 mL), then extracted with EtOAc (30 mL * 2). The combined organic layer was dried with Na₂SO₄, filtered and the solvent was removed under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®, 40 g Agela Flash Column, Eluent of 0~10% CH₂Cl₂/MeOH gradient) to give (R)-4-(2-azidoethyl)-1-((1-((benzyloxy)methyl)- 2,2-difluorocyclopropyl)methyl)piperidine (Int-65D). MS (ESI) [M+H]⁺: m/z 365. [0619] Step E: Ethyl 2-(1-(2-(1-(((R)-1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-4-yl)-3,3- dimethylbutanoate (Int-65E) [0620] To a solution of (R)-4-(2-azidoethyl)-1-((1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidine (Int-65D) (1.2 g, 3.29 mmol) in DCM (10 mL) was added tetrakis(acetontrile)copper(I)hexafluorophosphate (1.595 g, 4.28 mmol), ethyl 2- (tert-butyl)but-3-ynoate (1.329 g, 3.95 mmol) and DIEA (3.74 mL, 21.40 mmol) at 25 °C, then the mixture was stirred at 25 °C for 2 h. LCMS showed the starting material was consumed and desired MS was formed. The reaction was diluted with DCM (40 mL), washed with brine (20 mL x 2), the organic layer was dried over Na₂SO₄, filtered and the filtrate was concentrated in vacuo. The crude product was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0%-10 % MeOH in DCM gradient @ 30 mL/min) to give ethyl 2-(1-(2-(1-(((R)-1- ((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol- 4-yl)-3,3-dimethylbutanoate (Int-65E). MS (ESI) [M+H]⁺: m/z 533.4. [0621] Step F: Ethyl 2-(1-(2-(1-(((R)-2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-4-yl)-3,3- dimethylbutanoate (Int-65F) [0622] To a solution of ethyl 2-(1-(2-(1-(((R)-1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-4-yl)-3,3- dimethylbutanoate (Int-65E) (1.5 g, 2.82 mmol) in DCM (10 mL) was added boron trichloride solution (14.08 mL, 28.2 mmol) (2 M in DCM) at -78 °C. The mixture was stirred at -78 °C for 2 h. LCMS showed the starting material was consumed and desired MS was found. The reaction mixture was quenched with MeOH (5.0 mL). The reaction mixture was diluted with DCM (100 mL) and adjusted to pH 7 with NH₃·MeOH (7 M). The mixture was concentrated in vacuo, and the crude was purified by flash silica gel chromatography (ISCO®; 20 g Agela® Silica Flash Column, Eluent of 0~15% MeOH/DCM gradient @ 40 mL/min, dry loaded) to give ethyl 2-(1-(2-(1-(((R)-2,2- difluoro-1-(hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-4-yl)- 3,3-dimethylbutanoate (Int-65F). MS (ESI) [M+H]⁺: m/z 443.7. [0623] Step G: 2-(1-(2-(1-(((R)-2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-4-yl)-3,3- dimethylbutanoic acid (Int-65G) [0624] To a solution of ethyl 2-(1-(2-(1-(((R)-2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-4-yl)-3,3- dimethylbutanoate (Int-65F) (600 mg, 1.356 mmol) in MeOH (6 mL) and water (0.6 mL) was added NaOH (aq., 4 M in water) (5 mL) at 25 °C. The mixture was stirred at 60 °C for 16 h. LCMS showed the starting material was consumed and desired MS was found. The reaction mixture was diluted with water (5 mL), and then acidified with aq. HCl (1 M) to pH 7. The reaction mixture was purified by preparative HPLC (Column: Boston Green ODS 150 * 30 mm * 5 um; Condition: water (0.1% TFA)-ACN Begin B 20, End B 40 Gradient Time (min) 11, 100% B Hold Time (min) 2 FlowRate (mL/min) 25) to give 2-(1- (2-(1-(((R)-2,2-difluoro-1-(hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)-1H- 1,2,3-triazol-4-yl)-3,3-dimethylbutanoic acid (Int-65G). MS (ESI) [M+H]⁺: m/z 415.3. [0625] Step H: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(1-(2-(1-(((R)-2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-4-yl)-3,3- dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-65H) [0626] To a solution of 2-(1-(2-(1-(((R)-2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-4-yl)-3,3- dimethylbutanoic acid (Int-65G) (330 mg, 0.796 mmol) in DMF (3.0 mL) was added (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Int-28) (447 mg, 1.035 mmol) and PyBOP (829 mg, 1.592 mmol) at 25 °C. Finally, DIEA (0.695 mL, 3.98 mmol) was added under nitrogen atmosphere. The mixture was stirred at 25 °C for 2 h. LCMS showed the starting material was consumed and desired MS was found. The reaction mixture was concentrated in vacuum. The residue was purified by preparative TLC (SiO₂, DCM/MeOH=10/1) to give racemic (2S,4R)-4-((tert- butyldimethylsilyl)oxy)-1-(2-(1-(2-(1-(((R)-2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-4-yl)-3,3- dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int- 65H). MS (ESI) [M/2+H]⁺: m/z 414.9. [0627] Step I: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(1-(2-(1-(((R)-2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-4-yl)-3,3- dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-65-a & Int-65-b) [0628] The racemic (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(1-(2-(1-(((R)-2,2- difluoro-1-(hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-4-yl)- 3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int- 65H) (300 mg, 0.362 mmol) was separated by preparative SFC (Phenomenex-Cellulose-2 (250 mm * 30 mm,10 um); Condition: CO₂- MeOH (0.1% NH₃H₂O);Begin B--End B: 35-- 35; Gradient Time (min): 1; 100% B Hold Time (min): 1; FlowRate (mL/min): 70) to give (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(1-(2-(1-(((R)-2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-4-yl)-3,3- dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-65-a, the first eluting isomer from SFC) and (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(1-(2- (1-(((R)-2,2-difluoro-1-(hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3- triazol-4-yl)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Int-65-b, the second eluting isomer from SFC). [0629] Intermediate 66-a & 66-b: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(1-(2-(1- ((1-(hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-4-yl)-3,3- dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-66-a & Int-66-b) [0630] Step A: 1-((benzyloxy)methyl)cyclopropane-1-carbaldehyde (Int-66A) [0631] In a round bottom flask, to a solution of (1- ((benzyloxy)methyl)cyclopropyl)methanol (5 g, 26.0 mmol) in DCM (100 mL) was added DMP (11.58 g, 27.3 mmol) at 0 °C. The mixture was stirred at 20 °C for 2 h. TLC indicated that the reaction was completed. The mixture was quenched with water (100 mL) and extracted with DCM (100 mL * 3), and the organic layers were washed with brine (50 mL). The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®, 40 g Agela Silica Flash Column, Eluent of 10% ethyl acetate / petroleum ether gradient @ 30 mL/min) to give 1-((benzyloxy)methyl)cyclopropane-1-carbaldehyde (Int- 66A). ¹H NMR (400 MHz, CDCl₃) δ 9.07 (s, 1H), 7.42 - 7.30 (m, 5H), 4.58 (s, 2H), 3.72 (s, 2H), 1.32 - 1.24 (m, 2H), 1.18 - 1.08 (m, 2H). [0632] Step B: 4-(2-azidoethyl)-1-((1-((benzyloxy)methyl)cyclopropyl)methyl)piperidine (Int-66B) [0633] In a round bottom flask, to a solution of 4-(2-azidoethyl)piperidine (Int-65C) (2.92 g, 18.92 mmol) and 1-((benzyloxy)methyl)cyclopropane-1-carbaldehyde (Int-66A) (3 g, 15.77 mmol) in DCM (50 mL) was added Et₃N (7.69 mL, 55.2 mmol). The mixture was stirred at 20 °C for 1 h. Sodium triacetoxyborohydride (6.68 g, 31.5 mmol) was added to the above mixture, and the mixture was stirred at 20 °C for 3 h. LCMS indicated that the reaction was completed. The mixture was concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®, 80 g Agela Silica Flash Column, Eluent of 25% ethyl acetate / petroleum ether gradient @ 30 mL/min) to give 4-(2- azidoethyl)-1-((1-((benzyloxy)methyl)cyclopropyl)methyl)piperidine (Int-66B). MS (ESI) [M+H]⁺: m/z 329.2. [0634] Step C: Ethyl 2-(1-(2-(1-((1-((benzyloxy)methyl)cyclopropyl)methyl)piperidin-4- yl)ethyl)-1H-1,2,3-triazol-4-yl)-3,3-dimethylbutanoate (Int-66C) [0635] To a solution of 4-(2-azidoethyl)-1-((1- ((benzyloxy)methyl)cyclopropyl)methyl)piperidine (Int-66B) (2 g, 6.09 mmol) in DCM (60 mL) was added tetrakis(acetonitrile)copper(I) hexafluorophosphate (2.95 g, 7.92 mmol), ethyl 2-(tert-butyl)but-3-ynoate (1.229 g, 7.31 mmol) and DIEA (6.91 mL, 39.6 mmol). The mixture was stirred at 25 °C for 2 h. LCMS indicated that the reaction was completed. The mixture was added into water (50 mL) and extracted with DCM (50 mL * 3), the organic layers were washed with brine (50 mL). The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®, 20 g Agela Silica Flash Column, Eluent of 8% MeOH / DCM @ 30 mL/min) to give ethyl 2-(1-(2-(1-((1- ((benzyloxy)methyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-4-yl)-3,3- dimethylbutanoate (Int-66C). MS (ESI) [M+H]⁺: m/z 497.4. [0636] Step D: Ethyl 2-(1-(2-(1-((1-(hydroxymethyl)cyclopropyl)methyl)piperidin-4- yl)ethyl)-1H-1,2,3-triazol-4-yl)-3,3-dimethylbutanoate (Int-66D) [0637] In a round bottom flask, to a solution of ethyl 2-(1-(2-(1-((1- ((benzyloxy)methyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-4-yl)-3,3- dimethylbutanoate (Int-66C) (4 g, 8.05 mmol) in DCM (30 mL) was added trichloroborane (40.3 mL, 40.3 mmol) at -78 °C. The mixture was stirred at -78 °C for 2 h. LCMS indicated that the reaction was completed. The mixture was basified with 7 N NH₃/MeOH to pH 9, filtered, washed with DCM (50 mL) and concentrated in vacuum to give ethyl 2-(1- (2-(1-((1-(hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-4-yl)- 3,3-dimethylbutanoate (Int-66D). MS (ESI) [M+H]⁺: m/z 407.3. [0638] Step E: 2-(1-(2-(1-((1-(hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)- 1H-1,2,3-triazol-4-yl)-3,3-dimethylbutanoic acid (Int-66E) [0639] In a round bottom flask, to a solution of ethyl 2-(1-(2-(1-((1- (hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-4-yl)-3,3- dimethylbutanoate (Int-66D) (2.8 g, 6.89 mmol) in EtOH (30 mL) was added aq. NaOH (17.23 mL, 68.9 mmol) (4 M) at 20 °C. The mixture was stirred at 60 °C for 12 h. LCMS indicated that the reaction was completed. The mixture was concentrated in vacuum. The mixture was purified by preparative HPLC (Instrument EK, Column Boston Uni C18150 * 40 mm * 5 um, Condition water (0.2% FA)-ACN, Begin B 0, End B 30, Gradient Time (min) 10, 100% B Hold Time 2, Flow Rate (mL/min) 60, Injections 10) to give 2-(1-(2-(1- ((1-(hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-4-yl)-3,3- dimethylbutanoic acid (Int-66E). MS (ESI) [M+H]⁺: m/z 379.2. [0640] Step F: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(1-(2-(1-((1- (hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-4-yl)-3,3- dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-66F) [0641] To a solution of 2-(1-(2-(1-((1-(hydroxymethyl)cyclopropyl)methyl)piperidin-4- yl)ethyl)-1H-1,2,3-triazol-4-yl)-3,3-dimethylbutanoic acid (Int-66E) (500 mg, 1.321 mmol) in DMF (15 mL) was added HOBt (405 mg, 2.64 mmol), EDC (633 mg, 3.30 mmol) and DIEA (1.384 mL, 7.93 mmol), and the mixture was stirred at 20 °C for 10 min. Then (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Int-28) (627 mg, 1.453 mmol) was added to the above mixture. The mixture was stirred at 60 °C for 2 h. LCMS indicated that the reaction was completed. The mixture was concentrated in vacuum and purified by flash silica gel chromatography (ISCO®, 20 g Agela Silica Flash Column, Eluent of 0~20% MeOH / DCM gradient @ 30 mL/min) to give racemic (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(1-(2-(1-((1- (hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-4-yl)-3,3- dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-66F). MS (ESI) [M+H]⁺: m/z 792.4. [0642] Step G: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(1-(2-(1-((1- (hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-4-yl)-3,3- dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-66-a & Int-66-b) [0643] Racemic (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(1-(2-(1-((1- (hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-4-yl)-3,3- dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (400 mg, 0.505 mmol) was separated by preparative SFC (Instrument SFC-27, Column DAICEL CHIRALPAK IC (250 mm * 30 mm, 10 um), Condition CO₂-EtOH (0.1% NH₃H₂O), Begin B 55%, End B 55%, Gradient Time (min) 1, 100% B Hold Time 1, Flow Rate (mL/min) 140, Injections 100) to give (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(1-(2-(1-((1- (hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-4-yl)-3,3- dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-66-a, the first eluting isomer from SFC) as a yellow oil and (2S,4R)-4-((tert- butyldimethylsilyl)oxy)-1-(2-(1-(2-(1-((1-(hydroxymethyl)cyclopropyl)methyl)piperidin-4- yl)ethyl)-1H-1,2,3-triazol-4-yl)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Int-66-b, the second eluting isomer from SFC). MS (ESI) [M+H]⁺: m/z 792.4. [0644] Intermediate 67: (2S,4R)-1-((S)-2-(2-(7-azaspiro[3.5]nonan-2-yl)acetamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Int-67) [0645] Step A: Tert-butyl 2-(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)-7- azaspiro[3.5]nonane-7-carboxylate (Int-67A) [0646] To a stirred mixture of 2-(7-(tert-butoxycarbonyl)-7-azaspiro[3.5]nonan-2-yl)acetic acid (546 mg, 1.927 mmol), in N,N-dimethylformamide (10 mL) were added 2-(7-aza-1H- benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (806 mg, 2.120 mmol), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (900 mg, 1.927 mmol) and ethyldiisopropylamine (1.346 mL, 7.71 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was quenched by water (100 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic fractions were washed with brine (100 mL × 3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by C18 with the following conditions: Column, Xbridge C18, 19 × 150 mm; mobile phase: acetonitrile in water, 0% - 60% in 20 min; Detector, UV 254 nm. RT: 3 min. The collected fractions were combined and concentrated under reduced pressure to give tert-butyl 2-(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)-7-azaspiro[3.5]nonane-7-carboxylate (Int-67A). MS ESI calculated for C₃₇H₅₃N₅O₆S [M + H]⁺ 696.37; found 696.35. ¹H NMR: (300 MHz, CD₃OD) δ 8.87 (s, 1H), 7.53 - 7.32 (m, 4H), 4.67 - 4.45 (m, 4H), 4.35 (d, J = 15.5 Hz, 1H), 3.95 - 3.72 (m, 2H), 3.40 - 3.33 (m, 2H), 3.27 - 3.21 (m, 2H), 2.72 - 2.56 (m, 1H), 2.47 (s, 3H), 2.42 - 2.32 (m, 2H), 2.27 - 2.15 (m, 1H), 2.12 - 1.94 (m, 3H), 1.61 - 1.51 (m, 4H), 1.51 - 1.46 (m, 2H), 1.43 (s, 9H), 1.02 (s, 9H). [0647] Step B: (2S,4R)-1-((S)-2-(2-(7-azaspiro[3.5]nonan-2-yl)acetamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Int-67) [0648] To a stirred mixture of tert-butyl 2-(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)-7-azaspiro[3.5]nonane-7-carboxylate (Int-67A) (1g, 1.437 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (10 mL) at room temperature. The resulting mixture was stirred for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by C18 column chromatography with the following conditions: Column, Xbridge C18, 19 × 150 mm; mobile phase: acetonitrile in water, 0% - 30% in 12 min; Detector, UV 254 nm. RT: 3 min. The collected fractions were combined and concentrated under reduced pressure to give (2S,4R)-1-((S)-2-(2-(7-azaspiro[3.5]nonan- 2-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Int-67) 2,2,2-trifluoroacetate. MS ESI calculated for C₃₂H₄₅N₅O₄S [M - H]- 594.32; found 594.05.1H NMR (300 MHz, CD3OD) δ 8.88 (s, 1H), 7.51 - 7.36 (m, 4H), 4.66 - 4.47 (m, 4H), 4.36 (d, J = 15.5 Hz, 1H), 3.88 (d, J = 11.0 Hz, 1H), 3.84 - 3.75 (m, 1H), 3.12 (t, J = 5.8 Hz, 2H), 3.04 (t, J = 5.8 Hz, 2H), 2.73 - 2.59 (m, 1H), 2.47 (s, 3H), 2.40 (dd, J = 7.5, 3.1 Hz, 2H), 2.28 - 2.17 (m, 1H), 2.15 - 2.01 (m, 3H), 1.85 (t, J = 5.8 Hz, 2H), 1.74 (t, J = 5.8 Hz, 2H), 1.68 - 1.58 (m, 2H), 1.03 (s, 9H). [0649] Compounds in the table below were synthesized via a similar route as described in the above synthesis of Int-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. [0650] Intermediate 70: (2S,4R)-1-((S)-3,3-dimethyl-2-(2-(2-(piperidin-4- yl)ethoxy)acetamido)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Int-70) [0651] Step A: Tert-butyl 4-(2-(2-ethoxy-2-oxoethoxy)ethyl)piperidine-1-carboxylate (Int- 70A) [0652] To a solution of tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (1.5 g, 6.54 mmol) in dichloromethane (23 mL) were added rhodium(II) acetate dimer (2.89 g, 6.54 mmol) and ethyl 2-diazoacetate (1.493 g, 13.08 mmol) in dichloromethane (6 mL) at 0 °C. The reaction was stirred at 30 °C for 16 h.The reaction mixture was quenched by water (300 mL) and extracted with ethyl acetate (300 mL × 3). The combined organic layers were washed with brine (300 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with ethyl acetate / petroleum ether (1 - 50%) to afford tert-butyl 4-(2-(2-ethoxy-2- oxoethoxy)ethyl)piperidine-1-carboxylate (Int-70A). MS ESI calculated for C₁₄H₂₅NO₅ [M + H]⁺ 316.20; found 316.10. ¹H NMR (400 MHz, DMSO-d₆) δ 4.21 - 4.07 (m, 4H), 4.05 (s, 2H), 3.95 - 3.87 (m, 2H), 3.48 (t, J = 6.3 Hz, 2H), 1.68 - 1.60 (m, 2H), 1.60 - 1.48 (m, 1H), 1.48 - 1.40 (m, 2H), 1.38 (s, 9H), 1.26 - 1.15 (m, 3H), 1.04 - 0.89 (m, 2H). [0653] Step B: 2-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethoxy)acetic acid (Int-70B) [0654] To a solution of tert-butyl 4-(2-(2-ethoxy-2-oxoethoxy)ethyl)piperidine-1- carboxylate (Int-70A) (600 mg, 1.902 mmol) in methanol (6 mL) was added NaOH (6.34 mL, 38.0 mmol) at 25 °C. The reaction was stirred at 25 °C for 2 h. The mixture was filtered. The filtrate was acidified with concentrated hydrochloric acid to pH 5 and extracted with ethyl acetate (300 mL × 3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and to give crude 2-(2-(1-(tert- butoxycarbonyl)piperidin-4-yl)ethoxy)acetic acid (Int-70B). MS ESI calculated for C₁₄H₂₅NO₅ [M + H]⁺ 288.17; found 288.20. ¹H NMR (300 MHz, DMSO-d₆) δ 12.55 (s, 1H), 3.96 (s, 2H), 3.94 - 3.84 (m, 2H), 3.47 (t, J = 6.3 Hz, 2H), 2.66 (s, 2H), 1.71 - 1.57 (m, 2H), 1.38 (s, 12H), 1.05 - 0.86 (m, 2H). [0655] Step C: Tert-butyl 4-(2-(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- oxoethoxy)ethyl)piperidine-1-carboxylate (Int-70C) [0656] To a solution of 2-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethoxy)acetic acid (Int- 70B) (600 mg, 2.088 mmol) in DMF (1 mL) were added HATU (873 mg, 2.297 mmol) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (975 mg, 2.088 mmol) at 25 °C. Then to the resulting solution was added DIEA (1.459 mL, 8.35 mmol) at 0 °C and the mixture was stirred at 25 °C for 3 h. The reaction was purified by Combi-flash with the following conditions: Column: C¹⁸ Column, 40 g, 60 Å, 40 - 60 μm; Mobile Phase A: water, Mobile Phase B: MeCN; Flow rate: 100 mL/min; 0% B to 100% B in 20 min; Detector: UV 254 / 210 nm. The product-containing fractions were combined, roto-evaporated in vacuo to give tert-butyl 4-(2-(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- oxoethoxy)ethyl)piperidine-1-carboxylate (Int-70C). MS ESI calculated for C₃₆H₅₃N₅O₇S [M + H]⁺ 700.37; found 700.10. ¹H NMR (400 MHz, DMSO-d₆) δ 8.98 (s, 1H), 8.61 (t, J = 6.1 Hz, 1H), 7.50 - 7.32 (m, 5H), 4.56 (d, J = 9.6 Hz, 1H), 4.49 - 4.33 (m, 3H), 4.33 - 4.20 (m, 1H), 4.00 - 3.83 (m, 4H), 3.73 - 3.57 (m, 2H), 3.57 - 3.47 (m, 2H), 2.45 (s, 3H), 2.08 (s, 2H), 1.97 - 1.82 (m, 1H), 1.69 - 1.60 (m, 2H), 1.59 - 1.44 (m, 3H), 1.41 - 1.31 (m, 10H), 1.09 - 0.85 (m, 12H). [0657] Step D: (2S,4R)-1-((S)-3,3-dimethyl-2-(2-(2-(piperidin-4- yl)ethoxy)acetamido)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Int-70) [0658] To a solution of tert-butyl 4-(2-(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-oxoethoxy)ethyl)piperidine-1-carboxylate (Int-70C) (1 g, 1.429 mmol) in dichloromethane (10 mL) and 1,4-dioxane hydrochloride (10 mL, 84 mmol).The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by Combi-flash with the following conditions: Column: C¹⁸ Column, 120 g, 60 Å, 40 - 60 μm; Mobile Phase A: water, Mobile Phase B: MeCN; Flow rate: 80 mL/min; 0% B to 100% B in 30 min; Detector: UV 254 / 210 nm. The product- containing fractions were combined, roto-evaporated in vacuo to give (2S,4R)-1-((S)-3,3- dimethyl-2-(2-(2-(piperidin-4-yl)ethoxy)acetamido)butanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (Int-70). MS ESI calculated for C₃₁H₄₅N₅O₅S [M + H]⁺ 600.31; found 600.05. ¹H NMR (300 MHz, CD₃OD) δ 9.84 (s, 1H), 7.66 - 7.31 (m, 4H), 4.71 (s, 1H), 4.66 - 4.41 (m, 4H), 4.12 - 3.95 (m, 2H), 3.94 - 3.77 (m, 2H), 3.74 - 3.59 (m, 2H), 3.47 - 3.34 (m, 2H), 3.13 - 2.89 (m, 2H), 2.60 (s, 3H), 2.34 - 2.06 (m, 2H), 2.06 - 1.95 (m, 2H), 1.85 (s, 1H), 1.72 - 1.61 (m, 2H), 1.54 - 1.29 (m, 2H), 1.14 - 0.90 (m, 9H). [0659] Compounds in the table below were synthesized via a similar route as described in the above synthesis of Int-70 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. [0660] Intermediate 75: (2S,4R)-1-((S)-2-(2-((1r,3S)-3-((7-azaspiro[3.5]nonan-2- yl)methoxy)cyclobutoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-75) [0661] Step A: Ethyl 2-((1r,3r)-3-((7-azaspiro[3.5]nonan-2- yl)methoxy)cyclobutoxy)acetate (Int-75A) [0662] To a stirred mixture of ethyl 2-((1r,3r)-3-((trimethylsilyl)oxy)cyclobutoxy)acetate (2.5 g, 10.15 mmol) in DCM (25 mL) were added tert-butyl 2-formyl-7- azaspiro[3.5]nonane-7-carboxylate (4.11 g, 16.24 mmol), triethylsilane (4.72 g, 40.6 mmol) and TMSOTf (3.67 mL, 20.29 mmol) at -78 °C under argon atmosphere. The resulting mixture was stirred for 16 h while the temperature was slowly warmed from -78 °C to room temperature. The reaction mixture was quenched by water (200 mL) and extracted with dichloromethane (300 mL × 3). The combined organic fractions were concentrated under reduced pressure to afford ethyl 2-((1r,3r)-3-((7-azaspiro[3.5]nonan-2- yl)methoxy)cyclobutoxy)acetate (Int-75A). MS ESI calculated for C₁₇H₂₉NO₄ [M + H]⁺ 312.21; found 312.10. [0663] Step B: Tert-butyl 2-(((1r,3r)-3-(2-ethoxy-2-oxoethoxy)cyclobutoxy)methyl)-7- azaspiro[3.5]nonane-7-carboxylate (Int-75B) [0664] To a stirred mixture of ethyl 2-((1r,3r)-3-((7-azaspiro[3.5]nonan-2- yl)methoxy)cyclobutoxy)acetate (Int-75A) (2 g, 3.21 mmol) in EtOAc (10 mL) and water (10.00 mL) were added Boc₂O (1.118 mL, 4.82 mmol) and sodium bicarbonate (1.079 g, 12.84 mmol) at 25 °C. The resulting mixture was stirred for 16 h. The reaction mixture was quenched by water (100 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic fractions were washed with brine (100 mL × 3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1 ~ 60% ethyl acetate in petroleum ether to afford tert-butyl 2-(((1r,3r)-3-(2-ethoxy-2- oxoethoxy)cyclobutoxy)methyl)-7-azaspiro[3.5]nonane-7-carboxylate (Int-75B). MS ESI calculated for C₂₂H₃₇NO₆ [M – C₄H₈ + H]⁺ 356.26; found 356.20.¹H NMR (300 MHz, CDCl₃) δ 4.29 - 4.17 (m, 3H), 3.98 (s, 2H), 3.40 - 3.20 (m, 7H), 2.55 - 2.40 (m, 1H), 2.35 - 2.14 (m, 4H), 1.97 - 1.85 (m, 2H), 1.66 - 1.46 (m, 6H), 1.45 (s, 9H), 1.27 (t, J = 7.2 Hz, 3H). [0665] Step C: 2-((1r,3r)-3-((7-(tert-butoxycarbonyl)-7-azaspiro[3.5]nonan-2- yl)methoxy)cyclobutoxy)acetic acid (Int-75C) [0666] To a stirred mixture of tert-butyl 2-(((1r,3r)-3-(2-ethoxy-2- oxoethoxy)cyclobutoxy)methyl)-7-azaspiro[3.5]nonane-7-carboxylate (Int-75B) (1 g, 2.430 mmol) in MeOH (8 mL) was added aqueous NaOH (8 mL, 48.0 mmol) at 25 °C. The resulting mixture was stirred for 2 h. The pH value of the solution was adjusted to 5 ~ 6 with HCl (1 M, 50 mL). The reaction mixture was quenched by water (300 mL) and extracted with ethyl acetate (600 mL × 3). The combined organic fractions were washed with brine (300 mL × 3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 2-((1r,3r)-3-((7-(tert-butoxycarbonyl)-7- azaspiro[3.5]nonan-2-yl)methoxy)cyclobutoxy)acetic acid (Int-75C). MS ESI calculated for C₂₀H₃₃NO₆ [M + H]⁺ 328.23; found 328.20. ¹H NMR (400 MHz, CDCl₃) δ 4.30 - 4.20 (m, 1H), 4.16 - 4.12 (m, 1H), 4.02 (s, 2H), 3.39 - 3.21 (m, 6H), 2.53 - 2.41 (m, 1H), 2.32 - 2.18 (m, 4H), 1.94 - 1.85 (m, 2H), 1.57 - 1.53 (m, 2H), 1.52 - 1.47 (m, 2H), 1.44 (s, 11H). [0667] Step D: butyl 2-(((1S,3r)-3-(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-oxoethoxy)cyclobutoxy)methyl)-7-azaspiro[3.5]nonane-7-carboxylate (Int- 75D) [0668] To a stirred mixture of 2-((1r,3r)-3-((7-(tert-butoxycarbonyl)-7-azaspiro[3.5]nonan- 2-yl)methoxy)cyclobutoxy)acetic acid (Int-75C) (900 mg, 2.347 mmol) in DMF (9 mL) were added HATU (982 mg, 2.58 mmol), DIEA (1.640 mL, 9.39 mmol) and (2S,4R)-1-((S)- 2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide hydrochloride (1096 mg, 2.347 mmol) at 0 °C under argon atmosphere. The resulting mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was purified by Combi-flash with the following conditions: Column: AQ-C¹⁸ Column, 120 g, 60 Å, 40-60 μm; Mobile Phase A: water, Mobile Phase B: MeCN; Flow rate: 80 mL / min; 0% B to 100% B in 25 min; Detector: UV 254 / 210 nm. The collected fractions were combined and concentrated under reduced pressure to give tert-butyl 2-(((1S,3r)-3-(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-oxoethoxy)cyclobutoxy)methyl)-7- azaspiro[3.5]nonane-7-carboxylate (Int-75D). MS ESI calculated for C₄₂H₆₁N₅O₈S [M + H]⁺ 796.42; found 796.60.¹H NMR (400 MHz, CDCl₃) δ 8.70 (s, 1H), 7.43 - 7.30 (m, 5H), 7.14 (d, J = 8.7 Hz, 1H), 4.73 (t, J = 7.8 Hz, 1H), 4.62 - 4.45 (m, 3H), 4.35 (dd, J = 14.9, 5.3 Hz, 1H), 4.22 - 4.02 (m, 3H), 3.82 (s, 2H), 3.64 (dd, J = 11.2, 3.8 Hz, 1H), 3.37 - 3.31 (m, 2H), 3.29 - 3.26 (m, 3H), 2.52 (s, 3H), 2.50 - 2.42 (m, 1H), 2.26 - 2.18 (m, 4H), 2.15 - 2.06 (m, 1H), 2.01 (s, 4H), 1.95 - 1.85 (m, 2H), 1.59 - 1.52 (m, 2H), 1.52 - 1.47 (m, 2H), 1.44 (s, 9H), 0.95 (s, 9H). [0669] Step E: (2S,4R)-1-((S)-2-(2-((1r,3S)-3-((7-azaspiro[3.5]nonan-2- yl)methoxy)cyclobutoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-75) [0670] To a stirred mixture of tert-butyl 2-(((1S,3r)-3-(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-oxoethoxy)cyclobutoxy)methyl)-7-azaspiro[3.5]nonane-7-carboxylate (Int- 75D) (1.7 g, 2.136 mmol) in DCM (14 mL) was added hydrochloride (4 M in in 1,4- dioxane, 14 mL, 56 mmol) at 25 °C. The resulting mixture was stirred for 2 h. The reaction mixture was concentrated under reduced pressure to afford (2S,4R)-1-((S)-2-(2-((1r,3S)-3- ((7-azaspiro[3.5]nonan-2-yl)methoxy)cyclobutoxy)acetamido)-3,3-dimethylbutanoyl)-4- hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-75) hydrochloride. MS ESI calculated for C₃₇H₅₃N₅O₆S [M + H]⁺ 696.37; found 696.25. ¹H NMR (300 MHz, Methanol-d₄) δ 10.10 (s, 1H), 7.65 - 7.43 (m, 4H), 4.70 (s, 1H), 4.66 - 4.46 (m, 3H), 4.43 - 4.41 (m, 1H), 4.27 - 4.08 (m, 2H), 3.98 - 3.74 (m, 4H), 3.65 (s, 1H), 3.37 - 3.29 (m, 2H), 3.15 - 3.12 (m, 2H), 3.05 - 3.02 (m, 2H), 2.63 (s, 3H), 2.57 - 2.44 (m, 1H), 2.32 - 2.17 (m, 4H), 2.13 - 2.03 (m, 1H), 2.O2 - 1.91 (m, 2H), 1.89 - 1.87 (m, 2H), 1.77 - 1.74 (m, 2H), 1.71 - 1.57 (m, 2H), 1.03 (s, 9H).

[0671] Compounds in the table below were synthesized via a similar route as described in the above synthesis of Int-75 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. [0672] Intermediate 81: ((R)-1-((2-(2-(((S)-1-((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2- (((R)-2-((tert-butyldimethylsilyl)oxy)-1-(4-(1-ethyl-1H-pyrazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)amino)-2-oxoethyl)- 7-azaspiro[3.5]nonan-7-yl)methyl)-2,2-difluorocyclopropyl)methyl 4-nitrobenzenesulfonate (Int-81) [0673] Step A: (R)-2-(7-((2,2-difluoro-1-(hydroxymethyl)cyclopropyl)methyl)-7- azaspiro[3.5]nonan-2-yl)acetic acid (Int-81A) [0674] Methyl (R)-2-(7-((2,2-difluoro-1-(hydroxymethyl)cyclopropyl)methyl)-7- azaspiro[3.5]nonan-2-yl)acetate (Int-41) (1.4g, 4.41 mmol) and LiOH (0.317 g, 13.23 mmol) in THF (17.64 ml)/MeOH (2.206 ml)/water (2.206 ml) was stirred at room temperature for 18 h. The reaction was then acidifed to pH 1 and extracted with EtOAc. The organic layer was dried over MgSO₄, filtered and concentrated to give (R)-2-(7-((2,2- difluoro-1-(hydroxymethyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)acetic acid (Int- 81A). ESI-MS calculated: 303.350, observed m/z 303.9. [0675] Step B: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-N-((R)-2-((tert- butyldimethylsilyl)oxy)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)ethyl)-1-((2-(7-(((R)-2,2- difluoro-1-(hydroxymethyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)acetyl)-L- valyl)pyrrolidine-2-carboxamide (Int-81B) [0676] (R)-2-(7-((2,2-difluoro-1-(hydroxymethyl)cyclopropyl)methyl)-7- azaspiro[3.5]nonan-2-yl)acetic acid (Int-81A) (12.34 mg, 0.013 mmol), (2S,4R)-1-(L- valyl)-4-((tert-butyldimethylsilyl)oxy)-N-((R)-2-((tert-butyldimethylsilyl)oxy)-1-(4-(1- ethyl-1H-pyrazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Int-56A) (8.52 mg, 0.020 mmol), and HATU (10.03 mg, 0.026 mmol) were dissolved in MeCN (1 mL). To above mixture was added DIEA (18.44 μL, 0.106 mmol). The reaction was stirred at r.t. for 18 h. The crude was purified by RPLC (eluted with 0-100% MeCN/water in 18 min). Fractions containing desired product were combined and lyophilized to give the title compound (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-N-((R)-2-((tert-butyldimethylsilyl)oxy)-1-(4-(1- ethyl-1H-pyrazol-5-yl)phenyl)ethyl)-1-((2-(7-(((R)-2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)acetyl)-L- valyl)pyrrolidine-2-carboxamide (Int-81B). [0677] Step C: ((R)-1-((2-(2-(((S)-1-((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(((R)-2- ((tert-butyldimethylsilyl)oxy)-1-(4-(1-ethyl-1H-pyrazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)amino)-2-oxoethyl)- 7-azaspiro[3.5]nonan-7-yl)methyl)-2,2-difluorocyclopropyl)methyl 4-nitrobenzenesulfonate (Int-81) [0678] (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-N-((R)-2-((tert-butyldimethylsilyl)oxy)-1- (4-(1-ethyl-1H-pyrazol-5-yl)phenyl)ethyl)-1-((2-(7-(((R)-2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)acetyl)-L- valyl)pyrrolidine-2-carboxamide (Int-81B) (60.0 mg, 62.8 μmol), triethylamine (10.2 mg, 14 μL, 100 μmol) and N,N-dimethylpyridin-4-amine (12.3 mg, 1.6 eq., 100 μmol) in acetonitrile (0.50 mL) was cooled to 0 °C where a solution of 4-nitrobenzenesulfonyl chloride (19.5 mg, 1.4 eq., 87.9 μmol) in acetonitrile (0.5 mL) was added. The reaction was then allowed to warm to r.t. The reaction was complete by LCMS in 30 min. The reaction was then concentrated and purified by flash silica gel chromatography (ISCO®, 12 g Gold column, eluted with 0-00% EtOAc in hexane in 12 min) to obtain product ((R)-1-((2-(2- (((S)-1-((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(((R)-2-((tert-butyldimethylsilyl)oxy)-1- (4-(1-ethyl-1H-pyrazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan- 2-yl)amino)-2-oxoethyl)-7-azaspiro[3.5]nonan-7-yl)methyl)-2,2- difluorocyclopropyl)methyl 4-nitrobenzenesulfonate (Int-81). ESI-MS m/z calc’d for C₅₆H₈₅F₂N₇O₁₀SSi₂: 1142, found [M+H]⁺: 1142. [0679] Intermediate 82: ((R)-1-((4-(2-(1-((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)-1H-1,2,3-triazol-4-yl)ethyl)piperidin-1-yl)methyl)-2,2-difluorocyclopropyl)methyl 4- nitrobenzenesulfonate (Int-82) [0680] Step A: (2S,4R)-1-((S)-2-(4-(2-(1-(((R)-1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-1-yl)-3,3- dimethylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Int-82A) [0681] To a solution of (R)-1-((1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl)-4- (but-3-yn-1-yl)piperidine (Int-53) (250 mg,720 μmol) and (2S,4R)-1-((S)-2-azido-3,3- dimethylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Int-34) (411 mg, 720 μmol) in DCM (24.0 mL), was added tetrakis(acetonitrile)copper(I) hexafluorophosphate(536 mg, 1.44 mmol) and N- ethyl-N-isopropylpropan-2-amine (558 mg,4.32 mmol), stirred at r.t. for overnight. The mixture was concentrated under reduced pressure, the residue was purified by flash silica gel chromatography (ISCO®, 40 g gold silica gel column, eluted with 0-40% EtOAC/EtOH and hexane in 19 min) to give (2S,4R)-1-((S)-2-(4-(2-(1-(((R)-1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-1-yl)-3,3- dimethylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Int-82A). ESI-MS m/z calc’d for C₄₉H₆₉F₂N₇O₄SSi [M+H]⁺: 919; found: 919. [0682] Step B: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(4-(2-(1-(((R)-2,2- difluoro-1-(hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-1-yl)- 3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int- 82B) [0683] (2S,4R)-1-((S)-2-(4-(2-(1-(((R)-1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-1-yl)-3,3- dimethylbutanoyl)-4-((tert-butyldimethylsilyl)oxy)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Int-82A) (300mg,0.32mmol) was dissolved in DCM (1.8 ml), cooled to -78 deg. To this solution was added trichloroborane ( 2.61 mL, 1.00 molar in Hex, 2.61 mmol) dropwise, stirred at this temperature for 1 h, quenched with MeOH/DIEA 1/22 mL dropwise, diluted with DCM, washed with bicarbonate and brine, water, dried over MgSO₄, filtered and concentrated. purified by flash silica gel chromatography (ISCO®, 12 g column, eluted with 0-100% EtOAc/EtOH 3/1 in hexane in 19 min) to generate (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(4-(2-(1-(((R)-2,2- difluoro-1-(hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-1-yl)- 3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int- 82B). ESI-MS m/z calc’d for C₄₂H₆₃F₂N₇O₄SSi [M+H]⁺: 829; found: 829. [0684] Step C: ((R)-1-((4-(2-(1-((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)- 1H-1,2,3-triazol-4-yl)ethyl)piperidin-1-yl)methyl)-2,2-difluorocyclopropyl)methyl 4- nitrobenzenesulfonate (Int-82) [0685] (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(4-(2-(1-(((R)-2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-1-yl)-3,3- dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-82B) (32.0 mg, 38.6 μmol), N,N-dimethylpyridin-4-amine (7.55 mg, 61.8 μmol), triethylamine (6.26 mg, 61.8 μmol) in acetonitrile (386 μL)was cooled to 0 °C where a solution of 4- nitrobenzenesulfonyl chloride (12.0 mg, 54.1 μmol) in acetonitrile (0.5 mL) was added and the reaction was then allowed to warm to r.t. The reaction was complete by LCMS in 30 min. The reaction mixture was quenched with bicarbonate and extracted with DCM. The combined organic layers was washed with water, brine, dried over MgSO₄, concentrated to give ((R)-1-((4-(2-(1-((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)-1H- 1,2,3-triazol-4-yl)ethyl)piperidin-1-yl)methyl)-2,2-difluorocyclopropyl)methyl 4- nitrobenzenesulfonate (Int-82). ESI-MS m/z calc’d for C₄₈H₆₆F₂N₈O₈S₂Si [M+H]⁺: 1014.3; found: 1014.1. [0686] Compounds in the table below were synthesized via a similar route as described in the above synthesis of Int-82 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. Example Syntheses: [0687] Example 1: (2S,4R)-1-((2S)-2-(7-(((1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-(3- hydroxynaphthalen-1-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropyl)methyl)(methyl)amino)heptanamido)-3,3-dimethylbutanoyl)-4- hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Ex-1)

[0688] Step A: Tert-butyl 3-(2-((1-(((7-methoxy-7- oxoheptyl)(methyl)amino)methyl)cyclopropyl)methoxy)-8-(3- (methoxymethoxy)naphthalen-1-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [0689] To a stirred solution of tert-butyl 3-(8-(3-(methoxymethoxy)naphthalen-1-yl)-2- (methylsulfonyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-12) (30 mg, 0.045 mmol) and methyl 7-(((1- (hydroxymethyl)cyclopropyl)methyl)(methyl)amino)heptanoate (Int-38) (24 mg, 0.095 mmol) in THF (1 mL) at -20 °C was added LiHMDS (1 M in PhMe, 0.20 mL, 0.20 mmol) dropwise. The resulting mixture was quenched by addition of sat. NaHCO₃, diluted with EtOAc, and warmed to r.t. The organic layer was separated, passed through a phase separator, and concentrated in vacuo to give tert-butyl 3-(2-((1-(((7-methoxy-7- oxoheptyl)(methyl)amino)methyl)cyclopropyl)methoxy)-8-(3- (methoxymethoxy)naphthalen-1-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate, which was used directly in the next step without further purification. ESI m/z calc’d for C₄₆H₆₀N₆O₇S [(M+2H)/2]²⁺: 420; found: 420. [0690] Step B: 7-(((1-(((4-(8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8- (3-(methoxymethoxy)naphthalen-1-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropyl)methyl)(methyl)amino)heptanoic acid [0691] To a stirred solution of tert-butyl 3-(2-((1-(((7-methoxy-7- oxoheptyl)(methyl)amino)methyl)cyclopropyl)methoxy)-8-(3- (methoxymethoxy)naphthalen-1-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate in dioxane (1 mL) was added LiOH (1 N in water, 0.45 mL, 0.45 mmol). The resulting mixture was heated to 50 °C, cooled to r.t., and quenched by addition of 1 N HCl until pH < 4. The organic layer was separated, and the aqueous layer was extracted with DCM twice. The combined organics were dried over MgSO₄, filtered, and concentrated in vacuo to give 7-(((1-(((4-(8-(tert-butoxycarbonyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-(3-(methoxymethoxy)naphthalen-1- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropyl)methyl)(methyl)amino)heptanoic acid, which was used directly in the next step without further purification. ESI m/z calc’d for C₄₅H₅₈N₆O₇S [(M+2H)/2]²⁺: 413; found: 413. [0692] Step C: Tert-butyl 3-(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-(3- (methoxymethoxy)naphthalen-1-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [0693] To a stirred solution of 7-(((1-(((4-(8-(tert-butoxycarbonyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-(3-(methoxymethoxy)naphthalen-1- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropyl)methyl)(methyl)amino)heptanoic acid, (2S,4R)-1-((S)-2-amino- 3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (19 mg, 0.045 mmol), PyAOP (23 mg, 0.045 mmol) in DMF (1 mL) was added DIEA (39 uL, 0.23 mmol). The resulting mixture was stirred at RT overnight and then purified by reverse-phase preparative HPLC (C18, MeCN/water with 0.05% TFA modifier) to give tert-butyl 3-(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-(3- (methoxymethoxy)naphthalen-1-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (16.6 mg). ESI-MS m/z calc’d for C₆₇H₈₆N₁₀O₉S₂ [(M+2H)/2]²⁺: 619; found: 619. [0694] Step D: (2S,4R)-1-((2S)-2-(7-(((1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-(3- hydroxynaphthalen-1-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2- yl)oxy)methyl)cyclopropyl)methyl)(methyl)amino)heptanamido)-3,3-dimethylbutanoyl)-4- hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Ex-1) [0695] To a stirred solution of tert-butyl 3-(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-(3- (methoxymethoxy)naphthalen-1-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (20 mg, 0.015 mmol) in DCE (1 mL) was added HCl (4 N in dioxane, 0.30 mL, 1.2 mmol). The resulting mixture was stirred at r.t. for 15 min, concentrated in vacuo, and then purified by reverse-phase preparative HPLC (C18, MeCN/water with 0.05% TFA modifier) to give (2S,4R)-1-((2S)-2-(7-(((1-(((4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-8-(3-hydroxynaphthalen-1-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)(methyl)amino)heptanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Ex-1) (14.6 mg). ESI m/z calc’d for C₆₀H₇₄N₁₀O₆S₂ [(M+2H)/2]²⁺: 547; found: 547.¹H NMR (600 MHz, DMSO-d₆) δ 9.33 (d, J = 9.6 Hz, 1H), 9.14 – 9.04 (m, 2H), 9.00 – 8.96 (m, 1H), 8.86 – 8.82 (m, 1H), 8.57 – 8.52 (m, 1H), 7.83 (d, J = 8.3 Hz, 2H), 7.75 – 7.71 (m, 1H), 7.47 – 7.37 (m, 4H), 7.33 (s, 1H), 7.29 (s, 1H), 7.20 (t, J = 7.4 Hz, 1H), 4.53 (d, J = 9.3 Hz, 1H), 4.45 – 4.30 (m, 7H), 4.24 – 4.12 (m, 5H), 3.88 – 3.81 (m, 2H), 3.68 – 3.58 (m, 2H), 3.34 – 3.22 (m, 2H), 3.12 – 3.05 (m, 1H), 2.99 – 2.91 (m, 1H), 2.82 (d, J = 2.1 Hz, 3H), 2.44 (s, 3H), 2.27 – 2.21 (m, 1H), 2.11 – 2.01 (m, 2H), 1.92 – 1.85 (m, 4H), 1.67 – 1.59 (m, 2H), 1.52 – 1.41 (m, 2H), 1.30 – 1.21 (m, 4H), 0.91 (s, 9H), 0.87 – 0.80 (m, 3H), 0.77 – 0.72 (m, 1H). [0696] Ex-2 in the table below was 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. [0697] Example 3: (2S,4R)-1-((2S)-2-(2-((3S)-9-(((1R)-1-(((4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-8-(6-methyl-5-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)-1-oxa-9-azaspiro[5.5]undecan-3-yl)acetamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Ex-3)

[0698] Step A: Tert-butyl 3-(2-(((R)-2,2-difluoro-1-(((S)-3-(2-methoxy-2-oxoethyl)-1-oxa- 9-azaspiro[5.5]undecan-9-yl)methyl)cyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H- pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [0699] To a solution of tert-butyl 3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-14) (30 mg, 0.040 mmol) and methyl 2-((S)-9-(((R)-2,2-difluoro-1-(hydroxymethyl)cyclopropyl)methyl)-1- oxa-9-azaspiro[5.5]undecan-3-yl)acetate (Int-39) (20.63 mg, 0.059 mmol) in THF (1 mL) was added NaH (7.92 mg, 0.198 mmol, 60% in mineral oil) at 0 °C under N₂ atmosphere. The reaction mixture was stirred at 0 °C for 30 min. LCMS showed starting material was consumed and desired peak was formed. The reaction solution was quenched with aq. NH₄Cl (0.5 mL), extracted with EtOAc (3 x 2 mL). The organic layer was washed with brine (1 mL), dried over Na₂SO₄, filtered and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by preparative TLC (SiO₂, Petroleum ether: Ethyl acetate= 1:1 ) to give tert-butyl 3-(2-(((R)-2,2-difluoro-1- (((S)-3-(2-methoxy-2-oxoethyl)-1-oxa-9-azaspiro[5.5]undecan-9- yl)methyl)cyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate. MS (ESI) [M+H]⁺: m/z 1025.4. [0700] Step B: 2-((3S)-9-(((1R)-1-(((4-(8-(tert-butoxycarbonyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2- yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)-1-oxa-9-azaspiro[5.5]undecan-3-yl)acetic acid [0701] To a solution of tert-butyl 3-(2-(((R)-2,2-difluoro-1-(((S)-3-(2-methoxy-2- oxoethyl)-1-oxa-9-azaspiro[5.5]undecan-9-yl)methyl)cyclopropyl)methoxy)-8-(6-methyl-1- (tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (25 mg, 0.024 mmol) in THF:MeOH:H₂O=1:1:1 (0.5 mL) was added lithium hydroxide monohydrate (5 mg, 0.119 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 1 h. LCMS showed starting material was consumed and desired peak was formed. The reaction solution was acidified to pH 7 with HCl (1 M in H₂O), extracted with EtOAc (3 x 1 mL), washed with brine (0.5 mL), dried over Na₂SO₄, filtered and the solvent was evaporated under reduced pressure to give the crude 2-((3S)-9-(((1R)-1-(((4-(8-(tert-butoxycarbonyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2- yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)-1-oxa-9-azaspiro[5.5]undecan-3-yl)acetic acid. MS (ESI) [M+H]⁺: m/z 1011.4. [0702] Step C: Tert-butyl 3-(2-(((R)-2,2-difluoro-1-(((S)-3-(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)-1-oxa-9-azaspiro[5.5]undecan-9-yl)methyl)cyclopropyl)methoxy)-8- (6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate [0703] To a solution of 2-((3S)-9-(((1R)-1-(((4-(8-(tert-butoxycarbonyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2- yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)-1-oxa-9-azaspiro[5.5]undecan-3-yl)acetic acid (25 mg, 0.025 mmol) in DMF (0.3 mL) was added PyBOP (19.30 mg, 0.037 mmol) at 20 °C and the reaction solution was stirred at 20 °C for 10 min. Then a solution of (2S,4R)- 1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (15.97 mg, 0.037 mmol) and DIEA (8.64 μL, 0.049 mmol) in DMF (0.3 mL) was added to the reaction. The reaction mixture was stirred at 20 °C for 1 h. LCMS showed starting material was consumed and desired peak was formed. The reaction solution was diluted with EtOAc (3 mL), washed with water (2 x 1 mL). The organic layer was washed with brine (1 mL), dried over Na₂SO₄, filtered and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by preparative TLC (SiO₂, Ethyl acetate:MeOH=10:1) to give tert-butyl 3-(2-(((R)- 2,2-difluoro-1-(((S)-3-(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)-1- oxa-9-azaspiro[5.5]undecan-9-yl)methyl)cyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro- 2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. MS (ESI) [M/2+H]⁺: m/z 712.7. [0704] Step D: (2S,4R)-1-((2S)-2-(2-((3S)-9-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3- yl)-8-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-2-yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)-1-oxa-9- azaspiro[5.5]undecan-3-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Ex-3) [0705] To a solution of tert-butyl 3-(2-(((R)-2,2-difluoro-1-(((S)-3-(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)-1-oxa-9-azaspiro[5.5]undecan-9- yl)methyl)cyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (20 mg, 0.014 mmol) in DCM (0.3 mL) was added TFA (0.1 mL, 1.298 mmol) at 20 °C. The reaction mixture was stirred at 20 °C for 2 h. LCMS showed starting material was consumed and desired peak was formed. The reaction solution was removed by nitrogen flow to give the crude product. The crude product was purified by reverse preparative HPLC (Column: Boston Prime C18150 * 30 mm * 5 um; Condition: Water (0.05% NH₃H₂O+10 mM NH₄HCO₃)-ACN; Begin B: 5; End B: 80; Gradient Time (min): 10; 100% B Hold Time: 2; Flow Rate (mL/min): 25; Injections: 1) to give (2S,4R)-1-((2S)-2-(2-((3S)-9-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-(6- methyl-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2- yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)-1-oxa-9-azaspiro[5.5]undecan-3- yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Ex-3). MS (ESI) [M+H]⁺: m/z 1239.4. ¹H NMR (400MHz, CD₃OD) δ 8.87 (s, 1H), 8.68 (d, J=5.6 Hz, 1H), 7.81 (d, J=5.7 Hz, 1H), 7.73 (s, 1H), 7.44-7.47 (m, 2H), 7.38-7.44 (m, 3H), 4.49-4.65 (m, 8H), 4.29-4.37 (m, 2H), 3.90 (br d, J=10.8 Hz, 1H), 3.79 (dd, J=11.0, 3.8 Hz, 1H), 3.70 (br d, J=13.5 Hz, 1H), 3.61 (br s, 2H), 2.80 (br s, 1H), 2.73 (br s, 3H), 2.54 (br s, 1H), 2.47 (s, 3H), 2.36-2.44 (m, 2H), 2.18- 2.24 (m, 2H), 2.14 (br d, J=6.8 Hz, 2H), 2.02-2.11 (m, 2H), 1.92 (br d, J=11.0 Hz, 1H), 1.79 (br s, 4H), 1.56-1.66 (m, 2H), 1.42-1.52 (m, 2H), 1.26-1.41 (m, 8H), 1.03 (s, 9H). [0706] Ex-4 & 5 in the table below were synthesized via a similar route as described in the above synthesis of Ex-3 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.

[0707] Example 6: (2S,4R)-1-((2S)-2-(4-(2-(1-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan- 3-yl)-8-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-2-yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)piperidin-4-yl)ethyl)-1H- 1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Ex-6)

[0708] Step A: Tert-butyl 3-(2-(((R)-2,2-difluoro-1-((4-(4-(triisopropylsilyl)but-3-yn-1- yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)- 5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [0709] To a solution of tert-butyl 3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-14) (81.0 mg, 0.107 mmol), (R)-(2,2-difluoro-1-((4-(4-(triisopropylsilyl)but-3-yn-1-yl)piperidin-1- yl)methyl)cyclopropyl)methanol (Int-44) (80 mg, 0.192 mmol) in THF (1336 μL) at r.t. was added NaH (21.37 mg, 0.534 mmol). The reaction mixture was stirred at the same temperature for 1 h. Upon completion by LCMS, the reaction mixture was quenched with water and extracted with EtOAc (3x, 20.0 mL). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under vacuum. The crude was purified by silica gel chromatography (0-70% EtOAc/hexanes) to give tert-butyl 3-(2-(((R)-2,2-difluoro-1-((4-(4- (triisopropylsilyl)but-3-yn-1-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-8-(6-methyl-1- (tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (83.0 mg) as a colorless oil. ESI-MS m/z calc’d for C₅₇H₇₅F₅N₈O₄SSi [M+H]⁺: 1092; found: 1092. [0710] Step B: Tert-butyl 3-(2-(((R)-1-((4-(but-3-yn-1-yl)piperidin-1-yl)methyl)-2,2- difluorocyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)- 1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [0711] To tert-butyl 3-(2-(((R)-2,2-difluoro-1-((4-(4-(triisopropylsilyl)but-3-yn-1- yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)- 5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (83.0 mg, 0.076 mmol) in THF (1901 μL) was added 1.0 M TBAF in THF (133 μL, 0.133 mmol) at r.t. The reaction mixture was stirred at the same temperature overnight. Water was added, and the resulting mixture was extracted with EtOAc (3x, 10 mL). The combined organic layers were washed with brine, dried over ^MgSO ₄ ^{, filtered and concentrated under vacuum. The crude was purified by silica gel} chromatography (0-60% 3 : 1 EtOAc :EtOH mixture/hexanes) to give tert-butyl 3-(2-(((R)- 1-((4-(but-3-yn-1-yl)piperidin-1-yl)methyl)-2,2-difluorocyclopropyl)methoxy)-8-(6-methyl- 1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)- 1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (70.0 mg) as a colorless oil. ESI-MS m/z calc’d for C₄₈H₅₅F₅N₈O₄S [M+H]⁺: 935; found: 935. [0712] Step C: Tert-butyl 3-(2-(((R)-2,2-difluoro-1-((4-(2-(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)ethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-8-(6-methyl-1- (tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [0713] To a solution of tert-butyl 3-(2-(((R)-1-((4-(but-3-yn-1-yl)piperidin-1-yl)methyl)- 2,2-difluorocyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)- 1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (70.0 mg, 0.075 mmol) in DCM (1497 μL) was added (2S,4R)-1-((S)-2-azido-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Int-31) (41.0 mg, 0.090 mmol), tetrakis(acetonitrile)copper(I) hexafluorophosphate (55.8 mg, 0.150 mmol) and DIPEA (78 μL, 0.449 mmol) at r.t. The reaction mixture was stirred at the same temperature overnight before being diluted with DCM and washed with water. The organic layer was dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by reverse-phase preparative HPLC (Waters XBridge C18, MeCN/H2O with pH 10 NH₄OH modifier) and lyophilized to give tert-butyl 3-(2-(((R)-2,2-difluoro-1-((4-(2-(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)ethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-8-(6-methyl-1- (tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (59.0 mg) as a white powder. ESI-MS m/z calc’d for C₇₀H₈₃F₅N₁₄O₇S₂ [(M+2H)/2]²⁺: 696; found: 696. [0714] Step D: (2S,4R)-1-((2S)-2-(4-(2-(1-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3- yl)-8-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-2-yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)piperidin-4-yl)ethyl)-1H- 1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Ex-6) [0715] To tert-butyl 3-(2-(((R)-2,2-difluoro-1-((4-(2-(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)ethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-8-(6-methyl-1- (tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (59.0 mg, 0.042 mmol) in DCM (1000 μL) was added TFA (200 μL, 2.60 mmol), and the reaction mixture was stirred at r.t. for 1 h before diluted with 3 : 1 CHCl₃ : iPrOH mixture. The mixture was washed with sat aqueous NaHCO₃. The aqueous layer was extracted with the same CHCl₃ : iPrOH mixture (3x). The combined organic layers were dried over MgSO₄, filtered and concentrated under vacuum. The residue was purified by reverse-phase preparative HPLC (Waters XBridge C18, MeCN/H2O with pH 10 NH₄OH modifier) and lyophilized to give (2S,4R)-1-((2S)-2-(4-(2-(1-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-(6-methyl-5- (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2- yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-1- yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Ex-6) (24.0 mg) as a white powder. MS m/z calc’d for C₆₀H₆₇F₅N₁₄O₄S₂ [M+H]⁺: 1207; found: 1207. ¹H NMR (500 MHz, CD₃OD) δ 8.89 (d, J = 2.9 Hz, 1H), 8.71 (dd, J = 5.7, 3.5 Hz, 1H), 8.04 (s, 1H), 7.82 (d, J = 5.7 Hz, 1H), 7.75 (s, 1H), 7.53 – 7.42 (m, 5H), 5.51 (s, 1H), 4.66 – 4.44 (m, 5H),4.43 – 4.22 (m, 3H), 3.93 (dd, J = 11.0, 3.7 Hz, 1H), 3.80 – 3.66 (m, 3H), 3.61 (s, 2H), 2.94 – 2.82 (m, 2H), 2.75 (s, 4H), 2.68 (q, J = 7.5 Hz, 2H), 2.49 (d, J = 1.9 Hz, 3H), 2.45 – 2.37 (m, 1H),2.28 – 2.21 (m, 1H), 2.15 – 2.07 (m, 1H), 1.98 (d, J = 11.2 Hz, 1H), 1.83 (d, J = 30.2 Hz, 5H), 1.64 (s, 3H), 1.52 (s, 2H), 1.33 (d, J = 20.9 Hz, 2H), 1.20 (s, 1H), 1.07 (d, J = 9.7 Hz, 10H). [0716] Ex-7 to 12 in the table below were synthesized via a similar route as described in the above synthesis of Ex-6 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. [0717] Example 13: (2S,4R)-1-((2S)-2-(4-(2-(1-(((1R)-1-(((4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-8-(5-ethynyl-6-fluoro-1H-benzo[f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)- N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2- carboxamide (Ex-13)

[0718] Step A: Tert-butyl 3-(2-(((R)-2,2-difluoro-1-((4-(4-(trimethylsilyl)but-3-yn-1- yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-8-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)- 5-((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [0719] To a solution of tert-butyl 3-(8-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5- ((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)-2- (methylsulfinyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (Int-17) (400 mg, 0.440 mmol) and (R)-(2,2-difluoro-1-((4-(4- (trimethylsilyl)but-3-yn-1-yl)piperidin-1-yl)methyl)cyclopropyl)methanol (Int-48) (174 mg, 0.528 mmol) in MeCN (4 mL) was added TMP (622 mg, 4.40 mmol) at 25 °C under N₂ atmosphere. The mixture was stirred at 110 °C for 32 h or 16 h (MeCN was evaporated during this period). LCMS showed the starting material was consumed and desired MS was found. The mixture was evaporated under reduced pressure. The residue was purified by preparative TLC (SiO₂, CH₂Cl₂ : MeOH = 10 : 1) to give tert-butyl 3-(2-(((R)-2,2-difluoro- 1-((4-(4-(trimethylsilyl)but-3-yn-1-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-8-(6- fluoro-1-(tetrahydro-2H-pyran-2-yl)-5-((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate. MS (ESI) [M/2+H]⁺: m/z 587.7. [0720] Step B: Tert-butyl 3-(2-(((R)-1-((4-(but-3-yn-1-yl)piperidin-1-yl)methyl)-2,2- difluorocyclopropyl)methoxy)-8-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5- ((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [0721] To a solution of tert-butyl 3-(2-(((R)-2,2-difluoro-1-((4-(4-(trimethylsilyl)but-3-yn- 1-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-8-(6-fluoro-1-(tetrahydro-2H-pyran-2- yl)-5-((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (177 mg, 0.151 mmol) in MeOH (2 mL) was added K₂CO₃ (41.7 mg, 0.302 mmol) at 25 °C. The mixture was stirred at 25 °C for 4 h. LCMS showed the starting material was consumed and the desired MS was found. The solvent was removed under reduced pressure. The residue was purified by pre-TLC (SiO₂, CH₂Cl₂: MeOH = 10 : 1) to give tert-butyl 3-(2-(((R)-1-((4-(but-3-yn-1- yl)piperidin-1-yl)methyl)-2,2-difluorocyclopropyl)methoxy)-8-(6-fluoro-1-(tetrahydro-2H- pyran-2-yl)-5-((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate. MS (ESI) [M/2+H]⁺: m/z 551.5. [0722] Step C: Tert-butyl 3-(2-(((R)-1-((4-(2-(1-((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)-1H-1,2,3-triazol-4-yl)ethyl)piperidin-1-yl)methyl)-2,2- difluorocyclopropyl)methoxy)-8-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5- ((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [0723] To a solution of tert-butyl 3-(2-(((R)-1-((4-(but-3-yn-1-yl)piperidin-1-yl)methyl)- 2,2-difluorocyclopropyl)methoxy)-8-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5- ((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (160 mg, 0.122 mmol) in CH₂Cl₂ (2 mL) was added (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl- 1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide (Int-33) (57.3 mg, 0.122 mmol), Cu(CH₃CN)₄PF₆ (68.2 mg, 0.183 mmol) and DIEA (0.139 mL, 0.793 mmol) at 25 °C under N₂ atmosphere. The mixture was stirred at 40 °C for 2 h or 16 h. LCMS showed the starting material was consumed and the desired MS was found. The mixture was concentrated in vacuo to give crude tert-butyl 3-(2-(((R)-1-((4-(2-(1-((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)-1H-1,2,3-triazol-4-yl)ethyl)piperidin-1- yl)methyl)-2,2-difluorocyclopropyl)methoxy)-8-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5- ((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. MS (ESI) [M/2+H]⁺: m/z 786.3. [0724] Step D: (2S,4R)-1-((2S)-2-(4-(2-(1-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3- yl)-8-(6-fluoro-5-((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)- N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2- carboxamide [0725] To a solution of tert-butyl 3-(2-(((R)-1-((4-(2-(1-((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)-1H-1,2,3-triazol-4-yl)ethyl)piperidin-1-yl)methyl)-2,2- difluorocyclopropyl)methoxy)-8-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5- ((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (192 mg, 0.122 mmol) in IPA (2 mL) was added HCl/dioxane (2 mL) (2 M HCl in dioxane) at 25 °C under N₂ atmosphere. The mixture was stirred at 25 °C for 1 h. LCMS showed starting material was consumed and desired MS was formed. The mixture was concentrated in vacuum, and the residue was basified to pH 9 by sat. aq. NaHCO₃, extracted with CH₂Cl₂ (2 mL* 3), dried over Na₂SO₄, filtered and the solvent was evaporated under reduced pressure to give the crude product (2S,4R)-1-((2S)-2-(4-(2-(1-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)- 8-(6-fluoro-5-((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)- N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2- carboxamide. MS (ESI) [M/2+H]⁺: m/z 694.1. [0726] Step E: (2S,4R)-1-((2S)-2-(4-(2-(1-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3- yl)-8-(5-ethynyl-6-fluoro-1H-benzo[f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin- 2-yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-1- yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4- hydroxypyrrolidine-2-carboxamide (Ex-13) [0727] To a solution of (2S,4R)-1-((2S)-2-(4-(2-(1-(((1R)-1-(((4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-8-(6-fluoro-5-((triisopropylsilyl)ethynyl)-1H- benzo[f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)- N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2- carboxamide (169 mg, 0.122 mmol) in DMF (2 mL) was added CsF (370 mg, 2.437 mmol) at 25 °C. The mixture was stirred at 25 °C for 16 h. LCMS showed the starting material was consumed and desired MS was found. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by reverse preparative HPLC (Column: WEPURE XP-C1810 u 40 * 150 mm; Condition: Water (0.05% NH₃·H₂O +10 mM NH₄HCO₃) - ACN; Begin B--End B: 59--89; Gradient Time (min): 11; 100% B Hold Time (min): 3 ; Flow Rate (mL/min): 50) to give (2S,4R)-1-((2S)-2-(4-(2-(1-(((1R)-1-(((4- (3,8-diazabicyclo[3.2.1]octan-3-yl)-8-(5-ethynyl-6-fluoro-1H-benzo[f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)- N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2- carboxamide (Ex-13). MS (ESI) [M+H]⁺: m/z 616.0. ¹H NMR (400MHz, CD₃OD) δ 8.72 - 8.68 (m, 1H), 8.35 (s, 1H), 8.22 (dd, J = 6.0, 9.2 Hz, 1H), 7.87 (d, J = 5.2 Hz, 1H), 7.86 - 7.82 (m, 1H), 7.79 (d, J = 3.6 Hz, 1H), 7.53 - 7.50 (m, 1H), 7.49 - 7.44 (m, 2H), 7.43 - 7.40 (m, 2H), 7.40 - 7.36 (m, 1H), 6.31 - 6.28 (m, 1H), 5.26 (d, J = 10.3 Hz, 1H), 5.06 (t, J = 6.0 Hz, 1H), 4.63 (br s, 1H), 4.60 - 4.54 (m, 2H), 4.54 - 4.44 (m, 2H), 4.44 - 4.36 (m, 1H), 4.17 - 4.13 (m, 2H), 3.93 - 3.88 (m, 1H), 3.83 (d, J = 6.0 Hz, 2H), 3.82 - 3.73 (m, 2H), 3.67 - 3.59 (m, 3H), 2.86 (br t, J = 13.7 Hz, 2H), 2.75 (br d, J = 12.8 Hz, 1H), 2.70 - 2.64 (m, 2H), 2.53 (td, J = 6.6, 10.0 Hz, 1H), 2.39 (br d, J = 13.1 Hz, 1H), 2.21 (br dd, J = 7.7, 13.4 Hz, 1H), 2.05 - 1.95 (m, 2H), 1.94 - 1.86 (m, 2H), 1.84 (br s, 1H), 1.81 - 1.75 (m, 2H), 1.75 - 1.69 (m, 1H), 1.68 - 1.54 (m, 4H), 1.54 - 1.46 (m, 2H), 1.33 (t, J = 7.2 Hz, 4H), 1.26 - 1.15 (m, 2H), 1.11 (br d, J = 6.6 Hz, 3H), 0.74 (d, J = 6.7 Hz, 3H). [0728] Ex-14 in the table below was synthesized via a similar route as described in the above synthesis of Ex-13 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. [0729] Example 15: (2S,4R)-1-((2-(7-(((1R)-1-(((8-(5-acetyl-1H-thieno[3,2-f]indazol-4- yl)-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2- yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)acetyl)-L- valyl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide (Ex-15) [0730] Step A: 2-(7-(((1R)-1-(((4-(8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-(5-((triisopropylsilyl)ethynyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2- f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)acetic acid [0731] To a solution of tert-butyl 3-(2-(methylsulfinyl)-8-(5-((triisopropylsilyl)ethynyl)-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-16) (50 mg, 53.1 μmol) and (R)-2-(7-((2,2-difluoro-1-(hydroxymethyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2- yl)acetic acid (Int-56A) (32.2 mg, 106 μmol) was added 0.2 mL MeCN followed by 2,2,6,6-tetramethylpiperidine (375 mg, 2.65 mmol) then heated to 120 ºC for 1 h. To the reaction was added water, pH was adjusted to pH 4 with 1 M HCl and extracted with 3x DCM. The organic layer was then dried in vacuo and the residue was purified by silica gel chromatography eluting with gradient of 0-40% DCM/MeOH to give 52 mg 2-(7-(((1R)-1- (((4-(8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-(5- ((triisopropylsilyl)ethynyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)acetic acid. [0732] Step B: Tert-butyl 3-(2-(((R)-2,2-difluoro-1-((2-(2-(((S)-1-((2S,4R)-4-hydroxy-2- (((R)-2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3- methyl-1-oxobutan-2-yl)amino)-2-oxoethyl)-7-azaspiro[3.5]nonan-7- yl)methyl)cyclopropyl)methoxy)-8-(5-((triisopropylsilyl)ethynyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [0733] To 2-(7-(((1R)-1-(((4-(8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 8-(5-((triisopropylsilyl)ethynyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2- f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)acetic acid (20 mg, 16.9 μmol), (2S,4R)-1-(L-valyl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide (11.3 mg, 25.4 μmol) and 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (12.9 mg, 33.9 μmol) in 0.1 mL acetonitrile was added N-ethyl-N- isopropylpropan-2-amine (13.1 mg, 102 μmol) and stirred at 25 ºC overnight. Water and DCM were added and the aqueous layer was extracted three times with DCM then dried and concentrated in vacuo and purified by flash chromatography using gradient of 0-40% MeOH/DCM to give 11.2 mg, tert-butyl 3-(2-(((R)-2,2-difluoro-1-((2-(2-(((S)-1-((2S,4R)-4- hydroxy-2-(((R)-2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin- 1-yl)-3-methyl-1-oxobutan-2-yl)amino)-2-oxoethyl)-7-azaspiro[3.5]nonan-7- yl)methyl)cyclopropyl)methoxy)-8-(5-((triisopropylsilyl)ethynyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. [0734] Step C: Tert-butyl 3-(2-(((R)-2,2-difluoro-1-((2-(2-(((S)-1-((2S,4R)-4-hydroxy-2- (((R)-2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3- methyl-1-oxobutan-2-yl)amino)-2-oxoethyl)-7-azaspiro[3.5]nonan-7- yl)methyl)cyclopropyl)methoxy)-8-(5-ethynyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [0735] To tert-butyl 3-(2-(((R)-2,2-difluoro-1-((2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-(((R)-2- hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1- oxobutan-2-yl)amino)-2-oxoethyl)-7-azaspiro[3.5]nonan-7- yl)methyl)cyclopropyl)methoxy)-8-(5-((triisopropylsilyl)ethynyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (11.2 mg, 6.96 μmol) in 0.1 mL THF was added TBAF (1 M, 2.73 mg, 10.4 μL) then stirred at r.t. for 2 h. Brine was added to the reaction followed by extraction with EtOAc. The organic layers were dried over with MgSO4, filtered and concentrated in vacuo. The crude was purified by silica gel chromatography eluting with 0-40%, MeOH/DCM to give 9.0 mg tert-butyl 3-(2-(((R)-2,2- difluoro-1-((2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-(((R)-2-hydroxy-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)amino)-2-oxoethyl)- 7-azaspiro[3.5]nonan-7-yl)methyl)cyclopropyl)methoxy)-8-(5-ethynyl-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. [0736] Step D: (2S,4R)-1-((2-(7-(((1R)-1-(((8-(5-acetyl-1H-thieno[3,2-f]indazol-4-yl)-4- (3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2- yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)acetyl)-L- valyl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide (Ex-15) [0737] To tert-butyl 3-(2-(((R)-2,2-difluoro-1-((2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-(((R)-2- hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1- oxobutan-2-yl)amino)-2-oxoethyl)-7-azaspiro[3.5]nonan-7- yl)methyl)cyclopropyl)methoxy)-8-(5-ethynyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (9.0 mg, 6.9 μmol) in 0.2 mL DCM was added TFA (2 mg, 106.7μmol) and stirred at r.t. for 2 h. The reaction mixture was diluted with 3:1 CHCl₃:iPrOH and washed with sat. aq. NaHCO₃. The aqueous layer was extracted with CHCl₃/iPrOH mixture (3x). The combined organic layers were dried over MgSO₄, filtered and concentrated in vacuo. The residue was purified by reverse-phase preparative HPLC (C18, MeCN/water with 7 mM NH₄OH modifier) and lyophilized to give (2S,4R)-1- ((2-(7-(((1R)-1-(((8-(5-acetyl-1H-thieno[3,2-f]indazol-4-yl)-4-(3,8- diazabicyclo[3.2.1]octan-3-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)acetyl)-L-valyl)-4-hydroxy-N-((R)- 2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Ex-15). [0738] Example 16 & 17: (2S,4R)-1-(2-(3-((1-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan- 3-yl)-8-(5-ethynyl-6-fluoro-1H-benzo[f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-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-16 & Ex-17)

[0739] Step A: Tert-butyl 3-(2-(((R)-1-((4-(((tert-butyldiphenylsilyl)oxy)methyl)piperidin- 1-yl)methyl)-2,2-difluorocyclopropyl)methoxy)-8-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)- 5-((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [0740] To a solution of tert-butyl 3-(8-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5- ((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)-2- (methylsulfonyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-18) (200 mg, 0.216 mmol) and (R)-(1-((4- (((tert-butyldiphenylsilyl)oxy)methyl)piperidin-1-yl)methyl)-2,2- difluorocyclopropyl)methanol (108 mg, 0.227 mmol) in THF (2 mL) was added sodium hydride (26.0 mg, 1.082 mmol) (60% in mineral oil) at 25 °C. The mixture was stirred at 25 °C for 1 h. LCMS showed starting material was consumed and desired peak was formed. The mixture was quenched with saturated NH₄Cl solution (4 mL), extracted with EtOAc (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 5% MeOH in DCM gradient @ 30 mL/min) to give tert-butyl 3-(2-(((R)-1-((4-(((tert-butyldiphenylsilyl)oxy)methyl)piperidin- 1-yl)methyl)-2,2-difluorocyclopropyl)methoxy)-8-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)- 5-((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. MS (ESI) [M/2+H]⁺: m/z 659.8. [0741] Step B: Tert-butyl 3-(2-(((R)-2,2-difluoro-1-((4-(hydroxymethyl)piperidin-1- yl)methyl)cyclopropyl)methoxy)-8-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5- ((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [0742] To a solution of tert-butyl 3-(2-(((R)-1-((4-(((tert- butyldiphenylsilyl)oxy)methyl)piperidin-1-yl)methyl)-2,2-difluorocyclopropyl)methoxy)-8- (6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5-((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (260 mg, 0.197 mmol) in MeOH (3 mL) was added ammonium fluoride (73.1 mg, 1.973 mmol) at 25 °C. The mixture was stirred at 50 °C for 15 h. LCMS showed starting material was consumed and desired peak was formed. The mixture was cooled, 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 DCM gradient @ 30 mL/min) to give tert-butyl 3- (2-(((R)-2,2-difluoro-1-((4-(hydroxymethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-8- (6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5-((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate. MS (ESI) [M+H]⁺: m/z 540.6. [0743] Step C: Tert-butyl 3-(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)-8-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5- ((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [0744] To a solution of tert-butyl 3-(2-(((R)-2,2-difluoro-1-((4-(hydroxymethyl)piperidin- 1-yl)methyl)cyclopropyl)methoxy)-8-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5- ((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (81 mg, 0.075 mmol) and (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoyl)- N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-29) (44.9 mg, 0.075 mmol) in toluene (0.2 mL) was added cyanomethylenetributylphosphorane (0.098 mL, 0.375 mmol) at 25 °C under N₂ atmosphere. The mixture was stirred at 110 °C for 3 h. LCMS showed starting material was consumed and desired peak was formed. The mixture was cooled and purified directly by preparative TLC (SiO₂, DCM: MeOH = 10:1) to give tert-butyl 3-(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)-8-(6-fluoro-1- (tetrahydro-2H-pyran-2-yl)-5-((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate. MS (ESI) [M+H]⁺: m/z 831.1. [0745] Step D: (3R,5S)-1-(2-(3-((1-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-(6- fluoro-5-((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-2-yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)piperidin-4- yl)methoxy)isoxazol-5-yl)-3-methylbutanoyl)-5-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-3-yl 2,2,2-trifluoroacetate [0746] A solution of tert-butyl 3-(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)-8-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5- ((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (55 mg, 0.033 mmol) in TFA (1 mL, 12.98 mmol) was stirred at 25 °C for 15 h. LCMS showed starting material was consumed and desired peak was formed. The solvent was evaporated under reduced pressure to give the crude product (3R,5S)-1-(2-(3-((1-(((1R)-1-(((4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-8-(6-fluoro-5-((triisopropylsilyl)ethynyl)-1H- benzo[f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)methoxy)isoxazol-5-yl)-3-methylbutanoyl)-5- ((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-3-yl 2,2,2-trifluoroacetate. MS (ESI) [M+H]⁺: m/z 1457.4. [0747] Step E: (2S,4R)-1-(2-(3-((1-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-(6- fluoro-5-((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-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 [0748] To a solution of (3R,5S)-1-(2-(3-((1-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3- yl)-8-(6-fluoro-5-((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)methoxy)isoxazol-5-yl)-3-methylbutanoyl)-5- ((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-3-yl 2,2,2-trifluoroacetate (36 mg, 0.025 mmol) in MeOH (0.5 mL) was added sodium bicarbonate (20.75 mg, 0.247 mmol) at 25 °C. The mixture was stirred at 25 °C for 1 h. LCMS showed starting material was consumed and desired peak was formed. The mixture was filtered and the solvent was evaporated under reduced pressure to give the crude product (2S,4R)-1-(2-(3-((1-(((1R)-1- (((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-(6-fluoro-5-((triisopropylsilyl)ethynyl)-1H- benzo[f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-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. MS (ESI) [M+H]⁺: m/z 1362.1. [0749] Step F: (2S,4R)-1-(2-(3-((1-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-(5- ethynyl-6-fluoro-1H-benzo[f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-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-16 & Ex-17) [0750] To a solution of (2S,4R)-1-(2-(3-((1-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3- yl)-8-(6-fluoro-5-((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-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 (20 mg, 0.015 mmol) in DMF (0.5 mL) was added CsF (22.31 mg, 0.147 mmol) 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 mixture was filtered and the solvent was purified directly by reverse preparative HPLC (Column: Boston Prime C18150 * 30 mm * 5 um; Condition: Water (0.05% NH₃·H₂O + 10 mM NH₄HCO₃)-ACN; Begin B--End B: 51--81; Gradient Time (min): 10; 100% B Hold Time (min): 2; FlowRate (mL/min): 25) to give (2S,4R)-1-(2-(3- ((1-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-(5-ethynyl-6-fluoro-1H- benzo[f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-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-16 & Ex-17). MS (ESI) [M+H]⁺: m/z 1205.5. [0751] Ex-16: ¹H NMR (400MHz, CD₃OD) δ 8.79-8.92 (m, 1H), 8.69 (br d, J=5.6 Hz, 1H), 8.34 (s, 1H), 8.21 (br t, J=6.7 Hz, 1H), 7.87 (br dd, J=5.4, 3.0 Hz, 1H), 7.79 (s, 1H), 7.24-7.51 (m, 6H), 5.74-6.01 (m, 1H), 4.58-4.63 (m, 3H), 4.46-4.54 (m, 3H), 4.39 (br d, J=5.7 Hz, 2H), 4.16 (br d, J=10.1 Hz, 1H), 3.85-3.96 (m, 2H), 3.75 (br d, J=9.3 Hz, 2H), 3.60-3.68 (m, 4H), 2.72-2.92 (m, 3H), 2.33-2.54 (m, 6H), 2.15-2.25 (m, 2H), 1.98-2.11 (m, 2H), 1.90 (br s, 2H), 1.76-1.80 (m, 2H), 1.60 (br s, 2H), 1.43-1.50 (m, 2H), 1.31 (br s, 2H), 1.01-1.07 (m, 3H), 0.89 (br dd, J=10.8, 6.4 Hz, 3H). MS (ESI) [M+H]⁺: m/z 1205.5. [0752] Ex-17: ¹H NMR (400MHz, CD₃OD) δ 8.81-8.89 (m, 1H), 8.68 (br d, J=5.5 Hz, 1H), 8.34 (s, 1H), 8.21 (br dd, J=9.2, 6.0 Hz, 1H), 7.83-7.92 (m, 1H), 7.79 (s, 1H), 7.31- 7.48 (m, 6H), 5.84-6.01 (m, 1H), 4.56-4.65 (m, 3H), 4.47-4.52 (m, 2H), 4.36-4.46 (m, 3H), 4.12-4.19 (m, 1H), 3.86-3.94 (m, 2H), 3.70-3.79 (m, 2H), 3.61 (br d, J=18.4 Hz, 4H), 2.73- 2.93 (m, 3H), 2.33-2.49 (m, 6H), 2.13-2.22 (m, 2H), 2.01-2.11 (m, 2H), 1.87-1.95 (m, 2H), 1.77 (br s, 2H), 1.69 (br d, J=10.3 Hz, 2H), 1.60 (br d, J=3.1 Hz, 2H), 1.33 (br s, 2H), 1.01- 1.06 (m, 3H), 0.86-0.90 (m, 3H). [0753] Example 18 & 19: (2S,4R)-1-(2-(3-(2-(7-(((1R)-1-(((4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-8-(5-ethynyl-1H-thieno[3,2-f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)ethoxy)isoxazol-5-yl)-3- methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Ex-18 & Ex-19)

[0754] Step A: Tert-butyl 3-(2-(((R)-2,2-difluoro-1-((2-(2-methoxy-2-oxoethyl)-7- azaspiro[3.5]nonan-7-yl)methyl)cyclopropyl)methoxy)-8-(5-((triisopropylsilyl)ethynyl)-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [0755] To a solution of tert-butyl 3-(2-(methylsulfinyl)-8-(5-((triisopropylsilyl)ethynyl)-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-16) (200 mg, 0.212 mmol) in MeCN (0.5 mL) was added methyl (R)-2-(7-((2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)acetate (Int-41) (88 mg, 0.276 mmol) and TMP (300 mg, 2.122 mmol) at 25 °C and stirred at 100 °C for 20 h (MeCN was evaporated during this period). Then the reaction was monitored by LCMS that showed desired MS was found and the starting material was disappeared. The residue was purified by preparative TLC (SiO₂, petroleum ether:ethyl acetate =2:1) to give tert- butyl 3-(2-(((R)-2,2-difluoro-1-((2-(2-methoxy-2-oxoethyl)-7-azaspiro[3.5]nonan-7- yl)methyl)cyclopropyl)methoxy)-8-(5-((triisopropylsilyl)ethynyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. MS (ESI) [M+H]⁺: m/z 1196.1. [0756] Step B: Tert-butyl 3-(2-(((R)-2,2-difluoro-1-((2-(2-hydroxyethyl)-7- azaspiro[3.5]nonan-7-yl)methyl)cyclopropyl)methoxy)-8-(5-((triisopropylsilyl)ethynyl)-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [0757] To a solution of tert-butyl 3-(2-(((R)-2,2-difluoro-1-((2-(2-methoxy-2-oxoethyl)-7- azaspiro[3.5]nonan-7-yl)methyl)cyclopropyl)methoxy)-8-(5-((triisopropylsilyl)ethynyl)-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (180 mg, 0.151 mmol) in THF (3 mL) was added dropwise LiAlH₄ (1 M, 0.120 mL, 0.301 mmol) at 0 °C under N₂ atmosphere. The mixture was stirred at 0 °C for 1 h. LCMS showed the reaction is complete. The reaction mixture was quenched with Na₂SO₄·10H₂O until no gas generated. The mixture was stirred at 25 °C for 0.5 h. The mixture was filtered and the filter cake was washed with EtOAc (5 mL). The filtrate was dried over Na₂SO₄, filtered and the solvent was evaporated under reduced pressure. The residue was purified by preparative TLC (SiO₂, petroleum ether:ethyl acetate =1:1) to give tert-butyl 3-(2-(((R)-2,2-difluoro-1-((2-(2- hydroxyethyl)-7-azaspiro[3.5]nonan-7-yl)methyl)cyclopropyl)methoxy)-8-(5- ((triisopropylsilyl)ethynyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate. MS (ESI) [M+H]⁺: m/z 1168.0. [0758] Step C: Tert-butyl 3-(2-(((1R)-1-((2-(2-((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)ethyl)-7-azaspiro[3.5]nonan-7-yl)methyl)-2,2- difluorocyclopropyl)methoxy)-8-(5-((triisopropylsilyl)ethynyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [0759] To a solution of tert-butyl 3-(2-(((R)-2,2-difluoro-1-((2-(2-hydroxyethyl)-7- azaspiro[3.5]nonan-7-yl)methyl)cyclopropyl)methoxy)-8-(5-((triisopropylsilyl)ethynyl)-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50 mg, 0.043 mmol) in toluene (1 mL) was added (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(3- hydroxyisoxazol-5-yl)-3-methylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Int-29) (38.5 mg, 0.064 mmol) and CMBP (0.112 mL, 0.428 mmol) at 25 °C under N₂ atmosphere. The mixture was stirred at 100 °C for 3 h. LCMS showed the reaction is complete. The mixture was evaporated under reduced pressure, and the residue was purified by preparative TLC (SiO₂, petroleum ether:ethyl acetate =1:1) to give tert- butyl 3-(2-(((1R)-1-((2-(2-((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)ethyl)-7-azaspiro[3.5]nonan-7-yl)methyl)-2,2-difluorocyclopropyl)methoxy)-8-(5- ((triisopropylsilyl)ethynyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate. MS (ESI) [M/2+H]⁺: m/z 875.2. [0760] Step D: (2S,4R)-1-(2-(3-(2-(7-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8- (5-((triisopropylsilyl)ethynyl)-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-2-yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)-7-azaspiro[3.5]nonan-2- yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide [0761] A mixture of tert-butyl 3-(2-(((1R)-1-((2-(2-((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)ethyl)-7-azaspiro[3.5]nonan-7-yl)methyl)-2,2- difluorocyclopropyl)methoxy)-8-(5-((triisopropylsilyl)ethynyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (60 mg, 0.034 mmol) and TFA (0.5 mL, 0.034 mmol) was stirred at 25 °C for 12 h or 16 h. LCMS showed the reaction is complete. The mixture was evaporated under reduced pressure to give the crude product (2S,4R)-1-(2-(3-(2-(7-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-(5- ((triisopropylsilyl)ethynyl)-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-2-yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)-7-azaspiro[3.5]nonan-2- yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide. MS (ESI) [M+H]⁺: m/z 1404.4. [0762] Step E: (2S,4R)-1-(2-(3-(2-(7-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8- (5-ethynyl-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2- yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)-7-azaspiro[3.5]nonan-2- yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Ex-18 & Ex-19) [0763] To a solution of (2S,4R)-1-(2-(3-(2-(7-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan- 3-yl)-8-(5-((triisopropylsilyl)ethynyl)-1H-thieno[3,2-f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)ethoxy)isoxazol-5-yl)-3- methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (48 mg, 0.034 mmol) in DMF (1 mL) was added CsF (51.9 mg, 0.342 mmol) at 25 °C. The mixture was stirred at 25 °C for 12 h or 16 h. LCMS showed the reaction is complete. The mixture was filtered and the solvent was evaporated under reduced pressure to give the crude product. The residue was purified by reverse preparative HPLC (Column: Boston Green ODS 150 * 30 mm * 5 um; Condition: water (0.2 % FA)-ACN; Begin B--End B: 20-- 50; Gradient Time (min): 10; 100% B Hold Time (min): 2; FlowRate (mL/min): 25) to give (2S,4R)-1-(2-(3-(2-(7-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-(5-ethynyl-1H- thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)ethoxy)isoxazol-5-yl)-3- methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Ex-22 & Ex-23). [0764] Ex-18: ¹H NMR (400MHz, CD₃OD) δ 8.93 - 8.82 (m, 1H), 8.73 (d, J = 5.6 Hz, 1H), 8.30 (s, 1H), 7.89 - 7.80 (m, 3H), 7.49 - 7.37 (m, 4H), 5.96 (s, 1H), 4.60 (br t, J = 7.9 Hz, 4H), 4.56 (br s, 3H), 4.45 - 4.31 (m, 3H), 4.23 (br s, 1H), 4.11 - 4.02 (m, 2H), 3.88 - 3.62 (m, 8H), 2.85 - 2.77 (m, 2H), 2.49 (s, 3H), 2.40 (br d, J = 2.6 Hz, 2H), 2.29 - 2.22 (m, 2H), 2.13 - 2.07 (m, 1H), 1.95 - 1.81 (m, 6H), 1.79 - 1.75 (m, 1H), 1.66 - 1.61 (m, 1H), 1.53 (br s, 1H), 1.46 - 1.32 (m, 6H), 1.07 (d, J = 6.7 Hz, 3H), 0.93 (d, J = 6.6 Hz, 3H), 0.82 - 0.62 (m, 1H). MS (ESI) [M+H]⁺: m/z 1248.0. [0765] Ex-19: ¹H NMR (400MHz, CD₃OD) δ 8.90 - 8.87 (m, 1H), 8.73 (d, J = 5.6 Hz, 1H), 8.29 (s, 1H), 7.88 - 7.81 (m, 3H), 7.46 (s, 4H), 5.99 (d, J = 2.7 Hz, 1H), 4.61 (br s, 2H), 4.59 - 4.48 (m, 5H), 4.47 - 4.37 (m, 3H), 4.35 - 4.17 (m, 2H), 4.13 - 4.08 (m, 2H), 3.91 (dd, J = 4.1, 10.7 Hz, 1H), 3.85 - 3.76 (m, 4H), 3.69 (br d, J = 9.9 Hz, 2H), 2.83 (d, J = 4.5 Hz, 2H), 2.49 (s, 3H), 2.42 - 2.36 (m, 3H), 2.23 (br s, 1H), 2.13 - 2.08 (m, 1H), 1.91 - 1.85 (m, 5H), 1.62 - 1.54 (m, 3H), 1.46 (br d, J = 4.8 Hz, 2H), 1.42 - 1.33 (m, 5H), 1.09 - 1.02 (m, 4H), 0.90 (d, J = 6.6 Hz, 3H). MS (ESI) [M+H]⁺: m/z 1248.0.

[0766] Ex- 20 & 21 in the table below were synthesized using a similar procedure as described in the synthesis of Ex-19 by making the appropriate substitutions for starting material, intermediates, and/or reagents. 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. [0767] Example 22: (2S,4R)-1-(2-(4-(((1-(((1S)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)- 8-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2- yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)piperidin-4-yl)methoxy)methyl)-1H-1,2,3- triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Ex-22) [0768] Step A: Tert-butyl 3-(2-(((S)-2,2-difluoro-1-((4-((prop-2-yn-1- yloxy)methyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H- pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [0769] Stock solutions were prepared as following: 4-((prop-2-yn-1- yloxy)methyl)piperidine: 250 μL of stock solution was prepared by dissolving 15.3 mg of 4-((prop-2-yn-1-yloxy)methyl)piperidine (0.1 mmol) in MeCN (0.4 M); tert-butyl 3-(2- (((S)-2,2-difluoro-1-(((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)-8-(6-methyl-1- (tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-21): 200 μL of stock solution was prepared by dissolving 35.8 mg of tert-butyl 3-(2-(((S)-2,2-difluoro-1- (((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran- 2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (0.04 mmol) in MeCN (0.2 M); TMP: 500 μL of stock solution was prepared by dissolving 42.2 μL of TMP (35.3 mg, 0.25 mmol) in MeCN (0.5 M). [0770] The stock solution of tert-butyl 3-(2-(((S)-2,2-difluoro-1- (((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran- 2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-21) (25 μL, 5.0 μmol) was transferred to a 1 mL micro-vial inserted in a 96-well aluminum block by a pipette, followed by the stock solutions of 4-((prop-2-yn-1-yloxy)methyl)piperidine (25 μL, 10.0 μmol) and TMP (30 μL, 15 μmol). The plate was sealed and agitated on a tumble stirrer at 65 ºC overnight. The reaction mixture was transferred to a 96 deep-well plate and the solvent was evaporated on a GeneVac. The residue was dissolved in DMSO (100 mL) and treated with SPE, the elute was concentrated to afford tert-butyl 3-(2-(((S)-2,2-difluoro-1-((4-((prop-2-yn-1- yloxy)methyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H- pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5.0 μmol), which was used in the next step without further purification. [M+H]+ Found: 952. [0771] Step B: Tert-butyl 3-(2-(((1S)-2,2-difluoro-1-((4-(((1-(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)methoxy)methyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-8-(6- methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate [0772] Stock solutions were prepared as following: tert-butyl 3-(2-(((S)-2,2-difluoro-1-((4- ((prop-2-yn-1-yloxy)methyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-8-(6-methyl-1- (tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: 100 μL of stock solution was prepared by dissolving 4.6 mg of tert-butyl 3-(2-(((S)-2,2-difluoro-1-((4-((prop-2-yn-1- yloxy)methyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H- pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5 μmol) in EtOH (0.05 M); (2S,4R)-1-((S)- 2-azido-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Int-31): 250 μL of stock solution was prepared by dissolving 24.7 mg of (2S,4R)-1-((S)-2-azido-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Int-31) in EtOH (0.2 M); sodium ascorbate/copper (II) sulfate: 400 μL of stock solution was prepared by dissolving 7.9 mg of sodium ascorbate (40 μmol) and 10.0 mg of CuSO₄.5H₂O (40 μmol) in water (0.1 M). [0773] The stock solution of (2S,4R)-1-((S)-2-azido-3,3-dimethylbutanoyl)-4-hydroxy-N- (4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-31) (25 μL, 5.0 μmol) was transferred into a well on a 96 deep-well plate by a pipette, followed by the stock solutions of tert-butyl 3-(2-(((S)-2,2-difluoro-1-((4-((prop-2-yn-1-yloxy)methyl)piperidin-1- yl)methyl)cyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (100 μL, 5.0 μmol) and sodium ascorbate/copper (II) sulfate (10 μL, 1.0 μmol). The plate was sealed by an Agilent PlateLoc thermal plate sealer and vibrated on a LabRam at 10 G/25 °C overnight. The solvents were evaporated in a GeneVac. The residue was dissolved in DMSO (100 μL) and treated with SPE, the elute was concentrated to afford tert-butyl 3-(2-(((1S)-2,2-difluoro-1-((4-(((1-(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)methoxy)methyl)piperidin-1- yl)methyl)cyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (5.0 μmol), which was used directly in the next step without further purification. [M+H]⁺ Found: 1408. [0774] Step C: (2S,4R)-1-(2-(4-(((1-(((1S)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-(6- methyl-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2- yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)piperidin-4-yl)methoxy)methyl)-1H-1,2,3- triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Ex-22) [0775] To the well on a 96 deep-well plate containing dried tert-butyl 3-(2-(((1S)-2,2- difluoro-1-((4-(((1-(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)methoxy)methyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-8-(6-methyl-1- (tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5.0 μmol) was added DCM (100 μL) and TFA (50 μL). The plate was sealed and vibrated on a LabRam at 10 G/25 °C for 5 hours. The resulting reaction mixture was neutralized by the addition of ammonia in MeOH (7 M, 93 μL). The solvents were evaporated in a GeneVac. The residue was dissolved in DMSO (100 μL) and purified by micro-isolation to afford (2S,4R)-1-(2-(4-(((1- (((1S)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-(6-methyl-5-(trifluoromethyl)-1H - indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)methoxy)methyl)-1H-1,2,3-triazol-1-yl)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Ex-22). [M+H]⁺ Found:1225. [0776] Ex-23 in the table below was synthesized using a similar procedure as described in the synthesis of Ex-22 by making the appropriate substitutions for starting material, intermediates, and/or reagents. 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. [0777] Example 24: (2S,4R)-1-((2R)-2-(3-((1-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan- 3-yl)-8-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-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-24) [0778] Step A: Tert-butyl 3-(2-(((R)-2,2-difluoro-1-((4-(((5-((R)-1-((2S,4R)-4-hydroxy-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)cyclopropyl)methoxy)-8-(6-methyl-1- (tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [0779] To a stirred solution of triphenylphosphine (7.76 mg, 0.030 mmol, 1.8 eq.) in THF (110 μL) was added DIAD (5.75 μL, 0.030 mmol, 1.8 eq.) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 30 min. To the reaction mixture was then added a solution of (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((R)-2-(3-hydroxyisoxazol- 5-yl)-3-methylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (11.81 mg, 0.020 mmol, 1.2 eq.) in THF (110 μL) at 0 °C, after which a white precipitate formed. The resulting mixture was stirred for 10 minutes, then a solution of tert-butyl 3-(2- (((R)-2,2-difluoro-1-((4-(hydroxymethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-8-(6- methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (15 mg, 0.016 mmol, 1.0 eq.) in THF (110 μL) was added. After 5 minutes the ice bath was removed and the reaction was warmed to room temperature and stirred for ~4 h with LCMS monitoring. Next, TBAF (49.3 μL, 0.049 mmol, 3 eq.) was added and after 30 minutes, the deprotected product was observed in LCMS. The reaction mixture was quenched with 10 mL of NH₄Cl solution and extracting with EtOAc (3x, 25 mL total volume). The combined organic fractions were washed with brine (10 mL), dried over anhydrous Na₂SO₄ and filtered. The product was purified on a RediSep Gold 4 gram silica column, eluting with 20-100% 3:1 EtOAc:EtOH to give a 2 component product by TLC. The isolate was dissolved in a small volume (< 1mL) of DCM, then added a small volume of hexanes to ~1/1 ratio. A solid began to come out of solution, which was filtered and checked with TLC of the filtrate, which only showed target spot that corresponded to tert- butyl 3-(2-(((R)-2,2-difluoro-1-((4-(((5-((R)-1-((2S,4R)-4-hydroxy-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)cyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H- pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. ESI-MS m/z calc’d for C₆₉H₇₉F₅N₁₂O₉S₂ [M+2]/2⁺: 697; found: 697. [0780] Step B: (2S,4R)-1-((2R)-2-(3-((1-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)- 8-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-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-24) [0781] Tert-butyl 3-(2-(((R)-2,2-difluoro-1-((4-(((5-((R)-1-((2S,4R)-4-hydroxy-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)cyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro- 2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (6.6 mg, 4.78 μmol) was dissolved in 1,4-dioxane (100 μL). Then 4 M HCl (150 μL, 0.600 mmol) was added to dioxane and the mixture was stirred for 2 h with LCMS monitoring, then evaporated. Crude was dissolved in 4:1 CHCl₃:iPrOH and washed with aqueous NaHCO₃. The aqueous phase was extracted with additional 4:1 CHCl₃:iPrOH, then the combined organics were dried over MgSO₄, filtered and evaporated, and pumped in vacuum overnight. The product was purified on a Biotage 5.5 gram KP-NH silica column, eluting with 80-100% 3:1 EtOAc:EtOH in hexanes. A broad minor and broad major peak were seen; and the product corresponding to the major peak was collected and evaporated. The isolate was took up in acetonitrile (< 1 mL) and was added to a tared, barcoded vial. It was diluted with Optima grade water (< 1 mL), frozen and lyophilized overnight to give (2S,4R)-1-((2R)-2-(3-((1- (((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-(6-methyl-5-(trifluoromethyl)-1H- indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-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-24). ESI-MS m/z calc’d for C₅₉H₆₃F₅N₁₂O₆S₂ [M+2]/2⁺: 598; found: 598. [0782] Ex-25 in the table below was synthesized using a similar procedure as described in the synthesis of Ex-24 by making the appropriate substitutions for starting material, intermediates, and/or reagents. 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. [0783] Example 26: (2S,4R)-1-((2S)-2-(2-((3S)-9-(((1R)-1-(((4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-8-(5-ethynyl-1H-thieno[3,2-f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)-1-oxa-9-azaspiro[5.5]undecan-3-yl)acetamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Ex-26)

[0784] Step A: Tert-butyl 3-(2-(((R)-2,2-difluoro-1-(((S)-3-(2-methoxy-2-oxoethyl)-1-oxa- 9-azaspiro[5.5]undecan-9-yl)methyl)cyclopropyl)methoxy)-8-(5- ((triisopropylsilyl)ethynyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate [0785] In 20 ml vial, methyl 2-((S)-9-(((R)-2,2-difluoro-1-((((4- nitrophenyl)sulfonyl)oxy)methyl)cyclopropyl)methyl)-1-oxa-9-azaspiro[5.5]undecan-3- yl)acetate (Int-54) (38.0 mg, 33 μmol), tert-butyl 3-(2-hydroxy-8-(5- ((triisopropylsilyl)ethynyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Int-24) (30 mg, 33 μmol) and Cs₂CO₃ (321.7 mg, 67 μmol) were dissolved in DMF (0.6 ml). The reaction was stirred at 40 ºC for 1 h, extracted with EtOAc, and washed with water. The organic layer was dried over MgSO₄. The crude was purified by flash silica gel chromatography (ISCO®, 4 g gold column eluted with 0-100% EtOAc/EtOH in 12 min). Fractions containing desired product were combined and concentrated to give tert- butyl 3-(2-(((R)-2,2-difluoro-1-(((S)-3-(2-methoxy-2-oxoethyl)-1-oxa-9- azaspiro[5.5]undecan-9-yl)methyl)cyclopropyl)methoxy)-8-(5-((triisopropylsilyl)ethynyl)- 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate. ESI-MS m/z calc’d for C₆₃H₈₆F₂N₈O₇S₂Si₂1225.72, found [M+H]⁺: 1227.1. [0786] Step B: 2-((3S)-9-(((1R)-1-(((4-(8-(tert-butoxycarbonyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-(5-((triisopropylsilyl)ethynyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-2-yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)-1-oxa-9- azaspiro[5.5]undecan-3-yl)acetic acid [0787] Tert-butyl 3-(2-(((R)-2,2-difluoro-1-(((S)-3-(2-methoxy-2-oxoethyl)-1-oxa-9- azaspiro[5.5]undecan-9-yl)methyl)cyclopropyl)methoxy)-8-(5-((triisopropylsilyl)ethynyl)- 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (60 mg, 49 μmol) was dissolved in THF/MeOH 2:1 mL, and was added 1 N NaOH (1 mL). The reaction was stirred at room temperature for 18 h, neutralized to pH 4, concentrated, extracted with EtOAc, washed with water, and dried over MgSO₄. The organic layer was filtered and concentrated to give 2-((3S)-9-(((1R)-1-(((4-(8-(tert- butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-(5-((triisopropylsilyl)ethynyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-2-yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)-1-oxa-9- azaspiro[5.5]undecan-3-yl)acetic acid. ESI-MS m/z calc’d for C₆₂H₈₄F₂N₈O₇S₂Si₂1211.69, found [M+H]⁺: 1212.5. [0788] Step C: Tert-butyl 3-(2-(((R)-2,2-difluoro-1-(((S)-3-(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)-1-oxa-9-azaspiro[5.5]undecan-9-yl)methyl)cyclopropyl)methoxy)-8- (5-((triisopropylsilyl)ethynyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol- 4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate [0789] In a 20 ml vial, 2-((3S)-9-(((1R)-1-(((4-(8-(tert-butoxycarbonyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-(5-((triisopropylsilyl)ethynyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-2-yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)-1-oxa-9- azaspiro[5.5]undecan-3-yl)acetic acid (12.34 mg, 0.013 mmol) with (2S,4R)-1-((S)-2- amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (8.52 mg, 0.020 mmol), HATU (10.03 mg, 0.026 mmol) were dissolved in MeCN (1 mL). To above mixture was added DIEA (18.44 μL, 0.106 mmol). The reaction was stirred at r.t. for 18 h. The crude was purified by RPLC (eluted with 0-100% MeCN/water in 18 min). Fractions containing desired peaks were combined and lyophilized to give tert-butyl 3-(2-(((R)-2,2-difluoro-1-(((S)-3-(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)-1-oxa-9-azaspiro[5.5]undecan-9- yl)methyl)cyclopropyl)methoxy)-8-(5-((triisopropylsilyl)ethynyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. ESI-MS m/z calc’d for C₈₄H₁₁₂F₂N₁₂O₉S₃Si₂: 1624.24, found [M+H]⁺: 1624.9. [0790] Step D: (2S,4R)-1-((2S)-2-(2-((3S)-9-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3- yl)-8-(5-ethynyl-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2- yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)-1-oxa-9-azaspiro[5.5]undecan-3- yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Ex-26) [0791] A mixture of tert-butyl 3-(2-(((R)-2,2-difluoro-1-(((S)-3-(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)-1-oxa-9-azaspiro[5.5]undecan-9- yl)methyl)cyclopropyl)methoxy)-8-(5-((triisopropylsilyl)ethynyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (60 mg, 0.034 mmol) and TFA (0.5 mL, 0.034 mmol) was stirred at 25 °C for 12 h. LCMS showed the reaction was complete. The mixture was evaporated under reduced pressure to give the crude product. To a solution of the crude product in DMF (1 mL) was added CsF (51.9 mg, 0.342 mmol) at 25 °C. The mixture was stirred at 25 °C for 12 h. LCMS showed the reaction is complete. The mixture was filtered and the solvent was evaporated under reduced pressure. The residue was purified by reverse preparative HPLC to give (2S,4R)-1-((2S)-2-(2-((3S)-9- (((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-(5-ethynyl-1H-thieno[3,2-f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)-1-oxa-9-azaspiro[5.5]undecan-3-yl)acetamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Ex-26). ESI-MS m/z calc’d for C₆₄H₇₀F₂N₁₂O₆S₃: 1237.52, found [M+H]⁺: 1238.1.¹H NMR (499 MHz, methanol-d₄) δ 8.88 (d, J = 6.2 Hz, 1H), 8.72 (d, J = 5.7 Hz, 1H), 8.29 (s, 1H), 7.91 – 7.80 (m, 3H), 7.50 – 7.40 (m, 4H), 7.38 – 7.32 (m, 1H), 4.69 – 4.49 (m, 6H), 4.42 (s, 0H), 4.37 (d, J = 15.4 Hz, 2H), 4.27 (d, J = 12.4 Hz, 1H), 4.21 (d, J = 12.0 Hz, 1H), 3.92 (d, J = 11.0 Hz, 1H), 3.84 – 3.72 (m, 2H), 3.72 – 3.65 (m, 3H), 3.59 (dd, J = 10.4, 7.5 Hz, 1H), 3.37 (s, 1H), 3.31 – 3.24 (m, 1H), 2.82 (dd, J = 21.4, 8.6 Hz, 2H), 2.57 (s, 1H), 2.49 (d, J = 1.3 Hz, 3H), 2.47 – 2.40 (m, 2H), 2.37 (d, J = 13.4 Hz, 1H), 2.26 – 2.03 (m, 6H), 1.97 – 1.90 (m, 2H), 1.89 – 1.81 (m, 3H), 1.81 – 1.74 (m, 1H), 1.64 (s, 1H), 1.52 (d, J = 13.1 Hz, 1H), 1.48 – 1.42 (m, 2H), 1.40 – 1.29 (m, 6H), 1.07 – 1.00 (m, 8H), 0.92 (t, J = 6.6 Hz, 0H), 0.16 – 0.09 (m, 1H). [0792] Example 27: (2R,4S)-1-((2R)-2-(2-((3R)-9-(((1S)-1-(((4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-8-(5-cyclopropyl-6-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)-1-oxa-9-azaspiro[5.5]undecan-3-yl)acetamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide & (2S,4R)-1-((2S)-2-(2-((3S)-9-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3- yl)-8-(5-cyclopropyl-6-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-2-yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)-1-oxa-9- azaspiro[5.5]undecan-3-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Ex-27)

[0793] Step A: Tert-butyl 3-(2-(((R)-1-(((S)-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)-1-oxa-9-azaspiro[5.5]undecan-9-yl)methyl)- 2,2-difluorocyclopropyl)methoxy)-8-chloropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate [0794] Stock solutions were prepared as following: tert-butyl 3-(8-chloro-2- (methylsulfonyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-11L): 415 μL of stock solution was prepared by dissolving 21.2 mg of tert-butyl 3-(8-chloro-2- (methylsulfonyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (0.042 mmol) in MeCN (0.1 M); (2S,4R)-4-((tert- butyldimethylsilyl)oxy)-1-((S)-2-(2-((S)-9-(((R)-2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)-1-oxa-9-azaspiro[5.5]undecan-3-yl)acetamido)-3,3- dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-58): 620 μL of stock solution was prepared by dissolving 53.3 mg of the title compound (0.062 mmol) in MeCN (0.1 M); TMP: 300 μL of stock solution was prepared by dissolving 25.5 μL of TMP (21.2 mg, 0.15 mmol) in MeCN (0.5 M). [0795] To each of the four 1 mL micro-vials inserted in a 96-well aluminum block and equipped with stirring bar was dosed with 100 μL of tert-butyl 3-(8-chloro-2- (methylsulfonyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate stock solution (0.01 mmol) by a pipette, followed by the stock solutions of (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(2-((S)-9-(((R)- 2,2-difluoro-1-(hydroxymethyl)cyclopropyl)methyl)-1-oxa-9-azaspiro[5.5]undecan-3- yl)acetamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Int-58) (150 μL, 0.015 mmol) and TMP (60 μL, 0.03 mmol). The plate was sealed and agitated on a tumble stirrer at 65 ºC overnight. After cooled to 25 ºC, the solvent was evaporated in a GeneVac. The residue was dissolved in DMSO (100 μL) and treated with SPE, the elute was concentrated to afford tert-butyl 3-(2-(((R)-1-(((S)-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)-1- oxa-9-azaspiro[5.5]undecan-9-yl)methyl)-2,2-difluorocyclopropyl)methoxy)-8- chloropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (0.01 mmol), which was used directly in the next step without further purification. [M+H]⁺ Found: 1290. [0796] Step B: Tert-butyl 3-(2-(((R)-1-(((S)-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)-1-oxa-9-azaspiro[5.5]undecan-9-yl)methyl)- 2,2-difluorocyclopropyl)methoxy)-8-(5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-6- (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [0797] Stock solutions were prepared as following: tert-butyl 3-(2-(((R)-1-(((S)-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)-1- oxa-9-azaspiro[5.5]undecan-9-yl)methyl)-2,2-difluorocyclopropyl)methoxy)-8- chloropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate: 10 μL of stock solution was prepared by dissolving 1.3 mg of tert-butyl 3-(2- (((R)-1-(((S)-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)- 1-oxa-9-azaspiro[5.5]undecan-9-yl)methyl)-2,2-difluorocyclopropyl)methoxy)-8- chloropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (2.0 μmol) in 1,4-dioxane (0.1 M); (5-cyclopropyl-1-(tetrahydro-2H-pyran-2- yl)-6-(trifluoromethyl)-1H-indazol-4-yl)boronic acid (Int-9): 15 μL of stock solution was prepared by dissolving 1.1 mg of (5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-6- (trifluoromethyl)-1H-indazol-4-yl)boronic acid (Int-9) (3.0 μmol) in 1,4-dioxane (0.1 M); SPhos Pd G3: 800 μL of stock solution was prepared by dissolving 12.48 mg of SPhos Pd G3 (16 μmol) in 1,4-dioxane (0.02 M); K₂HPO₄: 500 μL of stock solution was prepared by dissolving 87.1 mg of K₂HPO₄ (0.5 mmol) in water (1.0 M). [0798] To a 1 mL micro-vial inserted in a 96-well aluminum block and equipped with stirring bar was dosed with 10 μL of tert-butyl 3-(2-(((R)-1-(((S)-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)-1-oxa-9-azaspiro[5.5]undecan-9- yl)methyl)-2,2-difluorocyclopropyl)methoxy)-8-chloropyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate stock solution (2.0 μmol) with a pipette, followed by the stock solutions of SPhos Pd G3 (25 μL, 0.5 μmol), (5- cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H-indazol-4-yl)boronic acid (Int-9) (15 μL, 3.0 μmol) and aq. K2HPO4 (10 μL, 10 μmol). The plate was sealed and agitated on a tumble stirrer at 90 ºC overnight. After cooled to 25 ºC, the solvent was evaporated in a GeneVac. The residue was dissolved in DMSO (100 μL) and treated with SPE, the elute was concentrated to afford tert-butyl 3-(2-(((R)-1-(((S)-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)-1-oxa-9-azaspiro[5.5]undecan-9- yl)methyl)-2,2-difluorocyclopropyl)methoxy)-8-(5-cyclopropyl-1-(tetrahydro-2H-pyran-2- yl)-6-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (2.0 μmol), which was used directly in the next step without further purification. [M+H]⁺ Found: 1565. [0799] Step C: (2R,4S)-1-((2R)-2-(2-((3R)-9-(((1S)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3- yl)-8-(5-cyclopropyl-6-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-2-yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)-1-oxa-9- azaspiro[5.5]undecan-3-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide & (2S,4R)-1-((2S)-2-(2-((3S)-9- (((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-(5-cyclopropyl-6-(trifluoromethyl)-1H- indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)-1-oxa-9-azaspiro[5.5]undecan-3-yl)acetamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Ex-27) [0800] To the well on a 96 deep-well plate containing dried tert-butyl 3-(2-(((R)-1-(((S)-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)-1- oxa-9-azaspiro[5.5]undecan-9-yl)methyl)-2,2-difluorocyclopropyl)methoxy)-8-(5- cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (2.0 μmol) was added DCM (100 μL) and TFA (50 μL). The plate was sealed and vibrated on a LabRam at 10 G/25 °C for 18 hours. The resulting reaction mixture was neutralized by the addition of ammonia in MeOH (7 M, 93 μL). The solvents were evaporated in a GeneVac. The residue was dissolved in DMSO (100 μL) and purified by micro-isolation to afford (2R,4S)-1-((2R)-2-(2-((3R)-9-(((1S)-1-(((4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-8-(5-cyclopropyl-6-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)-1-oxa-9-azaspiro[5.5]undecan-3-yl)acetamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide & (2S,4R)-1-((2S)-2-(2-((3S)-9-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3- yl)-8-(5-cyclopropyl-6-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-2-yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)-1-oxa-9- azaspiro[5.5]undecan-3-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Ex-27), [M+H]⁺ Found: 1266. [0801] Ex-28 in the table below was synthesized using a similar procedure as described in the synthesis of Ex-27 by making the appropriate substitutions for starting material, intermediates, and/or reagents. 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. [0802] Example 29: (2S,4R)-1-((2S)-2-(2-(3-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3- yl)-8-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-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-29) [0803] Step A: Tert-butyl 3-(2-(((R)-1-((9-(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)-3-azaspiro[5.5]undecan-3-yl)methyl)-2,2- difluorocyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [0804] (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(2-(3-(((R)-2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)-3-azaspiro[5.5]undecan-9-yl)acetamido)-3,3- dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-55) (56.9 mg, 0.066 mmol) was added to a vial. The vial was sealed and its contents were placed under an inert atmosphere by performing 3 vacuum / nitrogen cycles. The vial was chilled to 0 °C and THF (276 μL) was added through the septum followed by LiHMDS (133 μl, 0.133 mmol). The resulting mixture was allowed to stir for 30 minutes at 0 °C. A solution of azeotoped tert-butyl 3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-(methylsulfinyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-13) (41 mg, 0.055 mmol) in THF (276 μL) was added and the resulting mixture was allowed to stir for 1 h at room temperature. The reaction mixture was quenched with 20% v/v acetic acid/toluene and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0-20% DCM/Methanol). The desired fractions were pooled and concentrated under reduced pressure to afford tert-butyl 3-(2-(((R)-1-((9-(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)-3-azaspiro[5.5]undecan-3-yl)methyl)-2,2- difluorocyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate as a pale-yellow solid. [M/2+H]⁺: m/z 769. [0805] Step B: (2S,4R)-1-((2S)-2-(2-(3-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8- (6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-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-29) [0806] Tert-butyl 3-(2-(((R)-1-((9-(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)-3-azaspiro[5.5]undecan-3-yl)methyl)-2,2- difluorocyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (33 mg, 0.021 mmol) was dissolved in TFA and allowed to stir for 4 h at room temperature. The reaction mixture was concentrated under reduced pressure. The reaction mixture was diluted with 3:1 Chloroform:iPrOH and washed with saturated sodium bicarbonate, the biphasic mixture was passed through a phase separator cartridge and concentrated under reduced pressure. The reaction mixture was filtered and submitted directly for HPLC purification (purified by HPLC, eluting acetonitrile/water gradient with 0.1% Ammonium hydroxide modifier, linear gradient) and lyophilized to afford (2S,4R)-1-((2S)-2-(2-(3-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3- yl)-8-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-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-29) as an off-white solid. [M/2+H]⁺: m/z 619.¹H NMR (499 MHz, DMSO) δ 8.99 (s, 1H), 8.69 (d, J = 5.5 Hz, 1H), 8.56 (t, 1H), 7.80 – 7.75 (m, 2H), 7.72 (d, J = 5.6 Hz, 1H), 7.48 (s, 1H), 7.39 (q, 4H), 5.11 (s, 1H), 4.59 (t, 1H), 4.53 (d, J = 9.3 Hz, 1H), 4.47 – 4.36 (m, 3H), 4.36 – 4.33 (m, 1H), 4.26 – 4.11 (m, 2H), 3.99 (d, 1H), 3.70 – 3.60 (m, 3H), 3.52 (t, J = 14.2 Hz, 3H), 2.68 (s, 3H), 2.65 – 2.56 (m, 2H), 2.45 (s, 3H), 2.37 (t, J = 13.8 Hz, 1H), 2.32 – 2.19 (m, 4H), 2.19 – 2.12 (m, 1H), 2.06 – 1.97 (m, 2H), 1.95 – 1.86 (m, 1H), 1.78 – 1.65 (m, 2H), 1.58 (s, 4H), 1.41 (d, J = 37.0 Hz, 6H), 1.28 (s, 2H), 1.14 (s, 2H), 1.05 – 0.96 (m, 2H), 0.93 (s, 11H). [0807] Ex-30 in the table below was synthesized using a similar procedure as described in the synthesis of Ex-29 by making the appropriate substitutions for starting material, intermediates, and/or reagents. 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. [0808] Example 31: (2S,4R)-1-((2S)-2-(2-(3-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3- yl)-8-(5-ethynyl-6-fluoro-1H-benzo[f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin- 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)

[0809] Step A: Tert-butyl 3-(2-(((R)-1-((9-(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)-3-azaspiro[5.5]undecan-3-yl)methyl)-2,2- difluorocyclopropyl)methoxy)-8-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5- ((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [0810] To a solution of tert-butyl 3-(8-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5- ((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)-2- (methylsulfonyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-18) (60 mg, 0.065 mmol) and (2S,4R)-4-((tert- butyldimethylsilyl)oxy)-1-((S)-2-(2-(3-(((R)-2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)-3-azaspiro[5.5]undecan-9-yl)acetamido)-3,3- dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-55) (111 mg, 0.130 mmol) in THF (0.5 mL) was added NaH (7.79 mg, 0.195 mmol) (60% w/w in mineral oil) at 25 °C under N₂ atmosphere, and the mixture was stirred at 25 °C for 10 min. LCMS showed the starting material was consumed and desired MS was found. The reaction was quenched with saturated NH₄Cl solution (0.25 mL), extracted with EtOAc (5 mL), the oganic layer was dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by preparative TLC plate (SiO₂, DCM/MeOH=12/1) to give tert-butyl 3-(2-(((R)-1-((9-(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)- 3-azaspiro[5.5]undecan-3-yl)methyl)-2,2-difluorocyclopropyl)methoxy)-8-(6-fluoro-1- (tetrahydro-2H-pyran-2-yl)-5-((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate. MS (ESI) [M/2+H]⁺: m/z 852.2. [0811] Step B: (2S,4R)-1-((2S)-2-(2-(3-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8- (6-fluoro-5-((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-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 [0812] A mixture of tert-butyl 3-(2-(((R)-1-((9-(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)-3-azaspiro[5.5]undecan-3-yl)methyl)-2,2- difluorocyclopropyl)methoxy)-8-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5- ((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50 mg, 0.029 mmol) in TFA (1 mL, 12.98 mmol) was stirred at 25 °C for 16 h. LCMS showed the starting material was consumed and desired MS was found. The reaction was concentrated in vacuo, and basified with DIEA (3 drops). The reaction mixture was concentrated in vacuo to give (2S,4R)-1-((2S)-2-(2-(3-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-(6-fluoro-5- ((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-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. MS (ESI) [M/2+H]⁺: m/z 702.9. [0813] Step C: (2S,4R)-1-((2S)-2-(2-(3-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8- (5-ethynyl-6-fluoro-1H-benzo[f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-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) [0814] To a solution of (2S,4R)-1-((2S)-2-(2-(3-(((1R)-1-(((4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-8-(6-fluoro-5-((triisopropylsilyl)ethynyl)-1H- benzo[f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-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 (41.2 mg, 0.029 mmol) in DMF (1 mL) was added CsF (22.29 mg, 0.147 mmol) at 25 °C, and the mixture was stirred at 25 °C for 2 h. LCMS showed the starting material was consumed and desired MS was found. The reaction was filtered, and the filtrate was purified by preparative HPLC (Column: Boston Prime C18150 * 30 mm * 5 um; Condition: water (0.04% NH₃H₂O+10 mM NH₄HCO₃)-ACN Begin B 56, End B 86 Gradient Time (min) 10, 100% B Hold Time (min) 2 FlowRate (mL/min) 25) to give (2S,4R)-1-((2S)-2-(2-(3-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-(5-ethynyl-6- fluoro-1H-benzo[f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-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). MS (ESI) [M/2+H]⁺: m/z 624.8. ¹H NMR (400MHz, CD₃OD) δ 8.89 (s, 1H), 8.72 (d, J=5.5 Hz, 1H), 8.37 (s, 1H), 8.27 - 8.20 (m, 1H), 7.89 (d, J=5.6 Hz, 1H), 7.80 (d, J=4.5 Hz, 1H), 7.51 - 7.38 (m, 5H), 4.70 - 4.49 (m, 6H), 4.47 - 4.32 (m, 2H), 4.30 - 4.14 (m, 1H), 3.97 - 3.88 (m, 1H), 3.85 - 3.73 (m, 2H), 3.71 - 3.59 (m, 3H), 2.77 (br d, J=13.2 Hz, 1H), 2.48 (d, J=2.0 Hz, 3H), 2.45 - 2.29 (m, 5H), 2.25 - 2.04 (m, 4H), 1.82 (br d, J=10.7 Hz, 4H), 1.68 - 1.39 (m, 8H), 1.39 - 1.16 (m, 8H), 1.05 (s, 9H). [0815] Ex-32 to 36 in the table below were synthesized using a similar procedure as described in the synthesis of Ex-31 by making the appropriate substitutions for starting material, intermediates, and/or reagents. 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. [0816] Example 37: (2S,4R)-1-((2S)-2-(4-(3-(((((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan- 3-yl)-8-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)(methyl)amino)methyl)bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3- triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Ex-37) [0817] Step A: Tert-butyl 3-(2-(((R)-1-((((3-(1-((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)-1H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1- yl)methyl)(methyl)amino)methyl)-2,2-difluorocyclopropyl)methoxy)-8-(6-methyl-1- (tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [0818] To a solution of tert-butyl 3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-14) (50 mg, 0.066 mmol) and (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-((S)-2-(4-(3-(((((R)-2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)(methyl)amino)methyl)bicyclo[1.1.1]pentan-1-yl)-1H- 1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Int-59) (65.4 mg, 0.079 mmol) in THF (1 mL) was added NaH (13.19 mg, 0.330 mmol, 60 % in mineral oil) at 0 °C under N₂ atmosphere. The mixture was stirred at 0 °C for 30 min. LCMS showed the starting material was consumed and the desired MS was found. The reaction was quenched with water (0.5 mL), and then extracted with EtOAc (10 mL * 2). The combined organic layer was dried with Na₂SO₄, filtered and the solvent was removed under reduced pressure. The crude was purified by preparative TLC (SiO₂, DCM/MeOH=10/1) to give tert-butyl 3-(2-(((R)-1-((((3-(1-((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)-1H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1- yl)methyl)(methyl)amino)methyl)-2,2-difluorocyclopropyl)methoxy)-8-(6-methyl-1- (tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. MS (ESI) [M/2+H]⁺: m/z 752.7. [0819] Step B: (2S,4R)-1-((2S)-2-(4-(3-(((((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)- 8-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2- yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)(methyl)amino)methyl)bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3- triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Ex-37) [0820] A solution of tert-butyl 3-(2-(((R)-1-((((3-(1-((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)-1H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1- yl)methyl)(methyl)amino)methyl)-2,2-difluorocyclopropyl)methoxy)-8-(6-methyl-1- (tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (60 mg, 0.040 mmol) in TFA (1.0 mL) was stirred at 25 °C for 16 h. LCMS showed the starting material was consumed and the desired MS was found. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC (Column Boston Prime C18150 * 30 mm * 5 um Condition water (0.04% NH₃H₂O +10 mM NH₄HCO₃)-ACN Begin B 58 End B 88 Gradient Time (min) 10100 % B Hold Time 2 Flow Rate (mL/min) 25 Injections 1) to give (2S,4R)-1-((2S)-2-(4-(3-(((((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-(6- methyl-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2- yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)(methyl)amino)methyl)bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3- triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Ex-37). MS (ESI) [M+H]⁺: m/z 1205.5. ¹H NMR (400MHz, CD₃OD) δ 8.86-8.89 (m, 1H), 8.63-8.67 (m, 1H), 7.95-7.98 (m, 1H), 7.73-7.78 (m, 2H), 7.49-7.53 (m, 2H), 7.45-7.48 (m, 3H), 5.49 (s, 1H), 4.62-4.71 (m, 1H), 4.50-4.58 (m, 3H), 4.40-4.45 (m, 1H), 4.19-4.29 (m, 2H), 3.92 (ddd, J=3.70, 7.39, 11.09 Hz, 1H), 3.75-3.84 (m, 1H), 3.57-3.74 (m, 3H), 3.53 (br s, 2H), 2.78-2.91 (m, 1H), 2.74 (br d, J=1.31 Hz, 3H), 2.50-2.60 (m, 3H), 2.48 (d, J=1.19 Hz, 3H), 2.30 (s, 3H), 2.01 (d, J=6.20 Hz, 6H), 1.66-1.74 (m, 4H), 1.31-1.40 (m, 2H), 1.01 (d, J=6.20 Hz, 9H), 0.97 (d, J=2.86 Hz, 2H). [0821] Ex-38 to 41 in the table below were synthesized using a similar procedure as described in the synthesis of Ex-37 by making the appropriate substitutions for starting material, intermediates, and/or reagents. 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. [0822] Example 42: (2S,4R)-1-(2-(3-((1-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)- 8-(5-ethynyl-6-fluoro-1H-benzo[f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-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-42) [0823] Step A: Tert-butyl 3-(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)-8-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5- ((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [0824] To a solution of tert-butyl 3-(8-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5- ((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)-2- (methylsulfonyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-18) (50 mg, 0.054 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-64) (48.6 mg, 0.060 mmol) in THF (1 mL) was added NaH (15 mg, 0.375 mmol, 60% wt) at 25 °C. The mixture was stirred at 25 °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 residue. The residue was purified by preparative TLC (SiO₂, DCM: MeOH = 10:1) to give tert-butyl 3-(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)-8-(6-fluoro-1- (tetrahydro-2H-pyran-2-yl)-5-((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate. MS (ESI) [M/2+H]⁺: m/z 831.1. [0825] Step B: (3R,5S)-1-(2-(3-((1-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-(6- fluoro-5-((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-2-yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)piperidin-4- yl)methoxy)isoxazol-5-yl)-3-methylbutanoyl)-5-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-3-yl 2,2,2-trifluoroacetate [0826] A solution of tert-butyl 3-(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)-8-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5- ((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (37 mg, 0.022 mmol) in TFA (1 mL, 12.98 mmol) was stirred at 25 °C for 15 h. LCMS showed starting material was consumed and desired peak was formed. The solvent was evaporated under reduced pressure to give the crude product (3R,5S)-1-(2-(3-((1-(((1R)-1-(((4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-8-(6-fluoro-5-((triisopropylsilyl)ethynyl)-1H- benzo[f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)methoxy)isoxazol-5-yl)-3-methylbutanoyl)-5- ((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-3-yl 2,2,2-trifluoroacetate. MS (ESI) [M/2+H]⁺: m/z 729.8. [0827] Step C: (2S,4R)-1-(2-(3-((1-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-(6- fluoro-5-((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-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 [0828] To a solution of (3R,5S)-1-(2-(3-((1-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3- yl)-8-(6-fluoro-5-((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)methoxy)isoxazol-5-yl)-3-methylbutanoyl)-5- ((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-3-yl 2,2,2-trifluoroacetate (32 mg, 0.022 mmol) in MeOH (0.5 mL) was added sodium bicarbonate (18.44 mg, 0.220 mmol) at 25 °C. The mixture was stirred at 25 °C for 1 h. LCMS showed starting material was consumed and desired peak was formed. The mixture was filtered and the solvent was evaporated under reduced pressure to give the crude product (2S,4R)-1-(2-(3-((1-(((1R)-1- (((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-(6-fluoro-5-((triisopropylsilyl)ethynyl)-1H - benzo[f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-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. MS (ESI) [M+H]⁺: m/z 1362.1. [0829] Step D: (2S,4R)-1-(2-(3-((1-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-(5- ethynyl-6-fluoro-1H-benzo[f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-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-42) [0830] To a solution of (2S,4R)-1-(2-(3-((1-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3- yl)-8-(6-fluoro-5-((triisopropylsilyl)ethynyl)-1H-benzo[f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-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 (29 mg, 0.021 mmol) in DMF (0.5 mL) was added CsF (32.4 mg, 0.213 mmol) at 25 °C. The mixture was stirred at 25 °C for 15 h. LCMS showed starting material was consumed and desired peak was formed. The mixture was filtered and the filtrate was purified by reverse preparative HPLC (Column: YMC-Actus Triart C18150 * 30 mm * 5 um; Condition: water (10 mM- NH₄HCO₃)-MeOH; Begin B--End B: 68--98; Gradient Time (min): 14; 100% B Hold Time (min): 3; FlowRate (mL/min): 25) to give (2S,4R)-1-(2-(3-((1-(((1R)-1-(((4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-8-(5-ethynyl-6-fluoro-1H-benzo[f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-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-42). MS (ESI) [M/2+H]⁺: m/z 603.6. ¹H NMR (400MHz, CD₃OD) δ 8.80-8.89 (m, 1H), 8.68 (d, J=5.7 Hz, 1H), 8.34 (s, 1H), 8.17-8.25 (m, 1H), 7.86 (dd, J=5.5, 2.8 Hz, 1H), 7.79 (s, 1H), 7.24- 7.55 (m, 6H), 5.84-5.99 (m, 1H), 4.53-4.64 (m, 4H), 4.50 (br s, 1H), 4.35-4.46 (m, 3H), 4.16 (br t, J=10.7 Hz, 1H), 3.87-3.95 (m, 2H), 3.71-3.78 (m, 2H), 3.62 (br d, J=17.3 Hz, 4H), 2.87 (br s, 2H), 2.75 (br s, 1H), 2.43-2.48 (m, 3H), 2.35-2.42 (m, 2H), 2.17-2.25 (m, 1H), 1.96-2.09 (m, 2H), 1.86-1.94 (m, 2H), 1.78 (br d, J=4.4 Hz, 2H), 1.68 (br d, J=15.4 Hz, 2H), 1.60 (br s, 2H), 1.31 (br d, J=19.1 Hz, 2H), 1.12-1.24 (m, 2H), 1.04 (t, J=6.2 Hz, 3H), 0.89 (br dd, J=10.8, 6.6 Hz, 3H). [0831] Example 43: (2S,4R)-1-(2-(1-(2-(1-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3- yl)-8-(5-ethynyl-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2- yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-4- yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Ex-43)

[0832] Step A: Tert-butyl 3-(2-(((R)-1-((4-(2-(4-((R)-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)-1H-1,2,3-triazol-1-yl)ethyl)piperidin-1-yl)methyl)-2,2- difluorocyclopropyl)methoxy)-8-(5-((triisopropylsilyl)ethynyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [0833] To a solution of tert-butyl 3-(2-(methylsulfinyl)-8-(5-((triisopropylsilyl)ethynyl)-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-16) (40 mg, 0.042 mmol) and (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-(2-(1-(2-(1-(((R)-2,2-difluoro-1- (hydroxymethyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-4-yl)-3,3- dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Int-65) (35.2 mg, 0.042 mmol) in MeCN (1.0 mL) was added 2,2,6,6-tetramethylpiperidine (60.0 mg, 0.424 mmol) at 25 °C. The mixture solution was stirred at 100 °C for 72 h. LCMS showed the starting material was consumed and desired MS was found. The mixture was quenched with water (3 mL), and then extracted with EtOAc (10 mL x 2). The combined organic layer was dried with Na₂SO₄, filtered and the solvent was removed under reduced pressure. The residue was purified by preparative TLC (SiO₂, DCM/MeOH=20/1) to give tert-butyl 3-(2-(((R)-1-((4-(2-(4-((R)-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)-1H- 1,2,3-triazol-1-yl)ethyl)piperidin-1-yl)methyl)-2,2-difluorocyclopropyl)methoxy)-8-(5- ((triisopropylsilyl)ethynyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate. MS (ESI) [M/2+H]⁺: m/z 853.3. [0834] Step B: (2S,4R)-1-((2R)-2-(1-(2-(1-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3- yl)-8-(5-((triisopropylsilyl)ethynyl)-1H-thieno[3,2-f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-4-yl)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide [0835] A solution of tert-butyl 3-(2-(((R)-1-((4-(2-(4-((R)-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)-1H-1,2,3-triazol-1-yl)ethyl)piperidin-1-yl)methyl)-2,2- difluorocyclopropyl)methoxy)-8-(5-((triisopropylsilyl)ethynyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (45 mg, 0.026 mmol) in TFA (2 mL) was stirred at 25 °C for 16 h. LCMS showed starting material was consumed and desired MS was formed. The mixture was evaporated under reduced pressure to give the crude product. The crude product was basified with saturated aqueous NaHCO₃ (5 mL), and then extracted with DCM (15 mL x 3). The organic layer was dried over Na₂SO₄, filtered and the solvent was evaporated under reduced pressure to give (2S,4R)-1-((2R)-2- (1-(2-(1-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-(5-((triisopropylsilyl)ethynyl)- 1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-4-yl)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide. MS (ESI) [M/2+H]⁺: m/z 681.7. [0836] Step C: (2S,4R)-1-(2-(1-(2-(1-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8- (5-ethynyl-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2- yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-4- yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Ex-43) [0837] To a solution of (2S,4R)-1-((2R)-2-(1-(2-(1-(((1R)-1-(((4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-8-(5-((triisopropylsilyl)ethynyl)-1H-thieno[3,2-f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-4-yl)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (30 mg, 0.022 mmol) in DMF (1.0 mL) was added CsF (33.5 mg, 0.220 mmol) at 25 °C. The mixture was stirred at 25 °C for 16 h. LCMS showed the starting material was consumed and desired MS was found. The mixture was filtered and the filtrate was purified by preparative HPLC (Column: Boston Prime C18150 * 30 mm * 5 um; Condition: water (0.05% NH₃H₂O+10 mM NH₄HCO₃)-MeOH, End B 75 Gradient Time (min) 2.5, 100 % B Hold Time (min) 11 FlowRate (mL/min) 25) to give (2S,4R)-1-(2-(1-(2- (1-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-(5-ethynyl-1H-thieno[3,2-f]indazol- 4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-4-yl)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Ex-43). MS (ESI) [M/2+H]⁺: m/z 603.7. ¹H NMR (400MHz, CD₃OD) δ 8.81 - 8.72 (m, 1H), 8.63 (br d, J = 5.5 Hz, 1H), 8.20 (s, 1H), 7.83 (s, 1H), 7.77 (d, J = 5.6 Hz, 1H), 7.73 (br d, J = 1.0 Hz, 2H), 7.43 - 7.36 (m, 2H), 7.36 - 7.31 (m, 2H), 4.59 - 4.50 (m, 2H), 4.47 (br d, J = 7.9 Hz, 1H), 4.41 (br d, J = 6.6 Hz, 2H), 4.35 (s, 1H), 4.33 - 4.27 (m, 3H), 4.15 (br t, J = 12.9 Hz, 1H), 3.90 (s, 1H), 3.86 - 3.78 (m, 1H), 3.73 - 3.68 (m, 1H), 3.66 - 3.55 (m, 4H), 2.75 (br d, J = 2.6 Hz, 1H), 2.40 - 2.36 (m, 3H), 2.11 (br d, J = 7.7 Hz, 1H), 2.05 - 1.90 (m, 2H), 1.86 (br d, J = 5.4 Hz, 1H), 1.79 - 1.74 (m, 2H), 1.66 (br s, 2H), 1.52 (br s, 4H), 1.32 - 1.18 (m, 6H), 1.06 (br s, 2H), 0.94 (s, 9H), 0.87 - 0.79 (m, 1H). [0838] Ex-44 in the table below was synthesized using a similar procedure as described in the synthesis of Ex-43 by making the appropriate substitutions for starting material, intermediates, and/or reagents. 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. [0839] Example 45: (2R,4S)-1-((2R)-2-(2-((7-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan- 3-yl)-8-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-2-yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)-7-azaspiro[3.5]nonan-2- yl)oxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Ex-45)

[0840] Step A: Tert-butyl 3-(2-(((R)-2,2-difluoro-1-((2-(2-(((R)-1-((2R,4S)-4-hydroxy-2- ((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- yl)amino)-2-oxoethoxy)-7-azaspiro[3.5]nonan-7-yl)methyl)cyclopropyl)methoxy)-8-(6- methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate [0841] To a vial containing 10.3 mg (0.016 mmol, 1.2 eq.) of (2R,4S)-1-((R)-2-(2-((7- azaspiro[3.5]nonan-2-yl)oxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide HCl salt was added a solution of 11.1 mg (0.013 mmol, 1.0 eq.) tert-butyl 3-(2-(((S)-2,2-difluoro-1- (((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran- 2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-21) in 0.2 mL of acetonitrile. Cesium carbonate (12.2 mg, 0.038 mmol, 3.0 eq.) was then added and the reaction stirred for 20 hours at 65 ºC. LCMS shows reaction was not complete; then added additional amine HCl salt (5 mg), plus 6.6 μL (0.39 mmol, 3 eq.) of 2,2,6,6-tetramethylpiperidine. Heated to 85ºC over 72 hours. The reaction was filtered and evaporated to dryness to give tert-butyl 3-(2-(((R)-2,2-difluoro-1-((2-(2-(((R)-1-((2R,4S)-4-hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)- 7-azaspiro[3.5]nonan-7-yl)methyl)cyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H- pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, which was used directly in the next step without further purification. [0842] Step B: (2R,4S)-1-((2R)-2-(2-((7-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)- 8-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2- yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)-7-azaspiro[3.5]nonan-2- yl)oxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Ex-45) [0843] To the crude tert-butyl 3-(2-(((R)-2,2-difluoro-1-((2-(2-(((R)-1-((2R,4S)-4-hydroxy- 2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- yl)amino)-2-oxoethoxy)-7-azaspiro[3.5]nonan-7-yl)methyl)cyclopropyl)methoxy)-8-(6- methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate from the previous step, 0.65 mL of a 1:4 solution of TFA:DCM was added and the reaction stirred for an hour. The reaction was then added to a 20 mL vial containing 3 mL of a 4/1 solution of chloroform and 2 M NH₃ in iPrOH to neutralize/free base the crude. Added brine to the vial, mixed vigorously, then partitioned. The organic was dried over MgSO₄, filtered and evaporated. Purified on a C18 preparative HPLC column, eluting with 40-75% CH₃CN in water (NH₄OH modified) to give (2R,4S)-1-((2R)-2-(2-((7-(((1R)-1-(((4- (3,8-diazabicyclo[3.2.1]octan-3-yl)-8-(6-methyl-5-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)oxy)acetamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (Ex-45). ESI-MS m/z calc’d for C₆₁H₆₉F₅N₁₂O₆S₂ [M+H]⁺: 1225; found: 1225. [0844] Ex-46 to 52 in the table below were synthesized using a similar procedure as described in the synthesis of Ex-45 by making the appropriate substitutions for starting material, intermediates, and/or reagents. 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. [0845] Example 53: (2R,4S)-1-((2R)-2-(2-((2-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan- 3-yl)-8-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-2-yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)-2-azaspiro[4.5]decan-8- yl)oxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Ex-53)

[0846] Step A: Tert-butyl 3-(2-(((R)-2,2-difluoro-1-((8-(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-oxoethoxy)-2-azaspiro[4.5]decan-2-yl)methyl)cyclopropyl)methoxy)-8-(6- methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate [0847] To a vial containing 7.6 mg (0.011 mmol, 1.1 eq.) of (2R,4S)-1-((R)-2-(2-((2- azaspiro[4.5]decan-8-yl)oxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride was added a solution of 8.9 mg (0.010 mmol, 1.0 eq.) tert-butyl 3-(2-(((S)-2,2-difluoro-1- (((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran- 2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Int-21) in 0.16 mL of acetonitrile. Cs₂CO₃ (9.8 mg, 0.030 mmol, 3.0 eq.) was then added, followed by a 1.0 M solution of DIEA in CH₃CN (0.01 mL, 1.0 eq.) and a 1.0 M solution of 2,2,6,6-tetramethypiperidine (0.03 mL, 3.0 eq.) and the reaction was stirred for 48 h at 85 ºC. The reaction was filtered and the filter cake was rinsed with 1 mL CH₃CN. The combined filtrate was evaporated to dryness to give tert-butyl 3-(2-(((R)-2,2-difluoro-1-((8-(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-oxoethoxy)-2-azaspiro[4.5]decan-2-yl)methyl)cyclopropyl)methoxy)-8-(6- methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate, which was used directly in the next step without further purification. [0848] Step B: (2R,4S)-1-((2R)-2-(2-((2-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)- 8-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2- yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)-2-azaspiro[4.5]decan-8- yl)oxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Ex-53) [0849] The crude tert-butyl 3-(2-(((R)-2,2-difluoro-1-((8-(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-oxoethoxy)-2-azaspiro[4.5]decan-2-yl)methyl)cyclopropyl)methoxy)-8-(6- methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate from the previous step was treated with 0.1 mL dioxane and 0.1 mL of 4 N HCl in dioxane. After 3 h the deprotected product was evaporated to dryness and taken up in 0.2 mL DMSO. Two wells (A1 and A2) of an Oasis MCX 30 micron ion exchange extraction plate (30 mg resin) were wetted with 2% formic acid in water, then loaded with 1 mL of the 2% formic acid solution. Half of the DMSO solution was loaded into each well and mixed with the formic acid, then the solution was pulled through the resin. The beds were washed with 1 mL of water, then eluted with 5% NH₄OH in MeOH. The solvent was evaporated, then the wells combined for purification. The sample was chromatographed on a C18 column, eluting with 45-80% CH₃CN in water (0.1% NH₄OH modified) to give (2R,4S)-1- ((2R)-2-(2-((2-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-(6-methyl-5- (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2- yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)-2-azaspiro[4.5]decan-8- yl)oxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (Ex-53). ESI-MS m/z calc’d for C₆₂H₇₁F₅N₁₂O₆S₂ [M+2]/2⁺: 620.5; found: 620.7. [0850] Ex-54 to 60 in the table below were synthesized using a similar procedure as described in the synthesis of Ex-53 by making the appropriate substitutions for starting material, intermediates, and/or reagents. 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. [0851] Example 61: (2S,4R)-1-((2S)-2-(4-(2-(1-(((1R)-1-(((4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-8-(5-((triisopropylsilyl)ethynyl)-1H-thieno[3,2-f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)- N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2- carboxamide (Ex-61) [0852] Step A: Tert-butyl 3-(2-(((R)-1-((4-(2-(1-((S)-1-((2S,4R)-4-((tert- butyldimethylsilyl)oxy)-2-(((R)-2-((tert-butyldimethylsilyl)oxy)-1-(4-(1-ethyl-1H-pyrazol- 5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)-1H-1,2,3-triazol- 4-yl)ethyl)piperidin-1-yl)methyl)-2,2-difluorocyclopropyl)methoxy)-8-(5- ((triisopropylsilyl)ethynyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate [0853] In 20 ml vial, ((R)-1-((4-(2-(1-((S)-1-((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2- (((R)-2-((tert-butyldimethylsilyl)oxy)-1-(4-(1-ethyl-1H-pyrazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4- yl)ethyl)piperidin-1-yl)methyl)-2,2-difluorocyclopropyl)methyl 4-nitrobenzenesulfonate (Int-84) (38.0 mg, 33 μmol), tert-butyl 3-(2-hydroxy-8-(5-((triisopropylsilyl)ethynyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Int-24) (30 mg, 33 μmol) and Cs₂CO₃ (321.7 mg, 67 μmol) were dissolved in DMF (0.6 ml). The reaction was stirred at 40 ºC for 1 h, extracted with EtOAc, washed with water. The organic layer was dried over MgSO4. The crude was purified by flash silica gel chromatography (ISCO®, 4 g gold column eluted with 0-100% EtOAc/EtOH in 12 min). Fractions containing desired product were combined and concentrated to give tert-butyl 3-(2-(((R)-1-((4-(2-(1-((S)-1-((2S,4R)-4- ((tert-butyldimethylsilyl)oxy)-2-(((R)-2-((tert-butyldimethylsilyl)oxy)-1-(4-(1-ethyl-1H- pyrazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)-1H-1,2,3- triazol-4-yl)ethyl)piperidin-1-yl)methyl)-2,2-difluorocyclopropyl)methoxy)-8-(5- ((triisopropylsilyl)ethynyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate. ESI-MS m/z calc’d for C₉₅H₁₃₉F₂N₁₅O₈S₂Si₄: 1833.71, found [M+H]⁺: 1835.2. [0854] Step B: (2S,4R)-1-((2S)-2-(4-(2-(1-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3- yl)-8-(5-((triisopropylsilyl)ethynyl)-1H-thieno[3,2-f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)- N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2- carboxamide (Ex-61) [0855] Tert-butyl 3-(2-(((R)-1-((4-(2-(1-((S)-1-((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2- (((R)-2-((tert-butyldimethylsilyl)oxy)-1-(4-(1-ethyl-1H-pyrazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4- yl)ethyl)piperidin-1-yl)methyl)-2,2-difluorocyclopropyl)methoxy)-8-(5- ((triisopropylsilyl)ethynyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-thieno[3,2-f]indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (25.0 mg, 13.6 μmol) was dissolved in DCM (200 μL). To above solution was added TFA (200 μL). The mixture was stirred at room temperature for 2 h. The solvent was removed. The crude was diluted with DCM (2 mL), and washed with aq. sodium bicarbonate (0.5 mL). The organic phase was dried over MgSO₄, filtered and concentrated. The crude was treated with NH₃/MeOH (7M, 600 μL), and was stirred at r.t. for 1 h. Solvent was removed. The crude product was dried to give a mixture of a partial deprotected product. [0856] The crude was further dissolved in DMF (670 μL), added CsF (102 mg, 50 eq., 672 μmol), stirred at r.t. for 18 h. The crude was purified by Gilson (on a 19X100 mm, Waters XBridge C18 column, 5μ particle size, linear gradient 30% ACN/H2O to 100% ACN/H2O buffering with pH 10 ammonium hydroxide @ flow rate 20 mL/min over 15 min). Fractions containing desired product were combined and lyophilized to give (2S,4R)-1-((2S)-2-(4-(2- (1-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-(5-((triisopropylsilyl)ethynyl)-1H- thieno[3,2-f]indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)- N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2- carboxamide (Ex-61). ¹H NMR (499 MHz, Methanol-d4) δ 8.71 (d, J = 5.3 Hz, 1H), 8.29 (s, 1H), 7.90 – 7.81 (m, 3H), 7.55 – 7.41 (m, 4H), 6.32 (d, J = 1.7 Hz, 1H), 5.28 (d, J = 10.2 Hz, 1H), 5.08 (q, J = 7.0, 5.6 Hz, 1H), 4.65 (d, J = 10.5 Hz, 1H), 4.58 (q, J = 12.7, 10.5 Hz, 2H), 4.49 (s, 1H), 4.42 (s, 0H), 4.18 (q, J = 7.1 Hz, 2H), 3.95 – 3.89 (m, 1H), 3.85 (d, J = 5.6 Hz, 2H), 3.76 (d, J = 11.5 Hz, 1H), 3.64 (d, J = 15.7 Hz, 2H), 2.83 (dd, J = 6.3, 4.0 Hz, 1H), 2.69 (s, 1H), 2.55 (d, J = 6.3 Hz, 1H), 2.42 (dd, J = 12.6, 6.0 Hz, 1H), 2.27 – 2.19 (m, 1H), 2.02 (td, J = 11.2, 9.3, 4.5 Hz, 2H), 1.90 (s, 1H), 1.80 (s, 1H), 1.64 (s, 1H), 1.54 (s, 1H), 1.35 (t, J = 7.1 Hz, 4H), 1.24 (s, 1H), 1.13 (d, 1H). [0857] Ex-62 to 66 in the table below were synthesized using a similar procedure as described in the synthesis of Ex-61 by making the appropriate substitutions for starting material, intermediates, and/or reagents. 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.

[00858] Example 67: (2S,4R)-1-((S)-2-(4-(2-(1-(((R)-1-(((8-(2-amino-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-4-(3,8-diazabicyclo[3.2.1]octan-3- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)- N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2- carboxamide (Ex-67) [00859] Step A: tert-butyl 3-(8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [00860] A solution of 8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-ol (Int-11H) (1 g, 3.52 mmol) and ((1H-benzo[d][1,2,3]triazol-1- yl)oxy)tris(dimethylamino)phosphonium hexafluorophosphate(V) (2.338 g, 5.29 mmol) in MeCN (10 mL) was stirred at 25 °C for 1 h under N₂ atmosphere. Then, to the reaction was added N-ethyl-N-isopropylpropan-2-amine (3.08 mL, 17.62 mmol) and tert-butyl 3,8- diazabicyclo[3.2.1]octane-8-carboxylate (1.122 g, 5.29 mmol) in MeCN (10 mL) at 25 °C under N₂ atmosphere. The mixture was stirred at 80 °C for 2 h. LCMS showed the starting material was consumed and the desired MS was found. The mixture was cooled, diluted with water (20 mL), and extracted with EtOAc (10 mL x 3). The organic layer was dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 40% EtOAc in petroleum ether gradient @ 30 mL/min) to give tert-butyl 3-(8-chloro-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate. MS (ESI) [M+H]⁺: m/z 478.0. [00861] Step B: tert-butyl 3-(8-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate [00862] To a solution of tert-butyl 3-(8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.628 mmol) in 1,4-dioxane (3 mL) was added tert-butyl (3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2- yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (330 mg, 0.816 mmol), DPEPhos PdCl₂ (270 mg, 0.377 mmol) and Cs₂CO₃ (1227 mg, 3.77 mmol) at 25 °C under N₂ atmosphere. The mixture was stirred at 40 °C for 1 h. LCMS showed the starting material was consumed and desired MS was found. 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®; 4 g SepaFlash® Silica Flash Column, Eluent of 19% ethyl acetate in petroleum ether gradient @ 40 mL/min) to give tert-butyl 3-(8-(2-((tert- butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate. MS (ESI) [M+H]⁺: m/z 734.1. [00863] Step C: tert-butyl 3-(8-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [00864] To a solution of tert-butyl 3-(8-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (160 mg, 0.205 mmol) in CH₂Cl₂ (2 mL) was added mCPBA (92 mg, 0.451 mmol, wt 85 %) at 0 °C under N₂ atmosphere. The mixture was stirred at 25 °C for 1 h. LCMS showed the starting material was consumed and the desired MS was found. The mixture was quenched with sat. aq. Na₂SO₃ (2 mL) and sat. aq. NaHCO₃ (2 mL), and then extracted with CH₂Cl₂ (3 x 2 mL). The organic layer was dried over Na₂SO₄, filtered and the solvent was evaporated under reduced pressure to give tert- butyl 3-(8-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-2- (methylsulfonyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate. MS (ESI) [M+H]⁺: m/z 766.2. [00865] Step D: tert-butyl 3-(8-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-2-(((R)-2,2-difluoro-1-((4-(4-(trimethylsilyl)but-3-yn-1- yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [00866] To a solution of tert-butyl 3-(8-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (140 mg, 0.183 mmol) and (R)-(2,2- difluoro-1-((4-(4-(trimethylsilyl)but-3-yn-1-yl)piperidin-1-yl)methyl)cyclopropyl)methanol (Int-48) (60.2 mg, 0.183 mmol) in THF (1 mL) was added NaH (36.6 mg, 0.914 mmol) (60% Wt in mineral oil) at 25 °C under N₂ atmosphere. 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 quenched with saturated NH₄Cl solution (1 mL), extracted with EtOAc (3 x 1 mL), dried over Na₂SO₄, filtered and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by preparative TLC (SiO₂, Pet. ether:EtOAc=1:1) to give tert-butyl 3-(8-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-2-(((R)-2,2-difluoro-1-((4-(4-(trimethylsilyl)but-3-yn-1- yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. MS (ESI) [M/2+H]⁺: m/z 508.4. [00867] Step E: tert-butyl 3-(2-(((R)-1-((4-(but-3-yn-1-yl)piperidin-1-yl)methyl)-2,2- difluorocyclopropyl)methoxy)-8-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [00868] To a solution of tert-butyl 3-(8-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-2-(((R)-2,2-difluoro-1-((4-(4-(trimethylsilyl)but-3-yn-1- yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (64 mg, 0.063 mmol) in MeOH (0.6 mL) was added K₂CO₃ (17.42 mg, 0.126 mmol) at 25 °C. The mixture was stirred at 25 °C for 4 h. LCMS showed the starting material was consumed and the desired MS was found. The solvent was removed under reduced pressure. The residue was purified by pre-TLC (SiO₂, CH₂Cl₂: MeOH = 10 : 1) to give tert-butyl 3-(2-(((R)-1-((4-(but-3-yn-1-yl)piperidin-1- yl)methyl)-2,2-difluorocyclopropyl)methoxy)-8-(2-((tert-butoxycarbonyl)amino)-3-cyano- 7-fluorobenzo[b]thiophen-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate. MS (ESI) [M+H]⁺: m/z 943.3. [00869] Step F: tert-butyl 3-(8-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-2-(((R)-1-((4-(2-(1-((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)-1H-1,2,3-triazol-4-yl)ethyl)piperidin-1-yl)methyl)-2,2- difluorocyclopropyl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [00870] To a solution of tert-butyl 3-(2-(((R)-1-((4-(but-3-yn-1-yl)piperidin-1-yl)methyl)- 2,2-difluorocyclopropyl)methoxy)-8-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (41.5 mg, 0.035 mmol) in CH₂Cl₂ (0.4 mL) was added (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5- yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide (Int-33) (16.32 mg, 0.035 mmol), Cu(CH₃CN)₄PF₆ (19.44 mg, 0.052 mmol) and DIEA (0.039 mL, 0.226 mmol) at 25 °C under N₂ atmosphere. The mixture was stirred at 40 °C for 16 h. LCMS showed the starting material was consumed and the desired MS was found. The mixture was concentrated in vacuo to give crude tert-butyl 3-(8-(2-((tert-butoxycarbonyl)amino)-3- cyano-7-fluorobenzo[b]thiophen-4-yl)-2-(((R)-1-((4-(2-(1-((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)-1H-1,2,3-triazol-4-yl)ethyl)piperidin-1-yl)methyl)-2,2- difluorocyclopropyl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate. MS (ESI) [M/2+H]⁺: m/z 707.1. [00871] Step G: (2S,4R)-1-((S)-2-(4-(2-(1-(((R)-1-(((8-(2-amino-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-4-(3,8-diazabicyclo[3.2.1]octan-3- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)- N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2- carboxamide (Ex-67) [00872] To a solution of tert-butyl 3-(8-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-2-(((R)-1-((4-(2-(1-((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)-1H-1,2,3-triazol-4-yl)ethyl)piperidin-1-yl)methyl)-2,2- difluorocyclopropyl)methoxy)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (49.1 mg, 0.035 mmol) in IPA (0.5 mL) was added HCl/dioxane (1 M in dioxane) at 25 °C under N₂ atmosphere. The mixture was stirred at 25 °C for 2 h. LCMS showed the starting material was consumed and desired MS was formed. The mixture was concentrated in vacuum, the residue was basified to pH 9 by sat. aq. NaHCO₃, and extracted with CH₂Cl₂ (2 mL* 3). The 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 reverse preparative HPLC (Column: Boston Prime C18 150 * 30 mm * 5 um; Condition: water (Water (0.05% NH₃H₂O+10 mM NH₄HCO₃)-ACN; Begin B--End B: 50--80; Gradient Time (min): 2; 100% B Hold Time (min): 25 ; FlowRate (mL/min): 2) to give (2S,4R)-1-((S)-2-(4-(2-(1-(((R)-1-(((8-(2-amino-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-4-(3,8-diazabicyclo[3.2.1]octan-3- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)- N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2- carboxamide (Ex-67). MS (ESI) [M/2+H]⁺: m/z 607.2. ¹H NMR (400MHz, CD₃OD) δ 8.63 (d, J = 5.7 Hz, 1H), 7.85 (s, 1H), 7.73 (d, J = 5.6 Hz, 1H), 7.52 (d, J = 1.8 Hz, 1H), 7.50 - 7.45 (m, 2H), 7.43 (s, 2H), 7.41 (br d, J = 2.3 Hz, 1H), 7.07 (t, J = 8.9 Hz, 1H), 6.30 (d, J = 1.8 Hz, 1H), 5.26 (d, J = 10.1 Hz, 1H), 5.05 (t, J = 6.0 Hz, 1H), 4.63 - 4.59 (m, 2H), 4.59 - 4.54 (m, 1H), 4.47 (br s, 1H), 4.31 - 4.21 (m, 2H), 4.16 (q, J = 7.2 Hz, 2H), 3.93 - 3.88 (m, 1H), 3.83 (d, J = 6.1 Hz, 2H), 3.66 (br dd, J = 7.6, 12.2 Hz, 2H), 3.59 (br s, 2H), 2.87 (br dd, J = 11.5, 20.0 Hz, 2H), 2.79 - 2.73 (m, 1H), 2.66 (br t, J = 7.7 Hz, 2H), 2.54 (td, J = 6.6, 10.2 Hz, 1H), 2.41 (br d, J = 13.4 Hz, 1H), 2.21 (br dd, J = 8.3, 12.4 Hz, 1H), 2.05 - 1.95 (m, 2H), 1.95 - 1.81 (m, 2H), 1.77 (br s, 4H), 1.70 - 1.54 (m, 4H), 1.53 - 1.46 (m, 2H), 1.34 (t, J = 7.2 Hz, 4H), 1.29 (br s, 1H), 1.12 (br d, J = 6.6 Hz, 3H), 1.08 (br d, J = 2.3 Hz, 1H), 0.74 (d, J = 6.7 Hz, 3H). [00873] Example 68: (2S,4R)-1-((2S)-2-(4-((7-(((1R)-1-(((4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-8-(6-methyl-5-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)methyl)-1H-1,2,3-triazol-1-yl)-3- methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4- hydroxypyrrolidine-2-carboxamide (Ex-68)

[00874] Step A: 8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-ol (Int- 11H) [00875] To a solution of 4-(benzyloxy)-8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3- d]pyrimidine (2 g, 5.35 mmol) in TFA (0.412 mL, 5.35 mmol) was stirred at 25 °C for 1 h. The reaction was monitored by LCMS that showed the starting material was disappeared and desired MS was found. Most of the solvent was removed by concentrating in vacuo, then quenched with NaHCO₃ (20 mL), filtered and the filtered cake was collected and dried in vacuum to afford to 8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-ol (Int-11H). MS (ESI) [M+H]⁺: m/z 284.0. [00876] Step B: tert-butyl 3-(8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [00877] To a solution of 8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4- ol (Int-11H) (1.37 g, 4.83 mmol) in MeCN (15 mL) was added BOP (4.27 g, 9.66 mmol) and DIEA (2.53 mL, 14.48 mmol) at 25 °C. The mixture was stirred at 25 °C for 10 min. Then tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.230 g, 5.79 mmol) was added. The mixture was stirred at 25 °C for 16 h. LCMS showed starting material was consumed and desired peak was formed. The mixture was diluted with saturated NaHCO₃ aqueous solution (10 mL), extracted with EtOAc (20 mL * 3). The combined organic phase was washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 14% ethyl acetate in petroleum ether gradient @ 100 mL/min) to give tert-butyl 3-(8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. MS (ESI) [M+H]⁺: m/z 477.9. [00878] Step C: tert-butyl 3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [00879] To a solution of tert-butyl 3-(8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.7 g, 3.56 mmol) in toluene (15mL) was added (6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H- indazol-4-yl)boronic acid (Int-2) (1.517 g, 4.62 mmol), SPhos Pd G3 (1.387 g, 1.778 mmol) and K₂CO₃ (5.33 mL, 10.67 mmol) (2 M in H₂O) in glove box. The reaction was stirred at 50 °C for 16 h under N₂ atmosphere. LCMS showed the reaction was finished, the reaction was diluted with EtOAc (20 mL), washed with brine (30 mL), the organic layer was dried and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 12 g Agela® Silica Flash Column, Eluent of 0~35% THF in Pet. ether gradient @ 40 mL/min, dry loaded) to give tert-butyl 3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. MS (ESI) [M+H]⁺: m/z 726.0. [00880] Step D: tert-butyl 3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [00881] To a solution of tert-butyl 3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.8 g, 2.480 mmol) in DCM (15 mL) were added mCPBA (1.510 g, 7.44 mmol) (85% w/w) at 25 °C, and the reaction mixture was stirred at 25 °C for 1 h. LCMS showed the starting material was consumed and desired product was formed. The mixture was quenched by saturated Na₂SO₃ aqueous solution (5 mL), then the mixture was diluted with sat. NaHCO₃ aqueous solution (5 mL), extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®, 12 g Agela Flash Column, Pet.ether/EtOAc=1/1) to give tert- butyl 3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)-2- (methylsulfonyl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate. MS (ESI) [M+H]⁺: m/z 758.2. [00882] Step E: tert-butyl 3-(2-(((R)-2,2-difluoro-1-((2-(3-(trimethylsilyl)prop-2-yn-1-yl)- 7-azaspiro[3.5]nonan-7-yl)methyl)cyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H- pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [00883] To a solution of tert-butyl 3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.264 mmol) and (R)-(2,2-difluoro-1-((2-(3-(trimethylsilyl)prop-2-yn-1-yl)-7-azaspiro[3.5]nonan-7- yl)methyl)cyclopropyl)methanol (113 mg, 0.317 mmol) in THF (3 mL) was added NaH (52.8 mg, 1.320 mmol) (60% in mineral oil). The reaction was stirred at 20 °C for 3 h. LCMS showed the reaction was finished, the reaction mixture was quenched by poured into aq. NH₄Cl (10 mL), and then extracted with EtOAc (20 mL x 3). The organic layer was washed with brine (20 mL x 3), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 12 g Agela® Silica Flash Column, Eluent of 40~50% ethyl acetate in petroleum ether gradient @ 40 mL/min, dry loaded) to give tert-butyl 3-(2-(((R)-2,2-difluoro-1-((2-(3-(trimethylsilyl)prop- 2-yn-1-yl)-7-azaspiro[3.5]nonan-7-yl)methyl)cyclopropyl)methoxy)-8-(6-methyl-1- (tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. MS (ESI) [M+H]⁺: m/z 1033.4. [00884] Step F: tert-butyl 3-(2-(((R)-2,2-difluoro-1-((2-(prop-2-yn-1-yl)-7- azaspiro[3.5]nonan-7-yl)methyl)cyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H- pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [00885] To a solution of tert-butyl 3-(2-(((R)-2,2-difluoro-1-((2-(3-(trimethylsilyl)prop-2- yn-1-yl)-7-azaspiro[3.5]nonan-7-yl)methyl)cyclopropyl)methoxy)-8-(6-methyl-1- (tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (80 mg, 0.077 mmol) in DMF (2 mL) was added CsF (118 mg, 0.774 mmol). The reaction was stirred at 25 °C for 0.5 h. TLC Plate showed the reaction was finished. The reaction mixture was quenched with water (10 mL), extracted with EtOAc (20 mL x 3), the organic layers were washed with brine (10 mL x 4), dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by preparative TLC (SiO₂, Pet. ether:EtOAc=1:2) to give tert-butyl 3-(2-(((R)- 2,2-difluoro-1-((2-(prop-2-yn-1-yl)-7-azaspiro[3.5]nonan-7- yl)methyl)cyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate. MS (ESI) [M+H]⁺: m/z 961.5. [00886] Step G: tert-butyl 3-(2-(((R)-1-((2-((1-((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)-1H-1,2,3-triazol-4-yl)methyl)-7-azaspiro[3.5]nonan-7-yl)methyl)-2,2- difluorocyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [00887] To a solution of tert-butyl 3-(2-(((R)-2,2-difluoro-1-((2-(prop-2-yn-1-yl)-7- azaspiro[3.5]nonan-7-yl)methyl)cyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H- pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (63 mg, 0.066 mmol) in DCM (3 mL) was added (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5- yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide (Int-33) (36.9 mg, 0.079 mmol), tetrakis(acetonitrile)copper(I) hexafluorophosphate (73.3 mg, 0.197 mmol) and DIEA (0.057 mL, 0.328 mmol) at 25 °C under N₂ atmosphere. The mixture was stirred at 40 °C for 2 h. LCMS showed the starting material was consumed and the desired product was found. The reaction mixture was concentrated in vacuo and then purified by preparative TLC (SiO₂, DCM:MeOH=10:1) to give tert-butyl 3-(2-(((R)-1-((2-((1-((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)-1H-1,2,3-triazol-4-yl)methyl)-7- azaspiro[3.5]nonan-7-yl)methyl)-2,2-difluorocyclopropyl)methoxy)-8-(6-methyl-1- (tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. MS (ESI) [M+H]⁺: m/z 1430.7. [00888] Step H: (2S,4R)-1-((2S)-2-(4-((7-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3- yl)-8-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-2-yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)-7-azaspiro[3.5]nonan-2- yl)methyl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5- yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide (Ex-68) [00889] To a solution of tert-butyl 3-(2-(((R)-1-((2-((1-((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)-1H-1,2,3-triazol-4-yl)methyl)-7-azaspiro[3.5]nonan-7-yl)methyl)- 2,2-difluorocyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (110 mg, 0.077 mmol) in DCM (0.8 mL) was added TFA (0.2 mL, 2.60 mmol). The reaction was stirred at 20 °C for 3 h. LCMS showed the product was detected. The reaction mixture was concentrated in vacuo to remove TFA, and then diluted with NH3 (4 mL, 7 mol/L in MeOH), and then purified by reverse preparative HPLC (Column: henomenex Gemini-NX C18150 * 40 mm * 5 um, condition: water (0.04% NH₃H₂O+10 mM NH₄HCO₃)-ACN) to give (2S,4R)-1-((2S)-2-(4-((7-(((1R)- 1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-(6-methyl-5-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)methyl)-1H-1,2,3-triazol-1-yl)-3- methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4- hydroxypyrrolidine-2-carboxamide (Ex-68). MS (ESI) [M+H]⁺: m/z 1246.3. ¹H NMR (400MHz, CD₃OD) δ 8.68 (d, J = 5.7 Hz, 1H), 7.85 (d, J = 3.8 Hz, 1H), 7.81 (d, J = 5.6 Hz, 1H), 7.74 (s, 1H), 7.52 (d, J = 2.0 Hz, 1H), 7.49-7.45 (m, 2H), 7.44-7.41 (m, 3H), 6.30 (d, J = 1.9 Hz, 1H), 5.26 (d, J = 10.4 Hz, 1H), 5.06 (t, J = 6.1 Hz, 1H), 4.58-4.54 (m, 3H), 4.47 (br s, 1H), 4.37-4.23 (m, 2H), 4.16 (q, J = 7.3 Hz, 2H), 3.92-3.88 (m, 1H), 3.84-3.80 (m, 3H), 3.7-3.66 (m, 2H), 3.63 (br s, 2H), 2.76-2.73 (m, 6H), 2.55-2.50 (m, 2H), 2.40-2.33 (m, 3H), 2.24-2.18 (m, 2H), 2.03-1.96 (m, 1H), 1.87-1.77 (m, 6H), 1.61-1.58 (m, 1H), 1.54-1.52 (m, 2H), 1.42-1.39 (m, 3H), 1.36-1.34 (m, 3H), 1.33-1.32 (m, 3H), 1.11 (d, J = 6.6 Hz, 3H), 0.73 (br d, J = 5.6 Hz, 3H). [00890] Example 69: (2R)-2-((2S,4R)-1-((2S)-2-(4-(2-(1-(((1R)-1-(((4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-8-(6-methyl-5-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)- 4-hydroxypyrrolidine-2-carboxamido)-2-(4-(4-methylthiazol-5-yl)phenyl)ethyl dihydrogen phosphate (Ex-69)

[00891] Step A: ethyl (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4-hydroxypyrrolidine-2- carboxylate [00892] To a solution of cyclohexanamine (S)-2-azido-3-methylbutanoate (700 mg, 2.89 mmol) in DCM (10 ml) was added PyBOP (1503 mg, 2.89 mmol), DIEA (2.52 ml, 14.44 mmol) and ethyl (2S,4R)-4-hydroxypyrrolidine-2-carboxylate hydrochloride (1695 mg, 8.67 mmol) at 20 °C. The mixture was stirred for 2 h at 20 °C. LCMS showed the reaction was completed. The mixture was diluted with water (10 mL) and extracted with DCM (10 mL * 3). The organic layer was dried over Na₂SO₄, filtered and the filtrate was concentrated. The crude product was purified by Prep HPLC (condition: Preparative HPLC on EE instrument fitted with YMC-Actus Triart C18150 * 30 mm * 5 um using the mobile phase A-B: water (0.1%TFA)-ACN, Gradient: 20-40% B, 0-11.5 min; 100% B, 11.5-12.5 min; 10% B,12.5-14.5 min. FlowRate: 40 mL/min) to afford ethyl (2S,4R)-1-((S)-2-azido-3- methylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate. MS (ESI) [M+H]⁺: m/z 285.1. [00893] Step B: tert-butyl (R)-(2-hydroxy-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamate [00894] A mixture of tert-butyl (R)-(1-(4-bromophenyl)-2-hydroxyethyl)carbamate (1 g, 3.16 mmol), 4-methylthiazole (0.627 g, 6.33 mmol), potassium acetate (0.621 g, 6.33 mmol) and palladium(II) acetate (0.071 g, 0.316 mmol) in DMF (20 ml) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 100 °C for 12 h under nitrogen atmosphere. TLC showed the starting material was consumed and new spot was formed. The solution was extracted with ethyl acetate (40 mL x 2) and washed with saturated brine (200 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (ISCO; 12 g Agela Silica Flash Column, Eluent of 0~20% EtOAc/Pet. ether gradient @ 35 mL/min) to give tert-butyl (R)-(2-hydroxy-1-(4- (4-methylthiazol-5-yl)phenyl)ethyl)carbamate. ¹H NMR (400 MHz, CDCl₃) δ 8.68 (s, 1H), 7.47-7.42 (m, 2H), 7.40-7.35 (m, 2H), 5.33 (br d, J = 7.2 Hz, 1H), 4.83 (br d, J = 1.2 Hz, 1H), 4.02-3.78 (m, 2H), 2.54 (s, 3H), 1.46 (br s, 9H). [00895] Step C: tert-butyl (R)-(1-(4-(4-methylthiazol-5-yl)phenyl)-2- (phosphonooxy)ethyl)carbamate [00896] Tert-butyl (R)-(2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamate (600 mg, 1.794 mmol) and TEA (1.250 ml, 8.97 mmol) were dissolved in THF (10 ml), and the mixture was added dropwise at 0 °C to a stirring solution of POCl₃ (0.284 ml, 3.05 mmol) in THF (3 ml) and the corresponding mixture was left stirring at 0 °C for 2 h. LCMS showed the desired target was formed. The reaction mixture was poured into a solution of aq. HCl (1 M, 15 mL) while cooling with ice and then extracted with ethyl acetate (4 x 50 mL). Finally, the organic phases were washed with saturated sodium chloride solution (2 x 50 mL), dried over anhydrous Na₂SO₄ and concentrated under vacuum. The crude residues were purified by Prep HPLC (condition: Preparative HPLC on EE instrument fitted with YMC-Actus Triart C18150 * 30 mm * 5 um using the mobile phase A-B: water(0.1% TFA)-ACN, Gradient: 20-50% B, 0-11.5 min; 100% B, 11.5-12.5 min; 10% B,12.5-14.5 min. FlowRate: 40 mL/min) to give tert-butyl (R)-(1-(4-(4-methylthiazol-5-yl)phenyl)-2- (phosphonooxy)ethyl)carbamate. MS (ESI) [M+H]⁺: m/z 415.1. [00897] Step D: (R)-2-amino-2-(4-(4-methylthiazol-5-yl)phenyl)ethyl dihydrogen phosphate [00898] Tert-butyl (R)-(1-(4-(4-methylthiazol-5-yl)phenyl)-2- (phosphonooxy)ethyl)carbamate (200 mg, 0.483 mmol) was dissolved in MeOH (3 ml), and then 1,4-dioxane hydrochloride (1.207 ml, 2.413 mmol) was added, and the reaction was stirred at 25 °C for 1 h. LCMS showed starting material was consumed and the desired target was formed. The mixture was concentrated under reduced pressure to afford (R)-2- amino-2-(4-(4-methylthiazol-5-yl)phenyl)ethyl dihydrogen phosphate. MS (ESI) [M+H]⁺: m/z 314.9. [00899] Step E: 8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-ol (Int- 11H) [00900] A solution of 4-(benzyloxy)-8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3- d]pyrimidine (2.0 g, 5.35 mmol) in TFA (20 mL) was stirred at 25 °C for 30 min. LCMS showed the starting material was consumed and the desired mass was found. The solvent was removed under reduced pressure. The crude was basified by aq. Na₂CO₃, and then filtered to give the filtrate cake 8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-ol (Int-11H). MS (ESI) [M+H]⁺: m/z 284.1 [00901] Step F: tert-butyl 3-(8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [00902] To a solution of 8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4- ol (Int-11H) (500 mg, 1.762 mmol) in acetonitrile (5 mL) was added BOP (779 mg, 1.762 mmol), DIEA (0.308 mL, 1.762 mmol) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8- carboxylate (411 mg, 1.938 mmol) at 25 °C. The mixture was stirred at 60 °C for 2 h. LCMS showed the starting material was consumed and the desired mass was found. The solvent was removed under reduced pressure. The crude was purified by MPLC (ISCO®; 12 g SepaFlash® Silica Flash Column, eluent of 0~30% EtOAc/petroleum ether gradient @ 30 mL/min) to give tert-butyl 3-(8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. MS (ESI) [M+H]⁺: m/z 478.2. [00903] Step G: tert-butyl 3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [00904] To a solution of tert-butyl 3-(8-chloro-2-(methylthio)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (463.0 mg, 0.969 mmol) in toluene (5 mL) was added methanesulfonato(diadamantyl-N-butylphosphino)-2'-amino-1,1'- biphenyl-2-yl)palladium(II) dichloromethane adduct (79 mg, 0.097 mmol), (6-methyl-1- (tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)boronic acid (Int-2) (350 mg, 1.065 mmol) and K₂CO₃ (1.453 mL, 2.91 mmol) (2 M in water) at 25 °C under N₂ atmosphere. The mixture was stirred at 70 °C for 12 h. LCMS showed the starting material was consumed and the desired mass was found. The reaction was diluted with water (2.0 mL), and then extracted with EtOAc (20 mL * 2 ). The combined organic layer was dried with Na₂SO₄, filtered and the solvent was removed under reduced pressure. The crude was purified by MPLC (ISCO®; 12 g SepaFlash® Silica Flash Column, eluent of 0~30% EtOAc/petroleum ether gradient @ 30 mL/min) to give tert-butyl 3-(8-(6-methyl-1- (tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)-2- (methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate. MS (ESI) [M+H]⁺: m/z 726.3. [00905] Step H: tert-butyl 3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [00906] To a solution of tert-butyl 3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-(methylthio)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.413 mmol) in DCM (0.5 mL) was added mCPBA (252 mg, 1.240 mmol) at 25 °C. The mxiture was stirred at 25 °C for 3 h. LCMS showed the starting material was consumed and the desired mass was found. The mixture was quenched with aq. NaHCO₃ (6 mL) and aq. Na₂SO₃ (6 mL), and then extracted with DCM (30 mL * 2). The combined organic layer was dried with Na₂SO₄, filtered and the solvent was removed under reduced pressure. The crude was purified by MPLC (ISCO®; 12 g SepaFlash® Silica Flash Column, eluent of 0~20% MeOH/DCM gradient @ 30 mL/min) to give tert-butyl 3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. MS (ESI) [M+H]⁺: m/z 758.2. [00907] Step I: tert-butyl 3-(2-(((R)-2,2-difluoro-1-((4-(4-(trimethylsilyl)but-3-yn-1- yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)- 5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [00908] A solution of tert-butyl 3-(8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-(methylsulfonyl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (310 mg, 0.409 mmol) and (R)-(2,2-difluoro-1-((4-(4-(trimethylsilyl)but-3-yn-1-yl)piperidin-1- yl)methyl)cyclopropyl)methanol (Int-48) (202 mg, 0.614 mmol) in THF (0.5 mL) was added NaH (82 mg, 2.045 mmol) (60% in mineral oil) under N₂. The mixture was stirred at 25 °C for 30 min. LCMS showed the starting material was consumed and the desired mass was found. The mixture was quenched with H₂O (2 mL), and then extracted with EtOAc (10 mL * 2). The combined organic layer was dried with Na₂SO₄, filtered and the solvent was removed under reduced pressure. The crude was purified by prep-TLC (SiO₂, DCM/MeOH=10:1) to give tert-butyl 3-(2-(((R)-2,2-difluoro-1-((4-(4-(trimethylsilyl)but-3- yn-1-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran- 2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate. MS (ESI) [M+H]⁺: m/z 1007.3. [00909] Step J: tert-butyl 3-(2-(((R)-1-((4-(but-3-yn-1-yl)piperidin-1-yl)methyl)-2,2- difluorocyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [00910] To a solution of tert-butyl 3-(2-(((R)-2,2-difluoro-1-((4-(4-(trimethylsilyl)but-3- yn-1-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran- 2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (280 mg, 0.278 mmol) in MeOH (2 mL) was added CsF (422 mg, 2.78 mmol) at 25 °C. The mixture was stirred at 25 °C for 1 h. LCMS showed the starting material was consumed and the desired mass was found. The solution was filtered and concentrated in vacuo to give tert-butyl 3-(2-(((R)-1-((4-(but-3-yn-1- yl)piperidin-1-yl)methyl)-2,2-difluorocyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H- pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. MS (ESI) [M+H]⁺: m/z 935.4. [00911] Step K: tert-butyl 3-(2-(((R)-1-((4-(2-(1-((S)-1-((2S,4R)-2-(ethoxycarbonyl)-4- hydroxypyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)ethyl)piperidin-1- yl)methyl)-2,2-difluorocyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [00912] To a solution of tert-butyl 3-(2-(((R)-1-((4-(but-3-yn-1-yl)piperidin-1-yl)methyl)- 2,2-difluorocyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (240 mg, 0.257 mmol) in DCM (5 mL) was added ethyl (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate (73.0 mg, 0.257 mmol), tetrakis(acetonitrile)copper(I) hexafluorophosphate (143 mg, 0.385 mmol) and DIEA (0.291 mL, 1.668 mmol) at 20 °C under N₂. The mixture was stirred at 40 °C for 16 h. LCMS showed the reaction was completed. The reaction was directly concentrated to afford the crude product. The crude product was purified by MPLC (ISCO®; 4 g SepaFlash® Silica Flash Column, eluent of 0~10% MeOH/DCM gradient @ 30 mL/min) to give tert-butyl 3-(2-(((R)-1-((4-(2-(1-((S)-1-((2S,4R)-2-(ethoxycarbonyl)-4- hydroxypyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)ethyl)piperidin-1- yl)methyl)-2,2-difluorocyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate. MS (ESI) [M+H]⁺: m/z 1219.3. [00913] Step L: (2S,4R)-1-((2S)-2-(4-(2-(1-(((1R)-1-(((4-(8-(tert-butoxycarbonyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2- yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-1- yl)-3-methylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid [00914] To a solution of tert-butyl 3-(2-(((R)-1-((4-(2-(1-((S)-1-((2S,4R)-2- (ethoxycarbonyl)-4-hydroxypyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4- yl)ethyl)piperidin-1-yl)methyl)-2,2-difluorocyclopropyl)methoxy)-8-(6-methyl-1- (tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (240 mg, 0.197 mmol) in THF:H₂O = 3:1 (4 mL) was added lithium hydroxide hydrate (16.52 mg, 0.394 mmol) (4 M in H₂O) at 15 °C. The mixture was stirred at 15 °C for 2 h. LCMS showed the reaction was completed. The reaction was directly concentrated to afford (2S,4R)-1-((2S)-2-(4-(2-(1- (((1R)-1-(((4-(8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-(6-methyl-1- (tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-2-yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)piperidin-4-yl)ethyl)-1H- 1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid. MS (ESI) [M+H]⁺: m/z 1191.3. [00915] Step M: tert-butyl 3-(2-(((R)-2,2-difluoro-1-((4-(2-(1-((S)-1-((2S,4R)-4-hydroxy- 2-(((R)-1-(4-(4-methylthiazol-5-yl)phenyl)-2-(phosphonooxy)ethyl)carbamoyl)pyrrolidin-1- yl)-3-methyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)ethyl)piperidin-1- yl)methyl)cyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [00916] To a stirring solution of (2S,4R)-1-((2S)-2-(4-(2-(1-(((1R)-1-(((4-(8-(tert- butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-(6-methyl-1-(tetrahydro-2H-pyran-2- yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2- yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-1- yl)-3-methylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid (50 mg, 0.042 mmol) in DMSO:MeCN = 1:1 (2 mL) was added (R)-2-amino-2-(4-(4-methylthiazol-5- yl)phenyl)ethyl dihydrogen phosphate (17.15 mg, 0.055 mmol), DIEA (0.022 mL, 0.126 mmol) and HATU (19.15 mg, 0.050 mmol) at 20 °C, and the reaction mixture was stirred at 20 °C for 10 min. LCMS showed the starting material was consumed and desired mass was formed. The reaction mixture was filtered, and the filtrate was purified by Prep HPLC (condition: Preparative HPLC on EJ instrument fitted with Phenomenex Synergi C18150 * 30 MM * 4 um using the mobile phase A-B: water (0.1%TFA)-ACN, Gradient: 40-60% B, 0-10 min; 100% B, 10-12 min; 10% B,12-14 min. FlowRate: 25 mL/min) to give tert-butyl 3-(2-(((R)-2,2-difluoro-1-((4-(2-(1-((S)-1-((2S,4R)-4-hydroxy-2-(((R)-1-(4-(4- methylthiazol-5-yl)phenyl)-2-(phosphonooxy)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1- oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)ethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-8- (6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate. MS (ESI) [M/2+H]⁺: m/z 744.7. [00917] Step N: (2R)-2-((2S,4R)-1-((2S)-2-(4-(2-(1-(((1R)-1-(((4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-8-(6-methyl-5-(trifluoromethyl)-1H-indazol-4- yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)- 4-hydroxypyrrolidine-2-carboxamido)-2-(4-(4-methylthiazol-5-yl)phenyl)ethyl dihydrogen phosphate (Ex-69) [00918] To a solution of tert-butyl 3-(2-(((R)-2,2-difluoro-1-((4-(2-(1-((S)-1-((2S,4R)-4- hydroxy-2-(((R)-1-(4-(4-methylthiazol-5-yl)phenyl)-2- (phosphonooxy)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)-1H-1,2,3- triazol-4-yl)ethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-8-(6-methyl-1-(tetrahydro- 2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40 mg, 0.027 mmol) in DCM (1 mL) was added TFA (0.200 mL) at 20 °C. The mxiture was stirred at 20 °C for 30 min. LCMS showed the starting material was consumed and desired mass was found. The solvent was removed under reduced pressure. The crude was purified by Prep HPLC (condition: Preparative HPLC on EJ instrument fitted with Phenomenex Synergi C18 150*30MM*4um using the mobile phase A-B: water(0.1%TFA)-ACN, Gradient: 25-45% B, 0-10 min; 100% B, 10-12 min; 10% B,12-14 min. FlowRate: 25 mL/min) to afford (2R)- 2-((2S,4R)-1-((2S)-2-(4-(2-(1-(((1R)-1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-(6- methyl-5-(trifluoromethyl)-1H-indazol-4-yl)pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-2- yl)oxy)methyl)-2,2-difluorocyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-1- yl)-3-methylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-2-(4-(4-methylthiazol-5- yl)phenyl)ethyl dihydrogen phosphate (Ex-69). MS (ESI) [M+H]⁺: m/z 652.6. ¹H NMR (400MHz, CD₃OD) δ 8.78 - 8.93 (m, 1 H), 8.56 - 8.70 (m, 1 H), 7.75 - 7.96 (m, 2 H), 7.67 (s, 1 H), 7.22 - 7.51 (m, 5 H), 5.24 (d, J=10.13 Hz, 1 H), 5.04 - 5.15 (m, 1 H), 4.67 (br d, J=12.76 Hz, 1 H), 4.37 - 4.51 (m, 4 H), 4.32 (br d, J=12.99 Hz, 1 H), 4.04 - 4.26 (m, 4 H), 3.88 - 4.04 (m, 2 H), 3.69 - 3.88 (m, 3 H), 3.57 - 3.68 (m, 2 H), 3.24 - 3.31 (m, 1 H), 2.89 - 3.06 (m, 2 H), 2.69 (br t, J=7.27 Hz, 2 H), 2.64 (br s, 3 H), 2.42 - 2.51 (m, 1 H), 2.31 - 2.40 (m, 3 H), 2.18 (br dd, J=12.34, 7.45 Hz, 1 H), 1.94 - 2.11 (m, 6 H), 1.80 - 1.93 (m, 2 H), 1.44 - 1.74 (m, 6 H), 0.96 - 1.11 (m, 3 H), 0.60 - 0.75 (m, 3 H).

[00919] Examples 70 & 71: (2S,4R)-1-((2S)-2-(4-(2-(1-(((1R)-1-(((4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-9-methyl-8-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)- 9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)- N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2- carboxamide (Ex-70 & 71)

[00920] Step A: 2,4,8-trichloro-9-methyl-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine [00921] To a solution of 2,4,8-trichloro-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine (100 mg, 0.366 mmol) in THF (3 mL) was added NaH (51.2 mg, 1.280 mmol) at 0 °C under N₂ atmosphere, and then the mixture was stirred at 0 °C for 1 h. Then iodomethane (130 mg, 0.914 mmol) was added to the mixture and the resulting mixture was stirred at 15 °C for 16 h. The reaction was monitored by TLC Plate that showed the starting material was disappeared and new spot was found. [00922] Step B: tert-butyl 3-(2,8-dichloro-9-methyl-9H-pyrido[4',3':4,5]pyrrolo[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [00923] Tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (116 mg, 0.548 mmol) was added to the mixture of Step A. The mixture was stirred at 15 °C for 16 h. LCMS showed starting material was consumed and desired peak was formed. The mixture was cooled, quenched with sat. aq. NH₄Cl (5 mL), extracted with EtOAc (3 * 4 mL). The organic phase 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 30% ethyl acetate in petroleum ether gradient @ 40 mL/min) to give tert-butyl 3-(2,8-dichloro-9-methyl-9H- pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. MS (ESI) [M+H]⁺: m/z 463.0. [00924] Step C: tert-butyl 3-(8-chloro-9-methyl-2-(methylthio)-9H- pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [00925] To a solution of tert-butyl 3-(2,8-dichloro-9-methyl-9H- pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1 g, 2.158 mmol) in 2-propanol (10 mL) was added sodium methanethiolate (0.230 g, 3.28 mmol). The mixture was stirred at 20 °C for 16 h. LCMS showed the starting material was consumed and the desired MS was found. The reaction was quenched with H₂O (10 mL), extracted with EtOAc (10 mL * 3). The organic layer was dried over Na₂SO₄, filtered and concentrated in vacuo. The crude was purified by flash silica gel chromatography (ISCO®; 12 g Agela® Silica Flash Column, Eluent of 30% ethyl acetate in petroleum ether gradient @ 20 mL/min) to afford tert-butyl 3-(8-chloro-9-methyl-2-(methylthio)-9H- pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. MS (ESI) [M+H]⁺: m/z 475.0. [00926] Step D: tert-butyl 3-(9-methyl-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-(methylthio)-9H-pyrido[4',3':4,5]pyrrolo[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [00927] To a solution of tert-butyl 3-(8-chloro-9-methyl-2-(methylthio)-9H- pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (360 mg, 0.758 mmol) in toluene (2 mL) was added (6-methyl-1-(tetrahydro-2H-pyran-2- yl)-5-(trifluoromethyl)-1H-indazol-4-yl)boronic acid (298 mg, 0.909 mmol), (2- dicyclohexylphosphino-2',6'-dimethoxybiphenyl) [2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (296 mg, 0.379 mmol) and K₂CO₃ (1.137 mL, 2.274 mmol) (2 M in water). The reaction was stirred at 80 °C for 1 h under N₂ atmosphere. LCMS showed the starting material was consumed and the desired MS was found. The reaction mixture was concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 12 g Agela® Silica Flash Column, Eluent of 35% ethyl acetate in petroleum ether gradient @ 40 mL/min) to give tert-butyl 3-(9-methyl-8-(6-methyl-1-(tetrahydro-2H-pyran- 2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)-2-(methylthio)-9H-pyrido[4',3':4,5]pyrrolo[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. MS (ESI) [M+H]⁺: m/z 723.2. [00928] Step E: tert-butyl 3-(9-methyl-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5- (trifluoromethyl)-1H-indazol-4-yl)-2-(methylsulfonyl)-9H-pyrido[4',3':4,5]pyrrolo[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [00929] To a solution of tert-butyl 3-(9-methyl-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)- 5-(trifluoromethyl)-1H-indazol-4-yl)-2-(methylthio)-9H-pyrido[4',3':4,5]pyrrolo[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.277 mmol) in CH₂Cl₂ (4 mL) was added mCPBA (169 mg, 0.830 mmol). The mixture was stirred at 20 °C for 1 h. LCMS showed the starting material was consumed and new spot was found. The reaction was quenched with aq. NaHCO₃ (10 mL), extracted with EtOAc (50 mL * 3), the organic layer was dried over Na₂SO₄, filtered and concentrated in vacuo. The crude was purified by flash silica gel chromatography (ISCO®; 40 g Agela® Silica Flash Column, Eluent of 30% ethyl acetate in petroleum ether gradient @ 40 mL/min) to afford tert-butyl (1R,5S)-3-(9-methyl-8-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H- indazol-4-yl)-2-(methylsulfonyl)-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate. MS (ESI) [M+H]⁺: m/z 755.2. [00930] Step F: tert-butyl (1R,5S)-3-(2-(((R)-2,2-difluoro-1-((4-(4-(trimethylsilyl)but-3- yn-1-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-9-methyl-8-(6-methyl-1-(tetrahydro- 2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)-9H-pyrido[4',3':4,5]pyrrolo[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [00931] To a solution of tert-butyl (1R,5S)-3-(9-methyl-8-(6-methyl-1-(tetrahydro-2H- pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)-2-(methylsulfonyl)-9H- pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (160 mg, 0.212 mmol) and (R)-(2,2-difluoro-1-((4-(4-(trimethylsilyl)but-3-yn-1- yl)piperidin-1-yl)methyl)cyclopropyl)methanol (Int-48) (77 mg, 0.233 mmol) in THF (0.5 mL) was added NaH (42.4 mg, 1.060 mmol) (60% in mineral oil). The reaction was stirred at 20 °C for 2 h. LCMS showed the reaction was finished, the reaction mixture was quenched by aq. NH₄Cl (10 mL), and then extracted with EtOAc (10 mL * 3), the organic layer was washed with brine (10 mL * 3), dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 12 g Agela® Silica Flash Column, Eluent of 30% ethyl acetate in petroleum ether gradient @ 40 mL/min) to give tert-butyl (1R,5S)-3-(2-(((R)-2,2-difluoro-1-((4-(4-(trimethylsilyl)but-3-yn-1- yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-9-methyl-8-(6-methyl-1-(tetrahydro-2H- pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)-9H-pyrido[4',3':4,5]pyrrolo[2,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. MS (ESI) [M+H]⁺: m/z 1004.5. [00932] Step G: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((R)-1-((4-(but-3-yn-1- yl)piperidin-1-yl)methyl)-2,2-difluorocyclopropyl)methoxy)-9-methyl-8-(6-methyl-5- (trifluoromethyl)-1H-indazol-4-yl)-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine [00933] To a solution of tert-butyl (1R,5S)-3-(2-(((R)-2,2-difluoro-1-((4-(4- (trimethylsilyl)but-3-yn-1-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-9-methyl-8-(6- methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)-9H- pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (140 mg, 0.139 mmol) in DCM (0.8 mL) was added TFA (0.2 mL, 2.60 mmol). The reaction was stirred at 20 °C for 0.5 h. LCMS showed the starting material was consumed and the product was found. The reaction was quenched with aq. NaHCO₃ (10 mL), extracted with EtOAc (50 mL * 3). The combined organic layer was washed with brine (10 mL), dried over Na₂SO₄, filtered and concentrated in vacuo to afford racemic 4-((1R,5S)- 3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((R)-1-((4-(but-3-yn-1-yl)piperidin-1-yl)methyl)-2,2- difluorocyclopropyl)methoxy)-9-methyl-8-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)- 9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine. MS (ESI) [M+H]⁺: m/z 748.3. [00934] Step H: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((R)-1-((4-(but-3-yn-1- yl)piperidin-1-yl)methyl)-2,2-difluorocyclopropyl)methoxy)-9-methyl-8-(6-methyl-5- (trifluoromethyl)-1H-indazol-4-yl)-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine [00935] The racemic 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((R)-1-((4-(but-3- yn-1-yl)piperidin-1-yl)methyl)-2,2-difluorocyclopropyl)methoxy)-9-methyl-8-(6-methyl-5- (trifluoromethyl)-1H-indazol-4-yl)-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine (104 mg, 0.139 mmol) was separated by preparative SFC (column: DAICEL CHIRALPAK IC (250 mm * 30 mm, 5 um), condition: CO₂-EtOH (0.1% NH₃H₂O)) to give 4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-2-(((R)-1-((4-(but-3-yn-1-yl)piperidin-1-yl)methyl)-2,2- difluorocyclopropyl)methoxy)-9-methyl-8-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)- 9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine (the first eluting isomer from SFC) and 4- ((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((R)-1-((4-(but-3-yn-1-yl)piperidin-1- yl)methyl)-2,2-difluorocyclopropyl)methoxy)-9-methyl-8-(6-methyl-5-(trifluoromethyl)- 1H-indazol-4-yl)-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine the second eluting isomer from SFC). MS (ESI) [M+H]⁺: m/z 748.3. [00936] Step I: (2S,4R)-1-((2S)-2-(4-(2-(1-(((1R)-1-(((4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-9-methyl-8-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)- 9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)- N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2- carboxamide (Ex-70 & 71) [00937] To a solution of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((R)-1-((4-(but- 3-yn-1-yl)piperidin-1-yl)methyl)-2,2-difluorocyclopropyl)methoxy)-9-methyl-8-(6-methyl- 5-(trifluoromethyl)-1H-indazol-4-yl)-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine (30 mg, 0.040 mmol) in CH₂Cl₂ (2 mL) was added (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-N- ((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2- carboxamide (Int-33) (22.60 mg, 0.048 mmol), tetrakis(acetonitrile)copper(I) hexafluorophosphate (44.9 mg, 0.120 mmol) and DIEA (0.035 mL, 0.201 mmol) at 20 °C under N₂ atmosphere. The mixture was stirred at 40 °C for 2 h. LCMS showed the starting material was consumed and the desired product was found. The reaction mixture was concentrated in vacuo and then diluted with NH₃ (7 M in MeOH) (3 mL), and then purified by HPLC (Column: Boston Prime C18150 * 30 mm * 5 um, condition: Water (0.05% NH₃H₂O+10 mM NH₄HCO₃)-ACN) to give (2S,4R)-1-((2S)-2-(4-(2-(1-(((1R)-1-(((4- ((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-9-methyl-8-(6-methyl-5-(trifluoromethyl)-1H- indazol-4-yl)-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-2-yl)oxy)methyl)-2,2- difluorocyclopropyl)methyl)piperidin-4-yl)ethyl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)- N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2- carboxamide (Ex-70 & 71). [00938] Ex-70 (from first eluting isomer from SFC): ¹H NMR (400MHz, CD₃OD) δ 8.41 (d, J = 5.4 Hz, 1H), 7.91-7.83 (m, 2H), 7.75 (s, 1H), 7.52 (d, J = 1.9 Hz, 1H), 7.50 -7.46 (m, 2H), 7.44 - 7.41 (m, 2H), 7.36 (s, 1H), 6.30 (d, J = 2.1 Hz, 1H), 5.27 (d, J = 10.3Hz, 1H), 5.07 - 5.40 (m, 1H), 4.61 (s, 3H), 4.59 - 4.55 (m, 2H), 4.49 - 4.47 (m, 1H), 4.20 - 4.14 (m, 2H), 3.93 - 3.88 (m, 1H), 3.84 - 3.82 (m, 4H), 3.76 - 3.69 (m, 2H), 3.64 (s, 1H), 3.54 - 3.48 (m, 1H), 3.13 (br s, 1H), 3.11 (s, 3H), 2.96 - 2.88 (m, 2H), 2.74 (s, 3H), 2.71 - 2.66 (m, 2H), 2.59 - 2.51 (m, 1H), 2.49 - 2.43 (m, 1H), 2.23 - 2.17 (m, 2H), 2.06 - 1.99 (m, 3H), 1.93 (br s, 3H), 1.69 (br d, J = 2.1 Hz, 2H), 1.62 - 1.58 (m, 2H), 1.55 - 1.52 (m, 2H), 1.43 - 1.40 (m, 1H), 1.12 (br d, J = 6.7 Hz, 3H), 0.92 - 0.87 (m, 4H), 0.74 (br d, J = 6.6Hz, 3H). MS (ESI) [M+H]⁺: m/z 1217.4. [00939] Ex-71 (from second eluting isomer from SFC): ¹H NMR (400MHz, CD₃OD) δ 8.42 (d, J = 5.5 Hz, 1H), 7.88 - 7.85 (m, 2H), 7.75 (s, 1H), 7.52 (d, J = 1.8 Hz, 1H), 7.51 - 7.46 (m, 2H), 7.44 - 7.41 (m, 2H), 7.36 (s, 1H), 6.30 (d, J = 2.0 Hz, 1H), 5.27 (d, J = 10.3Hz, 1H), 5.07 - 5.40 (m, 1H), 4.61 (s, 3H), 4.59 - 4.55 (m, 2H), 4.49 - 4.47(m, 1H), 4.20 - 4.14 (m, 2H), 3.93 - 3.88 (m, 1H), 3.84 - 3.82 (m, 4H), 3.76 - 3.69 (m, 2H), 3.64-3.58 (m, 1H), 3.54 - 3.48 (m, 1H), 3.15 - 3.12 (m, 1H), 3.11 (s, 3H), 2.93 - 2.84 (m, 2H), 2.74 (s, 3H), 2.71 - 2.66 (m, 2H), 2.59 - 2.51 (m, 1H), 2.49 - 2.43 (m, 1H), 2.21 - 2.17 (m, 2H), 2.06 - 1.99 (m, 3H), 1.92 (br s, 3H), 1.72 - 1.66 (m, 2H), 1.62 - 1.58 (m, 2H), 1.53 - 1.49 (m, 2H), 1.41 - 1.39 (m, 1H), 1.12 (br d, J = 6.4 Hz, 3H), 0.92 - 0.87 (m, 4H), 0.74 (br d, J = 6.6Hz, 3H). MS (ESI) [M+H]⁺: m/z 1217.4. Assays [00940] HiBiT Potency Data [00941] 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 24 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.

Claims

We claim: 1. A compound of Formula (I) wherein: M^L is selected from the group consisting of: Ring C^L is selected from: (i) a 7- to 14-membered spirocyclic heterocyclylene 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 or a 7- to 10-membered bridged bicyclic heterocyclylene 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 C^L is unsubstituted or substituted by 1 to 3 R^CL substituents independently selected from the group consisting of halo, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, and C₁- C₃ alkoxy; Ring C^y is a 3- to 6-membered monocyclic or a 5- to 8-membered bridged bicyclic cycloalkylene; wherein Ring C^y is unsubstituted or substituted by 1 to 2 R^Cy substituents independently selected from the group consisting of halo, C₁-C₃ alkyl, and C₁-C₃ fluoroalkyl, each of L^b1, L^b2, L^b3, and L^b4 is independently -CH₂-, -O-, C₄-C₆ cycloalkylene, or absent; L^c is C₁-C₃ alkyl or H; L^e is selected from the group consisting of: R⁵ is H or C₁-C₃ alkyl; X^e, X^f, X^g, and X^h are independently selected from the group consisting of C, C(H), C(R^Le), N, O, and S; wherein at least one of X^e, X^f, X^g, and X^h is C, C(H), or C(R^Le); Xⁱ is C or N; each R^Le substituent is independently selected from the group consisting of halo, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, and C₁-C₃ alkoxy; R¹ is C₁-C₆ alkyl, -CH₂-C1, C₃-C₇ cycloalkyl, or C₃-C₇ heterocycloalkyl containing 1 to 2 heteroatoms selected from the group consisting of N, O, and S; wherein C¹ is C₃-C₇ cycloalkyl; R² is H, C₁-C₆ alkyl, -CH₂OH, or -CH₂OP(=O)(OH)₂; each R^c is independently fluoro or C₁-C₃ alkyl; each R³ is independently H, fluoro, C₁-C₃ alkyl, or C₁-C₃ fluoroalkyl; X^a, X^b, X^c and X^d are independently selected from the group consisting of C(H), C(R⁴), N, N(R⁴), S, and O; wherein at least one of X^a, X^b, X^c and X^d is C(H) or C(R⁴); R⁴ is halo, C₁-C₃ alkyl, or C₁-C₃ fluoroalkyl; W^A is S, O, or N(R^W1); R^W1 is selected from the group consisting of C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₃-C₆ cycloalkyl, and C₃-C₆ fluorocycloalkyl; Ring A is a saturated 5- to 8-membered N-containing monocyclic heterocyclyl or a saturated 8- to 10-membered N-containing bridged bicyclic heterocyclyl, wherein the saturated 8- to 10-membered N-containing bridged bicyclic heterocyclyl contains at least one further N atom in addition to the illustrated N atom; R^A is selected from the group consisting of C₁-C₃ alkyl, C₂-C₄ alkenyl, C₁-C₃ alkoxy, C₁- C₃ alkoxy(C₁-C₃)alkyl, halo, C₁-C₃ fluoroalkyl, hydroxy, C₁-C₃ hydroxyalkyl, CF₃- C(H)(OH)-, C(H)(F₂)-C(H)(OH)-, cyano, and C₁-C₃ cyanoalkyl; Y is (i) 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; (ii) a 12- to 14-membered tricyclic heterocyclyl, where at least 2 of the rings of the 12- to 14-membered tricyclic heterocyclyl are aromatic, the third ring is unsaturated or aromatic, wherein the 12- to 14-membered tricyclic heterocyclyl contains 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S; or (iii) phenyl or naphthyl; wherein Y is unsubstituted or substituted by 1 to 4 R^Y substituents independently selected from the group consisting of halo, hydroxy, C₁-C₃ alkyl, C₂-C₄ alkynyl, C₁-C₃ fluoroalkyl, C₃-C₆ cycloalkyl, C₃-C₆ fluorocycloalkyl, C₂- C₃ acyl, C₁-C₃ alkoxy, C₁-C₃ fluoroalkoxy, C₁-C₃ alkylthio, C₁-C₃ fluoroalkylthio, amino, C₁-C₃ alkylamino, C₁-C₃ dialkylamino, and cyano; or alternatively, 2 R^Y substituents, together with the carbon atom to which both are attached, form a 3- to 5-membered saturated carbocyclic ring; subscript i is 0, 1, or 2; subscript m is 0, 1, or 2; subscript n is 0, 1, 2, or 3; subscript o1 is 0 or 1; subscript o2 is 0 or 1; subscript o3 is 0 or 1; subscript o4 is 0 or 1; subscript o5 is 1,

2,

3,

4, or 5; and subscript u is 0 or 1; or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein the moiety is selected from the group consisting of: 3. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein M^L is 4. The compound of claim 3 or the pharmaceutically acceptable salt thereof, wherein M^L is selected from the group consisting of:

5. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein M^L is

6. The compound of claim 5 or the pharmaceutically acceptable salt thereof, wherein M^L is selected from the group consisting of:

7. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein M^L _is

8. The compound of claim 7 or the pharmaceutically acceptable salt thereof, wherein M^L _is

9. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein L^e

10. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein _W ^A _{is S.}

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

12. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein Y is unsubstituted or substituted phenyl, naphthyl, pyridyl, indazolyl, benzothienyl, benzoxazolyl, benzothiazolyl, or isoquinolinyl.

13. The compound of claim 12 or the pharmaceutically acceptable salt thereof, wherein Y is naphthyl or indazolyl, wherein Y is substituted by 1 to 3 R^Y substituents independently selected from the group consisting of halo, hydroxy, amino, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₃-C₆ cycloalkyl, C₃-C₆ fluorocycloalkyl, C₂-C₄ alkynyl, and cyano.

14. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein Y is selected from the group consisting of:

_{and wherein subscript s is 0, 1, 2,} 3, or 4.

15. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein Y wherein subscript s is 0, 1, 2, or 3.

16. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein Y is selected from the group consisting of: wherein subscript s is 0, 1, 2, or 3.

17. The compound of claim 16 or the pharmaceutically acceptable salt thereof, wherein Y is selected from the group consisting of:

18. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein R¹ is tert-butyl or isopropyl.

19. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein R² is H or methyl.

20. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein each R³ is H.

21. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein the moiety

22. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of Example Nos.1-71.

23. A pharmaceutical composition comprising the compound of any one of claims 1-22 or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

24. A pharmaceutical composition comprising the compound of any one of claims 1-22 or the pharmaceutically acceptable salt thereof, an additional anti -cancer agent, and a pharmaceutically acceptable carrier.

25. A method of degrading KRAS G12D protein in a cell, comprising administering the compound of any one of claims 1-22 or the pharmaceutically acceptable salt thereof, resulting in degradation of the KRAS G12D protein in the cell.

26. A method of treating cancer comprising administering a therapeutically effective amount of the compound of any one of claims 1-22 or the pharmaceutically acceptable salt thereof, to a subject in need of such treatment.

27. The method of claim 26, further comprising administering an additional active agent to the subject.

28. The compound of any one of claims 1-22 or the pharmaceutically acceptable salt thereof, for use in therapy, or use of the compound of any one of claims 1-22 or the pharmaceutically acceptable salt thereof, in therapy.

29. The compound of any one of claims 1-22 or the pharmaceutically acceptable salt thereof, for use in treating cancer, or use of a compound of any one of claims 1-22 or the pharmaceutically acceptable salt thereof, for treating cancer.

30. The compound of any one of claims 1-22 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 1-22 or the pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of cancer.

31. The compound of any one of claims 1-22 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 1-22 or the pharmaceutically acceptable salt thereof, and the additional anti -cancer agent for treating cancer.

32. The compound of any one of claims 1-22 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 1-22 or the pharmaceutically acceptable salt thereof, and the additional anti -cancer agent, for the preparation of a medicament for the treatment of cancer.

33. A pharmaceutical composition comprising the compound of any one of claims 1-22 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 1-22 or the pharmaceutically acceptable salt thereof, for treating cancer.

34. A pharmaceutical composition comprising the compound of any one of claims 1-22 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 1-22, or the pharmaceutically acceptable salt thereof, and the additional anti -cancer agent, for treating cancer.