Insulin growth factor-1 receptor (IGF-1r) inhibitors and methods of uses thereof

Abstract

The disclosure provides for compounds, compositions, and methods for modulating or inhibiting IGF-1R.

Description

WSGR Docket No. 67898-706.601INSULIN GROWTH FACTOR- 1 RECEPTOR (IGF-1R) INHIBITORS AND METHODS OF USES THEREOFCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 695,559 filed September 17, 2024, and U.S. Provisional Application Serial No. 63 / 774,388 filed March 19, 2025; which are hereby incorporated by reference in their entirety.BACKGROUND

[0002] Insulin-like growth factor 1 receptor (IGF-1R) is a transmembrane class II receptor tyrosine kinase (RTK) that plays a role in cell growth, differentiation, and cell survival. IGF-1R is broadly expressed across many cell types. Three ligands for IGF-IR have been characterized, insulin like growth factor 1 (IGF-1), insulin like growth factor 2 (IGF -2) and insulin. IGF-1 has a higher affinity for IGF-1R than IGF-2 while insulin binds with low affinity. Biological activities of IGF-1 and IGF-2 are modulated by six insulin growth factor binding proteins (IGFBP1-6) which regulate their bioavailability and compete for binding to IGF-1R.

[0003] IGF-lR-mediated signaling is implicated in a number of disorders associated with inflammation (Ruan, W, CurrMed Chem, 2020, 27, 7256-7263) and fibrosis (Zhu, Y, Biomolecules, 2022, 12, 1557) as well as cancers (Pellegrino, M. Front Immunol, 2024;15, 1356321). With respect to eye disease, IGF-1R is a driver of thyroid eye disease (TED), which is also referred to as Graves’ orbitopathy, Graves’ ophthalmology, Graves’ eye disease and thyroid associated ophthalmopathy (TAO). IGF-lR is also implicated in the pathogenesis of idiopathic orbital inflammation (IOI), which is also known as orbital inflammatory syndrome (OIS), nonspecific orbital inflammation (NSOI), orbital inflammatory syndrome, and orbital inflammatory pseudotumor. Other eye conditions include ischemic retinopathies (Raj ala, R. and Rajala, A. Aging Dis, 2024), age-related macular degeneration (AMD; Jacobo, S, Mol Cell, 2013, 33, 1976-1990), diabetic retinopathy (Poulaki, V, Am J Pathol, 2004, 165, 457-469) and pathologic retinal neovascularization (Pellegrino, M, Front Immunol, 2024, 15, 1356321).

[0004] The etiology of TED is unknown; however, it is classified as an autoimmune disease characterized by inflammation and expansion of orbital soft tissues in the eye, most markedly muscle and adipose tissue which results in proptosis (bulging of the eyes out of their sockets) and diplopia (double vision). The incidence of TED is 2.9 cases per 100,000 men and 16 cases per 100,000 women. Although the molecular mechanism behind the development of TED is not fully understood, infiltrating lymphocytes and orbital fibrocytes are implicated. Autoantibodies against thyroid-stimulating hormone receptor (TSHR) and IGF-1R are present in TED patients and are correlated with TED disease activity. IGF-1R forms a heterocomplex with TSHR in orbital fibroblasts and it has been shown that TSHR autoantibodies trigger and signal via IGF-1R, thus it is thought that blocking IGF-lR-mediated signaling can disrupt both TSHR- and IGF-lR-dependent pathogenic signaling by autoantibodies against either receptor.WSGR Docket No. 67898-706.601

[0005] The monoclonal antibody, teprotumumab, which targets IGF-1R has been approved to treat TED thus clinically validating IGF-1R as a good approach for the treatment of TED. Hence, targeting the kinase activity of IGF- 1R with small molecule inhibitors also represents a good strategy for the treatment of TED and may provide advantages over injectables, including patient preferred oral dosing.SUMMARY

[0006] Disclosed herein is a compound of Formula (I) or (II), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof:

[0007] Disclosed herein is a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof:

[0008] Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0009] Disclosed herein is a method of inhibiting IGF-1R activity in a subject in need thereof, comprising administering to the subject in need thereof a compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0010] Also disclosed herein is a method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject in need thereof a compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0011] In some embodiments, the disease or disorder is thyroid eye disease (TED).

[0012] In some embodiments, the disease or disorder is AMD (Age-related Macular Degeneration).WSGR Docket No. 67898-706.601

[0013] In some embodiments, the disease or disorder is Idiopathic orbital inflammation (IOI).

[0014] In some embodiments, the disease or disorder is an inflammatory disease.

[0015] In some embodiments, the disease or disorder is cancer.INCORPORATION BY REFERENCE

[0016] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.DETAILED DESCRIPTIONDefinitions

[0017] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0018] Reference throughout this specification to “some embodiments” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise.

[0019] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0020] ‘ ‘Oxo” refers to =0.

[0021] ‘ ‘Amino” refers to -NH2.

[0022] “Hydroxy” refers to -OH.

[0023] “Carboxyl” refers to -COOH.

[0024] “Alkyl” refers to a straight-chain or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2 -methyl- 1 -propyl, 2 -methyl -2 -propyl, 2-methyl-l- butyl, 3 -methyl- 1 -butyl, 2-methyl-3-butyl, 2,2-dimethyl-l -propyl, 2-methyl-l -pentyl, 3 -methyl- 1 -pentyl, 4-methyl-l -pentyl, 2-methyl-2-pentyl, 3 -methyl -2 -pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3-WSGR Docket No. 67898-706.601 dimethyl- 1 -butyl, 2 -ethyl- 1 -butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range, such as “Ci-Ce alkyl,” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a Ci-Cio alkyl. In some embodiments, the alkyl is a Ci-Ce alkyl, a Ci- C5alkyl, a C1-C4 alkyl, or a C1-C3 alkyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkyl is independently optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is independently optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is independently optionally substituted with halogen.

[0025] “Alkenyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans or Z or E conformation about the double bond(s) and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range, such as “C2-C6 alkenyl,” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkenyl is independently optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl is independently optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is independently optionally substituted with halogen.

[0026] “Alkynyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like. Whenever it appears herein, a numerical range, such as “C2-C6 alkynyl,” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkynyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkynyl is independently optionally substituted withWSGR Docket No. 67898-706.601 one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is independently optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is independently optionally substituted with halogen.

[0027] “Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkylene is independently optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, - OMe, -NH2, or -NO2. In some embodiments, the alkylene is independently optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is independently optionally substituted with halogen.

[0028] “Alkoxy” refers to a radical of the formula -Oalkyl where alkyl is defined as above. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkoxy is independently optionally substituted with one or more halogen, -CN, - COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is independently optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is independently optionally substituted with halogen.

[0029] “Aryl” refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to, anthracenyl, naphthyl, phenanthrenyl, azulenyl, phenyl, chrysenyl, fluoranthenyl, fluorenyl, as-indacenyl, s-indacenyl, indanyl, indenyl, phenalenyl, phenanthrenyl, pleiadenyl, pyrenyl, and triphenylenyl. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the aryl is independently optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl is independently optionally substituted with one or more halogen, methyl, ethyl, - CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is independently optionally substituted with halogen.

[0030] “Cycloalkyl” refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), spiro, and / or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having from threeWSGR Docket No. 67898-706.601 to fifteen carbon atoms (e.g., C3-C15 cycloalkyl), from three to ten carbon atoms (e.g., C3-C10 cycloalkyl), from three to eight carbon atoms (e.g., C3-C8 cycloalkyl), from three to six carbon atoms (e.g., C3-C6 cycloalkyl), from three to five carbon atoms (e.g., C3-C5 cycloalkyl), or three to four carbon atoms (e.g., C3-C4 cycloalkyl). In some embodiments, the cycloalkyl is a 3 - to 10-membered fully saturated cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6- membered fully saturated cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5 - to 6-membered fully saturated cycloalkyl or a 5 - to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include cycloalkyls comprising more than one ring. For example, a polycyclic cycloalkyl comprises two rings and is also known as a bicyclic cycloalkyl. In some embodiments, the bicyclic cycloalkyl is a fused bicyclic cycloalkyl. In some embodiments, the bicyclic cycloalkyl is a spiro bicyclic cycloalkyl. In some embodiments, the bicyclic cycloalkyl is a bridged bicyclic cycloalkyl. In another example, a polycyclic cycloalkyl comprises more than two rings. Polycyclic cycloalkyls include, for example, adamantyl, norbomyl, decalinyl, (ls,2s,3s,4s,6s,7s)-cubanyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, cis-decalinyl, trans-decalinyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclofl . 1. l]pentyl, bicyclo[3.1 ,0]hexyl, bicyclo[3. 1. l]heptyl, 7,7-dimethyl-bicyclo[2.2. l]heptanyl, spiro[4.2]heptyl, spiro[4.3]octyl, spiro[5.2]octyl, spiro[3.3]heptyl, and spiro [5.3] nonyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is independently optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, a cycloalkyl is independently optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is independently optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, - CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is independently optionally substituted with halogen.

[0031] ‘ ‘Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro. In some embodiments, halogen is chloro.

[0032] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2- trifluoroethyl, 1,2-difluoroethyl, 2-fluoroethyl, 3 -bromo-2 -fluoropropyl, 1,2-dibromoethyl, and the like.

[0033] “Haloalkoxy” refers to -O-haloalkyl, with haloalkyl as defined above.

[0034] “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.WSGR Docket No. 67898-706.601

[0035] “Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0036] “Deuteroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more deuteriums. In some embodiments, the alkyl is substituted with one deuterium. In some embodiments, the alkyl is substituted with one, two, or three deuteriums. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuteriums. Deuteroalkyl includes, for example, CDs, CH2D, CHD2, CH2CD3, CD2CD3, CHDCDs, CH2CH2D, or CH2CHD2. In some embodiments, the deuteroalkyl is CDs.

[0037] “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a Ci-Ce heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a Ci-Ce heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or two atoms selected from the group consisting of oxygen, nitrogen, and sulfur wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, - CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless stated otherwise specifically in the specification, a heteroalkyl is independently optionally substituted for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, a heteroalkyl is independently optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, - CF3, OH, -OMe, NH2, or -NO2. In some embodiments, a heteroalkyl is independently optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, OH, or -OMe. In some embodiments, the heteroalkyl is independently optionally substituted with halogen.

[0038] “Heterocycloalkyl” refers to a 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is a 3 - to 8-membered partially or fully saturated ring comprising one, two, or three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl is a 3 - to 8- membered fully saturated ring comprising one, two, or three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl is a 3 - to 6- membered partially or fully saturated ring comprising one or two heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl is a 3 - to 6- membered fully saturated ring comprising one or two heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In someWSGR Docket No. 67898-706.601 embodiments, the heterocycloalkyl is C-linked. In some embodiments, the heterocycloalkyl is N-linked. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen. Polycyclic heterocycloalkyls include heterocycloalkyls comprising more than one ring. For example, a polycyclic heterocycloalkyl comprises two rings and is also known as a bicyclic heterocycloalkyl. In some embodiments, the bicyclic heterocycloalkyl is a fused bicyclic heterocycloalkyl. In some embodiments, the bicyclic cycloalkyl is a spiro bicyclic heterocycloalkyl. In some embodiments, the bicyclic cycloalkyl is a bridged bicyclic heterocycloalkyl. In another example, a polycyclic heterocycloalkyl comprises more than two rings. Polycyclic heterocycloalkyls include, for example, 5 -oxabicyclo [2. l. l]hexyl, 2-oxabicyclo[2.1.1]hexyl, 2-oxabicyclo[2.1. l]hexyl, 2-oxabicyclo[2. 1. l]hexyl, 7 -oxabicyclo [2.2. l]heptyl, 2-oxabicyclo[2.2.2]octyl, and 2-oxabicyclo[2.2.1]heptyl. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C2-C15 heterocycloalkyl), from two to ten carbon atoms (e.g., C2-C10 heterocycloalkyl), from two to eight carbon atoms (e.g., C2-C8 heterocycloalkyl), from two to seven carbon atoms (e.g., C2-C7 heterocycloalkyl), from two to six carbon atoms (e.g., C2-C6 heterocycloalkyl), from two to five carbon atoms (e.g., C2-C5 heterocycloalkyl), or two to four carbon atoms (e.g., C2-C4 heterocycloalkyl). Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4- piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1 -oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1 ,3 -dihydroisobenzofuran- 1 -yl, 3 -oxo- 1 ,3 -dihydroisobenzofuran- 1 -yl, methyl -2 -oxo- 1 ,3 -dioxol-4-yl, and 2-oxo-l,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e., skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is aWSGR Docket No. 67898-706.6013- to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3 - to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5 - to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3 - to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6- membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5 - to 6-membered heterocycloalkenyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl is independently optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heterocycloalkyl is independently optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CFs, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl is independently optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is independently optionally substituted with halogen.

[0039] “Heteroaryl” refers to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl is a 5 - to 10-membered ring comprising one, two, or three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl is a 5 - to 6-membered fully aromatic ring comprising one, two, three, or four heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl is a 5- to 6-membered ring comprising one or two heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, the heteroaryl comprises one nitrogen. In some embodiments, the heteroaryl is C-linked. In some embodiments, the heteroaryl is N-linked. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized. In some embodiments, the heteroaryl is a 5 - to 10-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 6-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 5 -membered heteroaryl comprising 1, 2, or 3WSGR Docket No. 67898-706.601 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2- oxoazepinyl, oxazolyl, 1-oxidopyridinyl, 1 -oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1- phenyl-lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl is independently optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the heteroaryl is independently optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CFs, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl is independently optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is independently optionally substituted with halogen. In some embodiments, the heteroaryl is independently optionally substituted with on oxo to form an N-oxide.

[0040] The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), mono-substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, - CH2CF3, -CF2CH3, -CFHCHF2, etc ).

[0041] The term “one or more” when referring to an optional substituent means that the subject group is independently optionally substituted with one, two, three, or four, or more substituents. In some embodiments, the subject group is independently optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is independently optionally substituted with one, two, or three substituents. In some embodiments, the subject group is independently optionally substituted with one or two substituents. In some embodiments, the subject group is independently optionally substituted with one substituent. In some embodiments, the subject group is independently optionally substituted with two substituents. In some embodiments, the subject group is independently optionally substituted with three substituents.WSGR Docket No. 67898-706.601

[0042] An “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.

[0043] ‘ ‘Treatment” of an individual (e.g., a mammal, such as a human) or a cell is any type of intervention used in an attempt to alter the natural course of the individual or cell. In some embodiments, treatment includes administration of a pharmaceutical composition subsequent to the initiation of a pathologic event or contact with an etiologic agent and includes stabilization of the condition (e.g., condition does not worsen) or alleviation of the condition.

[0044] “Synergy” or “synergize” refers to an effect of a combination that is greater than additive of the effects of each component alone at the same doses.

[0045] As used herein, a “disease or disorder associated with IGF-1R” or, alternatively, “an IGF-1R- mediated disease or disorder” means any disease or other deleterious condition in which IGF-1R, or a mutant thereof, is known or suspected to play a role.Compounds

[0046] Described herein are compounds, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof useful in the treatment of a disease or disorder associated with IGF-1R.

[0047] Disclosed herein is a compound of Formula (I) or (II), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof:X1is N or CRX1;RX1is hydrogen, deuterium, halogen, -CN, -ORa, -SF5, -SRa, -NRcRd, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci- Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl;X2is N or CRX2;RX2is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -SF5, -SRa, -NRcRd, Ci-Cealkyl, Ci- Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl;U is N or C;T is N or C; provided that U and T are not both N;V is N or C;WSGR Docket No. 67898-706.601Y is N or CRY;RYis hydrogen, deuterium, halogen, -CN, -ORa, -SF5, -SRa, -NRcRd, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci- Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, or cycloalkyl;W is N or C;L1is absent or -[C(R’)2]q-; q is 1, 2, or 3; each R1is independently hydrogen, deuterium, halogen, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, or cycloalkyl; or two R1are taken together to form a cycloalkyl or heterocycloalkyl;Ring A is cycloalkyl or heterocycloalkyl; each R2is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)NRcRd, -OC(=O)Ra, - OC(=O)ORb, -SF5, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=NRb)(=O)Ra, -S(=O)2NRcRd, -NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -NRbS(=O)2NRcRd, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-C6deuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci- Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R2a; and / or two R2on the same atom are taken together to form an oxo; each R2ais independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)NRcRd, -OC(=O)Ra, - OC(=O)ORb, -SF5, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=NRb)(=O)Ra, -S(=O)2NRcRd, -NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -NRbS(=O)2NRcRd, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-C6deuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci- Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R; and / or two R2aon the same atom are taken together to form an oxo; m is 0, 1, 2, 3, or 4; each R3is independently deuterium, halogen, -CN, -NO2, -ORa, -SF5, -NRcRd, -C(=O)Ra, C(=O)ORb, - C(=O)NRcRd, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R; n is 0, 1, 2, or 3;R4is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)NRcRd, -OC(=O)Ra, -OC(=O)ORb, -SF5, -SRa, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, - NRbS(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6deuteroalkyl, Ci- Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl,WSGR Docket No. 67898-706.601 cycloalkyl, or heterocycloalkyl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R;Ring B is polycyclic cycloalkyl or polycyclic heterocycloalkyl; each R5is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)NRcRd, -OC(=O)Ra, - OC(=O)ORb, -SF5, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=NRb)(=O)Ra, -S(=O)2NRcRd, -NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -NRbS(=O)2NRcRd, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-C6deuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci- Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; and / or two R5on the same atom are taken together to form an oxo; p is 0, 1, 2, 3, 4, or 5;R6is hydrogen, deuterium, halogen, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; wherein the alkyl and heteroalkyl is independently optionally substituted with one or more R;R7is hydrogen, deuterium, halogen, -CN, -NO2, -ORa, -SF5, -NRcRd, -C(=O)Ra, C(=O)ORb, - C(=O)NRcRd, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R; each Rais independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rcand Rdare independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl independently optionally substituted with one or more R;L is absent or Ci-C3alkylene optionally substituted with one or more R; and each R is independently deuterium, halogen, -CN, -OH, -OCi-C3alkyl, -OCi-C3haloalkyl, - OC(=O)NHCi-C3alkyl, -OC(=O)N(Ci-C3alkyl)2, -SF5, -SCi-C3alkyl, -S(=O)Ci-C3alkyl, -S(=O)2Ci- C3alkyl, -S(=NH)(=O)Ci-C3alkyl, -S(=NCi-C3alkyl)(=O)Ci-C3alkyl, -S(=O)2NH2, -S(=O)2NHCI-WSGR Docket No. 67898-706.601Csalkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, -NHC(=O)NHCi-C3alkyl, NHC(=O)N(Ci-C3alkyl)2, -NHC(=O)Ci-C3alkyl, -NHC(=O)OCi-C3alkyl, -NHS(=O)2Ci-C3alkyl, - C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, -C(=O)NHCi-C3alkyl, -C(=O)N(Ci- C3alkyl)2, Ci-C3alkyl, Ci-C3haloalkyl, Ci-C3deuteroalkyl, Ci-C3hydroxyalkyl, Ci-C3aminoalkyl, Ci- C3heteroalkyl, C3-Cecycloalkyl, or heterocycloalkyl; and / or two R on the same atom are taken together to form an oxo.

[0048] In some embodiments of a compound of Formula (I) or (II), U is C and T is C. In some embodiments of a compound of Formula (I) or (II), U is N and T is C. In some embodiments of a compound of Formula (I) or (II), U is C and T is N.

[0049] In some embodiments of a compound of Formula (I) or (II), V is N. In some embodiments of a compound of Formula (I) or (II), V is C.

[0050] In some embodiments of a compound of Formula (I) or (II), W is N. In some embodiments of a compound of Formula (I) or (II), W is C.

[0051] In some embodiments of a compound of Formula (I) or (II), Y is CRY. In some embodiments of a compound of Formula (I) or (II), Y is N.

[0052] In some embodiments of a compound of Formula (I) or (II), RYis hydrogen, deuterium, halogen, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, or cycloalkyl. In some embodiments of a compound of Formula (I) or (II), RYis hydrogen, deuterium, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (I) or (II), RYis hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (I) or (II), RYis hydrogen.

[0053] Also disclosed herein is a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof:X1is N or CRX1;RX1is hydrogen, deuterium, halogen, -CN, -ORa, -SR. -SRa, -NRcRd, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci- Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl;X2is N or CRX2;RX2is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -SF5, -SRa, -NRcRd, Ci-Cealkyl, Ci- Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl;WSGR Docket No. 67898-706.601L1is absent or -|(CR')2| -: q is 1, 2, or 3; each R1is independently hydrogen, deuterium, halogen, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, or cycloalkyl; or two R1are taken together to form a cycloalkyl or heterocycloalkyl;Ring A is cycloalkyl or heterocycloalkyl; each R2is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)NRcRd, -OC(=O)Ra, - OC(=O)ORb, -SF5, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=NRb)(=O)Ra, -S(=O)2NRcRd, -NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -NRbS(=O)2NRcRd, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-C6deuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci- Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R2a; and / or two R2on the same atom are taken together to form an oxo; each R2ais independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)NRcRd, -OC(=O)Ra, - OC(=O)ORb, -SF5, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=NRb)(=O)Ra, -S(=O)2NRcRd, -NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -NRbS(=O)2NRcRd, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-C6deuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci- Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R; and / or two R2aon the same atom are taken together to form an oxo; m is 0, 1, 2, 3, or 4; each R3is independently deuterium, halogen, -CN, -NO2, -ORa, -SF5, -NRcRd, -C(=O)Ra, C(=O)ORb, - C(=O)NRcRd, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R; n is 0, 1, 2, or 3;R4is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)NRcRd, -OC(=O)Ra, -OC(=O)ORb, -SF5, -SRa, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, - NRbS(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6deuteroalkyl, Ci- Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R;Ring B is polycyclic cycloalkyl or polycyclic heterocycloalkyl; each R5is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)NRcRd, -OC(=O)Ra, - OC(=O)ORb, -SF5, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=NRb)(=O)Ra, -S(=O)2NRcRd, -NRcRd, -WSGR Docket No. 67898-706.601NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -NRbS(=O)2NRcRd, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-C6deuteroalkyl, Ci-C6haloalkyl, Ci-Cehydroxyalkyl, Ci- Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; and / or two R5on the same atom are taken together to form an oxo; p is 0, 1, 2, 3, 4, or 5;R6is hydrogen, deuterium, halogen, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; wherein the alkyl and heteroalkyl is independently optionally substituted with one or more R;R7is hydrogen, deuterium, halogen, -CN, -NO2, -ORa, -SF5, -NRcRd, -C(=O)Ra, C(=O)ORb, - C(=O)NRcRd, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R; each Rais independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rcand Rdare independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl independently optionally substituted with one or more R;L is absent or Ci-C3alkylene optionally substituted with one or more R; and each R is independently deuterium, halogen, -CN, -OH, -OCi-C3alkyl, -OCi-C3haloalkyl, - OC(=O)NHCi-C3alkyl, -OC(=O)N(Ci-C3alkyl)2, -SF5, -SCi-C3alkyl, -S(=O)Ci-C3alkyl, -S(=O)2Ci- C3alkyl, -S(=NH)(=O)Ci-C3alkyl, -S(=NCi-C3alkyl)(=O)Ci-C3alkyl, -S(=O)2NH2, -S(=O)2NHCI- C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, -NHC(=O)NHCi-C3alkyl, NHC(=O)N(Ci-C3alkyl)2, -NHC(=O)Ci-C3alkyl, -NHC(=O)OCi-C3alkyl, -NHS(=O)2Ci-C3alkyl, - C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, -C(=O)NHCi-C3alkyl, -C(=O)N(Ci- C3alkyl)2, Ci-C3alkyl, Ci-C3haloalkyl, Ci-C3deuteroalkyl, Ci-C3hydroxyalkyl, Ci-C3aminoalkyl, Ci- C3heteroalkyl, C3-Cecycloalkyl, or heterocycloalkyl;WSGR Docket No. 67898-706.601 and / or two R on the same atom are taken together to form an oxo.

[0054] In some embodiments of a compound of Formula (I), (II), (III), or (IV), X1is CRX1. In some embodiments of a compound of Formula (I), (II), (III), or (IV), X1is N.

[0055] In some embodiments of a compound of Formula (I), (II), (III), or (IV), RX1is hydrogen, deuterium, halogen, Ci-Cealkyl, Ci-Cedeuteroalkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (I), (II), (III), or (IV), RX1is hydrogen, deuterium, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (I), (II), (III), or (IV), RX1is hydrogen, deuterium, or Ci- Cealkyl. In some embodiments of a compound of Formula (I), (II), (III), or (IV), RX1is hydrogen or Ci- Cealkyl. In some embodiments of a compound of Formula (I), (II), (III), or (IV), RX1is hydrogen.

[0056] In some embodiments of a compound of Formula (I), (II), (III), or (IV), X2is CRX2. In some embodiments of a compound of Formula (I), (II), (III), or (IV), X2is N.

[0057] In some embodiments of a compound of Formula (I), (II), (III), or (IV), RX2is hydrogen, deuterium, halogen, -OH, -ORa, Ci-Cealkyl, Ci-Cedeuteroalkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (I), (II), (III), or (IV), RX2is hydrogen, deuterium, halogen, -OH, or Ci- Cealkyl. In some embodiments of a compound of Formula (I), (II), (III), or (IV), RX2is hydrogen, deuterium, -OH, or Ci-Cealkyl. In some embodiments of a compound of Formula (I), (II), (III), or (IV), RX2is hydrogen, -OH, or Ci-Cealkyl. In some embodiments of a compound of Formula (I), (II), (III), or (IV), RX2is hydrogen or -OH. In some embodiments of a compound of Formula (I), (II), (III), or (IV), RX2is hydrogen. In some embodiments of a compound of Formula (I), (II), (III), or (IV), RX2is -OH.WSGR Docket No. 67898-706.601

[0059] In some embodiments of a compound of Formula (

[0060] In some embodiments of a compound of Formula (WSGR Docket No. 67898-706.601

[0061] In some embodiments of a compound of Formula (some embodiments of a compound of Formula (embodiments of a compound of Formula (embodiments of a compound of Formula (

[0062] In some embodiments of a compound of Formula

[0063] In some embodiments of a compound of Formula (I), (II), (III), or (IV), L1is absent. In some embodiments of a compound of Formula (I), (II), (III), or (IV), L1is -[C(R1)2]q-. In some embodiments of a compound of Formula (I), (II), (III), or (IV), L1is -CH2-. In some embodiments of a compound of Formula (I), (II), (III), or (IV), L1is -CH2CH2-. In some embodiments of a compound of Formula (I), (II), (III), or (IV), L1is -CH2CH2CH2-.WSGR Docket No. 67898-706.601

[0064] In some embodiments of a compound of Formula (I), (II), (III), or (IV), q is 1 or 2. In some embodiments of a compound of Formula (I), (II), (III), or (IV), q is 2 or 3. In some embodiments of a compound of Formula (I), (II), (III), or (IV), q is 1. In some embodiments of a compound of Formula (I),(II), (III), or (IV), q is 2. In some embodiments of a compound of Formula (I), (II), (III), or (IV), q is 3.

[0065] In some embodiments of a compound of Formula (I), (II), (III), or (IV), each R1is independently hydrogen, deuterium, or Ci-Cealkyl. In some embodiments of a compound of Formula (I), (II), (III), or (IV), each R1is independently hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (I), (II), (III), or (IV), each R1is independently hydrogen. In some embodiments of a compound of Formula (I), (II), (III), or (IV), two R1are taken together to form a cycloalkyl or heterocycloalkyl.

[0066] In some embodiments of a compound of Formula (I), (II), (III), or (IV), Ring A is cycloalkyl. In some embodiments of a compound of Formula (I), (II), (III), or (IV), Ring A is Cs-Gcycloalkyl. In some embodiments of a compound of Formula (I), (II), (III), or (IV), Ring A is Cs-Cecycloalkyl. In some embodiments of a compound of Formula (I), (II), (III), or (IV), Ring A is Cs-Cscycloalkyl. In some embodiments of a compound of Formula (I), (II), (III), or (IV), Ring A is Cs-C^ycloalkyl. In some embodiments of a compound of Formula (I), (II), (III), or (IV), Ring A is cyclobutyl.

[0067] In some embodiments of a compound of Formula (I), (II), (III), or (IV), Ring A is heterocycloalkyl. In some embodiments of a compound of Formula (I), (II), (III), or (IV), Ring A is 3- to 8-membered heterocycloalkyl. In some embodiments of a compound of Formula (I), (II), (III), or (IV), Ring A is 3- to 6-membered heterocycloalkyl. In some embodiments of a compound of Formula (I), (II),(III), or (IV), Ring A is 3- to 5-membered heterocycloalkyl. In some embodiments of a compound of Formula (I), (II), (III), or (IV), Ring A is 3- to 4-membered heterocycloalkyl.

[0068] In some embodiments of a compound of Formula (I), (II), (III), or (IV), each R2is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci- Cehydroxyalkyl, or Ci-Ceaminoalkyl; wherein each alkyl is independently optionally substituted with one or more R2a. In some embodiments of a compound of Formula (I), (II), (III), or (IV), each R2is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, or Ci- Cehydroxyalkyl; wherein each alkyl is independently optionally substituted with one or more R2a.

[0069] In some embodiments of a compound of Formula (I), (II), (III), or (IV), each R2is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, C2- Cealkenyl, C2-Cealkynyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (I), (II), (III), or (IV), each R2is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (I), (II), (III), or (IV), each R2is independently deuterium, halogen, -OH, Ci- Cealkyl, Ci-Cedeuteroalkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (I), (II), (III), or (IV), each R2is independently deuterium, halogen, -OH, or Ci-Cealkyl. In some embodiments of a compound of Formula (I), (II), (III), or (IV), each R2is independently deuterium, halogen, -CN, -OH, - ORa, -NRcRd, Ci-Cealkyl, Ci-Cedeuteroalkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (I), (II), (III), or (IV), each R2is independently -OH or Ci-Cealkyl. In some embodiments of aWSGR Docket No. 67898-706.601 compound of Formula (I), (II), (III), or (IV), each R2is independently -OH, -ORa, or Ci-Cealkyl. In some embodiments of a compound of Formula (I), (II), (III), or (IV), each R2is independently -ORaor Ci- Cealkyl.

[0070] In some embodiments of a compound of Formula (I), (II), (III), or (IV), each R2ais independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci- Cehydroxyalkyl, Ci-Ceaminoalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (I), (II), (III), or (IV), each R2ais independently deuterium, halogen, -CN, -OH, - ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (I), (II), (III), or (IV), each R2ais independently deuterium, halogen, -NRcRd, Ci-Cealkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (I), (II), (III), or (IV), each R2ais independently deuterium, halogen, -NRcRd, Ci- Cealkyl, or heterocycloalkyl; wherein each alkyl and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (I), (II), (III), or (IV), each R2ais independently -NRcRd, or heterocycloalkyl independently optionally substituted with one or more R.

[0071] In some embodiments of a compound of Formula (I), (II), (III), or (IV), each R2ais independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cedeuteroalkyl, or Ci-Cehaloalkyl.In some embodiments of a compound of Formula (I), (II), (III), or (IV), each R2ais independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, or Ci-Cealkyl.

[0072] In some embodiments of a compound of Formula (I), (II), (III), or (IV), m is 0, 1, or 2. In some embodiments of a compound of Formula (I), (II), (III), or (IV), m is 1 or 2. In some embodiments of a compound of Formula (I), (II), (III), or (IV), m is 2 or 3. In some embodiments of a compound of Formula (I), (II), (III), or (IV), m is 0. In some embodiments of a compound of Formula (I), (II), (III), or (IV), m is 1. In some embodiments of a compound of Formula (I), (II), (III), or (IV), m is 2. In some embodiments of a compound of Formula (I), (II), (III), or (IV), m is 3.

[0073] In some embodiments of a compound of Formula (I), (II), (III), or (IV),WSGR Docket No. 67898-706.601

[0075] In some embodiments of a compound of Formula (I) or (III), each R3is independently deuterium, halogen, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci- Ceheteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (I) or (III), each R3is independently deuterium, halogen, Ci-Cealkyl, Ci-Cedeuteroalkyl, or Ci-Cehaloalkyl. InWSGR Docket No. 67898-706.601 some embodiments of a compound of Formula (I) or (III), each R3is independently deuterium, halogen, - CN, -ORa, -NRcRd, -C(=O)NRcRd, Ci-Cealkyl, Ci-Cedeuteroalkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (I) or (III), each R3is independently deuterium, halogen, or Ci- Cealkyl. In some embodiments of a compound of Formula (I) or (III), each R3is independently halogen or Ci-Cealkyl. In some embodiments of a compound of Formula (I) or (III), each R3is independently halogen.

[0076] In some embodiments of a compound of Formula (I) or (III), n is 0, 1, or 2. In some embodiments of a compound of Formula (I) or (III), n is 0 or 1. In some embodiments of a compound of Formula (I) or (III), n is 1 or 2. In some embodiments of a compound of Formula (I) or (III), n is 0. In some embodiments of a compound of Formula (I) or (III), n is 1. In some embodiments of a compound of Formula (I) or (III), n is 2.

[0077] In some embodiments of a compound of Formula (II) or (IV), R7is hydrogen, deuterium, halogen, -CN, -ORa, -NRcRd, -C(=O)NRcRd, Ci-Cealkyl, Ci-Cedeuteroalkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (II) or (IV), R7is hydrogen, deuterium, or halogen. In some embodiments of a compound of Formula (II) or (IV), R7is hydrogen or halogen. In some embodiments of a compound of Formula (II) or (IV), R7is halogen. In some embodiments of a compound of Formula (II) or (IV), R7is hydrogen.

[0078] In some embodiments of a compound of Formula (I), (II), (III), or (IV), R4is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cedeuteroalkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (I), (II), (III), or (IV), R4is hydrogen, deuterium, halogen, -ORa, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (I), (II), (III), or (IV), R4is hydrogen, deuterium, halogen, -ORa, or Ci-Cealkyl. In some embodiments of a compound of Formula (I), (II), (III), or (IV), R4is hydrogen, -ORa, or Ci-Cealkyl. In some embodiments of a compound of Formula (I), (II), (III), or (IV), R4is -ORaor Ci-Cealkyl. In some embodiments of a compound of Formula (I), (II), (III), or (IV), R4is hydrogen. In some embodiments of a compound of Formula (I), (II), (III), or (IV), R4is -ORa. In some embodiments of a compound of Formula (I), (II), (III), or (IV), R4is hydrogen, -CH,. -CH2CH3, -OCH3, -OCH2CH3, -OCH(CH3)CH3, or -OCH2CHF2. In some embodiments of a compound of Formula (I), (II), (III), or (IV), R4is hydrogen or -OCH2CH3.

[0079] In some embodiments of a compound of Formula (I), (II), (III), or (IV), R6is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cedeuteroalkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (I), (II), (III), or (IV), R6is hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (I), (II), (III), or (IV), R6is hydrogen.WSGR Docket No. 67898-706.601WSGR Docket No. 67898-706.601

[0083] In some embodiments of a compound of Formula (I), (II), (III), or (IV), Ring B is polycyclic cycloalkyl. In some embodiments of a compound of Formula (I), (II), (III), or (IV), Ring B is 5- to 10- membered polycyclic cycloalkyl. In some embodiments of a compound of Formula (I), (II), (III), or (IV), Ring B is 5- to 8-membered polycyclic cycloalkyl. In some embodiments of a compound of Formula (I),(II), (III), or (IV), Ring B is bicyclic cycloalkyl. In some embodiments of a compound of Formula (I),(II), (III), or (IV), Ring B is 5- to 10-membered bicyclic cycloalkyl. In some embodiments of a compound of Formula (I), (II), (III), or (IV), Ring B is 5- to 8-membered bicyclic cycloalkyl. In some embodiments of a compound of Formula (I), (II), (III), or (IV), Ring B isWSGR Docket No. 67898-706.601

[0084] In some embodiments of a compound of Formula (I), (II), (III), or (IV), Ring B is polycyclic heterocycloalkyl. In some embodiments of a compound of Formula (I), (II), (III), or (IV), Ring B is bicyclic heterocycloalkyl.

[0085] In some embodiments of a compound of Formula (I), (II), (III), or (IV), Ring B is 5- to 10- membered bicyclic heterocycloalkyl comprising one, two, or three heteroatoms selected from the group consisting of O, N, and S.

[0086] In some embodiments of a compound of Formula (I), (II), (III), or (IV), Ring B is 5- to 8- membered bicyclic heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O, N, and S.

[0087] In some embodiments of a compound of Formula (I), (II), (III), or (IV), Ring B is 6- to 8- membered bicyclic heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O, N, and S.

[0088] In some embodiments of a compound of Formula (I), (II), (III), or (IV), Ring B is 6- to 8- membered bicyclic heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O and N.

[0089] In some embodiments of a compound of Formula (I), (II), (III), or (IV), Ring B is 6- to 8- membered bicyclic heterocycloalkyl comprising one or two heteroatoms that are N.

[0090] In some embodiments of a compound of Formula (I), (II), (III), or (IV), Ring B is 6- to 8- membered bicyclic heterocycloalkyl comprising one or two heteroatoms that are O.

[0091] In some embodiments of a compound of Formula (I), (II), (III), or (IV), Ring B is

[0092] In some embodiments of a compound of Formula (I), (II), (III), or (IV), Ring B is

[0093] In some embodiments of a compound of Formula (I), (II), (III), or (IV), each R5is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cedeuteroalkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (I), (II), (III), or (IV), each R5is independently deuterium, halogen, -CN, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (I), (II), (III), or (IV), each R5is independently halogen, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (I), (II), (III), or (IV), each R5is independently halogen.

[0094] In some embodiments of a compound of Formula (I), (II), (III), or (IV), p is 0, 1, or 2. In some embodiments of a compound of Formula (I), (II), (III), or (IV), p is 0 or 1. In some embodiments of aWSGR Docket No. 67898-706.601 compound of Formula (I), (II), (III), or (IV), p is 1 or 2. In some embodiments of a compound of Formula (I), (II), (III), or (IV), p is 0. In some embodiments of a compound of Formula (I), (II), (III), or (IV), p is

[0096] In some embodiments of a compound of Formula (I), (II), (III), or (IV),

[0097] In some embodiments of a compound of Formula (I), (II), (III), or (IV),

[0099] In some embodiments of a compound of Formula (I), (II), (III), or (IV),

[0100] In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, -L-cycloalkyl, or -L- heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, eachWSGR Docket No. 67898-706.601Rais independently Ci-Cealkyl, Ci-Cehaloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl, Ci-Cehaloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl. In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl or Ci-Cehaloalkyl. In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl or -L-cycloalkyl. In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl.

[0101] In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, -L-cycloalkyl, or - L-heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, Ci-Cealkyl or Ci-Cehaloalkyl. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, Ci-Cealkyl, or -L- cycloalkyl. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen or Ci-Cealkyl. In some embodiments of a compound disclosed herein, each Rbis hydrogen. In some embodiments of a compound disclosed herein, each Rbis independently Ci-Cealkyl.

[0102] In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, -L- cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, -L-cycloalkyl, or -L- heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, Ci-Cealkyl or Ci-Cehaloalkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, Ci-Cealkyl, or -L-cycloalkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen or Ci-Cealkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare hydrogen. In some embodiments of a compound disclosed herein, each Rcand Rdare independently Ci-Cealkyl.

[0103] In some embodiments of a compound disclosed herein, Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl independently optionally substituted with one or more R.WSGR Docket No. 67898-706.601

[0104] In some embodiments of a compound disclosed herein, L is absent. In some embodiments of a compound disclosed herein, L is Ci-C3alkylene optionally substituted with one or more R. In some embodiments of a compound disclosed herein, L is Ci-C3alkylene. In some embodiments of a compound disclosed herein, L is -CH2-. In some embodiments of a compound disclosed herein, L is -CH2CH2-. In some embodiments of a compound disclosed herein, L is -CH2CH2CH2-.

[0105] In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, - OH, -OCi-C3alkyl, -OCi-C3haloalkyl, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, Ci-C3alkyl, Ci- C3haloalkyl, Ci-C3deuteroalkyl, Ci-C3hydroxyalkyl, Ci-C3aminoalkyl, Ci-C3heteroalkyl, C3- Cecycloalkyl, or heterocycloalkyl; and / or two R on the same atom are taken together to form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -OCi- C3alkyl, -OCi-C3haloalkyl, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, Ci-C3alkyl, Ci-C3haloalkyl, or Ci- C3deuteroalkyl; and / or two R on the same atom are taken together to form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -NH2, Ci-C3alkyl, or Ci- C3haloalkyl; and / or two R on the same atom are taken together to form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, Ci-C3alkyl, or Ci-C3haloalkyl; and / or two R on the same atom are taken together to form an oxo.

[0106] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.

[0107] In some embodiments the compound disclosed herein is selected from a compound found in Table 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.Table 1WSGR Docket No. 67898-706.601WSGR Docket No. 67898-706.601WSGR Docket No. 67898-706.601WSGR Docket No. 67898-706.601WSGR Docket No. 67898-706.601WSGR Docket No. 67898-706.601WSGR Docket No. 67898-706.601WSGR Docket No. 67898-706.601WSGR Docket No. 67898-706.601WSGR Docket No. 67898-706.601WSGR Docket No. 67898-706.601WSGR Docket No. 67898-706.601WSGR Docket No. 67898-706.601WSGR Docket No. 67898-706.601* Stereochemistry of the substituents on the oxabicyclo ring system was arbitrarily assigned.

[0108] The absolute label (abs) is added to a chiral center to denote that it is unambiguously a pure sample of the drawn stereoisomer.WSGR Docket No. 67898-706.601

[0109] The OR label (or) denotes a pure substance, but the absolute configuration of the stereochemical center is unknown. After chiral separation with pure structures isolated, multiple OR labels (OR indicates purity) with the same numerical value will indicates that a sample is one of a pair of pure enantiomers (but the absolute configuration of the stereochemical center is unknown).

[0110] The AND label (and) denotes both isomers are present at the depicted stereochemical center. Assigning different numerical values to the AND labels denotes that they are independent of each other. The use of AND labels with the same values indicate that the two stereocenters are relative to each other and can only change in concert.

[0111] In some embodiments the compound disclosed herein is selected from the group consisting of:WSGR Docket No. 67898-706.601WSGR Docket No. 67898-706.601WSGR Docket No. 67898-706.601WSGR Docket No. 67898-706.601WSGR Docket No. 67898-706.601

[0112] In some embodiments the compound disclosed herein is selected from the group consisting of:WSGR Docket No. 67898-706.601pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0113] In some embodiments the compound disclosed herein is selected from the group consisting of:thereof.Further Forms of Compounds Disclosed HereinIsomers / Stereoisomers

[0114] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center independently exists in the R configuration or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In someWSGR Docket No. 67898-706.601 embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.Labeled compounds

[0115] In some embodiments, the compounds described herein exist in their isotopically -labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as2H,3H,13C,14C,15N,180,170,31P,32P,35S,18F, and36C1, respectively. Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds, for example those into which radioactive isotopes, such as3H and14C, are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes, such as deuterium, i.e.,2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, one or more hydrogen in a compound disclosed herein has been replaced by a deuterium atom. In some embodiments, one or more alkyl substituents in a compound disclosed herein has been replaced by a deuteroalkyl substituents. In some embodiments, one or more -CH3 in a compound disclosed herein has been replaced by a -CDs.

[0116] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, biolumine scent labels, or chemiluminescent labels.Pharmaceutically acceptable salts

[0117] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.WSGR Docket No. 67898-706.601

[0118] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or a solvate, or stereoisomer thereof, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

[0119] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, but not limited to, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-l,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, gluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne- 1,6-dioate, hydroxybenzoate, y-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate.

[0120] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methane sulfonic acid, ethane sulfonic acid, 1,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 2 -naphthalene sulfonic acid, 4-methylbicyclo- [2.2.2]oct-2-ene-l-carboxylic acid, glucoheptonic acid, 4,4 ’-methylenebis-(3 -hydroxy-2 -ene-1 -carboxylic acid), 3 -phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. In some embodiments, other acids, such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, solvate, or stereoisomer thereof and their pharmaceutically acceptable acid addition salts.

[0121] In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary,WSGR Docket No. 67898-706.601 secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(CI.C4 alkyl)4 hydroxide, and the like.

[0122] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quatemization of any basic nitrogencontaining groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quatemization.Solvates

[0123] In some embodiments, the compounds described herein exist as solvates. The invention provides for methods of treating diseases by administering such solvates. The invention further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0124] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed with pharmaceutically acceptable solvents, such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared from an aqueous / organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.Tautomers

[0125] In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. In some embodiments, the 6-aminopyridazin-3-ol compounds disclosed herein exist as 6-aminopyridazinones (and vice versa):WSGR Docket No. 67898-706.601Method of Treatment

[0126] Disclosed herein is a method of inhibiting IGF-1R activity in a subject in need thereof, comprising administering to the subject in need thereof a compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0127] Also disclosed herein is a method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject in need thereof a compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0128] In some embodiments, the disease or disorder is thyroid eye disease (TED).

[0129] In some embodiments, the disease or disorder is AMD (Age-related Macular Degeneration).

[0130] In some embodiments, the disease or disorder is Idiopathic orbital inflammation (IOI).

[0131] In some embodiments, the disease or disorder is an inflammatory disease.

[0132] In some embodiments, the disease or disorder is cancer.Dosing

[0133] In certain embodiments, the compositions containing the compound(s) described herein are administered for therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose-escalation.Routes of Administration

[0134] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.

[0135] In certain embodiments, a compound as described herein is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation. In specific embodiments, long-acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ specific antibody. In such embodiments, the liposomes are targeted to and taken up selectively by the organ. In yet other embodiments, the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended-release formulation, or in the form of an intermediate release formulation.WSGR Docket No. 67898-706.601Pharmaceutical Compositions / Formulations

[0136] The compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.

[0137] In another aspect, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkinsl999), herein incorporated by reference for such disclosure.Combination

[0138] Disclosed herein are methods of treating a disease or disorder associated with SIK using a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, in combination with an additional therapeutic agent.

[0139] In some embodiments, the additional therapeutic agent is administered at the same time as the compound disclosed herein. In some embodiments, the additional therapeutic agent and the compound disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered prior than the administration of the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after the administration of the compound disclosed herein.EXAMPLES

[0140] The following examples are offered to illustrate, but not to limit the claimed invention. The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.

[0141] The following synthetic schemes are provided for purposes of illustration, not limitation. The following examples illustrate the various methods of making compounds described herein. It is understood that one skilled in the art may be able to make these compounds by similar methods or byWSGR Docket No. 67898-706.601 combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make, in a similar manner as described below by using the appropriate starting materials and modifying the synthetic route as needed. In general, starting materials and reagents can be obtained from commercial vendors or synthesized according to sources known to those skilled in the art or prepared as described herein.Intermediate 1INT-1

[0142] Intermediate 1 was prepared using the methods reported in Jin, M. et al., ACS Med. Chem.Lett., 2013, 4, 627-631.Intermediate 2Step 1: Preparation of 2-(bicyclo[l.l.l]pentan-l-yl)-7-chloroquinoline:

[0143] To a stirred mixture of bicyclo[l.l. l]pentane-l-carboxylic acid (343 mg, 3.06 mmol, 1.00 equiv.) and AgNOs (312 mg, 1.83 mmol, 0.60 equiv.) in 10% H2SO4 (10 mL) was added 7- chloroquinoline (500 mg, 3.06 mmol, 1.00 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C for 10 min under nitrogen atmosphere. To the above mixture was added a solution of (NH4)2S20s (697 mg, 3.06 mmol, 1.00 equiv.) in H2O (2mL) at 80°C. The resulting mixture was stirred at 80°C for an additional 30 min, then cooled to room temperature and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with H2O (1 x 10 mL), dried over anhydrous Na2SC>4, fdtered and concentrated. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (5: 1) to afford 2-{bicyclo[l.l.l]pentan-l-yl}-7- chloroquinoline) (230 mg, 32.76%) as a light yellow solid. LC-MS: (ES+H, m / z): [M+H]+=230.00. 'H NMR (400 MHz, CDCI3) 5 8.15 - 8.08 (m, 1H), 8.05 (d, J= 8.4 Hz, 1H), 7.69 (d, J= 8.6 Hz, 1H), 7.43 (dd, J= 8.7, 2.1 Hz, 1H), 7.34 (d, J= 8.5 Hz, 1H), 2.62 (s, 1H), 2.28 (s,6H).Step 2: Preparation of 2-(bicyclo[l.l.l]pentan-l-yl)-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinoline:

[0144] To a stirred mixture of 2-{bicyclo[l.l. l]pentan-l-yl}-7-chloroquinoline (222 mg, 0.966 mmol, 1.00 equiv.) and bis(pinacolato)diboron (270 mg, 1.063 mmol, 1.10 equiv.) in 1,4-dioxane (6 mL) wereWSGR Docket No. 67898-706.601 added potassium acetate (237 mg, 2.416 mmol, 2.50 equiv.) and tricyclohexylphosphine (54 mg, 0.193 mmol, 0.20 equiv.) and Pd2(dba)s (88 mg, 0.097 mmol, 0.10 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C for 3 h and then cooled to room temperature. The resulting mixture was diluted with dichloromethane (10 mL) and concentrated. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (5: 1) to afford 2-{bicyclo[l .1. l]pentan-l-yl}-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (150 mg, 48.31%) as a light yellow solid. LC-MS: (ES+H, m / z): [M+H]+=322.15.Intermediate 3Step 1: Preparation of 4,7-dichloro-2-(3-methylbicyclo[l.l.l]pentan-l-yl)quinoline:

[0145] A mixture of 3-methylbicyclo[l.l. l]pentane-l-carboxylic acid (318 mg, 2.53 mmol, 1.00 equiv.), 4,7-dichloroquinoline (500 mg, 2.53 mmol, 1.00 equiv.) and AgNOs (257 mg, 1.52 mmol, 0.60 equiv.) in 10% EESCEin water (10 mL) was stirred at 80°C for 10 min under nitrogen atmosphere. To the above mixture was added ammonium persulfate (576 mg, 2.53 mmol, 1.00 equiv., dissolved in water 10 mL) dropwise over 3 min at 80°C. The resulting mixture was stirred at 80°C for an additional 20min. The mixture was allowed to cool down to room temperature, and then poured into water (150 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were concentrated under reduced pressure and the crude residue was purified by normal-phase flash chromatography (EtOAc in Petroleum ether, 0% to 100% gradient in 35 min; detector, UV 254 nm) to afford 4,7-dichloro-2-{3- methy Ibicy clo [ 1.1.1] pentan- 1-yl} quinoline (350 mg, 49%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+= 277.95. ’H NMR (400 MHz, DMSO-d6) 5 8.17 (d, J= 8.9 Hz, 1H), 8.10 (d, J= 2.1 Hz, 1H), 7.73 (d, J= 9.8 Hz, 2H), 2.07 (s, 6H), 1.27 (s, 3H).Step 2: Preparation of 7-chloro-2-(3-methylbicyclo[l.l.l]pentan-l-yl)quinoline:

[0146] To a stirred mixture of 4,7-dichloro-2-{3-methylbicyclo[l.l. l]pentan-l-yl}quinoline (300 mg, 1.08 mmol, 1.00 equiv.) and N,N,N',N'-tetramethylethylenediamine (251 mg, 2.16 mmol, 2.00 equiv.) in THE (7 mL) were added NaBH4 (61 mg, 1.62 mmol, 1.50 equiv.) and Pd(dppf)C12 CH2CI2 (88 mg, 0.11 mmol, 0.10 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 2h under nitrogen atmosphere. The reaction was quenched by the addition of water (10 mL) at 0°C and the resulting mixture was diluted with water (60 mL) and extracted with EtOAc (3 x 60 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography (EtOAc in Petroleum ether, 0% to 5% gradient in 20 min; detector, UV 254 nm) toWSGR Docket No. 67898-706.601 afford 7-chloro-2-{3-methylbicyclo[l.l. l]pentan-l-yl}quinoline (166 mg, 63%) as a light yellow solid. LC-MS: (ES+H, m / z): [M+H]+= 244.05. 'HNMR (400 MHz, DMSO-6) 5 8.34 (d, J= 8.5 Hz, 1H), 8.03 - 7.96 (m, 2H), 7.58 (dd, J= 8.6, 2.1 Hz, 1H), 7.49 (d, J= 8.5 Hz, 1H), 2.06 (s, 6H), 1.27 (s, 3H).Step 3: Preparation of 2-(3-methylbicyclo[l.l.l]pentan-l-yl)-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoline:

[0147] To a stirred solution of 7-chloro-2-{ 3 -methylbicyclo [1.1.1 ]pentan-l-yl} quinoline (150 mg, 0.62 mmol, 1.00 equiv.), AcOK (181 mg, 1.85 mmol, 3.00 equiv.) and 4,4,5,5-tetramethyl-2- (tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (313 mg, 1.23 mmol, 2.00 equiv.) in dioxane (5 m ) were added tricyclohexylphosphine (35 mg, 0.12 mmol, 0.20 equiv.) and Pd2(dba)s (56 mg, 0.06 mmol, 0.10 equiv.) at room temperature. The resulting mixture was stirred at 80°C for 3h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature, then poured into water (80 m ) and extracted with CH2Q2 (3 x 50 mb). The combined organic layers were concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography (EtOAc in Petroleum ether 0% to 10% gradient in 20 min; detector, UV 254 run) to afford 2-{3-methylbicyclo[l.l. l]pentan-l-yl}-7- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline(250 mg, crude) as a yellow solid. EC-MS: (ES+H, m / z): [M+H]+= 336.15.Intermediate 4Step 1: Preparation of 3-(4,7-dichloroquinolin-2-yl)bicyclo[l.l.l]pentane-l-carbonitrile:

[0148] A mixture of 4,7-dichloroquinoline (800 mg, 4.03 mmol, 1.00 equiv.) and AgNOs (411 mg, 2.42 mmol, 0.60 equiv.) in H2SO4 (20 mb) was stirred at 80°C for 10 min under nitrogen atmosphere. To the above mixture was added a solution of ammonium persulfate (921 mg, 4.03 mmol, 1.00 equiv.) in H2O (5 mb) dropwise over 5 min at 80°C. The resulting mixture was stirred at 80°C for an additional 20 min. The mixture was allowed to cool down to room temperature and quenched by the addition of water (20 mb) at 0°C. The resulting mixture was extracted with EtOAc (3 x 100 mb) and the combined organic layers were concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / EtOAc (7 / 1) to afford 3 -(4, 7-dichloroquinolin-2-yl)bicyclo[l. l.l]pentane-l -carbonitrile (710 mg, 60.79%, 50% purity) as a yellow solid. EC-MS: (ES+H, m / z): [M+H]+=288.9.Step 2: Preparation of 3-(7-chloroquinolin-2-yl)bicyclo[l.l.l]pentane-l-carbonitrile:

[0149] To a stirred mixture of 3-(4,7-dichloroquinolin-2-yl)bicyclo[l.l.l]pentane-l-carbonitrile (700 mg, 2.42 mmol, 1.00 equiv.), [2-(dimethylamino)ethyl]dimethylamine (562 mg, 4.84 mmol, 2.00 equiv.)WSGR Docket No. 67898-706.601 and Pd(dppf)C12 CH2CI2 (98 mg, 0.12 mmol, 0.05 equiv.) in THF (10 mL) was added NaBH (183 mg, 4.84 mmol, 2.00 equiv.) at 0°C. The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The reaction was quenched by the addition of water (10 mL) at 0°C. The resulting mixture was diluted with water (60 mL) and extracted with EtOAc (3 x 60 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography (EtOAc in Petroleum ether, 0% to 50% gradient in 20 min; detector, UV 254 nm) to afford 3-(7-chloroquinolin-2-yl)bicyclo[l .1. l]pentane-l -carbonitrile (470 mg, 76.22%) as a light yellow solid. LC-MS: (ES+H, m / z): [M+H]+=254.9. 'H NMR (400 MHz, DMSO-tL) 5 8.42 (dd, J= 8.5, 2.0 Hz, 1H), 8.04 - 8.01 (m, 2H), 7.62 (dd, J= 8.8, 2.2 Hz, 1H), 7.55 (dd, J= 8.4, 2.0 Hz, 1H), 2.69 (s, 6H).Step 3: Preparation of 3-[7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinolin-2- yl] bi cyclo [1.1.1] pentane- 1-carbonitrile:

[0150] To a stirred solution of 3-(7-chloroquinolin-2-yl)bicyclo[l.l. l]pentane-l-carbonitrile (450 mg, 1.76 mmol, 1.00 equiv.) and bis(pinacolato)diboron (493 mg, 1.94 mmol, 1.10 equiv.) in 1,4-dioxane (10 mL) were added Pd2(dba)s (323 mg, 0.35 mmol, 0.20 equiv.), AcOK (433 mg, 4.41 mmol, 2.50 equiv.) and PC , (99 mg, 0.35mmol, 0.20 equiv.) at room temperature under air atmosphere. The resulting mixture was stirred at 80°C for 3 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and concentrated. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (5: 1) to afford 3-[7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinolin-2-yl]bicyclo[l.l. l]pentane-l-carbonitrile (320 mg, 52.31%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+=347.2.Step 1: Preparation of 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-4,7-dichloroquinoline:

[0151] A solution of 4,7-dichloroquinoline (1.00 g, 5.05 mmol, 1.00 equiv.), 7- oxabicyclo[2.2.1]heptane-l-carboxylic acid (718 mg, 5.05 mmol, 1.00 equiv.) and AgNCL (1.03 g, 6.06 mmol, 1.20 equiv.) in trifluoroacetic acid (40 mL, 5% in water) was stirred at 80°C for 20 min under nitrogen atmosphere. To the above mixture was added ammonium persulfate (5.76 g, 25.25 mmol, 5.00 equiv.) in H2O (20 mL) dropwise at 80°C. The resulting mixture was stirred at 80°C for an additional 30min and then cooled to room temperature. The resulting mixture was extracted with CH2Q2 (3x100 mL) and then the combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10: 1) to afford 2-(7-WSGR Docket No. 67898-706.601 oxabicyclo[2.2.1]heptan-l-yl)-4,7-dichloroquinoline (650 mg, 43.7%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+=294.0. ’H NMR (400 MHz, DMSO-6) 5 8.22 (d, J= 8.9 Hz, 1H), 8.14 (d, J= 2.1 Hz, 1H), 7.84 (s, 1H), 7.79 (dd, J = 9.0, 2.1 Hz, 1H), 4.76 (t, J= 4.9 Hz, 1H), 2.19 - 2.08 (m, 2H), 1.88 - 1.67 (m, 6H).Step 2: Preparation of 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-7-chloroquinoline:

[0152] To a stirred solution of 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-4,7-dichloroquinoline (400 mg, 1.36 mmol, 1.00 equiv.) and Pd(dppf)C12 CH2CI2 (56 mg, 0.07 mmol, 0.05 equiv.) in THF (10 m ) were added N,N,N',N'-tetramethylethylenediamine (316 mg, 2.72 mmol, 2.00 equiv.) and NaBEL (103 mg, 2.72 mmol, 2.00 equiv.) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2h under nitrogen atmosphere. The reaction was quenched with water at 0°C and then diluted with water (20 m ). The resulting mixture was extracted with CH2CI2 (3x20 mb). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5: 1) to afford 2-(7-oxabicyclo[2.2. l]heptan-l-yl)-7- chloroquinoline (200 mg, 56.6%) as a yellow solid. EC-MS: (ES+H, m / z): [M+H]+=260.1. 'HNMR (400 MHz, DMSO-d6) 5 8.42 (dd, J= 8.6, 0.8 Hz, 1H), 8.07 - 8.00 (m, 2H), 7.73 (d, J= 8.5 Hz, 1H), 7.63 (dd, J= 8.8, 2.1 Hz, 1H), 4.75 (t, J= 5.0 Hz, 1H), 2.18 - 2.08 (m, 2H), 1.94 - 1.65 (m, 6H).Step 3: Preparation of 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoline:

[0153] To a stirred mixture of 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-7-chloroquinoline (170 mg, 0.66 mmol, 1.00 equiv.) and 4,4,5,5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (249 mg, 0.98 mmol, 1.50 equiv.) in 1,4-dioxane (8 mb) were added AcOK (193 mg, 1.97 mmol, 3.00 equiv.), tricyclohexylphosphine (37 mg, 0.13 mmol, 0.20 equiv.) and Pd2(dba)s (60 mg, 0.07 mmol, 0.10 equiv.). The resulting mixture was stirred at 80°C for 16h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EA (5: 1) to afford 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-7- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (180 mg, 78.2%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+=352.3. ’H NMR (400 MHz, DMSO-6) 5 8.38 (d, J= 8.5 Hz, 1H), 8.31 (s, 1H), 8.00 - 7.93 (m, 1H), 7.81 - 7.63 (m, 2H), 4.75 (t, J= 4.8 Hz, 1H), 2.22 - 2.08 (m, 2H), 1.85 (tdd, J = 14.4, 8.3, 4.5 Hz, 4H), 1.76 - 1.67 (m, 2H), 1.35 (s, 12H).Intermediate 6WSGR Docket No. 67898-706.601Step 1: Preparation of 4,7-dichloro-2-{2-oxabicyclo[2.1.1]hexan-4-yl}quinoline :

[0154] A solution of 4,7-dichloroquinoline (1.85 g, 9.36 mmol, 1.50 equiv.) in trifluoroacetic acid (10 mL) was treated with 2-oxabicyclo[2.1.1]hexane-4-carboxylic acid (800 mg, 6.24 mmol, 1.00 equiv.) and AgNOs (1.27 g, 7.49 mmol, 1.20 equiv.) at 80 °C for 10 min under nitrogen atmosphere followed by the addition of ammonium persulfate (2.85 g, 12.48 mmol, 2.00 equiv.) in H2O (5 mL) dropwise at 80 °C. The resulting mixture was stirred at 80 °C for 20 min under nitrogen atmosphere and then cooled to room temperature. The aqueous layer was extracted with CH2Q2 (3 x 50 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (10: 1) (10: 1) to afford 4,7-dichloro-2-{2- oxabicyclo[2.1.1]hexan-4-yl}quinoline (160 mg, 9.15%) as off-white solid. LC-MS: (ES+H, m / z): [M+H]+=280.00.Step 2: Preparation of 7-chloro-2-{2-oxabicyclo[2.1.1]hexan-4-yl}quinoline:

[0155] To a stirred solution of 4,7-dichloro-2-{2-oxabicyclo[2.1.1]hexan-4-yl}quinoline (120 mg, 0.42 mmol, 1.00 equiv.) and Pd^ppQCh CELCh (35 mg, 0.04 mmol, 0.10 equiv.) in THF (2 mL) were added N,N,N',N'-tetramethylethylenediamine (99 mg, 0.85 mmol, 2.00 equiv.) and NaBEL (32 mg, 0.85 mmol, 2.00 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h and then quenched with sat. NH4CI (aq.) at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL), filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (5: 1) to afford 7- chloro-2-{2-oxabicyclo[2. 1. l]hexan-4-yl} quinoline (80 mg, 76.01%) as off-white solid. 'H NMR (400 MHz, DMSO-d6) 5 8.42 (dd, J= 8.5, 0.9 Hz, 1H), 8.05 - 7.99 (m, 2H), 7.68 - 7.59 (m, 2H), 4.65 (t, J = 1.0 Hz, 1H), 3.99 (s, 2H), 2.28 (dt, J= 4.6, 1.4 Hz, 2H), 1.92 (dd, J= 4.6, 1.8 Hz, 2H).Step 3: Preparation of 2-{2-oxabicyclo[2.1.1]hexan-4-yl}-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)quinoline:

[0156] To a stirred solution of 7-chloro-2-{2-oxabicyclo[2.1. l]hexan-4-yl}quinoline (80 mg, 0.32 mmol, 1.00 equiv.) and bis(pinacolato)diboron (91 mg, 0.35 mmol, 1.10 equiv.) in 1,4-dioxane (1 mL) were added AcOK (80 mg, 0.81 mmol, 2.50 equiv.) and Pd2(dba)s (15 mg, 0.01 mmol, 0.05 equiv.) and XPhos (15 mg, 0.03 mmol, 0.10 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 3 h under nitrogen atmosphere and then cooled to room temperature andWSGR Docket No. 67898-706.601 concentrated. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (10: 1) to afford 2-{2-oxabicyclo[2.1.1]hexan-4-yl}-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoline (80 mg, crude) as a black oil. LC-MS: (ES+H, m / z): [M+H]+=338.15.Intermediate 7Step 1: Preparation of 4,7-dichloro-2-(3-(difluoromethyl)bicyclo[l.l.l]pentan-l-yl)quinoline:

[0157] A solution of 4,7-dichloroquinoline (1.00 g, 5.05 mmol, 1.00 equiv.), 3- (difluoromethyl)bicyclo [1.1.1] pentane -1 -carboxy lie acid (819 mg, 5.05 mmol, 1.00 equiv.) and AgNOs (1.03 g, 6.06 mmol, 1.2 equiv.) in trifluoroacetic acid (50 mL, 5% in water) was stirred at 80°C for lOmin under nitrogen atmosphere. To the above mixture was added ammonium persulfate (5.76 g, 25.25 mmol, 5.00 equiv.) in H2O (10 mL) dropwise at 80°C. The resulting mixture was stirred at 80°C for an additional 30min. The mixture was cooled to room temperature and extracted with EtOAc (3x100 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10: 1) to afford 4,7-dichloro-2-(3- (difluoromethyl)bicyclo[l.l.l]pentan-l-yl)quinoline (800 mg, 50.4%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+=313.8. 'H NMR (400 MHz, DMSO-6) 5 8.19 (d, J= 9.0 Hz, 1H), 8.12 (d, J= 2.1 Hz, 1H), 7.84 (s, 1H), 7.76 (dd, J= 9.0, 2.1 Hz, 1H), 6.19 (t, J = 56.2 Hz, 1H), 2.27 (s, 6H).Step 2: Preparation of 7-chloro-2-(3-(difluoromethyl)bicyclo[l.l.l]pentan-l-yl)quinoline:

[0158] To a stirred solution of 4,7-dichloro-2-(3-(difluoromethyl)bicyclo[l. l.l]pentan-l-yl)quinoline (350 mg, 1.11 mmol, 1.00 equiv.) and Pd(dppf)C12 CH2Q2 (45 mg, 0.06 mmol, 0.05 equiv.) in THF (10 mL) were added N,N,N',N'-tetramethylethylenediamine (259 mg, 2.23 mmol, 2.00 equiv.) and NaBEL (84 mg, 2.23 mmol, 2.00 equiv.) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2h under nitrogen atmosphere. The reaction was quenched with water at 0°C.The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with CH2CI2 (3x20 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10: 1) to afford 7-chloro-2-(3- (difluoromethyl)bicyclo[l.l.l]pentan-l-yl)quinoline (200 mg, 64.1%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+=279.9. 'H NMR (400 MHz, DMSO-6) 5 8.40 (d, J= 8.5 Hz, 1H), 8.06 - 7.98 (m, 2H), 7.61 (dd, J= 8.7, 2.1 Hz, 1H), 7.58 (d, J= 8.4 Hz, 1H), 6.19 (t, J= 56.3 Hz, 1H), 2.26 (s, 6H).WSGR Docket No. 67898-706.601Step 3: Preparation of 2-(3-(difluoromethyl)bicyclo[l.l.l]pentan-l-yl)-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoline:

[0159] To a stirred mixture of 7-chloro-2-(3-(difluoromethyl)bicyclo[l.l. l]pentan-l-yl)quinoline (190 mg, 0.68 mmol, 1.00 equiv.) and 4,4,5,5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2- dioxaborolane (259 mg, 1.02 mmol, 1.50 equiv.) in 1,4-dioxane (10 mL) were added AcOK (200 mg, 2.04 mmol, 3.00 equiv.), XPhos (65 mg, 0.14 mmol, 0.20 equiv.) and Pd2(dba)s (62 mg, 0.07 mmol, 0.10 equiv.). The resulting mixture was stirred at 100°C for 2h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and the crude product was used in directly without further purification. LC-MS: (ES+H, m / z): [M+H]+=372.2.Intermediate 8Step 1: Preparation of 2-{bicyclo[l.l.l]pentan-l-yl}-4,7-dichloroquinoline :

[0160] To a stirred mixture of bicyclofl. l.l]pentane-l-carboxylic acid (2.00g, 17.8 mmol, 1.00 equiv.) and 4,7-dichloroquinoline (3.53 g, 17.8 mmol, 1.00 equiv.) in 5% trifluoroacetic acid water solution (100 mL) were added AgNOs (1.82 g, 10.7 mmol, 0.60 equiv.) at room temperature. The resulting mixture was stirred at 80°C for 10 min under nitrogen atmosphere. To the above mixture was added the solution of (NH4)2S20s (4.07 g, 17.8 mmol, 1.00 equiv.) in H2O dropwise over 5 min at 80°C. The resulting mixture was stirred at 80°C for an additional 30 min. The mixture was allowed to cool down to room temperature and dissolved in water (40 mL). The resulting mixture was extracted with CH2CI2 (3 x 70 mL) and the combined organic layers were washed with sat. aq. NaHCCL (30 mL), brine (1 x 20 mL), dried over anhydrous Na2SC>4, filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (5: 1) to afford 2- {bicyclo [1.1.1 ]pentan- l-yl}-4,7-dichloroquinoline (1.20 g, 44.9%) as a light yellow solid. LC-MS: (ES+H, m / z): [M+H]+=264.00Step 2: Preparation of 2-{bicyclo[l.l.l]pentan-l-yl}-7-chloro-4-ethoxyquinoline :

[0161] A solution of NaH (122 mg, 3.04 mmol, 4.00 equiv., 60%wt) in NMP (6 mL) was treated with EtOH (279 mg, 6.06 mmol, 8.00 equiv.) at 0 °C for 10 min under nitrogen atmosphere. To the above mixture was added the solution of 2-{bicyclo[l.l. l]pentan-l-yl}-4,7-dichloroquinoline (200 mg, 0.76 mmol, 1.00 equiv.) in NMP (1 mL) dropwise at 0 °C. The resulting mixture was stirred at roomWSGR Docket No. 67898-706.601 temperature for 5 h. The reaction was then quenched with sat. NH4CI (aq.) at 0°C. The resulting mixture was diluted with H2O (30 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na2SC>4, fdtered and concentrated. The residue was purified by reversed-phase flash chromatography (column, C18 gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 50% to 80% gradient in 10 min; detector, UV 254 nm) to provide 2- {bicyclo[l. l.l]pentan-l-yl}-7-chloro-4-ethoxyquinoline (190 mg, 91.7%) as a light yellow solid. LC- MS: (ES+H, m / z): [M+H]+=274.05. 'HNMR (400 MHz, DMSO-6) 5 8.08 (d, J= 8.9 Hz, 1H), 7.91 (d,J= 2.1 Hz, 1H), 7.51 (dd, J= 8.9, 2.2 Hz, 1H), 6.90 (s, 1H), 4.32 (m, 2H), 2.58 (s, 1H), 2.18 (s, 6H), 1.47(t, J = 6.9 Hz, 3H).Step 3: Preparation of 2-{bicyclo[l.l.l]pentan-l-yl}-4-ethoxy-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoline:

[0162] To a stirred mixture of 2-{bicyclo[l.l. l]pentan-l-yl}-7-chloro-4-ethoxyquinoline (140 mg, 0.51 mmol, 1.00 equiv.) and bis(pinacolato)diboron (143 mg, 0.56 mmol, 1.10 equiv.) in 1,4-dioxane (5 mL) was added potassium acetate (126 mg, 1.28 mmol, 2.50 equiv.), XPhos (49 mg, 0.10 mmol, 0.20 equiv.), and Pd2(dba)s (47 mg, 0.05 mmol, 0. 10 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 3 h under nitrogen atmosphere and then cool to room temperature. The residue was dissolved in water (10 mL) extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 20 mL), dried over anhydrous Na2SO4, fdtered and concentrated to afford 2-{bicyclo[l.l. l]pentan-l-yl}-4-ethoxy-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoline (150 mg, 80.3%) as a brown solid. LC-MS: (ES+H, m / z): [M+H]+=366.20.Intermediate 91 2 INT-9Step 1: Preparation of 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-7-chloro-4-ethoxyquinoline:

[0163] A solution of 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-4,7-dichloroquinoline (100 mg, 0.34 mmol, 1.00 equiv.) in sodium ethanolate (1 mL, 2.55 mmol, 7.50 equiv., 20% in EtOH) and EtOH (1 mL) was stirred at 60 °C for 4h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3x20 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5: 1), to afford 2-(7-oxabicyclo[2.2. l]heptan-l- yl)-7-chloro-4-ethoxyquinoline (70 mg, 67.7%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+=304.1. ’H NMR (400 MHz, DMSO-6) 5 8.13 (d, J= 8.9 Hz, 1H), 7.94 (d, J= 2.1 Hz, 1H), 7.56 (dd, J= 8.9, 2.1 Hz, 1H), 7.12 (s, 1H), 4.74 (t, J= 5.0 Hz, 1H), 4.33 (q, J= 6.9 Hz, 2H), 2.18 - 2.05 (m, 2H), 1.93 - 1.64 (m, 6H), 1.48 (t, J= 7.0 Hz, 3H).WSGR Docket No. 67898-706.601Step 2: Preparation of 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-4-ethoxy-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoline:

[0164] To a stirred mixture of 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-4,7-dichloroquinoline (60 mg, 0.20 mmol, 1.00 equiv.) and 4,4,5,5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (75 mg, 0.30 mmol, 1.50 equiv.) in 1,4-dioxane (5 mL) were added AcOK (58 mg, 0.59 mmol, 3.00 equiv.), XPhos (20 mg, 0.04 mmol, 0.20 equiv.) and Pd2(dba)s (18 mg, 0.02 mmol, 0.10 equiv.). The resulting mixture was stirred at 100°C for 2h under nitrogen atmosphere and then cooled to room temperature. The resulting mixture was used in the next step directly without further purification. LC- MS: (ES+H, m / z): [M+H]+=396.3.Intermediate 10Step 1: Preparation of 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-7-chloro-4-methoxyquinoline :

[0165] A solution of 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-4,7-dichloroquinoline (100 mg, 0.34 mmol, 1.00 equiv.) and MeONa (184 mg, 3.40 mmol, 10.0 equiv.) in methanol (10.00 mL) was stirred at 60°C for 4 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and diluted with water (50 mL). The resulting mixture was extracted with CH2CI2 (3 x 100 mL). The combined organic layers were washed with brine (2x50 mL), dried over anhydrous Na2SC>4, filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EA (5: 1) to afford 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-7-chloro-4-methoxyquinoline (70 mg, 71.0%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+= 290.0.Step 2: Preparation of 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-4-methoxy-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoline:

[0166] A mixture of 2-(7-oxabicyclo [2.2.1 ]heptan-l-yl)-7-chloro-4-methoxy quinoline (60 mg, 0.21 mmol, 1 equiv.), 4,4,5,5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (79 mg, 0.31 mmol, 1.50 equiv.), Pd2(dba)s (38 mg, 0.04 mmol, 0.20 equiv.), tricyclohexylphosphine (23 mg, 0.08 mmol, 0.40 equiv.) and AcOK (61 mg, 0.62 mmol, 3.00 equiv.) in dioxane (2 mL) was stirred at 110°C for 4 h under nitrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with DCM (2x30 mL). The filtrate was concentrated under reduced pressure to afford 2-(7- oxabicyclo[2.2.1]heptan-l-yl)-4-methoxy-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (60 mg, crude) as a brown oil. LC-MS: (ES+H, m / z): [M+H]+= 382.0.Intermediate 11WSGR Docket No. 67898-706.601Step 1: Preparation of 3-fluoro-N-methoxy-N-methylbicyclo[l.l.l]pentane-l-carboxamide:

[0167] To a stirred mixture of 3-fluorobicyclo[l. l.l]pentane-l-carboxylic acid (2.00 g, 15.37 mmol, 1.00 equiv.) and methoxy(methyl)aminehydrochloride (1.50 g, 15.37 mmol, 1.00 equiv.) in DCM (50 mL) were added DMAP (188 mg, 1.54 mmol, 0.10 equiv.), EDCI (3.58 g, 23.06 mmol, 1.50 equiv.) and triethylamine (1.56 g, 15.37 mmol, 1.00 equiv.) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 12h under nitrogen atmosphere. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1x100 mL), dried over anhydrous Na2SC>4, filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with ClLCL / McOH (10: 1) to afford 3- fhioro-N-methoxy-N-methylbicyclo[l. l.l]pentane-l-carboxamide (1.40 g, 53%) as a yellow oil. LC-MS: (ES+H, m / z): [M+H]+=174.1. 'HNMR (300 MHz, DMSO-6) 5 3.65 (s, 3H), 3.11 (s, 3H), 2.35 (d, J = 2.6 Hz, 6H).Step 2: Preparation of l-{3-fluorobicyclo[l.l.l]pentan-l-yl}ethanone:

[0168] To a stirred mixture of 3 -fluoro-N-methoxy-N-methylbicyclo[ 1.1. l]pentane-l -carboxamide (1.20 g, 6.93 mmol, 1.00 equiv.) in THE (30 mL) was added chloro(methyl)magnesium(3M in THF) (2.77 mL, 8.32 mmol, 1.2 equiv.) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C for 2 h under nitrogen atmosphere. The reaction was quenched by the addition of sat. NH4CI (aq.) (100 mL) at 0°C. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1x100 mL), dried over anhydrous Na2SO4., filtered and concentrated to afford l-{3-fluorobicyclo[l.l.l]pentan-l-yl}ethanone (700 mg, 79%) as a yellow oil. ’H NMR (400 MHz, DMSO-6) 5 2.31 (d, J= 2.6 Hz, 6H), 2.16 (d, J= 1.4 Hz, 3H).Step 3: Preparation of 7-bromo-2-{3-fluorobicyclo[l.l.l]pentan-l-yl}quinoline:

[0169] To a stirred mixture of l-{3-fluorobicyclo[l.l.l]pentan-l-yl}ethanone (230 mg, 1.80 mmol, 1.20 equiv.) and 2-amino-4-bromobenzaldehyde (300 mg, 1.50 mmol, 1.00 equiv.) in EtOH (10 mL) was added KOH (84 mg, 1.50 mmol, 1.00 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C for 2 h under nitrogen atmosphere. The mixture was then allowed to cool down to room temperature, diluted with water (30 mL), and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (1x30 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with PEWSGR Docket No. 67898-706.601 / EA (5: 1) to afford 7-bromo-2-{3-fluorobicyclo[l.l.l]pentan-l-yl}quinoline (250 mg, 57%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+=292.0. ’H NMR (400 MHz, DMSO-6) 5 8.39 (d, J= 8.4 Hz, 1H), 8.17 (d, J= 2.0 Hz, 1H), 7.95 (d, J= 8.7 Hz, 1H), 7.73 (dd, J= 8.6, 2.0 Hz, 1H), 7.59 (d, J= 8.5 Hz, 1H), 2.52 (d, J = 2.6 Hz, 6H).Step 4: Preparation of 2-(3-fluorobicyclo[l.l.l]pentan-l-yl)-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoline:

[0170] To a stirred mixture of 7-bromo-2-{ 3 -fluorobicyclo [1.1.1 ]pentan-l-yl} quinoline (150 mg, 0.51 mmol, 1.00 equiv.) and 4,4,5,5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (195 mg, 0.77 mmol, 1.50 equiv.) in dioxane (10 mL) were added Pd(dppf)C12 (37 mg, 0.05 mmol, 0.10 equiv.) and AcOK (151 mg, 1.54 mmol, 3.00 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 110°C for 2 h and then cooled to room temperature. The crude product was used without further purification. LC-MS: (ES+H, m / z): [M+H]+=340.1.Intermediate 127 8 INT-12Step 1: Preparation of (ls,3s)-3-(benzyloxy)-l-methylcyclobutoxy)(tert-butyl)dimethylsilane: To a stirred solution of (ls,3r)-3-(benzyloxy)-l-methylcyclobutan-l-ol (20.00 g, 104.02 mmol, 1.00 equiv.) and Imidazole (21.25 g, 312.08 mmol, 3.00 equiv.) in CH2CI2 (400 mL) was added tert- butyl(chloro)dimethylsilane (31.36 g, 208.05 mmol, 2.00 equiv.) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 25°C for 16h under nitrogen atmosphere. Desired product could be detected by HNMR. The resulting mixture was diluted with water (400 mL). The resulting mixture was extracted with CH2Q2 (3 x 400mL). The combined organic layers were washed with brine (3 x 400 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (8: 1), to afford (ls,3s)-3-(benzyloxy)-l-methylcyclobutoxy)(tert-butyl)dimethylsilane (23 g, 72.1%) as a yellow oil. 'HNMR (400 MHz, DMSO-6) 57.34 - 7.18 (m, 5H), 4.29 (s, 2H), 3.63 (dd, J = 6.9 Hz, 1H), 2.29 (dd, J= 11.7, 6.0, 2.8 Hz, 2H), 1.92 (dd, J= 11.6, 7.2, 1.9 Hz, 2H), 1.19 (s, 3H), 0.79 (s, 9H), 0.00 (s, 6H).WSGR Docket No. 67898-706.601Step 2: Preparation of (lr,3s)-3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutan-l-ol:To a stirred solution of tert-butyldimethyl[(ls,3r)-3-(benzyloxy)-l-methylcyclobutoxy]silane (5.00 g, 16.31 mmol, 1.00 equiv.) and Pd / C (1.50 g, 14.09 mmol, 0.86 equiv.) in methanol (50 mL) was added HO Ac (0.10 g, 1.63 mmol, 0.10 equiv.) in portions at 25°C. The resulting mixture was stirred at 25°C for 24 h under hydrogen atmosphere. Desired product could be detected by HNMR. The resulting mixture was filtered, and the filter cake was washed with methanol (4 x 60 mL). The filtrate was concentrated under reduced pressure to provide (lr,3s)-3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutan-l-ol (2.9 g, crude) as a yellow oil. ' H NMR (400 MHz, DMSO-6) 5 4.91 (s, 1H), 3.77 - 3.66 (m, 1H), 2.24 (dd, J = 11.2, 6.8, 2.6 Hz, 2H), 1.97 - 1.78 (m, 2H), 1.17 (s, 3H), 0.79 (s, 9H), 0.00 (s, 6H).Step 3: Preparation of (ls,3r)-3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutyl 4-nitrobenzoate: To a stirred solution of (lr,3s)-3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutan-l-ol (3.90 g, 18.02 mmol, 1.00 equiv.) and P-nitrobenzoic acid (3.31 g, 19.82 mmol, 1.10 equiv.) in THF (160 mL) were added PPh; (23.64 g, 90.11 mmol, 5.00 equiv.) and DIAD (17.49 g, 86.51 mmol, 4.80 equiv.) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 25 °C for 2h under nitrogen atmosphere. Desired product could be detected by HNMR. The resulting mixture was diluted with water (300mL) and was extracted with EtOAc (3 x 300mL). The combined organic layers were washed with brine (3x300 mL), dried over anhydrous Na2SC>4, filtered, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (50: 1) to afford (ls,3r)-3-[(tert- butyldimethylsilyl)oxy] -3 -methylcyclobutyl 4-nitrobenzoate (4 g, 60.7%) as a yellow solid. ’H NMR (400 MHz, DMSO-d6) 5 8.28 - 8.23 (m, 2H), 8.12 - 8.05 (m, 2H), 5.25-5.17 (m, 4.5 Hz, 1H), 2.47 (dd, J = 11.4, 7.3, 3.6 Hz, 2H), 2.23 - 2.14 (m, 2H), 1.37 (s, 3H), 0.78 (s, 9H), 0.00 (s, 6H).Step 4: Preparation of (ls,3r)-3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutan-l-ol:To a stirred solution of (ls,3r)-3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutyl 4-nitrobenzoate (1.00 g, 2.73 mmol, 1.00 equiv.) in THF (40 mL) and H2O (10 mL) was added LiOH.H2O (0.23 g, 5.47 mmol, 2.00 equiv.) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 25°C for Ih under nitrogen atmosphere. Desired product could be detected by HNMR. The resulting mixture was diluted with water (50mL). The resulting mixture was extracted with EtOAc (3 x 50mL). The combined organic layers were washed with NaHCOs (3x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in (ls,3r)-3-[(tert-butyldimethylsilyl)oxy]- 3-methylcyclobutan-l-ol (550 mg, crude) as a yellow oil. ’H NMR (400 MHz, DMSO-tL) 5 4.83 (d, J= 4.9 Hz, IH), 4.23 - 4.08 (m, IH), 2.26 - 2.18 (m, 2H), 1.85 - 1.73 (m, 2H), 1.33 (s, 3H), 0.79 (s, 9H), 0.00 (s, 6H).Step 5: Preparation of 4-chloro-3-iodo-l-[(lr,3s)-3-[(tert-butyldimethylsilyl)oxy]-3- methylcyclobutyl]pyrazolo[4,3-c]pyridine:

[0171] To a solution of DIAD (1447 mg, 7.15 mmol, 4.00 equiv.) in THF (70 mL) under N2 at 0 °C was added PPh; (2346 mg, 8.94 mmol, 5.00 equiv.). The resulting mixture was stirred at 25 °C for an additional 1 h. The mixture was then added dropwise to a mixture of 4-chloro-3-iodo-lH-pyrazolo[4,3- c]pyridine (500 mg, 1.78 mmol, 1.00 equiv.) and (ls,3r)-3-[(tert-butyldimethylsilyl)oxy]-3-WSGR Docket No. 67898-706.601 methylcyclobutan-l-ol (387 mg, 1.78 mmol, 1.00 equiv.) in THF (30 mL) under N2 at 0°C and then heated to 50 °C. After 2 h, the reaction was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / EtOAc (7: 1) to afford 4- chloro -3-iodo-l-[(lr,3s)-3 - [(tert-butyldimethylsilyl)oxy] -3 -methylcyclobutyl] pyrazolo [4,3 -c] pyridine (345 mg, 37.1%) as a white solid. 'H NMR (400 MHz, DMSO-6) 3 8.06 (d, J= 6.0 Hz, 1H), 7.75 (d, J = 6.1 Hz, 1H), 4.99 - 4.86 (m, 1H), 2.69 - 2.43 (m, 4H), 1.36 (s, 3H), 1.19 - 1.02 (m, 3H), 0.77 (s, 9H), 0.01 (s, 6H).Step 6: Preparation of 3-iodo-N-[(4-methoxyphenyl)methyl]-l-[(lr,3s)-3-[(tert- butyldimethylsilyl)oxy]-3-methylcyclobutyl]pyrazolo[4,3-c]pyridin-4-amine:

[0172] A solution of 4-chloro-3-iodo-l-[(lr,3s)-3-[(tert-butyldimethylsilyl)oxy]-3- methylcyclobutyl]pyrazolo[4,3-c]pyridine (300 mg, 0.62 mmol, 1.00 equiv.) and (4- methoxyphenyl)methanamine (172 mg, 1.25 mmol, 2.00 equiv.) in DMSO (4 mL) was stirred at 120 °C for 16 h under nitrogen atmosphere and then cooled to room temperature and concentrated. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 70% to 90% gradient in 10 min; detector, UV 254 nm) to afford 3-iodo- N-[(4-methoxyphenyl)methyl]-l-[(lr,3s)-3-[(tert-butyldimethylsilyl)oxy]-3- methylcyclobutyl]pyrazolo[4,3-c]pyridin-4-amine (280 mg, 77.1%) as a yellow oil. 'H NMR (300 MHz, DMSO-d6) 37.76 (d, J= 6.2 Hz, 1H), 7.34 - 7.26 (m, 2H), 6.97 - 6.85 (m, 3H), 6.42 (t, J= 5.6 Hz, 1H), 4.81 (m, J= 8.0 Hz, 1H), 4.66 (d, J= 5.6 Hz, 2H), 3.71 (s, 3H), 2.75 - 2.53 (m, 4H), 1.45 (s, 3H), 0.87 (s, 9H), 0.10 (s, 6H).Step 7: Preparation of (ls,3r)-3-{4-amino-3-iodopyrazolo[4,3-c]pyridin-l-yl}-l-methylcyclobutan- l-ol:

[0173] A solution of 3-iodo-N-[(4-methoxyphenyl)methyl]-l-[(lr,3s)-3-[(tert-butyldimethylsilyl)oxy]- 3-methylcyclobutyl]pyrazolo[4,3-c]pyridin-4-amine (270 mg, 0.46 mmol, 1.00 equiv.) in trifluoroacetic acid (4 mL) was stirred at 70 °C for 3 h under nitrogen atmosphere. The reaction was then cooled to room temperature and concentrated. The residue was then basified to pH 9 with saturated NaHCOs (aq. 20 mL) and extracted with EtOAc (3 x 20 mL). The resulting mixture was concentrated under vacuum to afford (ls,3r)-3-{4-amino-3-iodopyrazolo[4,3-c]pyridin-l-yl}-l-methylcyclobutan-l-ol (220 mg, crude) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+=345.00.Intermediate 13WSGR Docket No. 67898-706.601Step 1: Preparation of N-methoxy-N-methyl-2-oxabicyclo[2.1.1]hexane-l-carboxamide:

[0174] To a stirred mixture of 2 -oxabicyclo [2. 1.1] hexane -1 -carboxylic acid (250 mg, 1.95 mmol, 1.00 equiv.) and N,O-dimethylhydroxylamine hydrochloride (285 mg, 2.93 mmol, 1.50 equiv.) in THF (10 mL) was added EtsN (494 mg, 4.88 mmol, 2.50 equiv.) dropwise at room temperature under nitrogen atmosphere. To the above mixture was added 1-propanephosphonic acid cyclic anhydride (50% in ethyl acetate) (2.48 g, 3.90 mmol, 2.00 equiv., 50%) dropwise over 3 min at 0°C. The resulting mixture was stirred at 0°C for an additional 2h. The resulting mixture was then diluted with water (50 mL) and extracted with CH2CI2 (3 x 50 mL). The combined organic layers were washed with brine (1x50 mL), dried over anhydrous Na2SC>4, filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / MeOH (20: 1) to afford N-methoxy-N-methyl-2- oxabicyclo[2.1.1]hexane-l-carboxamide (210 mg, 63%) as a light yellow oil. LC-MS: (ES+H, m / z): [M+H]+=172.1. 'H NMR (400 MHz, DMSO-6) 5 3.73 (s, 2H), 3.67 (s, 3H), 3.25 - 3.03 (m, 3H), 2.87 (t, J= 3.3 Hz, 1H), 1.98 (ddd, J= 4.9, 3.3, 1.8 Hz, 2H), 1.61 (dd, J= 4.7, 1.8 Hz, 2H).Step 2: Preparation of l-{2-oxabicyclo[2.1.1]hexan-l-yl}ethanone:

[0175] To a stirred mixture ofN-methoxy-N-methyl-2-oxabicyclo[2.1.1]hexane-l-carboxamide (210 mg, 1.23 mmol, 1.00 equiv.) in THF (4 mL) was added chloro(methyl)magnesium (0.8 mL, 2.45 mmol, 2.00 equiv., 3M in THF) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C for 2h under nitrogen atmosphere. The reaction was quenched with sat. aq. NH4CI (20 mL) at 0°C and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1 x 20 mL), dried over anhydrous Na2SC>4, filtered, and concentrated to provide l-{2-oxabicyclo[2.1.1]hexan-l- yl}ethanone (106 mg, 68%) as a light yellow oil. 'H NMR (400 MHz, DMSO-t / e) 5 3.77 (s, 2H), 2.92 (td, J = 32, 1.6 Hz, 1H), 2.19 (s, 3H), 2.04 (ddd, J= 4.8, 3.2, 1.7 Hz, 2H), 1.55 (dd, J= 4.4, 1.8 Hz, 2H).Step 3: Preparation of 7-bromo-2-{2-oxabicyclo[2.1.1]hexan-l-yl}quinoline:

[0176] To a stirred mixture of l-{2-oxabicyclo[2.1.1]hexan-l-yl}ethanone (106 mg, 0.84 mmol, 1.00 equiv.) and 2-amino-4-bromobenzaldehyde (168 mg, 0.84 mmol, 1.00 equiv.) in EtOH (3 mL) was added NaOH (50 mg, 1.26 mmol, 1.50 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C for 2h under nitrogen atmosphere. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1x20 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified byWSGR Docket No. 67898-706.601 reversed-phase flash chromatography (column, Cl 8 gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 40% to 60% gradient in 10 min; detector, UV 254 nm) to provide 7-bromo-2-{2- oxabicyclo[2.1.1]hexan-l-yl}quinoline (65 mg, 27%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+=290.0. ’H NMR (400 MHz, DMSO-6) 5 8.43 (dd, J= 8.6, 0.9 Hz, 1H), 8.21 (d, J= 2.0 Hz, 1H), 7.98 (d, J= 8.7 Hz, 1H), 7.76 (dd, J= 8.7, 2.0 Hz, 1H), 7.72 (d, J= 8.5 Hz, 1H), 3.91 (s, 2H), 3.06 (t, J= 3.2 Hz, 1H), 2.29 (ddd, J= 4.7, 3.2, 1.8 Hz, 2H), 1.78 (dd, J= 4.5, 1.8 Hz, 2H).Step 4: Preparation of 2-{2-oxabicyclo[2.1.1]hexan-l-yl}-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)quinoline:

[0177] To a stirred mixture of 7-bromo-2-{2-oxabicyclo[2.1.1]hexan-l-yl}quinoline (60 mg, 0.21 mmol, 1.00 equiv.) and bis(pinacolato)diboron (105 mg, 0.41 mmol, 2.00 equiv.) in dioxane (3 m ) were added Pd(dppf)Ch CH2Q2 (17 mg, 0.021 mmol, 0.10 equiv.) and AcOK (61 mg, 0.62 mmol, 3.00 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100°C for 2h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and the crude product was used directly without further purification. LC-MS: (ES+H, m / z): [M+H]+=338.1.Intermediate 14Step 1: Preparation of 2-(bicyclo[l.l.l]pentan-l-yl)-5-chloroquinoline:

[0178] A mixture of 5 -chloroquinoline (500 mg, 3.05 mmol, 1.0 equiv.), bicyclofl. l.l]pentane-l- carboxylic acid (342 mg, 3.05 mmol, 1.0 equiv.) and AgNCh (623 mg, 3.66 mmol, 1.2 equiv.) in 5% trifluoroacetic acid water solution (8 mb) was stirred at 80 °C for 20 min under nitrogen atmosphere. To the above mixture was added (NH4)2S20s (3.49 g, 15.28 mmol, 5.0 equiv.) in H2O (2 mb) dropwise over 10 min. The resulting mixture was stirred at 80°C for an additional 30 min. The mixture was allowed to cool down to room temperature and diluted with EtOAc (200 mb). The resulting mixture was washed with 3x50 mb of H2O, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by reversed-phase flash chromatography (column, C18; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 10% to 100% gradient in 40 min; detector, UV 254 nm) to afford 2-{bicyclo[l .1. l]pentan-l- yl} -5 -chloroquinoline (150 mg, 20.6%) as a brown solid. LC-MS: (ES+H, m / z): [M+H]+= 230.1. 'H NMR (400 MHz, DMSO-6) 5 8.51 (dd, J= 8.7, 0.9 Hz, 1H), 8.01 - 7.95 (m, 1H), 7.76 - 7.72 (m, 2H), 7.62 (d, J= 8.7 Hz, 1H), 2.62 (s, 1H), 2.23 (s, 6H).Step 2: Preparation of 2-(bicyclo[l.l.l]pentan-l-yl)-5-chloro-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoline:

[0179] A mixture 2-{bicyclo[l.l.l]pentan-l-yl}-5-chloroquinoline (200 mg, 0.87 mmol, 1.0 equiv.), bis(pinacolato)diboron (442 mg, 1.74 mmol, 2.0 equiv.), Chloro(l,5-cyclooctadiene)iridium(I) dimer (59WSGR Docket No. 67898-706.601 mg, 0.09 mmol, 0.1 equiv.), Dtbpy (47 mg, 0.17 mmol, 0.2 equiv.) in THF (10 mL) was stirred at 80°C for overnight under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with EtOAc (80 mL). The resulting mixture was washed with water (3 x 40 mL), dried over anhydrous Na2SC>4, fdtered and concentrated. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (0%-25% gradient in 35 min) to afford 2- {bicyclofl .1. l]pentan-l-yl}-5-chloro-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (400 mg, crude) as a yellow oil. LC-MS: (ES+H, m / z): [M+H]+= 356.3. 'H NMR (400 MHz, DMSO-6) 5 8.56 - 8.53 (m, 1H), 8.27 (t, J= 1.0 Hz, 1H), 7.82 (d, J= 1.0 Hz, 1H), 7.71 (d, J= 8.7 Hz, 1H), 2.67 (s, 1H), 2.28 (s, 6H), 1.40 (s, 12H).Intermediate 15Step 1: Preparation of 7-chloro-4-methoxyquinoline:

[0180] To a stirred solution of 4,7-dichloroquinoline (10.00 g, 50.49 mmol, 1.00 equiv.) in MeOH (120 mL) was added MeONa (30% in MeOH) (90.93 g, 504.92 mmol, 10.00 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere and then concentrated. The residue was dissolved in EtOAc (300 mL) and washed with water (3 x 200 mL), dried over anhydrous Na2SO4, filtered, and concentrated to afford 7-chloro-4- methoxyquinoline (8.00 g, 81.8%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+= 194.1. 'HNMR (400 MHz, DMSO-d6) 5 8.78 (d, J= 5.2 Hz, 1H), 8.15 (d, J= 8.9 Hz, 1H), 8.00 (d, J= 2.1 Hz, 1H), 7.58 (dd, J= 8.9, 2.2 Hz, 1H), 7.07 (d, J= 5.3 Hz, 1H), 4.06 (s, 3H).Step 2: Preparation of 2-(2-oxabicyclo [2.2.2] octan-l-yl)-7-chloro-4-methoxy quinoline:

[0181] To a stirred mixture of 7-chloro-4-methoxy quinoline (100 mg, 0.52 mmol, 1.00 equiv.) and 2- oxabicyclo[2.2.2]octane-l-carboxylic acid (97 mg, 0.62 mmol, 1.20 equiv.) in 5% trifluoroacetic acid (water solution) (5 mL) were added AgNOs (105 mg, 0.62 mmol, 1.20 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C for 20 min and then a mixture of ammonium persulfate (dissolved in 1.5 mL H2O) (589 mg, 2.58 mmol, 5.00 equiv.) was added dropwise at 80°C. The resulting mixture was stirred at 80°C for 30 min and then cooled down to room temperature. The resulting mixture was diluted with EtOAc (70 mL), washed with water (3 x 30 mL), dried over anhydrous Na2SO4, fdtered and concentrated. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (0%-50% gradient in 30 min) to afford 2-(2-WSGR Docket No. 67898-706.601 oxabicyclo[2.2.2]octan-l-yl)-7-chloro-4-methoxyquinoline (85 mg, 54.3%) as a light yellow solid. LC- MS: (ES+H, m / z): [M+H]+= 304.2. 'HNMR (400 MHz, DMSO-6) 5 8.09 (d, J= 8.9 Hz, 1H), 7.88 (d, J = 2.1 Hz, 1H), 7.52 (dd, J= 8.9, 2.1 Hz, 1H), 7.19 (s, 1H), 4.05 (s, 3H), 2.31 - 2.23 (m, 2H), 1.93 - 1.76 (m, 7H), 1.27 - 1.22 (m, 2H).Step 3: Preparation of 2-(2-oxabicyclo[2.2.2]octan-l-yl)-4-methoxy-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoline:

[0182] To a stirred mixture of 2-(2-oxabicyclo[2.2.2]octan-l-yl)-7-chloro-4-methoxyquinoline (70 mg, 0.23 mmol, 1.00 equiv.) and bis(pinacolato)diboron (70 mg, 0.28 mmol, 1.20 equiv.) in Dioxane (5 m ) were added Pd2(dba)s (21 mg, 0.02 mmol, 0.10 equiv.), XPhos (22 mg, 0.05 mmol, 0.20 equiv.) and AcOK (68 mg, 0.69 mmol, 3.00 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100°C for 3h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The crude product mixture was used in the next step directly without further purification. LC-MS: (ES+H, m / z): [M+H]+= 396.2.Intermediate 16Step 1: Preparation of 3-chloro-N-methoxy-N-methylbicyclo[l.l.l]pentane-l-carboxamide:

[0183] To a stirred mixture of 3 -chlorobicyclo [1.1.1 ] pentane -1 -carboxylic acid (500 mg, 3.41 mmol, 1.00 equiv.) and methoxy(methyl)aminehydrochloride (499 mg, 5.12 mmol, 1.50 equiv.) in THF (10 mb) were added propanephosphonic acid cyclic anhydride (50% in DCM) (4.34 g, 6.82 mmol, 2.00 equiv.) and triethylamine (863 mg, 8.53 mmol, 2.50 equiv.) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2h under nitrogen atmosphere. The resulting mixture was diluted with water (30 mb) and extracted with CH2CI2 (3 x 50 mb). The combined organic layers were washed with brine (1 x 50 mb) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / MeOH (10: 1) to afford 3-chloro-N-methoxy-N-methylbicyclo[l.l. l]pentane-l- carboxamide (330 mg, 51%) as a yellow oil. EC-MS: (ES+H, m / z): [M+H]+=190.1. 'H NMR (300 MHz, DMSO-d6) 5 3.65 (s, 3H), 3.09 (s, 3H), 2.43 (s, 6H).Step 2: Preparation of l-{3-fluorobicyclo[l.l.l]pentan-l-yl}ethanone:

[0184] To a stirred solution of 3 -chloro-N-methoxy-N-methylbicyclo[ 1.1. l]pentane-l -carboxamide (250 mg, 1.32 mmol, 1.00 equiv.) in THF (10 mb) was added chloro(methyl)magnesium(3M in THF) (0.53 mb, 1.58 mmol, 1.20 equiv.) dropwise at 0 °C under nitrogen atmosphere. The resulting mixtureWSGR Docket No. 67898-706.601 was stirred at 0 °C for Ih under nitrogen atmosphere. The reaction was quenched by the addition of sat. NH4CI (aq.) (30 mL) at 0°C. The mixture was allowed to warm to room temperature and the resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (1 x 30 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure to afford l-{3-chlorobicyclo[l.l. l]pentan-l-yl}ethanone (130 mg, 68%) as a yellow oil. ’H NMR (400 MHz, DMSO-6) 5 2.40 (s, 6H), 2.12 (s, 3H).Step 3: Preparation of 7-bromo-2-{3-chlorobicyclo[l.l.l]pentan-l-yl}quinoline:

[0185] To a stirred mixture of l-{3-chlorobicyclo[l.l.l]pentan-l-yl}ethanone (120 mg, 0.83 mmol, 1.00 equiv.) and 2-amino-4-bromobenzaldehyde (166 mg, 0.83 mmol, 1.00 equiv.) in EtOH (10 mL) was added KOH (47 mg, 0.83 mmol, 1.00 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C for 2h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (1x30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5: 1) to afford 7-bromo-2-{3- chlorobicyclo[l. l.l]pentan-l-yl} quinoline (90 mg, 35%) as a yellow oil. LC-MS: (ES+H, m / z): [M+H]+=308.0.Step 4: Preparation of 2-(3-chlorobicyclo[l.l.l]pentan-l-yl)-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoline:

[0186] To a stirred mixture of 7-bromo-2-{3-chlorobicyclo[l.l.l]pentan-l-yl}quinoline (70 mg, 0.23 mmol, 1.00 equiv.) and 4,4,5,5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (86 mg, 0.34 mmol, 1.50 equiv.) in dioxane (5 mL) were added Pd(dppf)C12 (17 mg, 0.02 mmol, 0.10 equiv.) and AcOK (67 mg, 0.68 mmol, 3.00 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 110°C for 2h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was used in the next step directly without further purification. LC-MS: (ES+H, m / z): [M+H]+=356.2.Intermediate 17Step 1: Preparation of 5-{[(3-bromo-2-fluorophenyl)amino]methylidene}-2,2-dimethyl-l,3-dioxane- 4, 6-dione:WSGR Docket No. 67898-706.601

[0187] To a stirred solution of 3 -bromo-2 -fluoroaniline (10.0 g, 52.60 mmol, 1.0 equiv.) in EtOH (200 mL) was added 5-(methoxymethylidene)-2,2-dimethyl-l,3-dioxane-4, 6-dione (11.7 g, 63.10 mmol, 1.2 equiv.) in portions at room temperature under N2 atmosphere. The resulting mixture was stirred at 80°C for Ih under N2 atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with diethyl ether (200 mL). The resulting mixture was filtered, the filter cake was washed with diethyl ether (3 x 50 mL). The filtrate was concentrated under reduced pressure to afford 5- {[(3-bromo-2-fluorophenyl)amino]methylidene}-2,2-dimethyl-l,3-dioxane-4, 6-dione (12.0 g, 66.6%) as a light yellow solid. LC-MS: (ES-H, m / z): [M-H] = 343.90. ’H NMR (400 MHz, DMSO-6) 5 11.33 (d, J = 14.0 Hz, IH), 8.67 (d, J= 14.0 Hz, IH), 7.91 - 7.77 (m, IH), 7.58 (ddt, J= 7.9, 6.9, 2.7 Hz, IH), 7.24 (tdd, J= 8.1, 2.6, 1.4 Hz, IH), 1.69 (s, 6H).Step 2: Preparation of 7-bromo-8-fluoroquinolin-4-ol:

[0188] A solution of 5-{[(3-bromo-2-fluorophenyl)amino]methylidene}-2,2-dimethyl-l,3-dioxane- 4,6-dione (12.0 g, 34.81 mmol, 1.0 equiv.) in diphenyl ether (200 mL) was stirred at 240°C for Ih under N2 atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with diethyl ether (200 mL). The resulting mixture was filtered and the filter cake was washed with diethyl ether (3 x 50 mL). The filtrate was concentrated under reduced pressure to afford 7-bromo-8- fluoroquinolin-4-ol (5.00 g, 59.2%) as a light yellow solid. LC-MS: (ES+H, m / z): [M+H]+= 241.90. 'H NMR (300 MHz, DMSO-6) 5 12.00 (s, IH), 7.88 (d, J= 7.5 Hz, IH), 7.82 (dd, J= 8.8, 1.4 Hz, IH), 7.54 (dd, J= 8.8, 6.3 Hz, IH), 6.13 (d, J= 7.4 Hz, IH).Step 3: Preparation of 7-bromo-4-chloro-8-fluoroquinoline:

[0189] To a stirred solution of 7-bromo-8-fluoroquinolin-4-ol (4.00 g, 16.52 mmol, 1.0 equiv.) in toluene (40 mL) was added phosphoryl trichloride (5.07 g, 33.02 mmol, 2.0 equiv.) dropwise at room temperature under N2 atmosphere. The resulting mixture was stirred at 100°C for Ih under N2 atmosphere. The mixture was allowed to cool down to room temperature. The cooled reaction mixture was poured over ice and then the mixture was neutralized to pH 8 with saturated sodium carbonate. The aqueous layer was extracted with CH2Q2 (3x100 mL). The organic layer was dried over anhydrous Na2SC>4, concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / EtOAc (0%-50% gradient in 30 min) to afford 7-bromo-4- chloro-8-fluoroquinoline (3.00 g, 69.6%) as a grey solid. LC-MS: (ES+H, m / z): [M+H]+= 259.90. 'H NMR (300 MHz, DMSO-6) 5 8.93 (dd, J= 4.8, 0.6 Hz, IH), 7.99 (d, J= 4.7 Hz, 2H), 7.94 (d, J= 4.7 Hz, IH).Step 4: Preparation of 2-(bicyclo[l.l.l]pentan-l-yl)-7-bromo-4-chloro-8-fluoroquinoline:

[0190] A mixture of 7-bromo-4-chloro-8-fluoroquinoline (400 mg, 1.54 mmol, 1.0 equiv.), bicyclofl. l.l]pentane-l-carboxylic acid (207 mg, 1.84 mmol, 1.2 equiv.) and AgNOs (313 mg, 1.84 mmol, 1.2 equiv.) in 10% H2SO4 water solution (18 mL) was stirred at 80 °C for 20 min under nitrogen atmosphere, followed by the addition of (NH4)2S20s (1.75 g, 7.67 mmol, 4.9 equiv.) with H2O (4 mL) dropwise over 10 min. The resulting mixture was stirred at 80°C for an additional 30 min. The resulting mixture was diluted with water (20 mL), extracted with EtOAc (3x50 mL), dried over anhydrous Na2SC>4,WSGR Docket No. 67898-706.601 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / EtOAc (0%-30% gradient in 30 min) to afford 2- (bicyclo[l.l.l]pentan-l-yl)-7-bromo-4-chloro-8-fhioroquinoline (200 mg, 30.9%) as a yellow solid. LC- MS: (ES+H, m / z): [M+H]+= 326.0. 'HNMR (400 MHz, DMSO-6) 5 7.92 (dd, J= 2.3, 0.9 Hz, 2H), 7.85 (s, 1H), 2.61 (s, 1H), 2.24 (s, 6H).Step 5: Preparation of 2-(bicyclo[l.l.l]pentan-l-yl)-7-bromo-4-ethoxy-8-fluoroquinoline:

[0191] To a stirred solution of 2-{bicyclo[EE l]pentan-l-yl}-7-bromo-4-chloro-8-fluoroquinoline (200 mg, 0.61 mmol, 1.0 equiv.) in EtOH (3 mL) were added 20% sodium ethanolate (1.5 g, 4.29 mmol, 7.0 equiv.) at room temperature. The resulting mixture was stirred at 50°C for overnight under nitrogen atmosphere. The resulting mixture was diluted with EtOAc (80 mL) and washed with water (2 x 30 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / EtOAc (0%-30% gradient in 30 min) to afford 2-(bicyclo[l.l. l]pentan-l-yl)-7-bromo-4-ethoxy-8- fluoroquinoline (110 mg, 42.7%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+= 336.1. 'HNMR (400 MHz, DMSO-d6) 5 7.88 (dd, J= 9.0, 1.4 Hz, 1H), 7.75 (dd, J= 9.0, 6.3 Hz, 1H), 7.06 (s, 1H), 4.40 (q, J = 6.9 Hz, 2H), 2.65 (s, 1H), 2.26 (s, 6H), 1.53 (t, J= 7.0 Hz, 3H).Step 6: Preparation of 2-(bicyclo[l.l.l]pentan-l-yl)-4-ethoxy-8-fluoro-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoline:

[0192] A mixture of 2-{bicyclo[l.l.l]pentan-l-yl}-7-bromo-4-ethoxy-8-fluoroquinoline (80 mg, 0.24 mmol, 1.0 equiv.), bis(pinacolato)diboron (362 mg, 1.43 mmol, 6.0 equiv.), Pd(dppf)C12 (10 mg, 0.04 mmol, 0.2 equiv.), AcOK (117 mg, 1.19 mmol, 5.0 equiv.) in 1,4-dioxane (6 mL) was stirred at 120°C for 2h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / MeOH (0%-10% gradient in 30 min) to afford 2-(bicyclo| 1 .1. l]pentan-l-yl)-4-ethoxy-8-fluoro-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (100 mg, crude) as a yellow oil. LC-MS: (ES+H, m / z): [M+H]+= 384.2.Intermediate 18Step 1: Preparation of l-((ls,3s)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutyl)-4-chloro-lH- pyrr olo [3,2-c] pyridine :

[0193] To a stirred mixture of 4-chloro-lH-pyrrolo[3,2-c]pyridine (200 mg, 1.31 mmol, 1.00 equiv.) and (lr,3r)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutan-l-ol (312 mg, 1.44 mmol, 1.10 equiv.) in toluene (10 mL) were added CMBP ((cyanomethylene)tributylphosphorane) (1266 mg, 5.24 mmol, 4.00WSGR Docket No. 67898-706.601 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C for overnight under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and diluted with EtOAc (100 mL). The resulting mixture was washed with 3 x 50 mL of water and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (0%-10% gradient in 30 min) to afford l-((ls,3s)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutyl)-4-chloro-lH- pyrrolo[3,2-c]pyridine [3 ,2 -c] pyridine (300 mg, 65.2%) as a light yellow oil. LC-MS: (ES+H, m / z): [M+H]+= 351.2 .1HNMR (400 MHz, DMSO-6) 5 7.90 (d, J= 5.8 Hz, 1H), 7.58 (d, J= 3.3 Hz, 1H), 7.49 (d, J= 5.8 Hz, 1H), 6.52 (d, J= 2.7 Hz, 1H), 4.68 - 4.58 (m, 1H), 2.71 - 2.59 (m, 2H), 2.40 - 2.28 (m, 2H), 1.40 (s, 3H), 0.77 (s, 9H), 0.00 (s, 6H).Step 2: Preparation of 3-bromo-l-((ls,3s)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutyl)-4- chloro- IH-pyrrolo [3,2-c] pyridine:

[0194] To a stirred solution of l-((ls,3s)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutyl)-4- chloro-lH-pyrrolo [3,2-c] pyridine [3,2-c]pyridine (250 mg, 0.71 mmol, 1.00 equiv.)in CH2CI2 (10 mL) were added NBS (140 mg, 0.78 mmol, 1.10 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2h under nitrogen atmosphere and diluted with CH2CI2 (70 mL). The organic layer was washed with 3 x 30 mL of brine and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (0%-10% gradient in 30 min) to afford 3 -bromo- 1 -(( 1 s,3 s)-3 -((tert-butyldimethylsilyl)oxy)-3 -methylcyclobutyl)-4-chloro- 1H- pyrrolo[3,2-c]pyridine (250 mg, 81.6%) as a light brown solid. LC-MS: (ES+H, m / z): [M+H]+= 429.0. ' HNMR (400 MHz, DMSO-6) 5 7.95 (d, J= 5.8 Hz, 1H), 7.87 (s, 1H), 7.57 (d, J= 5.8 Hz, 1H), 4.68 - 4.58 (m, 1H), 2.68 - 2.59 (m, 2H), 2.40 - 2.31 (m, 2H), 1.39 (s, 3H), 0.77 (s, 9H), 0.00 (s, 6H).Step 3: Preparation of 3-bromo-l-((ls,3s)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutyl)-N- (4-methoxybenzyl)-lH-pyrrolo[3,2-c]pyridin-4-amine:

[0195] To a stirred mixture of 3-bromo-l-((ls,3s)-3-((tert-butyldimethylsilyl)oxy)-3- methylcyclobutyl)-4-chloro-lH-pyrrolo[3,2-c]pyridine (200 mg, 0.47 mmol, 1.00 equiv.) and (4- methoxyphenyl)methanamine (638 mg, 4.65mmol, 10.00 equiv.) in DMSO (5 mL) were added DIEA (902 mg, 6.98 mmol, 15.00 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 140°C for 2 days under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and diluted with EtOAc (100 mL). The organic layer was washed with 3 x 50 mL of water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (0%-50% gradient in 30 min) to afford 3-bromo-l-((ls,3s)-3-((tert-butyldimethylsilyl)oxy)- 3-methylcyclobutyl)-N-(4-methoxybenzyl)-lH-pyrrolo[3,2-c]pyridin-4-amine (220 mg, 89.1%) as a light yellow oil. LC-MS: (ES+H, m / z): [M+H]+= 530.3. ’HNMR (400 MHz, DMSO-6) 5 7.57 (d, J= 6.0 Hz, 1H), 7.38 (s, 1H), 7.23 - 7.17 (m, 2H), 6.81 - 6.75 (m, 2H), 6.72 (d, J= 6.1 Hz, 1H), 6.16 (t, J= 5.8 Hz,WSGR Docket No. 67898-706.6011H), 4.54 (d, J= 5.8 Hz, 2H), 4.49 - 4.39 (m, 1H), 3.63 (s, 3H), 2.64 - 2.55 (m, 2H), 2.37 - 2.30 (m, 2H), 1.37 (s, 3H), 0.78 (s, 9H) 0.00 (s, 6H).Step 4: Preparation of (ls,3s)-3-(4-amino-3-bromo-lH-pyrrolo[3,2-c]pyridin-l-yl)-l- methylcyclobutan-l-ol:

[0196] To a stirred solution of trifluoroacetic acid (2 mL) were added 3-bromo-l-((ls,3s)-3-((tert- butyldimethylsilyl)oxy)-3-methylcyclobutyl)-N-(4-methoxybenzyl)-lH-pyrrolo[3,2-c]pyridin-4-amine (200 mg, 0.34 mmol, 1.00 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 60°C for Ih under nitrogen atmosphere. The mixture was allowed to cool down to room temperature, quenched by the addition of ice water (15 mL) at 0°C and basified to pH 7-8 with saturated NaHCOs (aq.). The aqueous layer was extracted with EtOAc (3 x 50 mL) and the organic layer was dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with ClLCL / McOH (0%-25% gradient in 30 min) to afford (ls,3s)-3-(4-amino-3-bromo-lH-pyrrolo[3,2-c]pyridin-l-yl)-l-methylcyclobutan-l- ol (120 mg, crude) as a light yellow oil. LC-MS: (ES+H, m / z): [M+H]+= 296.1.1HNMR (400 MHz, DMSO-d6) 57.86 (s, IH), 7.64 (d, J= 6.8 Hz, IH), 7.16 - 7.05 (m, 3H), 5.29 (s, IH), 4.72 - 4.60 (m, IH), 2.64 - 2.54 (m, 2H), 2.48 - 2.41 (m, 2H), 1.35 (s, 3H).Intermediate 19Step 1: Preparation of 5-{[(3-chloro-2-fluorophenyl)amino]methylidene}-2,2-dimethyl-l,3-dioxane- 4, 6-dione:

[0197] To a stirred solution of 3 -chloro-2 -fluoroaniline (10.0 g, 68.7 mmol, 1.00 equiv.) in EtOH (200 mL) was added 5-(methoxymethylidene)-2,2-dimethyl-l,3-dioxane-4, 6-dione (15.3 g, 82.4 mmol, 1.20 equiv.) in portions at room temperature under N2 atmosphere. The resulting mixture was stirred at 80°C for Ih under N2 atmosphere. The mixture was allowed to cool down to room temperature and diluted with diethyl ether (200 mL). The resulting mixture was filtered and the filter cake was washed with diethyl ether (3 x 50 mL). The filtrate was concentrated under reduced pressure to afford 5-{[(3-chloro-2- fluorophenyl)amino]methylidene}-2,2-dimethyl-l,3-dioxane-4, 6-dione (12.0 g, 58.2%) as a light yellow solid. LC-MS: (ES-H, m / z): [M-H] = 298.05. 'H NMR (400 MHz, DMSO-6) 5 11.32 (d,J= 14.0 Hz, IH), 8.67 (d, J= 14.0 Hz, IH), 7.82 (ddd, J= 8.6, 7.4, 1.5 Hz, IH), 7.47 (ddd, J= 8.3, 6.9, 1.5 Hz, IH), 7.30 (td, J= 8.3, 1.6 Hz, IH), 1.69 (s, 6H).WSGR Docket No. 67898-706.601Step 2: Preparation of 7-chloro-8-fluoroquinolin-4-ol:

[0198] A solution of 5-{[(3-chloro-2-fluorophenyl)amino]methylidene}-2,2-dimethyl-l,3-dioxane- 4, 6-dione (12.0 g, 40.0 mmol, 1.00 equiv.) in diphenyl ether (200 mL) was stirred at 240°C for Ih under N2 atmosphere. The mixture was allowed to cool down to room temperature and diluted with diethyl ether (200 mL). The resulting mixture was fdtered and the fdter cake was washed with diethyl ether (3 x 50 mL). The fdtrate was concentrated under reduced pressure to afford 7-chloro-8-fluoroquinolin-4-ol (3.18 g, 40.1%) as a light yellow solid. LC-MS: (ES+H, m / z): [M+H]+= 198.0. ’H NMR (400 MHz, DMSO-d6) 5 11.97 (s, IH), 7.89 (dd, J= 8.6, 1.6 Hz, 2H), 7.53 - 7.31 (m, IH), 6.13 (d, J= 7.4 Hz, IH). Step 3: Preparation of 4,7-dichloro-8-fluoroquinoline:

[0199] To a stirred solution of 7-chloro-8-fluoroquinolin-4-ol (3.18 g, 16.0 mmol, 1.00 equiv.) in toluene (40 mL) was added phosphoryl trichloride (4.94 g, 32.1 mmol, 2.00 equiv.) dropwise at room temperature under N2 atmosphere. The resulting mixture was stirred at 100°C for Ih under N2 atmosphere. The mixture was allowed to cool down to room temperature, poured over ice water and the mixture was neutralized to pH 8 with saturated aq. sodium carbonate. The aqueous layer was extracted with CH2Q2 (3x100 mL). The organic layer was dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (0%-50% gradient in 30 min) to afford 4,7-dichloro-8-fluoroquinoline (3.10 g, 89.1%) as a light yellow solid. LC-MS: (ES+H, m / z): [M+H]+= 216.00.1H NMR (300 MHz, DMSO-tL) 5 8.95 (d, J = 4.7 Hz, IH), 8.07 (dd, J= 9.2, 1.6 Hz, IH), 7.96 - 7.87 (m, 2H).Step 4: Preparation of 2-(bicyclo[l.l.l]pentan-l-yl)-4,7-dichloro-8-fluoroquinoline:

[0200] To a stirred mixture of 4,7-dichloro-8-fluoroquinoline (300 mg, 1.39 mmol, 1.00 equiv.) and bicyclo[l. l.l]pentane-l-carboxylic acid (187 mg, 1.67 mmol, 1.20 equiv.) in 10% H2SO4 (water solution) (10 mL) were added AgNCL (283 mg, 1.67 mmol, 1.20 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C for 20 min under nitrogen atmosphere. To the above mixture was added ammonium persulfate (dissolved in 3.5 mL H2O, 1584 mg, 6.95 mmol, 5.00 equiv.) dropwise at 80°C under nitrogen atmosphere. The resulting mixture was stirred at 80°C for 30 min under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and diluted with EtOAc (130 mL). The organic layer was washed with 3 x 20 mL of water and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (0%-10% gradient in 30 min) to afford 2-(bicyclo[l. l.l]pentan-l-yl)-4,7-dichloro-8-fluoroquinoline (170 mg, crude) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+= 282.0. ' HNMR (400 MHz, DMSO-tL) 5 8.00 (dd, J= 9.1, 1.6 Hz, IH), 7.86 (d, J= 1.4 Hz, IH), 7.85 - 7.81 (m, IH), 2.61 (s, IH), 2.24 (s, 6H).19FNMR (377 MHz, DMSO-tL) 5 -124.83.Step 5: Preparation of 2-(bicyclo[l.l.l]pentan-l-yl)-7-chloro-8-fluoroquinoline:

[0201] To a stirred mixture of 2-(bicyclo[l. l.l]pentan-l-yl)-4,7-dichloro-8-fluoroquinoline (160 mg, 0.57 mmol, 1.00 equiv.) and Pd(dppf)C12 (21 mg, 0.03 mmol, 0.05 equiv.) in THF (5 mL) were added N,N,N',N'-tetramethylethylenediamine (132 mg, 1.13 mmol, 2.00 equiv.) and NaBFL (43 mg, 1.13 mmol,WSGR Docket No. 67898-706.6012.00 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for Ih under nitrogen atmosphere and quenched with water (2 mL) at 0°C. The resulting mixture was extracted with EtOAc (80 mL) and the organic layer was washed with 3 x 20 mL of water. The organic layer was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (0%-10% gradient in 30 min) to afford 2- (bicyclo[l.l.l]pentan-l-yl)-7-chloro-8-fluoroquinoline (60 mg, 42.7%) as a light yellow solid. LC-MS: (ES+H, m / z): [M+H]+= 248.0. 'HNMR (400 MHz, DMSO-6) 5 8.43 (d, J= 8.5 Hz, IH), 7.84 (d, J = 8.8 Hz, IH), 7.73 - 7.65 (m, IH), 7.61 (d, J= 8.5 Hz, IH), 2.62 (s, IH), 2.23 (s, 6H).19FNMR (377 MHz, DMSO-d6) 5 -127.22.Step 6: Preparation of 2-(bicyclo[l.l.l]pentan-l-yl)-8-fluoro-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoline:

[0202] To a stirred mixture of 2-(bicyclo[l. l.l]pentan-l-yl)-7-chloro-8-fluoroquinoline (35 mg, 0.14 mmol, 1.00 equiv.) and bis(pinacolato)diboron (108 mg, 0.42 mmol, 3.00 equiv.) in dioxane (3 mL) were added Pd2(dba)s (13 mg, 0.01 mmol, 0.10 equiv.), XPhos (14 mg, 0.03 mmol, 0.20 equiv.) and AcOK (42 mg, 0.42 mmol, 3.00 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C for 3h under nitrogen atmosphere, cooled to room temperature and concentrated. The residue was used in the next step directly without further purification. LC-MS: (ES+H, m / z): [M+H]+= 340.2.Intermediate 20Step 1: Preparation of 4,7-dichloro-8-fluoro-2-{7-oxabicyclo[2.2.1]heptan-l-yl}quinoline:

[0203] A mixture of 4,7-dichloro-8-fluoroquinoline (600 mg, 2.77 mmol, 1.00 equiv.), 7- oxabicyclo[2.2.1]heptane-l-carboxylic acid (394 mg, 2.77 mmol, 1.00 equiv.) and AgNOs (566 mg, 3.33 mmol, 1.20 equiv.) in 5% TFA water solution (20 mL) was stirred at 80°C for 10 min under nitrogen atmosphere and then treated with (NH4)2S20s (6.34 g, 27.7 mmol, 10.0 equiv.) in H2O (4 mL) dropwise over 10 min. The resulting mixture was stirred at 80°C for an additional Ih and diluted with water (30 mL). The aqueous layer was extracted with EtOAc (3x100 mL), dried over anhydrous Na2SO4 and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (0%-10% gradient in 20 min) to afford 4,7- dichloro-8-fluoro-2-{7-oxabicyclo[2.2.1]heptan-l-yl}quinoline (280 mg, 32.3%) as a white solid. LC- MS: (ES+H, m / z): [M+H]+= 312.1. 'HNMR (400 MHz, DMSO-6) 5 8.04 (dd, J= 9.2, 1.5 Hz, IH), 7.93 (s, IH), 7.89 (dd, J= 9.2, 6.7 Hz, IH), 4.77 (t, J= 4.9 Hz, IH), 2.16 - 2.10 (m, 2H), 1.94 - 1.66 (m, 6H).Step 2: Preparation of 7-chloro-8-fluoro-2-{7-oxabicyclo[2.2.1]heptan-l-yl}quinoline:WSGR Docket No. 67898-706.601

[0204] To a stirred solution of 4,7-dichloro-8-fluoro-2-{7-oxabicyclo[2.2.1]heptan-l-yl}quinoline (130 mg, 0.41 mmol, 1.00 equiv.) in THF (5 mL) were added Pd(dppf)C12CH2C12 (17 mg, 0.02 mmol, 0.05 equiv.), N,N,N',N'-tetramethylethylenediamine (96 mg, 0.83 mmol, 2.00 equiv.) and NaBEL (23 mg, 0.62 mmol, 1.50 equiv.) in portions at 25°C under N2 atmosphere. The resulting mixture was stirred at 25°C for Ih under N2 atmosphere and quenched with H2O (2 mL) at 0°C. The resulting mixture was extracted with EtOAc (80 mL) and the organic layer was washed with water (2x30 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (0%-30% gradient in 30 min) to afford 7-chloro-8-fluoro-2-{7-oxabicyclo[2.2.1]heptan-l-yl}quinoline (65 mg, 56.2%). LC- MS: (ES+H, m / z): [M+H]+= 278.1. H NMR (400 MHz, DMSO-tL) 5 8.49 (dd, J= 8.6, 1.6 Hz, IH), 7.88 (dd, J= 8.9, 1.5 Hz, IH), 7.81 (d, J= 8.6 Hz, IH), 7.73 (dd, J= 8.9, 6.7 Hz, IH), 4.76 (t, J = 5.0 Hz, IH), 2.16 (td, J= 9.9, 3.6 Hz, 2H), 1.93 - 1.73 (m, 4H), 1.73 - 1.67 (m, 2H).Step 3: Preparation of 8-fluoro-2-{7-oxabicyclo[2.2.1]heptan-l-yl}-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoline:

[0205] To a stirred solution of 7-chloro-8-fluoro-2-{7-oxabicyclo[2.2.1]heptan-l-yl}quinoline (50 mg, 0.18 mmol, 1.00 equiv.) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2- dioxaborolane (182 mg, 0.72 mmol, 4.00 equiv.) in 1,4-dioxane (4 mL) was added Pd2(dba)s (16 mg, 0.01 mmol, 0.10 equiv.), tricyclohexylphosphane (10 mg, 0.03 mmol, 0.20 equiv.) and AcOK (53 mg, 0.54 mmol, 3.00 equiv.) in portions at 25°C under N2 atmosphere. The resulting mixture was stirred at 80°C for 16h under N2 atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was used in the next step directly without further purification.Intermediate 21Step 1: Preparation of 6-bromo-l-chloropyrrolo[l,2-a]pyrazine:

[0206] A mixture of l-chloropyrrolo[l,2-a]pyrazine (1.00 g, 6.55 mmol, 1.00 equiv.) and NBS (1.17 g, 6.55 mmol, 1.00 equiv.) in MeCN (30 mL) was stirred at room temperature overnight under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and the residue was purifiedWSGR Docket No. 67898-706.601 by silica gel column chromatography, eluted with PE / EA (5: 1) to afford 6-bromo-l-chloropyrrolo[l,2- a]pyrazine (1.36 g, 90%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+=230.9.1H NMR (400 MHz, CDCh) 5 7.82 (dd, J= 4.9, 1.0 Hz, 1H), 7.46 (d, J= 4.9 Hz, 1H), 6.99 (dd, J= 4.4, 1.0 Hz, 1H), 6.93 (d, J= 4.4 Hz, 1H).Step 2: Preparation of 6-{3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutyl}-l-chloropyrrolo[l,2- a] pyrazine:

[0207] Part B: To a stirred solution of (lr,3s)-3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutan-l- ol (1636 mg, 7.56 mmol, 3.50 equiv.) and 5, 7-di-tert-butyl-3 -phenylbenzo [d]oxazol-3-ium tetrafluoroborate (2732 mg, 6.91 mmol, 3.20 equiv.) in MTBE (20 mb) were added pyridine (547 mg, 6.91 mmol, 3.20 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 10 min at room temperature under nitrogen atmosphere.

[0208] Part A: To a stirred mixture of 6-bromo-l-chloropyrrolo[l,2-a]pyrazine (500 mg, 2.16 mmol, 1.00 equiv.) and l-azabicyclo[2.2.2]octane (420 mg, 3.78 mmol, 1.75 equiv.) in N,N-dimethylacetamide (20 mb) was added [4,4'-Bis(tert-butyl)-2,2'-bipyridine]nickel dibromide (105 mg, 0.22 mmol, 0.10 equiv.) and [Ir(dtbbpy)(ppy)2]pfe (99 mg, 0.11 mmol, 0.05 equiv.) at room temperature under nitrogen atmosphere.

[0209] The precipitated solids of Part B were fdtered out. The filtrate of Part B was added to the mixture of Part A dropwise under nitrogen atmosphere. The resulting mixture was stirred for 16 h at room temperature under nitrogen atmosphere with the irradiation by 455 nm blue light. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography ( C18, MeCN in Water (0.1% HCOOH), 70% to 90% gradient in 10 min; detector, UV 254 nm) to provide 6-{3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutyl}-l-chloropyrrolo[l,2- a]pyrazine (300 mg, 39%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+=351.2.Step 3: Preparation of 8-bromo-l-chloro-6-[(lr,3s)-3-[(tert-butyldimethylsilyl)oxy]-3- methyl cyclobutyl] pyrr olo [1 ,2-a] pyrazine:

[0210] A mixture of 6-{3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutyl}-l-chloropyrrolo[l,2- a]pyrazine (300 mg, 0.86 mmol, 1.00 equiv.) and NBS (152 mg, 0.86 mmol, 1.00 equiv.) in CH2CI2 (20 mb) was stirred at room temperature for 2h under nitrogen atmosphere. The resulting mixture was diluted with water (20 mb) and extracted with CH2CI2 (3 x 20 mb). The combined organic layers were washed with brine (1x20 mb) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10: 1) to afford 8-bromo-l-chloro-6-[(lr,3s)-3-[(tert-butyldimethylsilyl)oxy]-3- methylcyclobutyl]pyrrolo[l,2-a]pyrazine (Compound 5, 160 mg, 44%) as a white solid and 8-bromo-6- ((lr,3r)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutyl)-l-chloropyrrolo[l,2-a]pyrazine (Compound 6, 52 mg, 14%). Compound 5: LC-MS: (ES+H, m / z): [M+H]+= 429.1 'H NMR (400 MHz, DMSO-d6) 5 8.02 (d, J= 4.9 Hz, 1H), 7.28 (d, J= 4.9 Hz, 1H), 6.95 (s, 1H), 3.41 - 3.27 (m, 1H), 2.52 (td, J= 8.1, 2.7 Hz, 2H), 2.15 - 2.04 (m, 2H), 1.43 (s, 3H), 0.77 (s, 9H), 0.00 (s, 6H).WSGR Docket No. 67898-706.601

[0211] Compound 6: LC-MS: (ES+H, m / z): [M+H]+= 429.1 'H NMR (400 MHz, DMSO-6) 57.80 (d, J= 4.9 Hz, 1H), 7.23 (d, J= 4.9 Hz, 1H), 7.00 (s, 1H), 3.64 - 3.60 (m, 1H), 2.55 (dd, J= 12.5, 9.8 Hz, 2H), 2.22 - 2.11 (m, 2H), 1.16 (s, 3H), 0.78 (s, 9H), 0.00 (s, 6H).Step 4: Preparation of 8-bromo-N-[(4-methoxyphenyl)methyl]-6-[(lr,3s)-3-[(tert- butyldimethylsilyl)oxy] -3-methylcyclobutyl] pyrrolo [1,2-a] pyrazin-l-amine:

[0212] To a stirred mixture of 8-bromo-l-chloro-6-[(lr,3s)-3-[(tert-butyldimethylsilyl)oxy]-3- methylcyclobutyl]pyrrolo[l,2-a]pyrazine (Compound 5, 160 mg, 0.37 mmol, 1.00 equiv.) and 4- methoxy-benzylamine, (511 mg, 3.72 mmol, 10.00 equiv.) in DMSO (8 mL) was added DIEA (722 mg, 5.58 mmol, 15.00 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 140°C for 4h under nitrogen atmosphere and diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 5: 1, Rf=0.5) to afford 8-bromo-N-[(4- methoxyphenyl)methyl]-6-[(lr,3s)-3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutyl]pyrrolo[l,2- a]pyrazin-l -amine (140 mg, 71%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+=530.2. 'HNMR (400 MHz, DMSO-d6) 57.29 (d, J= 4.9 Hz, 1H), 7.26 - 7.21 (m, 2H), 6.95 (d, J= 4.9 Hz, 1H), 6.86 - 6.78 (m, 2H), 6.55 (s, 1H), 5.70 (s, 1H), 4.55 (d, J= 5.7 Hz, 2H), 3.66 (s, 3H), 3.21 (d, J= 8.8 Hz, 1H), 2.48 (dd, J= 8.3, 2.9 Hz, 2H), 2.05 (t, J= 10.1 Hz, 2H), 1.41 (s, 3H), 0.78 (s, 9H), 0.00 (s, 6H).Step 5: Preparation of (ls,3s)-3-(l-amino-8-bromopyrrolo[l,2-a]pyrazin-6-yl)-l-methylcyclobutan- l-ol:

[0213] A mixture of 8-bromo-N-[(4-methoxyphenyl)methyl]-6-[(lr,3s)-3-[(tert- butyldimethylsilyl)oxy]-3-methylcyclobutyl]pyrrolo[l,2-a]pyrazin-l-amine (140 mg, 0.26 mmol, 1.00 equiv.) and trifluoroacetic acid (4 mL) in CH2CI2 (4 mL) was stirred at 50°C for 4h under nitrogen atmosphere. The resulting mixture was diluted with water (20 mL) and basified to pH 8 with saturated Na2COs (aq.). The resulting mixture was extracted with CH2Q2 (2 x 50 mL). The combined organic layers were washed with brine (1x50 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (Cl 8, MeCN in Water (10 mmol / L NH4HCO3), 10% to 20% gradient in 10 min; detector, UV 254 run) to provide (ls,3s)-3-(l-amino-8-bromopyrrolo[l,2-a]pyrazin-6-yl)-l-methylcyclobutan-l-ol (70 mg, 77%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+=296.0.Intermediate 22Step 1: Preparation of 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-7-chloro-4-ethoxy-8-fluoroquinoline:WSGR Docket No. 67898-706.601

[0214] To a stirred solution of 4,7-dichloro-8-fluoro-2-{7-oxabicyclo[2.2.1]heptan-l-yl}quinoline (100 mg, 0.32 mmol, 1.00 equiv.) in EtOH (5 mL) were added sodium ethanolate (20% in ethanol) (1.09 g, 3.20 mmol 10.0 equiv.) dropwise at 25°C under nitrogen atmosphere. The resulting mixture was stirred at 25°C for 16h under nitrogen atmosphere and then diluted with EtOAc (80 mL). The organic layer was washed with water (2 x 30 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (0%-30% gradient in 30 min) to afford 2-(7-oxabicyclo[2.2.1]heptan- l-yl)-7-chloro-4-ethoxy-8-fluoroquinoline (70 mg, 67.9%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+= 322.1. 'H NMR (400 MHz, DMSO-6) 5 7.94 (dd, J= 9.0, 1.6 Hz, 1H), 7.64 (dd, J= 9.1, 6.7 Hz, 1H), 7.19 (s, 1H), 4.75 (t, J= 5.0 Hz, 1H), 4.35 (q, J= 7.0 Hz, 2H), 2.14 (td, J = 9.9, 3.8 Hz, 2H), 1.84 - 1.75 (m, 4H), 1.74 - 1.64 (m, 2H), 1.48 (t, J= 7.0 Hz, 3H).Step 2: Preparation of 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-4-ethoxy-8-fluoro-7-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)quinoline:

[0215] To a stirred solution of 7-chloro-4-ethoxy-8-fluoro-2-{7-oxabicyclo[2.2. l]heptan-l- yl}quinoline (60 mg, 0.18 mmol, 1.00 equiv.) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l,3,2-dioxaborolane (189 mg, 0.72 mmol, 4.00 equiv.) in toluene (5 mL) were added Pd(dba)2 (21 mg, 0.03 mmol, 0.20 equiv.) and S-Phos (30 mg, 0.07 mmol, 0.40 equiv.) in portions at 25°C under nitrogen atmosphere. The resulting mixture was stirred at 100°C for 18h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was used in the next step directly without further purification. LC-MS: (ES+H, m / z): [M+H]+= 414.3.Intermediate 23Step 1: Preparation of l-methyl-4-methylidenecyclohexan-l-ol:

[0216] To a stirred solution of 4-methylidenecyclohexan-l-one (3.00 g, 27.23 mmol, 1.00 equiv.) in diethyl ether (100 mL) was added MeMgBr (10 mL, 29.96 mmol, 1.10 equiv., 3.0 M in 2-MeTHL)WSGR Docket No. 67898-706.601 dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C for 2 h and quenched by the addition of NH4CI aq. (100 mL) at 0°C. The resulting mixture was extracted with diethyl ether (3 x 100 mL). The combined organic layers were washed with brine (2 x 200 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure to afford 1- methyl-4-methylidenecyclohexan-l-ol (3.2 g, crude) as a yellow oil. The residue was used in the next step directly without further purification. 'H NMR (400 MHz, CDCh) 5 4.63 (s, 2H), 2.41 - 2.29 (m, 2H), 2.17 - 2.06 (m, 2H), 1.73 - 1.61 (m, 2H), 1.58 - 1.43 (m, 3H), 1.24 (s, 3H).Step 2: Preparation of l-(iodomethyl)-4-methyl-7-oxabicyclo[2.2.1]heptane:

[0217] To a stirred mixture of 1 -methyl -4-methylidenecyclohexan-l-ol (3.10 g, 24.56 mmol, 1.00 equiv.) and Na2COs (3.64 g, 34.39 mmol, 1.40 equiv.) in MeCN (150 mL) was added Iodine (24.94 g, 98.26 mmol, 4 equiv.) in portions. The resulting mixture was stirred at 25°C for 2 h and quenched by the addition of Na2S20s aq. (150 mL) at 25°C. The resulting mixture was concentrated under reduced pressure to remove MeCN, diluted with H2O (150 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layer was washed with brine (2 x 300 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure to afford l-(iodomethyl)-4-methyl-7- oxabicyclo[2.2.1]heptane (4.5 g, crude) as a yellow oil. The resulting mixture was used in the next step directly without further purification. 'HNMR (400 MHz, CDCh) 5 3.49 (s, 2H), 1.89 - 1.81 (m, 2H), 1.80 - 1.71 (m, 4H), 1.70 - 1.61 (m, 2H), 1.45 (s, 3H).Step 3: Preparation of {4-methyl-7-oxabicyclo[2.2.1]heptan-l-yl}methyl acetate:

[0218] A mixture of l-(iodomethyl)-4-methyl-7-oxabicyclo[2.2.1]heptane (4.40 g, 17.45 mmol, 1.00 equiv.) and AcOK (8.56 g, 87.27 mmol, 5.00 equiv.) in DMSO (80 mL) was stirred at 90°C for 24 h. The mixture was allowed to cool down to room temperature, diluted with H2O (500 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layer was washed with brine (2 x 300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford {4- methyl-7-oxabicyclo[2.2.1]heptan-l-yl}methyl acetate (3.2 g, crude) as a yellow oil. The resulting mixture was used in the next step directly without further purification. ’H NMR (400 MHz, CDCh) 5 4.32 (s, 2H), 2.09 (s, 3H), 1.78 - 1.66 (m, 4H), 1.63 - 1.53 (m, 4H), 1.47 (s, 3H).Step 4: Preparation of {4-methyl-7-oxabicyclo[2.2.1]heptan-l-yl}methanol:

[0219] To a stirred solution of {4-methyl-7-oxabicyclo[2.2.1]heptan-l-yl}methyl acetate (3.10 g, 16.83 mmol, 1.00 equiv.) in methanol (30 mL) was added MeONa (6.06 g, 33.65 mmol, 2.00 equiv., 30% in MeOH) dropwise. The resulting mixture was stirred at 25 °C for 2h, diluted with H2O (200 mL) and extracted with Et2O (3 x 100 mL). The combined organic layer was washed with brine (2 x 200 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure to afford {4-methyl-7-oxabicyclo[2.2.1]heptan-l-yl}methanol (2.0 g, crude) as a yellow oil. The resulting mixture was used in the next step directly without further purification. ’H NMR (400 MHz, CDCh) 5 3.82 (s, 2H), 2.36 (s, 1H), 1.86 - 1.68 (m, 4H), 1.65 - 1.50 (m, 4H), 1.47 (s, 3H).Step 5: Preparation of 4-methyl-7-oxabicyclo[2.2.1]heptane-l-carboxylic acid:WSGR Docket No. 67898-706.601

[0220] To a stirred solution of {4-methyl-7-oxabicyclo[2.2.1]heptan-l-yl}methanol (1.80 g, 12.66 mmol, 1.00 equiv.) in acetone (20 mL) was added Jones reagent (15.8 mL, 2 M in water, 31.65 mmol,2.50 equiv.) dropwise slowly at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 25°C for 3 h and quenched by the addition of Na2SOs aq. (50 mL) at 0°C. The resulting mixture was diluted with H2O (50 mL) and extracted with EtOAc (2 x 50 mL). The aqueous layer was acidified to pH 3 with HC1 (I M) and extracted with EtOAc (3 x 100 mL). The combined organic layer was washed with brine (2 x 150 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 4-methyl-7-oxabicyclo[2.2.1]heptane-l-carboxylic acid (500 mg, crude) as a yellow oil. The resulting mixture was used in the next step directly without further purification. ’H NMR (400 MHz, CDCh) 5 9.20 (s, 1H), 2.86 - 2.34 (m, 2H), 2.10 - 1.93 (m, 3H), 1.82 - 1.64 (m, 3H), 1.60 - 1.48 (m, 3H).Step 6: Preparation of N-(2-acetyl-5-bromophenyl)-4-methyl-7-oxabicyclo[2.2.1]heptane-l- carboxamide:

[0221] To a stirred solution of 4-methyl-7-oxabicyclo[2.2.1]heptane-l-carboxylic acid (219 mg, 1.40 mmol, 1.00 equiv.), l-(2-amino-4-bromophenyl)ethanone (300 mg, 1.40 mmol, 1.00 equiv.) and TCFH (786 mg, 2.80 mmol, 2.00 equiv.) in MeCN (10 mL) was added 1 -methyl- IH-imidazole (575 mg, 7.00 mmol, 5.00 equiv.) dropwise at 0°C. The resulting mixture was stirred at 25°C for 16 h, diluted with H2O (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with brine (2 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in CH2Q2 (0% to 10% gradient in 15 min) to afford N-(2-acetyl-5-bromophenyl)-4-methyl-7- oxabicyclo[2.2.1]heptane-l-carboxamide (260 mg, 53.67%) as off-white solid. LC-MS: (ES+H, m / z): [M+H]+=351.85. 'H NMR (400 MHz, DMSO-tL) 5 12.07 (s, 1H), 8.92 (d, J= 2.0 Hz, 1H), 8.03 (d, J = 8.5 Hz, 1H), 7.44 (dd, J= 8.5, 2.1 Hz, 1H), 2.63 (s, 3H), 2.06 - 1.95 (m, 2H), 1.92 - 1.73 (m, 4H), 1.70 -1.51 (m, 2H), 1.52 (s, 3H).Step 7: Preparation of 7-bromo-2-{4-methyl-7-oxabicyclo[2.2.1]heptan-l-yl}-lH-quinolin-4-one:

[0222] A mixture of N-(2-acetyl-5-bromophenyl)-4-methyl-7-oxabicyclo[2.2. l]heptane-l- carboxamide (200 mg, 0.57 mmol, 1.00 equiv.) and NaOH (91 mg, 2.27 mmol, 4.00 equiv.) in 1,4- dioxane (5 mL) was stirred at 80°C for 2 h. The mixture was allowed to cool down to room temperature, diluted with H2O (50 mL), and extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with brine (2 x 50 mL) and dried over anhydrous Na2SO4. After fdtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc in petroleum ether (10% to 40% gradient in 20 min) to afford 7-bromo-2-{4-methyl- 7-oxabicyclo[2.2.1]heptan-l-yl}-lH-quinolin-4-one (100 mg, 52.70%) as off-white solid. LC-MS: (ES+H, m / z): [M+H]+=334.00.Step 8: Preparation of 7-bromo-4-methoxy-2-{4-methyl-7-oxabicyclo[2.2.1]heptan-l-yl}quinoline:

[0223] A solution of 7-bromo-2-{4-methyl-7-oxabicyclo[2.2. l]heptan-l-yl}-lH-quinolin-4-one (75 mg, 0.22 mmol, 1.00 equiv.) in acetone (3 mL) was treated with K2CO3 (31 mg, 0.22 mmol, 1.00 equiv.)WSGR Docket No. 67898-706.601 at 60°C for 2 h under nitrogen atmosphere followed by the addition of dimethyl sulfate (28 mg, 0.22 mmol, 1.00 equiv.) dropwise at 25°C. The resulting mixture was stirred at 60°C for additional 2 h, cooled to room temperature, diluted with H2O (50 mL), and extracted with EtOAc (3 x 20 mL). The combined organic layer was washed with brine (2 x 30 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc in petroleum ether (10% to 40% gradient in 20 min) to afford 7- bromo-4-methoxy-2-{4-methyl-7-oxabicyclo[2.2.1]heptan-l-yl}quinoline (70 mg, 89.57%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+=348.10 'HNMR (400 MHz, DMSO-6) 5 8.09 (d, J= 2.0 Hz, 1H), 8.02 (d, J= 8.8 Hz, 1H), 7.64 (dd, J= 8.9, 2.0 Hz, 1H), 7.10 (s, 1H), 4.05 (s, 3H), 2.30 - 2.11 (m, 2H), 1.94 - 1.77 (m, 4H), 1.70 - 1.54 (m, 2H), 1.53 (s, 3H).Step 9: Preparation of 4-methoxy-2-{4-methyl-7-oxabicyclo[2.2.1]heptan-l-yl}-7-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline:

[0224] A mixture of 7-bromo-4-methoxy-2-{4-methyl-7-oxabicyclo[2.2.1]heptan-l-yl}quinoline (60 mg, 0.17 mmol, 1.00 equiv.), PimEE (48 mg, 0.19 mmol, 1.10 equiv.), AcOK (51 mg, 0.52 mmol, 3.00 equiv.), XPhos (16 mg, 0.03 mmol, 0.20 equiv.) and Pd2(dba)s (16 mg, 0.02 mmol, 0.10 equiv.) in 1,4- dioxane (2 mL) was stirred at 80°C for 4 h under nitrogen atmosphere. The resulting mixture was used in the next step directly without further purification. LC-MS: (ES+H, m / z): [M+H]+=396.20.Intermediate 24Step 1: Preparation of (lr,3s)-3-methyl-3-[(triethylsilyl)oxy]cyclobutan-l-amine:

[0225] To a stirred mixture of (ls,3r)-3-amino-l-methylcyclobutan-l-ol HC1 salt (10 g, 72.91 mmol, 1.00 equiv.) and imidazole (14.89 g, 218.74 mmol, 3.00 equiv.) in CH2CI2 (200 mL) was added chlorotriethylsilane (21.98 g, 145.82 mmol, 2.00 equiv.) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for overnight under nitrogen atmosphere and then diluted with CH2CI2 (200 mL). The combined organic layers were washed with NaHCOs(aq) (2x50 mL), dried over anhydrous Na2SC>4, filtered, and concentrated. The residue was purified by silica gel column chromatography (CH2Q2 / MeOH (20: 1)) to afford (lr,3s)-3-methyl-3-[(triethylsilyl)oxy]cyclobutan-l- amine (12 g, 76%) as a colorless oil. LC-MS: (ES+H, m / z): [M+H]+=216.1. 'HNMR (400 MHz, CDC13) 52.98 (tt, J= 8.4, 7.0 Hz, 1H), 2.41 (ddt, J= 11.6, 7.2, 2.6 Hz, 2H), 1.87 - 1.77 (m, 2H), 1.31 (t,J= 1.0 Hz, 3H), 0.96 (t, J= 7.9 Hz, 9H), 0.58 (q, J= 7.9 Hz, 6H).Step 2: Preparation of 4-chloro-7-((ls,3s)-3-methyl-3-((triethylsilyl)oxy)cyclobutyl)-7H-pyrrolo[2,3- djpyrimidine:WSGR Docket No. 67898-706.601

[0226] To a stirred solution of 2-(4,6-dichloropyrimidin-5-yl)acetaldehyde (3.00 g, 15.71 mmol, 1.00 equiv.) and (lr,3s)-3-methyl-3-[(triethylsilyl)oxy]cyclobutan-l-amine (3.38 g, 15.71 mmol, 1.00 equiv.) in EtOH (30 mL) was added DIEA (6.09 g, 47.12 mmol, 3.00 equiv.) at room temperature. The resulting mixture was stirred at 80°C for 6h under nitrogen atmosphere. The mixture was then cooled to room temperature and concentrated. The residue was purified by normal -phase flash chromatography (EtOAc / PE, 0%to 15% gradient over 20 min) to afford 4-chloro-7-[(lr,3s)-3-methyl-3- [(triethylsilyl)oxy]cyclobutyl]pyrrolo[2,3-d]pyrimidine (2.3 g, 39%) as a yellow liquid. LC-MS: (ES+H, m / z): [M+H]+= 352.2. 'HNMR (400 MHz, DMSO-6) 5 8.62 (s, 1H), 7.85 (d, J= 3.7 Hz, 1H), 6.69 (d, J = 3.6 Hz, 1H), 4.85 (p, J= 8.4 Hz, 1H), 2.67 (d, J= 8.4 Hz, 4H), 1.48 (s, 3H), 0.95 (t, J= 7.9 Hz, 9H), 0.60 (q, J = 7.9 Hz, 6H).Step 3: Preparation of (ls,3s)-3-(5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-l- methylcyclobutan-l-ol:

[0227] A solution of 4-chloro-7-[(lr,3s)-3-methyl-3-[(triethylsilyl)oxy]cyclobutyl]pyrrolo[2,3- d]pyrimidine (800 mg, 2.27 mmol, 1.00 equiv.) and 1 -bromopyrrolidine-2, 5-dione (405 mg, 2.27 mmol, 1.00 equiv.) in MeCN (20 mL) was stirred at 25°C for 2h under nitrogen atmosphere. The resulting mixture was poured into water (100 mL) and extracted with CH2Q2 (3 x 80mL). The combined organic layers were concentrated under reduced pressure and the crude product was purified by normal-phase flash chromatography (EtOAc / PE, 20% to 45% gradient over 25 min) to afford (ls,3r)-3-{5-bromo-4- chloropyrrolo[2,3-d]pyrimidin-7-yl}-l-methylcyclobutan-l-ol (580 mg, 80%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+= 315.85. ’H NMR (400 MHz, DMSO-6) 5 8.66 (s, 1H), 8.25 (s, 1H), 5.25 (s, 1H), 5.00 - 4.85 (m, 1H), 2.61 - 2.55 (m, 4H), 1.35 (s, 3H).Step 4: Preparation of (ls,3s)-3-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-l- methylcyclobutan-l-ol:

[0228] A solution of (ls,3r)-3-{5-bromo-4-chloropyrrolo[2,3-d]pyrimidin-7-yl}-l-methylcyclobutan-l- ol (550 mg, 1.74 mmol, 1.00 equiv.) and ammonium hydroxide (7 mL) in i-PrOH (14 mL) was stirred at 80°C for 24h under nitrogen atmosphere. The mixture was then cooled to room temperature and concentrated under reduced pressure to afford (ls,3r)-3-{4-amino-5-bromopyrrolo[2,3-d]pyrimidin-7- yl}-l-methylcyclobutan-l-ol (450 mg, 87%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+= 296.95. 'HNMR (400 MHz, DMSO-6) 5 8.08 (s, 1H), 7.69 (s, 1H), 6.70 (s, 2H), 5.26 (s, 1H), 4.80 (p, J= 8.5 Hz, 1H), 2.50 - 2.43 (m, 4H), 1.32 (s, 3H).Intermediate 25WSGR Docket No. 67898-706.601Step 1: Preparation of N-methoxy-N,4-dimethyl-2-oxabicyclo[2.1.1]hexane-l-carboxamide:

[0229] To a stirred solution of 4-methyl-2-oxabicyclo[2.1.1]hexane-l-carboxylic acid (200 mg, 1.40 mmol, 1.00 equiv.), N,O-dimethylhydroxylamine hydrochloride (274 mg, 2.81 mmol, 2.00 equiv.) and EtsN (355 mg, 3.51 mmol, 2.50 equiv.) in THF (5 mL) was added a solution of propanephosphonic acid cyclic anhydride(1.79 g, 2.81 mmol, 2.00 equiv., 50% in CH2CI2) in THF (3 mL) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h, diluted with water (20 mL) and extracted with CH2CI2 (4 x 50 mL). The combined organic layers were washed with sat. NaHCOs (aq.) (3 x 50 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CTLCL / MeOH (0%~6% in 15 min) to afford N-methoxy-N,4-dimethyl-2- oxabicyclo[2.1.1]hexane-l-carboxamide (183 mg, 70.2%) as a colorless oil. LC-MS: (ES+H, m / z): [M+H]+=186.05. ’H NMR (400 MHz, DMSO-tL) 3 3.66 (s, 3H), 3.54 (s, 2H), 3.15 (s, 3H), 1.80 (dd, J = 4.6, 1.7 Hz, 2H), 1.69 (dd, J= 4.6, 1.7 Hz, 2H), 1.29 (s, 3H).Step 2: Preparation of l-{4-methyl-2-oxabicyclo[2.1.1]hexan-l-yl}ethanone:

[0230] To a stirred solution ofN-methoxy-N,4-dimethyl-2-oxabicyclo[2.1.1]hexane-l-carboxamide (150 mg, 0.81 mmol, 1.00 equiv.) in diethyl ether (5 mL) was added methyllithium(0.76 mL, 1.21 mmol, 1.50 equiv., 1.6M in diethyl ether) dropwise at -20 °C under nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 2 h under nitrogen atmosphere. To the above mixture was added methyllithium (0.76 mL, 1.21 mmol, 1.5 equiv., 1.6M in diethyl ether) dropwise at -20 °C. The resulting mixture was allowed to warm to room temperature overnight, quenched with sat. NFLC1 (aq.) (10 mL) at 0 °C and extracted with Et2O (4 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure to afford l-{4-methyl-2-oxabicyclo[2.1.1]hexan-l-yl}ethanone (90 mg, crude) as a colorless oil. The crude product was used in the next step directly without further purification.Step 3: Preparation of 7-bromo-2-{4-methyl-2-oxabicyclo[2.1.1]hexan-l-yl}quinoline:

[0231] To a stirred solution of l-{4-methyl-2-oxabicyclo[2.1.1]hexan-l-yl}ethanone (85 mg, 0.60 mmol, 1.00 equiv.) and 2-amino-4-bromobenzaldehyde (121 mg, 0.60 mmol, 1.00 equiv.) in EtOH (3 mL) was added NaOH (48 mg, 1.21 mmol, 2.00 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by silica gelWSGR Docket No. 67898-706.601 column chromatography, eluted with petroleum ether / ethyl acetate (10% ~ 35% in 15 min) to afford 7- bromo-2-{4-methyl-2-oxabicyclo[2.1.1]hexan-l-yl}quinoline (88 mg, 47.7%) as a brown yellow liquid.LC-MS: (ES+H, m / z): [M+H]+=304.00. 'H NMR (400 MHz, DMSO-6) 3 8.42 (d, J= 8.5 Hz, 1H), 8.22 (dd, J= 20.1, 2.0 Hz, 1H), 7.98 (dd, J= 8.8, 6.6 Hz, 1H), 7.79 - 7.67 (m, 2H), 3.72 (s, 2H), 2.12 (dd, J = 4.4, 1.7 Hz, 2H), 1.85 (dd, J= 4.4, 1.7 Hz, 2H), 1.41 (s, 3H).Step 4: Preparation of (2-{4-methyl-2-oxabicyclo[2.1.1]hexan-l-yl}-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinolone) :

[0232] To a stirred solution of 7-bromo-2-{4-methyl-2-oxabicyclo[2.1.1]hexan-l-yl}quinoline (85 mg, 0.27 mmol, 1.00 equiv.) and bis(pinacolato)diboron (85 mg, 0.33 mmol, 1.20 equiv.) in 1,4-dioxane (3 m ) were added AcOK (68 mg, 0.69 mmol, 2.50 equiv.), XPhos (26 mg, 0.05 mmol, 0.20 equiv.) and Pd2(dba)s (25 mg, 0.02 mmol, 0.10 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The resulting mixture (2-{4-methyl-2- oxabicyclo[2. 1. l]hexan-l-yl}-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinolone) was used in the next step directly without further purification. LC-MS: (ES+H, m / z): [M+H]+=352.20.Intermediate 26Step 1: Preparation of 7-chloro-8-fluoro-4-methoxy-2-{7-oxabicyclo[2.2.1]heptan-l-yl}quinoline:

[0233] To a stirred solution of 4,7-dichloro-2-{7-oxabicyclo[2.2.1]heptan-l-yl}quinoline (110 mg, 0.35 mmol, 1.00 equiv) in methanol (5 mb) was added sodium methoxide (30% in methanol) (634 mg, 3.52 mmol, 10.0 equiv) dropwise at 25°C under nitrogen atmosphere. The resulting mixture was stirred at 50°C for 6h under nitrogen atmosphere and diluted with DCM. The organic layer was washed with water (2x30 mb) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (0%-50% gradient in 30 min) to afford 7-chloro-8-fluoro-4-methoxy-2-{7- oxabicyclo[2.2.1]heptan-l-yl}quinoline (80 mg, 73.7%) as a white oil. LC-MS: (ES+H, m / z): [M+H]+= 308.0. ’H NMR (300 MHz, DMSO-dd) 5 7.93 (dd, J= 9.1, 1.6 Hz, 1H), 7.65 (dd, J= 9.0, 6.7 Hz, 1H), 7.23 (s, 1H), 4.76 (t, J = 5.0 Hz, 1H), 4.09 (s, 3H), 2.19 - 2.12 (m, 2H), 1.82 (ddd, J= 21.6, 10.4, 4.2 Hz, 4H), 1.75 - 1.70 (m, 2H).Step 2: Preparation of 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-8-fluoro-4-methoxy-7-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline:

[0234] To a stirred solution of 7-chloro-4-methoxy-2-{7-oxabicyclo[2.2.1]heptan-l-yl}quinoline (60 mg, 0.20 mmol, 1.00 equiv) and PimEE (210 mg, 0.82 mmol, 4.00 equiv) in toluene (5 mb) were added Pd(dba)2 (23 mg, 0.04 mmol, 0.20 equiv) and S-Phos (34 mg, 0.08 mmol, 0.40 equiv) in portions at 25°C under nitrogen atmosphere. The resulting mixture was stirred at 100°C for 16h under nitrogenWSGR Docket No. 67898-706.601 atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was used in the next step directly without further purification. LC-MS: (ES+H, m / z): [M+H]+= 399.1.Intermediate 27Step 1: Preparation of 3-{4-amino-3-iodopyrazolo[3,4-d]pyrimidin-l-yl}cyclobutan-l-one:

[0235] To a stirred solution of 3-iodo-lH-pyrazolo[3,4-d]pyrimidin-4-amine (2.00 g, 7.66 mmol, 1.00 equiv.) in DMF (40 mL) was added NaH (0.40 g, 9.96 mmol, 1.30 equiv., 60%) in portions at 0°C under N2 atmosphere. The resulting mixture was stirred at 0°C for 0.5h, then treated with 3-bromocyclobutan-l- one (1.48 g, 9.96 mmol, 1.30 equiv.) in portions. The resulting mixture was stirred at 25°C for Ih and diluted with EtOAc (300 mL). The organic layer was washed with 3 x 100 mL of water and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Q2 / MeOH (0%-10% gradient in 30 min) to afford 3-{4-amino-3-iodopyrazolo[3,4-d]pyrimidin-l-yl}cyclobutan-l-one (1.00 g, 39.6%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+= 329.90. ' H NMR (400 MHz, DMSO-6) 5 8.23 (d, J= 1.4 Hz, IH), 5.63 - 5.43 (m, IH), 3.64 (d, J= 7.0 Hz, 4H).Intermediate 28Step 1: Preparation of 2-{bicyclo[l.l.l]pentan-l-yl}-7-bromo-4-chloro-8-fluoroquinoline:

[0236] A mixture of 7-bromo-4-chloro-8-fluoroquinoline (300 mg, 1.15 mmol, 1.00 equiv.), bicyclofl. l.l]pentane-l-carboxylic acid (154 mg, 1.38 mmol, 1.20 equiv.) and AgNOs (234 mg, 1.38 mmol, 1.20 equiv.) in 10% H2SO4 water solution (20 mL) was stirred at 80°C for 10 min under nitrogen atmosphere, then treated with ammonium persulfate (1.31 g, 5.76 mmol, 5.00 equiv.) in H2O (4 mL) dropwise over 10 min. The resulting mixture was stirred at 80°C for additional 0.5h, diluted with water (30 mL), extracted with EtOAc (3x100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (0%-10% gradient in 20 min) to afford 2-{bicyclo[l.l. l]pentan-l- yl}-7-bromo-4-chloro-8-fluoroquinoline (200 mg, 53.2%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+= 327.9, 'H NMR (300 MHz, DMSO-6) 5 7.92 - 7.89 (m, 2H), 7.86 (s, IH), 2.62 (s, IH), 2.24 (s, 6H).Step 2: Preparation of 2-(bicyclo[l.l.l]pentan-l-yl)-7-bromo-8-fluoro-4-methoxyquinoline:WSGR Docket No. 67898-706.601

[0237] To a stirred solution of 2-{bicyclo[l.l. l]pentan-l-yl}-7-bromo-4-chloro-8-fluoroquinoline (180 mg, 0.55 mmol, 1.00 equiv.) in methanol (5 mb) were added sodium methoxide (30% in methanol) (992 mg, 5.51 mmol, 10.0 equiv.) dropwise at 25°C under nitrogen atmosphere. The resulting mixture was stirred at 50°C for 6h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature, diluted with EtOAc (100 mL). The organic layer was washed with 2 x 30 mb of water and dried over anhydrous Na2SC>4. After fdtration, the fdtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (0%-50% gradient in 30 min) to afford 2-(bicyclo[l.l.l]pentan-l-yl)-7-bromo-8-fluoro-4-methoxyquinoline (100 mg, 56.3%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+= 322.0. ’H NMR (400 MHz, DMSO-6) 5 7.82 (dd, J= 9.0, 1.4 Hz, 1H), 7.69 (dd, J= 9.0, 6.2 Hz, 1H), 7.03 (s, 1H), 4.08 (s, 3H), 2.60 (s, 1H), 2.22 (s, 6H).Step 3: Preparation of 2-(bicyclo[l.l.l]pentan-l-yl)-8-fluoro-4-methoxy-7-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)quinoline:

[0238] To a stirred solution of 2-{bicyclo[l.l. l]pentan-l-yl}-7-bromo-8-fluoro-4-methoxyquinoline (60 mg, 0.18 mmol, 1.00 equiv.) and PimEE (70 mg, 0.28 mmol, 1.50 equiv.) in 1,4-dioxane (5 mL) were added Pd2(dba)s (17 mg, 0.02 mmol, 0.10 equiv.), tricyclohexylphosphane (10 mg, 0.04 mmol, 0.20 equiv.) and AcOK (55 mg, 0.56 mmol, 3.00 equiv.) in portions at 25°C under nitrogen atmosphere. The resulting mixture was stirred at 80°C for 2h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was used in the next step directly without further purification. LC-MS: (ES+H, m / z): [M+H]+= 370.1.Intermediate 29Step 1: Preparation of N-(2-acetyl-5-bromo-4-fluorophenyl)-7-oxabicyclo[2.2.1]heptane-l- carboxamide:

[0239] To a stirred solution of l-(2-amino-4-bromo-5-fluorophenyl)ethanone (300 mg, 1.29 mmol, 1.00 equiv.) and 7-oxabicyclo[2.2.1]heptane-l-carboxylic acid (202 mg, 1.42 mmol, 1.10 equiv.) in MeCN (10 mL) were added TCFH (725 mg, 2.58 mmol, 2.00 equiv.) and 1 -methyl- IH-imidazole (530 mg, 6.46 mmol, 5.00 equiv.) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight, diluted with EtOAc (lOOmL). The organic layer was washed with water (2x30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / EtOAc (0% to 30% gradient in 10 min) to afford N-(2-acetyl-5-bromo-4-fluorophenyl)-7-WSGR Docket No. 67898-706.601 oxabicyclo[2.2.1]heptane-l-carboxamide (240 mg, 52.0%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+= 356.1 'H NMR (400 MHz, DMSO-6) 5 11.82 (s, 1H), 8.97 (d, J= 6.6 Hz, 1H), 8.08 (d, J= 9.6 Hz, 1H), 4.75 (t, J= 5.0 Hz, 1H), 2.64 (s, 3H), 1.97 - 1.89 (m, 2H), 1.86 - 1.76 (m, 2H), 1.75 - 1.60 (m, 4H).Step 2: Preparation of 7-bromo-6-fluoro-2-{7-oxabicyclo[2.2.1]heptan-l-yl}-lH-quinolin-4-one:

[0240] A mixture of N-(2-acetyl-5-bromo-4-fluorophenyl)-7-oxabicyclo[2.2. l]heptane-l-carboxamide (200 mg, 0.56 mmol, 1.00 equiv.) and NaOH (67 mg, 1.68 mmol, 3.00 equiv.) in dioxane (6 m ) was stirred at 80°C for 3h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature, diluted with water (30 m ) and extracted with EtOAc (3 x 30 mb). The combined organic layers were washed with brine (1x20 mb) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / EtOAc (0% to 80% gradient in 40 min) to afford 7-bromo-6-fluoro-2-{7- oxabicyclo[2.2.1]heptan-l-yl}-lH-quinolin-4-one (100 mg, 52.6%) as a yellow solid. EC-MS: (ES+H, m / z): [M+H]+= 337.9. ’HNMR (400 MHz, DMSO-6) 5 11.55 (s, 1H), 8.22 (d, J= 6.0 Hz, 1H), 7.82 (d, J= 9.0 Hz, 1H), 6.10 (s, 1H), 4.80 (t, J= 5.1 Hz, 1H), 2.18 - 2.06 (m, 2H), 1.89 (td, J= 13.1, 12.3, 5.8 Hz, 2H), 1.74 (ddt, J= 13.1, 9.4, 4.4 Hz, 4H).19F NMR (377 MHz, DMSO-6) 5 -114.62.Step 3: Preparation of 7-bromo-6-fluoro-4-methoxy-2-{7-oxabicyclo[2.2.1]heptan-l-yl}quinoline:

[0241] To a stirred solution of 7-bromo-6-fluoro-2-{7-oxabicyclo[2.2.1]heptan-l-yl}-lH-quinolin-4- one (75 mg, 0.222 mmol, 1.00 equiv.) in acetone (5 mb) were added K2CO3 (30 mg, 0.22 mmol, 1.00 equiv.) in portions at 25°C under nitrogen atmosphere. The resulting mixture was stirred at 60°C for 2h under nitrogen atmosphere, cooled to room temperature and treated with dimethyl sulfate (28 mg, 0.22 mmol, 1.00 equiv.) dropwise. The resulting mixture was stirred at 60°C for an additional 2h, cooled to room temperature, diluted with H2O (40 mb), and extracted with EtOAc (3 x 30 mb). The combined organic layers were washed with brine (2 x 30 mb) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / EtOAc (0% to 30% gradient in 30 min) to afford 7-bromo- 6-fluoro-4-methoxy-2-{7-oxabicyclo[2.2.1]heptan-l-yl}quinoline (70 mg, 96.0%) as a white solid. EC- MS: (ES+H, m / z): [M+H]+= 352.1. H NMR (400 MHz, DMSO-6) 5 8.29 (d, J= 6.7 Hz, 1H), 7.90 (d, J = 9.4 Hz, 1H), 7.18 (s, 1H), 4.75 (t, J= 5.0 Hz, 1H), 4.06 (s, 3H), 2.22 - 2.02 (m, 2H), 1.91 - 1.58 (m, 6H).Step 4: Preparation of 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-6-fluoro-4-methoxy-7-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline:

[0242] To a stirred solution of 7-bromo-6-fluoro-4-methoxy-2-{7-oxabicyclo[2.2.1]heptan-l- yl}quinoline (60 mg, 0.17 mmol, 1.00 equiv.) and PimEE (65 mg, 0.25 mmol, 1.5 equiv.) in 1,4-dioxane (6 mb) were added Pd2(dba)s (15 mg, 0.02 mmol, 0.10 equiv.), XPhos (16.24 mg, 0.034 mmol, 0.2 equiv.) and AcOK (50 mg, 0.51 mmol, 3.00 equiv.) in portions at 25°C under nitrogen atmosphere. The resulting mixture was stirred at 80°C for 2h under nitrogen atmosphere. The mixture was allowed to coolWSGR Docket No. 67898-706.601 down to room temperature. The resulting mixture was used in the next step directly without further purification. LC-MS: (ES+H, m / z): [M+H]+= 400.1.Intermediate 30Step 1: Preparation of l-(2-amino-4-chloro-5-fluorophenyl)ethanone:

[0243] To a stirred solution of 2-bromo-5-chloro-4-fluoroaniline (5.00 g, 22.27 mmol, 1.00 equiv.) in DMF (50 mL) were added tributyl(l-ethoxyethenyl)stannane (8.85 g, 24.50 mmol, 1.10 equiv.) and dichlorobis(triphenylphosphine)palladium(II) (940 mg, 1.33 mmol, 0.06 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 12 h under nitrogen atmosphere, cooled to room temperature and treated with HCl(aq) (8 mL, 6 mol / L) dropwise. The resulting mixture was stirred at room temperature for an additional 3 h, diluted with H2O (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (1 x 40 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (7: 1) to afford l-(2-amino-4-chloro-5-fluorophenyl)ethanone (1.10 g, 23.9%) as a yellow solid. 'H NMR (400 MHz, CDCh) 8 7.45 (d, J= 10.0 Hz, 1H), 6.70 (d, J= 6.2 Hz, 1H), 2.53 (s, 3H).Step 2: Preparation of N-(2-acetyl-5-chloro-4-fluorophenyl)bicyclo[l.l.l]pentane-l-carboxamide:

[0244] To a stirred solution of l-(2-amino-4-chloro-5-fluorophenyl)ethanone (500 mg, 2.66 mmol, 1.00 equiv.) and bicy clo [ 1.1.1] pentane -1 -carboxy lie acid (358 mg, 3.19 mmol, 1.20 equiv.) in MeCN (10 mL) were added TCFH (2.24 g, 7.99 mmol, 3.00 equiv.) and 1 -methyl- IH-imidazole (1.09 g, 13.32 mmol, 5.00 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere, diluted with H2O (50 mL) and extracted with EtOAc (3 x 60 mL). The combined organic layers were washed with brine (1 x 40 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (7: 1) to afford N-(2- acetyl-5-chloro-4-fluorophenyl)bicyclo[l.l.l]pentane-l-carboxamide (600 mg, 79.9%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+=281.90.Step 3: Preparation of 2-{bicyclo[l.l.l]pentan-l-yl}-7-chloro-6-fluoro-lH-quinolin-4-one:

[0245] A solution ofN-(2-acetyl-5-chloro-4-fluorophenyl)bicyclo[l.l. l]pentane-l-carboxamide (500 mg, 1.77 mmol, 1.00 equiv.) and NaOH (212 mg, 5.32 mmol, 3.00 equiv.) in 1,4-dioxane (8 mL) wasWSGR Docket No. 67898-706.601 stirred at 110 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature, diluted with H2O (50 mL), and extracted with ClLC L McOH (10: 1) (3 x 50 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (5: 1) to afford 2-{bicyclo[l.l.l]pentan-l-yl}-7-chloro-6-fluoro-lH- quinolin-4-one (240 mg, 51.2%) as a yellow solid.1H NMR (300 MHz, DMSO-6) 3 11.43 (s, 1H), 7.89 (d, J= 6.3 Hz, 1H), 7.84 (d, J= 9.6 Hz, 1H), 5.86 (d, J= 1.6 Hz, 1H), 2.61 (s, lH), 2.18 (s, 6H).Step 4: Preparation of 2-{bicyclo[l.l.l]pentan-l-yl}-4,7-dichloro-6-fluoroquinoline:

[0246] A solution of 2-{bicyclo[l.l.l]pentan-l-yl}-7-chloro-6-fluoro-lH-quinolin-4-one (240 mg, 0.91 mmol, 1.00 equiv.) in phosphoryl trichloride (6 mL) was stirred at 110 °C for 3 h under nitrogen atmosphere. The mixture was cooled to room temperature, concentrated under reduced pressure, and diluted with ice water (20 mL). The mixture was basified to pH 7 with saturated NaHCOs (aq.) and extracted with CH2CI2 (3 x 50 mL). The combined organic layers were concentrated under reduced pressure to afford 2-{bicyclo[l. l.l]pentan-l-yl}-4,7-dichloro-6-fluoroquinoline (250 mg, crude) as a brown oil. LC-MS: (ES+H, m / z): [M+H]+=282.20.Step 5: Preparation of 2-{bicyclo[l.l.l]pentan-l-yl}-7-chloro-6-fluoro-4-methoxyquinoline:

[0247] To a stirred solution of 2-{bicyclo[l.l. l]pentan-l-yl}-4,7-dichloro-6-fluoroquinoline (250 mg, 0.88 mmol, 1.00 equiv.) in methanol (10 mL) was added HC1 in MeOH (4.0 M) (258 mg, 7.08 mmol, 8.00 equiv.) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 3 h, cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (10: 1) to afford 2- {bicyclo[l. l.l]pentan-l-yl}-7-chloro-6-fluoro-4-methoxyquinoline (150 mg, 60.9%) as a white solid. ’H NMR (300 MHz, DMSO-6) 3 8.12 (d, J= 7.2 Hz, 1H), 7.88 (d, J= 10.0 Hz, 1H), 6.96 (d, J= 0.8 Hz, 1H), 4.06 (s, 3H), 2.59 (s, 1H), 2.20 (s, 6H).Step 6: Preparation of 2-{bicyclo[l.l.l]pentan-l-yl}-6-fluoro-4-methoxy-7-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)quinoline:

[0248] To a stirred solution of 2-{bicyclo[l.l. l]pentan-l-yl}-7-chloro-6-fluoro-4-methoxyquinoline (110 mg, 0.39 mmol, 1.00 equiv.) and PimEL (110 mg, 0.43 mmol, 1.10 equiv.) in 1,4-dioxane (3 mL) were added AcOK (97 mg, 0.99 mmol, 2.50 equiv.), Pd2(dba)s (18 mg, 0.02 mmol, 0.05 equiv.) and XPhos (18 mg, 0.04 mmol, 0.10 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C for 2 h under nitrogen atmosphere. The crude product (2- {bicyclofl . 1. l]pentan-l-yl}-6-fluoro-4-methoxy-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinoline) was used in the next step directly without further purification. LC-MS: (ES+H, m / z): [M+H]+=288.10.Intermediate 31WSGR Docket No. 67898-706.601Step 1: Preparation of N-methoxy-N-methylbicyclo[l.l.l]pentane-l-carboxamide:

[0249] To a stirred solution of bicyclo[l. l.l]pentane-l-carboxylic acid (600 mg, 5.35 mmol, 1.00 equiv.), EDCI (1246 mg, 8.03 mmol, 1.50 equiv.) and methoxy(methyl)aminehydrochloride (522 mg, 5.35 mmol, 1.00 equiv.) in CH2CI2 (17 mL) were added DMAP (65 mg, 0.54 mmol, 0.10 equiv.) and Et3N (541 mg, 5.35 mmol, 1.00 equiv.) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16h under nitrogen atmosphere, poured into water (100 mL) and extracted with CH2CI2 (3 x 80 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography (silica gel; mobile phase, MeOH in CH2Q2, 0% to 20% gradient in 25 min; detector, UV 254 nm) to afford N-methoxy-N- methy lbicyclo[ 1.1.1] pentane -1 -carboxamide (560 mg, 67%) as a light yellow liquid. LC-MS: (ES+H, m / z): [M+H]+= 156.1. 'HNMR (400 MHz, DMSO-6) 5 3.64 (s, 3H), 3.07 (s, 3H), 2.43 (s, 1H), 2.05 (s, 6H).Step 2: Preparation of l-(bicyclo[l.l.l]pentan-l-yl)ethan-l-one:

[0250] To a stirred solution of N-methoxy-N-methy lbicyclo[ 1.1.1] pentane -1 -carboxamide (370 mg, 2.38 mmol, 1.00 equiv.) in diethyl ether (4 mL) were added methylmagnesium bromide(3 M solution in diethyl ether) (1.99 mL, 5.97 mmol, 2.50 equiv.) dropwise at 0°C under nitrogen atmosphere. The reaction was quenched by the addition of sat. NH4C1 (aq.) (10 mL) at 0°C. The resulting mixture was Poured into water (80 mL) and extracted with diethyl ether (3 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure to afford l-{bicyclo[l.l.l]pentan-l-yl}ethanone (280 mg, crude) as a light yellow liquid.1H NMR (400 MHz, DMSCUU) 5 2.45 (s, 1H), 2.05 (s, 3H), 1.98 (s, 6H).Step 3: Preparation of 2-(bicyclo[l.l.l]pentan-l-yl)-7-bromo-6-fluoroquinoline:

[0251] To a stirred solution of 2-amino-4-bromo-5-fluorobenzaldehyde (435 mg, 1.20 mmol, 1.00 equiv.) and 1 - {bicyclo [l. l.l]pentan-l-yl} ethanone (220 mg, 1.20 mmol, 1.00 equiv.) in EtOH (8 mL) was added NaOH (80 mg, 1.20 mmol, 1 equiv.) at room temperature. The resulting mixture was stirred at 50°C for 4h under nitrogen atmosphere. The mixture was cooled to room temperature, poured into water (100 mL), and extracted with CH2Q2 (3 x 80mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography (silica gel; mobile phase, EtOAc in Petroleum ether, 20% to 60% gradient in 20 min; detector, UV 254 nm) to afford 2- {bicyclofl . 1. l]pentan-l-yl}-7-bromo-6-fluoroquinoline (300 mg, 51%) as a light yellow solid. LC-MS:WSGR Docket No. 67898-706.601(ES+H, m / z): [M+H]+= 291.95. 'H NMR (400 MHz, DMSO-6) 5 8.41 - 8.25 (m, 2H), 7.95 (d, J= 9.3 Hz, 1H), 7.55 (dd, J= 8.4, 0.8 Hz, 1H), 2.60 (d, J= 5.3 Hz, 1H), 2.20 (s, 6H).Step 4: Preparation of 2-(bicyclo[l.l.l]pentan-l-yl)-6-fluoro-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoline:

[0252] To a stirred solution of 2-{bicyclo[l.l.l]pentan-l-yl}-7-bromo-6-fluoroquinoline (100 mg, 0.34 mmol, 1.00 equiv.) and PimEE (174 mg, 0.69 mmol, 2.00 equiv.) in dioxane (5 mL) were added AcOK (101 mg, 1.03 mmol, 3.00 equiv.) and Pd^ppQCECTECE (28 mg, 0.034 mmol, 0.10 equiv.) at room temperature. The resulting mixture was stirred at 100°C for 3h under nitrogen atmosphere. The resulting mixture was used in the next step directly without further purification. LC-MS: (ES+H, m / z): [M+H]+= 340.1.Intermediate 32Step 1: Preparation of N-[(3-amino-5-oxo-4H-l,2,4-triazin-6-yl)methyl]-3-oxocyclobutane-l- carboxamide:

[0253] To a 0°C solution of 3-amino-6-(aminomethyl)-l,2,4-triazin-5(4h)-one acetate (5.00 g, 24.85 mmol, 1.00 equiv.) in H2O (60 mL) was added NaHCOs (10.44 g, 124.26 mmol, 5.00 equiv.). The resulting mixture was warmed to room temperature and treated with 2,5-dioxopyrrolidin-l-yl 3- oxocyclobutane-1 -carboxylate (5.25 g, 24.85 mmol, 1.00 equiv.) in THF:MeCN (1: 1, 120 mL). The mixture was stirred at room temperature for 20 hours, then concentrated to 30 mL. The precipitate was filtered and washed with water (60 mL x 3), Et20 (60 mL x 3), and then dried under vacuum to give N- [(3 -amino-5-oxo-4H-l, 2, 4-triazin-6-yl)methyl] -3 -oxocyclobutane- 1 -carboxamide (2.40 g) as a white solid. 'H NMR (400 MHz, DMSO-6) 5 12.02 (s, 1H), 8.33 (t, J= 5.7 Hz, 1H), 6.81 (s, 2H), 4.12 (d, J = 5.6 Hz, 2H), 3.24 - 3.07 (m, 5H).Step 2: Preparation of 3-{2-amino-4-chloroimidazo[4,3-f] [l,2,4]triazin-7-yl}cyclobutan-l-one:

[0254] To a 0°C solution of N-[(3-amino-5-oxo-4H-l,2,4-triazin-6-yl)methyl]-3-oxocyclobutane-l- carboxamide (3.70 g, 15.597 mmol, 1.00 equiv.) in MeCN (80 mL) was added POCI3 (4.78 g, 31.194WSGR Docket No. 67898-706.601 mmol, 2.00 equiv.). The mixture was stirred at 85°C for 3 h under nitrogen atmosphere, cooled to 0°C and basified to pH 9 with saturated K2CO3 solution. The mixture was stirred at 0°C for 0.5 h. The precipitate was fdtered, washed with ice water (30 mL x 3), and then lyophilized to give 3-{2-amino-4- chloroimidazo[4,3-f][l,2,4]triazin-7-yl}cyclobutan-l-one (2.00 g, 54%) as an off-white solid. ’H NMR (400 MHz, DMSO-d6) 5 11.03 (s, 1H), 7.56 (s, 1H), 6.24 (d, J= 9.1 Hz, 2H), 3.97 - 3.89 (m, 1H), 3.53 - 3.41 (m, 4H).Step 3: Preparation of 2-amino-5-bromo-7-(3-oxocyclobutyl)imidazo[5,l-f| [l,2,4]triazin-4(3H)-one:

[0255] To a stirred mixture of 2-amino-7-(3-oxocyclobutyl)imidazo[5,l-f][l,2,4]triazin-4(3H)-one (35g, 160 mmol, 1.00 equiv.) in THF (700 mL) and N,N-dimethylacetamide (140 mL) were added NBS (31.3 g, 176 mmol, 1.10 equiv.) in portions at 25°C. The resulting mixture was stirred at 25°C for 16h under nitrogen atmosphere. The reaction was poured into brine (800 mL) and quenched by the addition of Na2SOs(50 g) and NaHCC>3(40 g) at 25°C. The resulting mixture was extracted with THF (5 x 500 mL). The combined organic layers were washed with brine (2 x 100 mL) and dried over anhydrous Na2SC>4. After fdtration, the fdtrate was concentrated under reduced pressure to get a residue. The residue was purified by silica gel column chromatography, eluted with CH2Q2 / MeOH (30: 1) to afford 2-amino-5- bromo-7-(3-oxocyclobutyl)imidazo[5,l-f][l,2,4]triazin-4(3H)-one (18 g, 37.8%) as a white solid. LC- MS: (ES+H, m / z): [M+H]+=297.9. 'HNMR (400 MHz, DMSO-tL) 5 10.64 (s, 1H), 6.23 (s, 2H), 3.91 (tt, J= 9.0, 6.6 Hz, 1H), 3.55 - 3.35 (m, 4H).Step 4: Preparation of 5-bromo-7-(3-oxocyclobutyl)imidazo[5,l-f| [l,2,4]triazin-4(3H)-one:

[0256] To a stirred solution of 2-amino-5-bromo-7-(3-oxocyclobutyl)imidazo[5,l-f][l,2,4]triazin- 4(3H)-one (5.50 g, 18.45 mmol, 1.00 equiv.) in THF (60 mL) was added tert-butylnitrite (9.51 g, 92.25 mmol, 5.00 equiv.) dropwise at 25°C under nitrogen atmosphere. The resulting mixture was stirred at 40°C for 4 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature, filtered, and the filter cake was washed with DCM (2 x 30 mL). The filter cake was dried under reduced pressure to afford 5-bromo-7-(3-oxocyclobutyl)imidazo[5,l-f][l,2,4]triazin-4(3H)-one (3.1 g, 59.3%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+=283.0. ’H NMR (400 MHz, DMSO-tL) 5 11.93 (s, 1H), 7.95 (d, J= 3.6 Hz, 1H), 4.03 (tt, J= 9.0, 6.6 Hz, 1H), 3.61 - 3.40 (m, 4H).Step 5: Preparation of 3-{4-amino-5-bromoimidazo[4,3-f] [l,2,4]triazin-7-yl}cyclobutan-l-one:

[0257] To a stirred solution of lH-l,2,4-triazole (1.10 g, 15.89 mmol, 9.00 equiv.) in pyridine (10 mL) was added phosphoryl trichloride (1.08 g, 7.06 mmol, 4.00 equiv.) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 30 min under nitrogen atmosphere. To the above mixture was added 5-bromo-7-(3-oxocyclobutyl)-3H-imidazo[4,3- f] [1,2, 4]triazin -4-one (500 mg, 1.77 mmol, 1.00 equiv.) in pyridine (10 mL) dropwise at 0°C. The resulting mixture was stirred at room temperature for 2.5h and then treated with ammonia (3.5 M in isopropanol) (57 mL, 114.80 mmol, 65.00 equiv) dropwise at 0°C. The resulting mixture was stirred at room temperature for 2h and quenched with ice water (6 mL) at 0°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / MeOH (10: 1) to afford 3-{4-amino-5-bromoimidazo[4,3-f][l,2,4]triazin-7-WSGR Docket No. 67898-706.601 yl}cyclobutan-l-one (700 mg, crude) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+=281.9. ’H NMR (400 MHz, DMSO-d6) 5 8.64 - 8.36 (m, 1H), 7.89 (s, 1H), 7.24 - 7.00 (m, 1H), 4.07 (tt, J= 9.0, 6.6 Hz, 1H), 3.59 - 3.39 (m, 4H).Step 6: Preparation of (ls,3s)-3-(4-amino-5-bromoimidazo[5,l-f| [l,2,4]triazin-7-yl)-l- methylcyclobutan-l-ol:

[0258] In a 25-mL round bottom flask, to a solution of 3-{4-amino-5-bromoimidazo[4,3- f][l,2,4]triazin-7-yl}cyclobutan-l-one (150 mg, 0.53 mmol, 1.00 equiv.) in THF (5 m ) was added dropwise methylmagnesium chloride (3.0 M in THF) (198 mg, 2.66 mmol, 5.00 equiv.) at -78°C under N2 atmosphere. The reaction mixture was stirred at -30°C for 2 h, quenched with saturated NH4CI solution (5 m ) at -30°C and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with methanol / dichloromethane (1:9) to afford (ls,3s)-3-(4-amino-5- bromoimidazo[5,l-f][l,2,4]triazin-7-yl)-l-methylcyclobutan-l-ol (78 mg, 49.0%) as a white solid. TC- MS: (ES+H, m / z): [M+H]+=298.1 ’H NMR (400 MHz, CD3OD) 57.79 (d, J= 1.0 Hz, 1H), 3.74 - 3.52 (m, 1H), 2.55 - 2.45 (m, 4H), 1.47 (s, 3H).Intermediate 33Step 1: Preparation of N-(2-acetyl-5-chloro-4-fluorophenyl)-7-oxabicyclo[2.2.1]heptane-l- carboxamide:

[0259] To a stirred solution of l-(2-amino-4-chloro-5-fluorophenyl)ethanone (360 mg, 1.91 mmol, 1.00 equiv.) and 7-oxabicyclo[2.2.1]heptane-l-carboxylic acid (272 mg, 1.91 mmol, 1.00 equiv.) in MeCN (10 mb) were added 1 -methyl- IH-imidazole (787 mg, 9.59 mmol, 5.00 equiv.) and TCFH (1.62 g, 5.75 mmol, 3.00 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 4 h under nitrogen atmosphere, diluted with water (20 mb) and extracted with ethyl acetate (3 x 40 mb). The combined organic layers were washed with brine (2 x 30 mb) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (0%~I0% in 15 min) to afford N-(2-acetyl-5-chloro-4-fluorophenyl)-7- oxabicyclo[2.2.1]heptane-l-carboxamide (416 mg, 69.5%) as an off-white solid. EC-MS: (ES+H, m / z):WSGR Docket No. 67898-706.601[M+H]+=312.10. 'H NMR (400 MHz, DMSO-6) 3 11.87 (s, 1H), 8.84 (d, J= 7.2 Hz, 1H), 8.16 (dd, J = 10.1, 1.2 Hz, 1H), 4.76 (t, J= 5.0 Hz, 1H), 2.64 (s, 3H), 1.97 - 1.88 (m, 2H), 1.85 - 1.76 (m, 2H), 1.74- 1.59 (m, 4H).Step 2: Preparation of 7-chloro-6-fluoro-2-{7-oxabicyclo[2.2.1]heptan-l-yl}-lH-quinolin-4-one:

[0260] A solution of N-(2-acetyl-5-chloro-4-fluorophenyl)-7-oxabicyclo[2.2. l]heptane-l-carboxamide (350 mg, 1.12 mmol, 1.00 equiv.) and NaOH (134 mg, 3.36 mmol, 3.00 equiv.) in 1,4-dioxane (8 mL) was stirred at 110 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (15%~40% in 15 min) to afford 7-chloro-6-fluoro-2-{7- oxabicyclo[2.2.1]heptan-l-yl}-lH-quinolin-4-one (265 mg) as a brown yellow solid. LC-MS: (ES+H, m / z): [M+H]+= 294.10. ’H NMR (400 MHz, DMSO-6) 3 11.58 (s, 1H), 8.07 (d, J= 6.4 Hz, 1H), 7.86 (d, J = 9.5 Hz, 1H), 6.10 (s, 1H), 4.79 (t, J = 5.1 Hz, 1H), 2.17 - 2.06 (m, 2H), 1.94 - 1.81 (m, 2H), 1.78- 1.69 (m, 4H).Step 3: Preparation of 4,7-dichloro-6-fluoro-2-{7-oxabicyclo[2.2.1]heptan-l-yl}quinoline:

[0261] To a stirred solution of 7-chloro-6-fluoro-2-{7-oxabicyclo[2.2.1]heptan-l-yl}-lH-quinolin-4- one (250 mg, 0.85 mmol, 1.00 equiv.) in toluene (5 mL) was added a solution of phosphoryl trichloride (391 mg, 2.55 mmol, 3.00 equiv.) in toluene (3 mL) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 2 h, cooled to room temperature and poured into sat. Na2COs (15 mL) at 0 °C. The above mixture was extracted with ethyl acetate (5 x 30 mL). The combined organic layers were washed with brine (3 x 20 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure to afford 4,7-dichloro-6-fluoro-2-{7-oxabicyclo[2.2.1]heptan-l- yl}quinoline (266 mg) as a black solid. LC-MS: (ES+H, m / z): [M+H]+=312.10. ' H NMR (400 MHz, DMSO-d6) 3 8.35 (d, J= 7.2 Hz, 1H), 8.11 (d, J = 9.9 Hz, 1H), 7.87 (s, 1H), 4.76 (t, J = 5.0 Hz, 1H), 2.13- 2.09 (m, 2H), 1.89 - 1.78 (m, 4H), 1.75 - 1.70 (m,2H).Step 4: Preparation of 7-chloro-6-fluoro-2-{7-oxabicyclo[2.2.1]heptan-l-yl}quinoline:

[0262] To a stirred solution of 4,7-dichloro-6-fluoro-2-{7-oxabicyclo[2.2.1]heptan-l-yl}quinoline (250 mg, 0.80 mmol, 1.00 equiv.) and N,N,N',N'-tetramethylethylenediamine (186 mg, 1.60 mmol, 2.00 equiv.) in THE (10 mL) were added Pd(dppf)C12 CH2CI2 (32 mg, 0.04 mmol, 0.05 equiv.) and NaBEL (60 mg, 1.60 mmol, 2.00 equiv.) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 45 min, quenched with water (15 mL) at 0 °C and extracted with ethyl acetate (4 x 30 mL). The combined organic layers were dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (0% ~ 10% in 15 min) to afford 7-chloro-6- fluoro-2-{7-oxabicyclo[2.2.1]heptan-l-yl}quinoline (92 mg, 41.3%) as a colorless oil. LC-MS: (ES+H, m / z): [M+H]+=278.10. 'H NMR (400 MHz, DMSO-6) 3 8.39 (d, J = 8.6 Hz, 1H), 8.25 - 8.18 (m, 1H), 8.08 - 8.00 (m, 1H), 7.76 (d, J= 8.7 Hz, 1H), 4.75 (t, J= 5.0 Hz, 1H), 2.13 - 2.09 (m, 2H), 1.89 - 1.68 (m, 6H).WSGR Docket No. 67898-706.601Step 5: Preparation of (6-fluoro-2-{7-oxabicyclo[2.2.1]heptan-l-yl}-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinolone) :

[0263] To a stirred solution of 7-chloro-6-fluoro-2-{7-oxabicyclo[2.2.1]heptan-l-yl}quinoline (40 mg, 0.14 mmol, 1.00 equiv.) and bis(pinacolato)diboron (40 mg, 0.15 mmol, 1.10 equiv.) in 1,4-dioxane (3 mL) were added AcOK (35 mg, 0.36 mmol, 2.50 equiv.), XPhos (13 mg, 0.02 mmol, 0.20 equiv.) and Pd2(dba)s (13 mg, 0.01 mmol, 0.10 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The resulting mixture (6-fluoro-2-{7- oxabicyclo[2.2.1]heptan-l-yl}-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinolone) was used in the next step directly without further purification. LC-MS: (ES+H, m / z): [M+H]+=370.15.Intermediate 34Step 1: Preparation of 2-{bicyclo[l.l.l]pentan-l-yl}-4,7-dichloroquinoline :

[0264] To a stirred mixture of bicyclofl. l.l]pentane-l-carboxylic acid (0.57 g, 5.05 mmol, 1.00 equiv.) and AgNOs (1.03 g, 6.06 mmol, 1.20 equiv.) in H2SO4 (60 mL,10% in H2O) was added 4,7- dichloroquinoline (1.00 g, 5.05 mmol, 1.00 equiv.) at room temperature. The resulting mixture was stirred at 80°C for 10 min under nitrogen atmosphere. To the above mixture was added (NH4)2S20s (5.76 g, 25.25 mmol, 5.00 equiv.) in H2O (10 mL) at 80°C. The resulting mixture was stirred at 80°C for 30 min, cooled to room temperature, diluted with H2O (30 mL), and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with H2O (2 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc in petroleum ether (0% to 10% gradient in 20 min) to afford 2-{bicyclo[l. l. l]pentan-l-yl}-4,7-dichloroquinoline (400 mg, 30.0%) as a light yellow solid. LC- MS: (ES+H, m / z): [M+H]+=264.00. 'HNMR (400 MHz, DMSO-6) 5 8.16 (d, J= 8.9 Hz, 1H), 8.09 (d, J= 2.1 Hz, 1H), 7.77 - 7.68 (m, 2H), 2.60 (s, 1H), 2.21 (s, 6H).Step 2: Preparation of 2-{bicyclo[l.l.l]pentan-l-yl}-7-chloro-4-methoxyquinoline:

[0265] A solution of 2-{bicyclo[l.l.l]pentan-l-yl}-4,7-dichloroquinoline (350 mg, 1.33 mmol, 1.00 equiv.) in HC1 (4.0 M in MeOH, 3.5 mL) was stirred at 60°C for 3 h. The mixture was cooled to room temperature and concentrated under vacuum to afford 2-{bicyclo[l. l.l]pentan-l-yl}-7-chloro-4- methoxyquinoline (350 mg, crude) as off-white solid. The crude product was used in the next step directly without further purification. LC-MS: (ES+H, m / z): [M+H]+=259.95 'H NMR (400 MHz, DMSO-d6) 5 8.88 (s, 1H), 8.29 (d, J= 8.5 Hz, 1H), 7.85 (d, J= 8.6 Hz, 1H), 7.30 (s, 1H), 4.34 (s, 3H), 2.71 (s, 1H), 2.52 (s, 6H).Step 3: Preparation of 2-{bicyclo[l.l.l]pentan-l-yl}-4-methoxy-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoline:WSGR Docket No. 67898-706.601

[0266] A mixture of 2-{bicyclo[l.l.l]pentan-l-yl}-7-chloro-4-methoxyquinoline (100 mg, 0.39 mmol, 1.00 equiv.), PimEE (108 mg, 0.42 mmol, 1.10 equiv.), AcOK (113 mg, 1.16 mmol, 3.00 equiv.), XPhos (37 mg, 0.08 mmol, 0.20 equiv.) and Pd2(dba)s (35 mg, 0.04 mmol, 0.10 equiv.) in 1,4-dioxane (5 mb) was stirred at 80°C for 3 h under nitrogen atmosphere. The resulting mixture was used in the next step directly without further purification. LC-MS: (ES+H, m / z): [M+H]+=352.10.Intermediate 35Step 1: Preparation of N-(2-acetyl-5-bromophenyl)-4-methyl-2-oxabicyclo[2.1.1]hexane-l- carboxamide:

[0267] To a stirred mixture of l-(2-amino-4-bromophenyl)ethanone (500 mg, 2.34 mmol, 1.00 equiv.) and 4-methyl-2-oxabicyclo[2.1.1]hexane-l-carboxylic acid (332 mg, 2.37 mmol, 1.00 equiv.) in MeCN (15 m ) were added TCFH (1310 mg, 4.67 mmol, 2.00 equiv.) and 1 -methyl- IH-imidazole (959 mg, 11.68 mmol, 5.00 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 4h under nitrogen atmosphere and diluted with EtOAc (200 mb). The organic layer was washed with 3 x 40 mb of water and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (0%-30% gradient in 30 min) to afford N-(2-acetyl- 5-bromophenyl)-4-methyl-2-oxabicyclo[2.1.1]hexane-l-carboxamide (500 mg, 63.3%) as a light yellow solid. EC-MS: (ES+H, m / z): [M+H]+= 338.0. ’HNMR (400 MHz, DMSO-6) 5 12.11 (s, 1H), 8.90 (d, J = 2.1 Hz, 1H), 8.03 (d, J= 8.6 Hz, 1H), 7.45 (dd, J= 8.5, 2.1 Hz, 1H), 3.72 (s, 2H), 2.64 (s, 3H), 2.00 (dd, J= 4.3, 1.7 Hz, 2H), 1.70 (dd, J= 4.3, 1.7 Hz, 2H), 1.34 (s, 3H).Step 2: Preparation of 7-bromo-2-(4-methyl-2-oxabicyclo[2.1.1]hexan-l-yl)quinolin-4(lH)-one:

[0268] To a stirred solution of N-(2-acetyl-5-bromophenyl)-4-methyl-2-oxabicyclo[2.1.1]hexane-l- carboxamide (500 mg, 1.48 mmol, 1.00 equiv.) in dioxane (15 mb) was added t-BuOK (331 mg, 2.96 mmol, 2.00 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C for 4h, cooled to room temperature and diluted with EtOAc (220 mb). The organic layer was washed with 3 x 50 mb of water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / MeOH (0%-10% gradient in 30 min) to afford 7-bromo-2-(4-methyl-2- oxabicyclo[2.1.1]hexan-l-yl)quinolin-4(lH)-one (430 mg, 90.8%) as a light yellow solid. EC-MS: (ES+H, m / z): [M+H]+= 320.1 ' HNMR (400 MHz, DMSO-6) 5 11.48 (s, 1H), 7.99 (d, J= 1.9 Hz, 1H),WSGR Docket No. 67898-706.6017.96 (d, J= 8.6 Hz, 1H), 7.44 (dd, J= 8.6, 1.9 Hz, 1H), 6.08 (s, 1H), 3.71 (s, 2H), 2.08 (dd, J= 4.5, 1.7 Hz, 2H), 1.85 (dd, J= 4.4, 1.7 Hz, 2H), 1.39 (s, 3H).Step 3: Preparation of 7-bromo-4-methoxy-2-(4-methyl-2-oxabicyclo[2.1.1]hexan-l-yl)quinoline:

[0269] To a stirred solution of 7-bromo-2-(4-methyl-2-oxabicyclo[2.1. l]hexan-l-yl)quinolin-4(lH)- one (300 mg, 0.94 mmol, 1.00 equiv.) in acetone (10 mL) was added K2CO3 (129 mg, 0.94 mmol, 1.00 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 60°C for 2h, cool to room temperature and treated with dimethyl sulfate (118 mg, 0.94 mmol, 1.00 equiv.) dropwise. The resulting mixture was stirred at 60°C for an additional 2h, cooled to room temperature and diluted with EtOAc (150 mL). The organic layer was washed with 3 x 30 mL of water and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (0%- 25% gradient in 30 min) to afford 7-bromo-4-methoxy-2-(4-methyl -2 -oxabicyclo [2.1.1 ]hexan-l- yl)quinoline (280 mg, 89.4%) as a light brown solid. LC-MS: (ES+H, m / z): [M+H]+= 334.0. 'HNMR (400 MHz, DMSO-d6) 5 8.11 (d, J= 2.0 Hz, 1H), 8.05 (d, J= 8.8 Hz, 1H), 7.68 (dd, J= 8.8, 2.1 Hz, 1H), 7.14 (s, 1H), 4.06 (s, 3H), 3.72 (s, 2H), 2.12 (dd, J= 4.4, 1.6 Hz, 2H), 1.83 (dd, J= 4.4, 1.7 Hz, 2H), 1.40 (s, 3H).Step 4: Preparation of 4-methoxy-2-(4-methyl-2-oxabicyclo[2.1.1]hexan-l-yl)-7-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline:

[0270] To a stirred mixture of 7-bromo-4-methoxy-2-(4-methyl-2-oxabicyclo[2.1.1]hexan-l- yl)quinoline (110 mg, 0.33 mmol, 1.00 equiv.) and bis(pinacolato)diboron (100 mg, 0.40 mmol, 1.20 equiv.) in dioxane (5 mL) were added Pd2(dba)s (30 mg, 0.03 mmol, 0.10 equiv.), XPhos (31 mg, 0.07 mmol, 0.20 equiv.) and AcOK (97 mg, 0.90 mmol, 3.00 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C for 3h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was used in the next step directly without further purification.LC-MS: (ES+H, m / z): [M+H]+= 382.2.Intermediate 36Step 1: Preparation of 7-bromo-6-fluoro-2-(4-methyl-2-oxabicyclo[2.1.1]hexan-l-yl)quinoline:

[0271] To a stirred solution of 2-amino-4-bromo-5-fluorobenzaldehyde (150 mg, 0.69 mmol, 1.00 equiv.) and l-{4-methyl-2-oxabicyclo[2.1.1]hexan-l-yl}ethanone (96 mg, 0.69 mmol, 1.00 equiv.) in EtOH (10 mL) was added NaOH (28 mg, 0.69 mmol, 1.00 equiv.) at room temperature. The resulting mixture was stirred at 50°C for 4h cooled to room temperature, poured into water (80 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were concentrated under reduced pressure. TheWSGR Docket No. 67898-706.601 residue was purified by normal-phase flash chromatography (silica gel; mobile phase, EtOAc in Petroleum ether, 0% to 20% gradient in 20 min; detector, UV 254 nm) to afford 7-bromo-6-fluoro-2-{4- methyl -2 -oxabicyclo [2. l.l]hexan-l-yl} quinoline (150 mg, 67%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+= 322.0. ’HNMR (400 MHz, DMSO-6) 5 8.39 (dd, J= 10.2, 7.7 Hz, 2H), 8.01 (d, J= 9.3 Hz, 1H), 7.74 (dd, J= 8.5, 0.8 Hz, 1H), 3.71 (s, 2H), 2.11 (dd, J= 4.4, 1.7 Hz, 2H), 1.85 (dd, J= 4.4, 1.7 Hz, 2H), 1.41 (s, 3H).Step 2: Preparation of 6-fluoro-2-(4-methyl-2-oxabicyclo[2.1.1]hexan-l-yl)-7-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)quinoline:

[0272] To a stirred solution of 7-bromo-6-fluoro-2-{4-methyl-2-oxabicyclo[2.1.1]hexan-l- yl}quinoline (80 mg, 0.25 mmol, 1.00 equiv.) and PimEE (126 mg, 0.50 mmol, 2.00 equiv.) in dioxane (5 mL) were added AcOK (73 mg, 0.74 mmol, 3.00 equiv.) and Pd^ppQCECTECf (20 mg, 0.030 mmol, 0.10 equiv.) at room temperature. The resulting mixture was stirred at 100°C for 3h under nitrogen atmosphere. The resulting mixture was used in the next step directly without further purification. LC-MS: (ES+H, m / z): [M+H]+= 370.2.Intermediate 37Step 1: Preparation of (2-amino-4-bromo-3-fluorophenyl)methanol:

[0273] To a stirred solution of 2-amino-4-bromo-3-fluorobenzoic acid (600 mg, 2.56 mmol, 1.00 equiv.) in THF (10 mL) was added borane (1.0M in THF) (20.5 mL, 20.51 mmol, 8.00 equiv.) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 50°C for 12h, quenched by the addition of MeOH (20 mL) at 0°C and diluted with water (50 mL). The resulting mixture was extracted with CH2Q2 (3 x 50 mL). The combined organic layers were washed with brine (1x50 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / MeOH (10: 1) to afford (2-amino-4-bromo-3-fluorophenyl)methanol (450 mg, 80%) as a yellow solid. LC-MS: (ES-H, m / z): [M- H]' =217.9. ’HNMR (400 MHz, DMSO-6) 56.89 (dd, J= 8.2, 1.4 Hz, 1H), 6.76 (dd, J= 8.2, 6.3 Hz, 1H), 5.22 - 5.11 (m, 3H), 4.40 (d, J= 5.5 Hz, 2H).Step 2: Preparation of 2-amino-4-bromo-3-fluorobenzaldehyde:

[0274] To a stirred mixture of (2-amino-4-bromo-3-fluorophenyl)methanol (350 mg, 1.59 mmol, 1.00 equiv.) in DCM (10 mL) was added Mn02 (415 mg, 4.77 mmol, 3.00 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 12h,WSGR Docket No. 67898-706.601 cooled to room temperature, diluted with water (30 mL), and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (1x30 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5: 1) to afford 2-amino-4-bromo-3-fluorobenzaldehyde (280 mg, 81%) as a white solid. LC-MS: (ES-H, m / z): [M-H]’ =215.8. ’H NMR (400 MHz, DMSO-6) 5 9.87 (d, J= 2.0 Hz, 1H), 7.41 (dd, J= 8.5, 1.4 Hz, 1H), 7.23 (s, 2H), 6.93 (dd, J= 8.5, 5.9 Hz, 1H).Step 3: Preparation of 7-bromo-8-fluoro-2-{4-methyl-2-oxabicyclo[2.1.1]hexan-l-yl}quinoline:

[0275] To a stirred mixture of 2-amino-4-bromo-3-fluorobenzaldehyde (156 mg, 0.71 mmol, 1.00 equiv.) and l-{4-methyl-2-oxabicyclo[2.1.1]hexan-l-yl}ethanone (100 mg, 0.71 mmol, 1.00 equiv.) in dioxane (10 mL) was added NaOH (29 mg, 0.71 mmol, 1.00 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C for 2h, cooled down to room temperature, diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (1 x 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5: 1) to afford 7-bromo-8-fluoro-2-{4-methyl-2-oxabicyclo[2.1. l]hexan-l- yl}quinoline (120 mg, 52%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+=322.0. 'H NMR (400 MHz, DMSO-d6) 5 8.49 (dd, J= 8.6, 1.6 Hz, 1H), 7.83 - 7.81 (m, 2H), 7.79 (d, J= 3.2 Hz, 1H), 2.34 (dd, .7= 4.3, 1.7 Hz, 1H), 2.15 (dd, J= 4.4, 1.7 Hz, 2H), 1.86 (dd, J= 4.4, 1.7 Hz, 2H), 1.81 (dd, J= 4.3, 1.7 Hz, 1H), 1.41 (s, 3H).Step 4: Preparation of 8-fluoro-2-{4-methyl-2-oxabicyclo[2.1.1]hexan-l-yl}-7-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)quinoline:

[0276] To a stirred mixture of 7-bromo-8-fluoro-2-{4-methyl-2-oxabicyclo[2.1.1]hexan-l- yl}quinoline (100 mg, 0.31 mmol, 1.00 equiv.) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2- dioxaborolane) (95 mg, 0.37 mmol, 1.20 equiv.) in dioxane (10 mL) were added Pd(dppf)Ch (23 mg, 0.03 mmol, 0.10 equiv.) and AcOK (91 mg, 0.93 mmol, 3.00 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100°C for 2h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was used in the next step directly without further purification. LC-MS: (ES+H, m / z): [M+H]+=370.1.Intermediate 38Step 1: Preparation of 7-chloro-3-fluoroquinoline:

[0277] A solution of 7-chloroquinolin-3-amine (1.00 g, 5.60 mmol, 1.00 equiv.) was treated with tetrafluoroboric acid (40% in H2O) (2 mL, 0.56 mmol, 2.00 equiv., 40%) at 0°C for 15 min under nitrogen atmosphere followed by the addition of NaNCE (386 mg, 5.60 mmol, 1.00 equiv.) in H2O (5 mL) dropwise at 0°C. The resulting mixture was stirred at 0°C for 20min. The precipitated solids wereWSGR Docket No. 67898-706.601 collected by filtration and washed with cold EtOH (3x10 mL) and cold Et2O (3x10 mL). The precipitated solids were dried under reduced pressure. To the above solids was added 1,2-dichlorobenzene (10 mL) dropwise at room temperature. The resulting mixture was stirred at 110°C for 2h, cooled down to room temperature and diluted with EtOAc (200 mL). The organic layer was washed with water (3x50 mL), brine (1x50 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / EtOAc (0%-10%) to afford 7-chloro-3 -fluoroquinoline (600 mg, 59.0%) as a yellow solid. LC- MS: (ES+H, m / z): [M+H]+= 182.05. ’H NMR (400 MHz, CDC13) 5 8.82 (d, J= 2.8 Hz, 1H), 8.13 (d, J = 2.1 Hz, 1H), 7.80 - 7.70 (m, 2H), 7.54 (dd, J= 8.6, 2.1 Hz, 1H).19E NMR (376 MHz, CDC13) 5 -127.53.Step 2: Preparation of 7-chloro-3-fluoro-2-{7-oxabicyclo[2.2.1]heptan-l-yl}quinoline:

[0278] A mixture of 7-chloro-3 -fluoroquinoline (80 mg, 0.43 mmol, 1.00 equiv.), 7- oxabicyclo[2.2.1]heptane-l-carboxylic acid (224 mg, 1.58 mmol, 3.60 equiv.) and AgNOs (89 mg, 0.53 mmol, 1.20 equiv.) in 5% TFA water solution (10 mL) was stirred at 80°C for 20 min under nitrogen atmosphere, followed by the addition of ammonium persulfate (1.00 g, 4.40 mmol, 10 equiv.) in H2O (7 mL) dropwise over 10 min. The resulting mixture was stirred at 80°C for 40 min, cooled to room temperature, diluted with water (50 mL), and extracted with EtOAc (3x50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (Cl 8; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 10% to 50% gradient in 40 min; detector, UV 254 nm) to afford 7-chloro-3-fluoro- 2-{7-oxabicyclo[2.2.1]heptan-l-yl}quinoline (35 mg, 28.6%) as a brown solid. LC-MS: (ES+H, m / z): [M+H]+= 278.1. ' H NMR (400 MHz, DMSO-6) 5 8.31 (d, J= 11.6 Hz, 1H), 8.08 (d, J= 2.1 Hz, 1H), 8.03 (d, J= 8.8 Hz, 1H), 7.69 (dd, J= 8.7, 2.1 Hz, 1H), 4.74 (t, J= 5.1 Hz, 1H), 2.10 - 1.98 (m, 4H), 1.90 - 1.82 (m, 2H), 1.77 - 1.67 (m, 2H).Step 3: Preparation of 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-3-fluoro-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoline:

[0279] To a stirred solution of 7-chloro-3-fluoro-2-{7-oxabicyclo[2.2.1]heptan-l-yl}quinoline (30 mg, 0.11 mmol, 1.00 equiv.) and PimEL (41 mg, 0.16 mmol, 1.50 equiv.) in dioxane (5 mL) were added Pd2(dba)s (9 mg, 0.01 mmol, 0.10 equiv.) and XPhos (10 mg, 0.02 mmol, 0.20 equiv.) in portions at room temperature. The resulting mixture was stirred at 100°C for 2h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was used in the next step directly without further purification. LC-MS: (ES+H, m / z): [M+H]+= 370.2.Intermediate 39WSGR Docket No. 67898-706.601Step 1: Preparation of tert-butyl N-{7-bromopyrrolo[2,l-f| [l,2,4]triazin-4-yl}-N-(tert- but oxy carb onyl) carb am ate :

[0280] To a stirred mixture of 7-bromopyrrolo[2,l-f][l,2,4]triazin-4-amine (10 g, 46.94 mmol, 1.00 equiv.) and EtsN (14.25 g, 140.82 mmol, 3.00 equiv.) in DCM (400 mL) were added DMAP (5.73 g, 46.94 mmol, 1.00 equiv.) and BOC2O (35.86 g, 164.29 mmol, 3.5 equiv.) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight. The organic layer was washed with NaHCOs(aq, 2x100 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / EtOAc (0% to 50% gradient in 40 min) to afford tert-butyl N-{7- bromopyrrolo[2,l-f][l,2,4]triazin-4-yl}-N-(tert-butoxycarbonyl)carbamate (12 g, 61.8%) as a light yellow solid. LC-MS: (ES+H, m / z): [M+H]+= 413.2. 'HNMR (300 MHz, DMSO-6) 5 8.70 (s, 1H), 7.30 (d, J = 4.8 Hz, 1H), 7.05 (d, J = 4.8 Hz, 1H), 1.40 (s, 18H).Step 2: Preparation of tert-butyl N-(tert-butoxycarbonyl)-N-(7-{5,8-dioxaspiro[3.4]octan-2- yl}pyrrolo[2,l-f| [l,2,4]triazin-4-yl)carbamate :

[0281] To a stirred mixture of tert-butyl N-{7-bromopyrrolo[2,l-f][l,2,4]triazin-4-yl}-N-(tert- butoxycarbonyl)carbamate (500 mg, 1.21 mmol, 1.00 equiv.) and 2-bromo-5,8-dioxaspiro[3.4]octane (467 mg, 2.42 mmol, 2.00 equiv.) in N,N-dimethylacetamide (10 mL) was added Zinc (158 mg, 2.42 mmol, 2.00 equiv.), Nal (45 mg, 0.30 mmol, 0.25 equiv.), pyridine-2,6-dicarboximidamide dihydrochloride (28 mg, 0.12 mmol, 0.10 equiv.), dichloro(dimethoxyethane)nickel (26 mg, 0.12 mmol, 0.10 equiv.), and trifluoroacetic acid (13 mg, 0. 12 mmol, 0. 1 equiv.) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 60°C overnight cooled to room temperature and diluted with EtOAc (lOOmL). The organic layer was washed with water (3 x 50 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / EtOAc (0% to 30% gradient in 30 min) to afford tert-butyl N-(tert-butoxycarbonyl)-N-(7-{5,8-dioxaspiro[3.4]octan-2-yl}pyrrolo[2,l- f][l,2,4]triazin-4-yl)carbamate (120 mg, 22.2%) as a yellow oil. LC-MS: (ES+H, m / z): [M+H]+= 447.3. 'HNMR (300 MHz, DMSO-6) 5 8.52 (s, 1H), 7.10 (d, J = 4.6 Hz, 1H), 6.82 (d, J = 4.7 Hz, 1H), 3.91WSGR Docket No. 67898-706.601(ddd, J = 6.6, 5.7, 1.3 Hz, 2H), 3.83 (ddd, J = 7.4, 5.8, 1.4 Hz, 2H), 3.74 (p, J = 8.5 Hz, 1H), 2.80 - 2.73 (m, 2H), 2.60 - 2.52 (m, 2H), 1.41 (s, 18H).Step 3: Preparation of 3-{4-aminopyrrolo[2,l-f][l,2,4]triazin-7-yl}cyclobutan-l-one:

[0282] A solution of tert-butyl N-(7-{5,8-dioxaspiro[3.4]octan-2-yl}pyrrolo[2,l-f][l,2,4]triazin-4- yl)carbamate (500 mg, 1.44 mmol, 1.00 equiv.) and HC1 (5 mL,2N,aq) in acetone (5 mL) was stirred at 50°C for 2h under nitrogen atmosphere. The mixture cooled to room temperature, diluted with water (lOmL), and basified to pH 9 with saturated NH4OH (aq.). The resulting mixture was extracted with EtOAc (3 x 50 mL) and the organic layer was dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure to provide 3-{4-aminopyrrolo[2,l-f][l,2,4]triazin-7- yl}cyclobutan-l-one (200 mg, 68.5%) as a brown solid. LC-MS: (ES+H, m / z): [M+H]+= 203.0. 'HNMR (300 MHz, DMSO-d6) 57.84 (s, 1H), 7.79 - 7.61 (m, 2H), 6.86 (d, J = 4.4 Hz, 1H), 6.65 (d, J = 4.4 Hz, 1H), 3.98 (ddd, J = 9.2, 6.8, 2.4 Hz, 1H), 3.54 - 3.47 (m, 2H), 3.34 - 3.27 (m, 2H).Step 4: Preparation of 3-{4-amino-5-bromopyrrolo[2,l-f|[l,2,4]triazin-7-yl}cyclobutan-l-one:

[0283] A mixture of 3-{4-aminopyrrolo[2,l-f][l,2,4]triazin-7-yl}cyclobutan-l-one (160 mg, 0.79 mmol, 1.00 equiv.) and NBS (140 mg, 0.79 mmol, 1.00 equiv.) in DMF (5 mL) was stirred at room temperature for 1.5h under nitrogen atmosphere. The resulting mixture was diluted with EtOAc (lOOmL). The organic layer was washed with water (3 x 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to provide 3-{4-amino-5-bromopyrrolo[2,l- f][l,2,4]triazin-7-yl}cyclobutan-l-one (160 mg, crude) as a brown solid. LC-MS: (ES+H, m / z): [M+H]+= 281.0 ’H NMR (400 MHz, DMSO-6) 57.86 (s, 1H), 6.89 (s, 1H), 3.99 - 3.91 (m, 1H), 3.52 - 3.44 (m, 2H), 3.34 - 3.28 (m, 2H).Step 5: Preparation of (ls,3s)-3-(4-amino-5-bromopyrrolo[2,l-f|[l,2,4]triazin-7-yl)-l- methylcyclobutan-l-ol:

[0284] To a stirred mixture of 3-{4-amino-5-bromopyrrolo[2,l-f][l,2,4]triazin-7-yl}cyclobutan-l-one (140 mg, 0.50 mmol, 1.00 equiv.) in THF (10 mL) was added chloro(methyl)magnesium (0.83 mL, 2.50 mmol, 5 equiv. ,3M / L in THF) dropwise at -78°C under nitrogen atmosphere. The resulting mixture was stirred at -78°C to -30°C for 3h under nitrogen atmosphere. The reaction was quenched with sat. NH4CI (aq.2mL) at -20°C, diluted with water (20 mL) and extracted with EtOAc (3 x 30mL). The combined organic layers were washed with brine (1 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / MeOH (0% to 10% gradient in 30 min) to afford (ls,3s)-3-(4- amino-5-bromopyrrolo[2,l-f][l,2,4]triazin-7-yl)-l-methylcyclobutan-l-ol (70 mg, 47.3%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+= 296.9. ’HNMR (400 MHz, DMSO-6) 57.87 (s, 1H), 7.83 - 6.20 (bro, 2H), 6.73 (s, 1H), 5.05 (s, 1H), 3.45 - 3.32 (m, 1H), 2.42 (tt, J= 8.0, 2.5 Hz, 2H), 2.20 (td, J= 9.5, 2.8 Hz, 2H), 1.39 (s, 3H).Intermediates 40 and 41WSGR Docket No. 67898-706.601Step 1: Preparation of 6-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-nitropyrimidin-4- amine:

[0285] To a stirred solution of 4,6-dichloro-5-nitropyrimidine (25.00 g, 128.88 mmol, 1.00 equiv.) in MeCN (200 mL) were added bis [(4-methoxyphenyl)methyl] amine (33.17 g, 128.88 mmol, 1.00 equiv.) and EtsN (26.08 g, 257.77 mmol, 2.00 equiv.) portion-wise at room temperature. The resulting mixture was stirred at 0°C for Ih under nitrogen atmosphere and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (0%-20% gradient in 30 min) to afford 6-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-nitropyrimidin-4-amine (40 g, 74.8%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+= 415.1. ’H NMR (400 MHz, CDC13) 5 8.45 (s, IH), 7.08 - 7.03 (m, 4H), 6.88 - 6.84 (m, 4H), 4.56 (s, 4H), 3.80 (s, 6H).Step 2: Preparation of (ls,3r)-3-[(6-{bis[(4-methoxyphenyl)methyl]amino}-5-nitropyrimidin-4- yl)amino]-l-methylcyclobutan-l-ol:

[0286] To a stirred solution of 6-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-nitropyrimidin-4-amine (20.00 g, 48.21 mmol, 1.00 equiv.) and (ls,3s)-3-amino-l-methylcyclobutan-l-ol hydrochloride (6.52 g, 48.21 mmol, 1.00 equiv.) in MeCN (200 mL) was added EtsN (14.64 g, 144.63 mmol, 3.00 equiv.) portion-wise at room temperature. The resulting mixture was stirred at 80°C for 2h under nitrogen atmosphere and then cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc (0%-50% gradient in 30 min)) to afford ( 1 s,3r)-3-[(6-{bis[(4- methoxyphenyl)methyl]amino}-5-nitropyrimidin-4-yl)amino]-l-methylcyclobutan-l-ol (20 g, 86.5%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+= 480.25. 'H NMR (400 MHz, CDC13) 5 8.33 (d, J= 6.9 Hz, IH), 8.12 (s, IH), 7.04 - 6.97 (m, 4H), 6.85 - 6.76 (m, 4H), 4.49 (s, 4H), 4.24 - 4.23 (m, IH), 3.79 (s, 6H), 2.68 - 2.61 (m, 2H), 2.17 - 2.09 (m, 2H), 1.45 (s, 3H).Step 3: Preparation of (ls,3r)-3-[(5-amino-6-{bis[(4-methoxyphenyl)methyl]amino}pyrimidin-4- yl)amino]-l-methylcyclobutan-l-ol:

[0287] To a stirred mixture of ammonium chloride (37.14 g, 694.42 mmol, 16.65 equiv.), water (100 mL), Zinc (21.51 g, 329.06 mmol, 7.89 equiv.) and EtOH (200 mL) was added (ls,3r)-3-[(6-{bis[(4-WSGR Docket No. 67898-706.601 methoxyphenyl)methyl]amino}-5-nitropyrimidin-4-yl)amino]-l-methylcyclobutan-l-ol (20.00 g, 41.70 mmol, 1.00 equiv.) in THF (200 mL) dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for Ih. The resulting mixture was fdtered and the fdter cake was washed with EtOAc (3x100 mL). The combined fdtrate was concentrated under reduced pressure, diluted with water (400 mL), and extracted with EtOAc (3 x 400 mL). The combined organic layers were washed with brine (l x 400 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (PE / EtOAc (40%-80% gradient in 30 min)) to afford (ls,3r)-3-[(5-amino-6-{bis[(4-methoxyphenyl)methyl]amino}pyrimidin-4-yl)amino]-l- methylcyclobutan-l-ol (14 g, 74.6%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+= 450.25. 'HNMR (300 MHz, CDCls) 58.13 (s, IH), 7.17 - 7.11 (m, 4H), 6.84 - 6.79 (m, 4H), 4.76 (d, J= 7.3 Hz, IH), 4.21 (s, 4H), 3.78 (s, 6H), 2.68 - 2.61 (m, 2H), 2.10 - 2.03 (m, 2H), 1.43 (s, 3H).Step 4: Preparation of 6-{bis[(4-methoxyphenyl)methyl]amino}-9-[(lr,3s)-3-hydroxy-3- methylcyclobutyl]-7H-purin-8-one:

[0288] To a stirred solution of (ls,3r)-3-[(5-amino-6-{bis[(4- methoxyphenyl)methyl]amino}pyrimidin-4-yl)amino]-l-methylcyclobutan-l-ol (14.00 g, 31.14 mmol, 1.00 equiv.) and DIEA (6.03 g, 46.71 mmol, 1.50 equiv.) in CH2CI2 (240 mL) was added ditrichloromethyl carbonate (4.62 g, 15.57 mmol, 0.50 equiv.) portion-wise at 0°C. The resulting mixture was stirred at 0°C for Ih under a nitrogen atmosphere. The reaction was quenched with 2N NaOH (aq.) at 0°C and then diluted with water (lOOmL) and basified to pH 9 with 2N NaOH (aq.). The resulting mixture was extracted with CH2CI2 (3 x 300 mL) and the combined organic layers were washed with brine (1 x 500 mL), dried over anhydrous Na2SO4, fdtered and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (30%-70% gradient in 30 min) to afford 6- {bis[(4-methoxyphenyl)methyl]amino}-9-[(lr,3s)-3-hydroxy-3-methylcyclobutyl]-7H-purin-8-one (10 g, 67.5%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+= 476.25. 'H NMR (400 MHz, CDCI3) 5 8.31 (d, J = 3.7 Hz, 2H), 7.20 - 7.15 (m, 4H), 6.90 - 6.85 (m, 4H), 4.75 (s, 4H), 4.65 (tt, J = 9.3, 5.9 Hz, IH), 3.80 (s, 6H), 2.86 - 2.81 (m,2H), 2.71 - 2.62 (m, 2H), 1.40 (s, 3H).Step 5: Preparation of 6-amino-9-[(lr,3s)-3-hydroxy-3-methylcyclobutyl]-7H-purin-8-one:

[0289] To a stirred solution of 6-{bis[(4-methoxyphenyl)methyl]amino}-9-[(lr,3s)-3-hydroxy-3- methylcyclobutyl]-7H-purin-8-one (400 mg, 0.84 mmol, 1.00 equiv.) in CH2Q2 (2 mL) was added trifluoroacetic acid (2 mL) in portions at room temperature. The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere and then concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (C18 silica gel; mobile phase: MeCN in Water (lOmmol / L NH4HCO3), 0% to 50% gradient in 30 min; detector, UV 254 nm) to afford 6-amino-9- [(lr,3s)-3-hydroxy-3-methylcyclobutyl]-7H-purin-8-one (170 mg, 85.9%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+= 236. 10.1H NMR (400 MHz, DMSO-6) 5 9.48 (s, IH), 8.04 (s, IH), 6.42 (s, 2H), 5.21 (s, IH), 4.42 - 4.26 (m, IH), 3.00 - 2.95 (m, 2H), 2.31 - 2.26 (m, 2H), 1.31 (s, 3H).Step 6: Preparation of (E)-N'-(l-((ls,3s)-3-hydroxy-3-methylcyclobutyl)-2-oxo-2,3-dihydro-lH- imidazo[4,5-c]pyridin-4-yl)-N,N-dimethylformimidamide:WSGR Docket No. 67898-706.601

[0290] A mixture of 4-amino-l-[(lr,3s)-3-hydroxy-3-methylcyclobutyl]-3H-imidazo[4,5-c]pyridin-2- one (400 mg, 1.71 mmol, 1.0 equiv.) in dimethoxymethyldimethylamine (6 mL) was stirred at 40°C for Ih under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / MeOH (0%- 15% gradient in 35 min) to afford (E)-N'-(l-((ls,3s)-3-hydroxy-3-methylcyclobutyl)-2-oxo-2,3-dihydro-lH- imidazo[4,5-c]pyridin-4-yl)-N,N-dimethylformimidamide (380 mg, 55.1%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+= 290.3 'H NMR (400 MHz, DMSO-6) 5 10.83 (s, IH), 8.55 (s, IH), 7.82 (d, J = 5.4 Hz, IH), 7.12 (d, J= 5.5 Hz, IH), 5.33 (s, IH), 4.42 (p, J = 8.8 Hz, IH), 3.07 (d, J= 11.6 Hz, 6H), 2.73 (td, J= 9.3, 2.9 Hz, 2H), 2.37 (tt, J= 8.6, 2.5 Hz, 2H), 1.34 (s, 3H).Intermediate 42Step 1: Preparation of methyl (ls,3s)-3-(3-bromo-4-chloro-lH-pyrazolo[3,4-d]pyrimidin-l- yl)cyclobutane-l-carboxylate:

[0291] To a stirred mixture of PPhs (11.24 g, 42.83 mmol, 2.00 equiv.) in THF (300 mL) was added DIAD (7.80 g, 38.55 mmol, 1.80 equiv.) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h and treated with 3-bromo-4-chloro-lH-pyrazolo[3,4- d]pyrimidine (5.00 g, 21.41 mmol, 1.00 equiv.) and methyl (lr,3r)-3-hydroxycyclobutane-l-carboxylate (3.07 g, 23.56 mmol, 1.10 equiv.) in THF (200 mL) at 0°C. The resulting mixture was stirred at 60°C for additional 2 h and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / EtOAc (5: 1) to afford methyl (ls,3s)-3-(3-bromo-4-chloro- lH-pyrazolo[3,4-d]pyrimidin-l-yl)cyclobutane-l-carboxylate (2.40 g, 32.4%) as a white solid.LC-MS: (ES+H, m / z): [M+H]+=345.00. 'H NMR (400 MHz, DMSO-6) 5 8.91 - 8.86 (m, IH), 5.41 (p, J= 8.4 Hz, IH), 3.67 (s, 3H), 3.15 (tt, J= 9.8, 7.9 Hz, IH), 2.89 - 2.67 (m, 4H).Step 2: Preparation of ((ls,3s)-3-(3-bromo-4-chloro-lH-pyrazolo[3,4-d]pyrimidin-l- yl)cyclobutyl)methanol:

[0292] To a stirred mixture of methyl (ls,3s)-3-{3-bromo-4-chloropyrazolo[3,4-d]pyrimidin-l- yl} cyclobutane -1 -carboxylate (2.30 g, 6.65 mmol, 1.00 equiv.) in THF (70 mL) was added diisobutylaluminum hydride(13.3 mL, 13.30 mmol, 1.0 M in hexanes, 2.00 equiv.) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h and quenched by the addition of sat. NH4CI (aq.,20 mL) at 0°C. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 30 mL) and dried- I l l -WSGR Docket No. 67898-706.601 over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure to afford ((ls,3s)-3-(3-bromo-4-chloro-lH-pyrazolo[3,4-d]pyrimidin-l-yl)cyclobutyl)methanol (1.80 g, 85.1%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+=317.001H NMR (400 MHz, DMSO-6) 5 8.92 - 8.77 (m, 1H), 5.29 (p, J= 8.2 Hz, 1H), 4.71 (d, J= 54.8 Hz, 1H), 3.48 (d, J= 5.4 Hz, 2H), 2.49 - 2.27 (m, 5H).Step 3: Preparation of ((ls,3s)-3-(4-amino-3-bromo-lH-pyrazolo[3,4-d]pyrimidin-l- yl)cyclobutyl)methanol:

[0293] To a stirred mixture of [(ls,3s)-3-{3-bromo-4-chloropyrazolo[3,4-d]pyrimidin-l- yl}cyclobutyl]methanol (1.70 g, 5.353 mmol, 1.00 equiv.) in i-PrOH (34.00 m ) was added NH3H2O (15 m ) dropwise at room temperature. The resulting mixture was stirred at 100°C overnight and concentrated under reduced pressure to afford ((ls,3s)-3-(4-amino-3-bromo-lH-pyrazolo[3,4- d]pyrimidin-l-yl)cyclobutyl)methanol (1.50 g) as a yellow solid. EC-MS: (ES+H, m / z): [M+H]+=298.10 'HNMR (400 MHz, DMSO-6) 5 8.20 (s, 1H), 5.16 - 5.02 (m, 1H), 3.46 (d, J= 5.4 Hz, 2H), 2.45 - 2.18 (m, 5H).Intermediate 43Y=83.7%1 I NT-43Step 1: Preparation of 2-{bicyclo[l.l.l]pentan-l-yl}quinolin-7-amine:

[0294] To a stirred solution of 2-{bicyclo[l.l. l]pentan-l-yl}-7-chloroquinoline (300 mg, 1.31 mmol, 1.00 equiv.) and NH3H2O (457 mg, 13.06 mmol, 10.00 equiv.) in DMSO (10 mb) were added Cui (12 mg, 0.065 mmol, 0.05 equiv.), K3PO4 (305 mg, 1.43 mmol, 1.10 equiv.) and N,N'-bis({5-methyl-[l,l'- biphenyl]-2-yl})ethanediamide (27 mg, 0.065 mmol, 0.05 equiv.) in portions at 25°C under nitrogen atmosphere. The resulting mixture was stirred at 140°C for 16h, diluted with water (20 mb) and extracted with EtOAc (3 x 20 mb). The combined organic layers were washed with brine (3x20 mb) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Q2 / MeOH (10: 1) to afford 2- {bicyclo[l. l.l]pentan-l-yl}quinolin-7-amine (230 mg, 83.7%) as a white solid. EC-MS: (ES+H, m / z): [M+H]+=211.15. ’H NMR (400 MHz, DMSO-6) 5 7.93 (d, J= 8.2 Hz, 1H), 7.54 (dd, J= 8.6, 1.3 Hz, 1H), 6.99 (dd, J= 8.3, 1.4 Hz, 1H), 6.91 (dt, J= 8.7, 1.8 Hz, 1H), 6.87 (t, J= 1.8 Hz, 1H), 5.63 (s, 2H), 2.56 (d, J= 1.4 Hz, 1H), 2.54 (d, J= 1.4 Hz, 1H), 2.13 (d, J= 1.4 Hz, 5H).Intermediate 44WSGR Docket No. 67898-706.601Step 1: Preparation of 2-(3-(benzyloxy)cyclobutylidene)acetonitrile:

[0295] To a stirred solution of diethyl (cyanomethyl)phosphonate (70.37 g, 397.24 mmol, 1.40 equiv.) in THF (1000 mL) were added EtsN (57.43 g, 567.49 mmol, 2.00 equiv.) and anhydrous lithium bromide (34.50 g, 397.24 mmol, 1.40 equiv.) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1.5h and treated with added 3-(benzyloxy)cyclobutan-l-one (50.00 g, 283.74 mmol, 1.00 equiv.) dropwise. The resulting mixture was stirred at room temperature for 16h, filtered, and the filter cake was washed with THF (2 x 300 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (10: 1) to afford 2-(3-(benzyloxy)cyclobutylidene)acetonitrile (46.00 g, 81.3%) as a yellow liquid. LC- MS: (ES+H, m / z): [M+H]+=200.1. 'HNMR (400 MHz, CDC13) 5 7.44 - 7.28 (m, 5H), 5.22 (qd, J= 2.6, 1.7 Hz, 1H), 4.47 (d, J= 1.9 Hz, 2H), 4.22 - 4.13 (m, 1H), 3.29 - 3.17 (m, 1H), 3.11 - 3.02 (m, 1H), 2.99 - 2.83 (m, 2H).Step 2: Preparation of 2-(3-(benzyloxy)cyclobutyl)acetonitrile:

[0296] To a stirred solution of 2-(3-(benzyloxy)cyclobutylidene)acetonitrile (20.00 g, 100.38 mmol, 1.00 equiv.) in THF (400 mL) was added Pd / C (5.00 g). The resulting mixture was stirred at room temperature for 16h under latm hydrogen atmosphere. The mixture was filtered through a Celite pad and concentrated under reduced pressure to provide 2-(3-(benzyloxy)cyclobutyl)acetonitrile (20.00 g, 99.0%) as a yellow liquid. LC-MS: (ES+H, m / z): [M+H]+=202.0.1H NMR (400 MHz, CDC13) 5 7.42 - 7.27 (m, 5H), 4.41 (d, J= 3.5 Hz, 2H), 4.27 - 4.18 (m, 0.5H), 3.97 - 3.85 (m, 0.5H), 2.75 - 2.48 (m, 2H), 2.46 (d, J= 7.0 Hz, 2H), 2.35 - 2.26 (m, 1H), 2.17 - 2.11 (m, 1H), 1.84- 1.72 (m, 1H).Step 3: Preparation of 2-(3-hydroxycyclobutyl)acetonitrile:

[0297] To a stirred solution of 2-(3-(benzyloxy)cyclobutyl)acetonitrile (20.00 g, 99.37 mmol, 1.00 equiv.) and Nal (47.66 g, 317.98 mmol, 3.20 equiv.) in MeCN (400 mL) were added chlorotrimethylsilane (42.83 mL, 337.86 mmol, 3.40 equiv.) dropwise at 50°C under nitrogen atmosphere. The resulting mixture was stirred at 50°C for Ih, cooled to room temperature and diluted with sat. NaHCOs (aq.) (500 mL) and sat. Na2S20s(aq.) (500 mL). The resulting mixture was extracted with EtOAc (3x1000 mL). The combined organic layers were washed with brine (3x500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to provideWSGR Docket No. 67898-706.6012-(3-hydroxycyclobutyl)acetonitrile (33.00 g, crude) as a yellow liquid. ’H NMR (400 MHz, CDC13) 5 4.22 - 4.05 (m, 1H), 2.70 - 2.54 (m, 1H), 2.52 - 2.44 (m, 2H), 2.40 - 2.25 (m, 1H), 2.16 - 2.05 (m, 1H), 2.04 - 1.89 (m, 1H), 1.81 - 1.67 (m, 1H).Step 4: Preparation of 2-(3-oxocyclobutyl)acetonitrile:

[0298] To a stirred solution of 2-(3-hydroxycyclobutyl)acetonitrile (33.00 g, assumed 33%, 98.97 mmol, 1.00 equiv.) in THF (400 mb) was added Dess-Martin periodinane (37.78 g, 89.07 mmol, 0.90 equiv.) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 50°C for 2h, filtered, and the filter cake was washed with THF (3x100 mb). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1: 1) to afford 2-(3-oxocyclobutyl)acetonitrile (10.00 g, 92.5%) as a yellow liquid. ’H NMR (400 MHz, CDCh) 5 3.39 - 3.27 (m, 2H), 3.03 - 2.93 (m, 2H), 2.89 - 2.78 (m, 1H), 2.71 (d, J= 6.7 Hz, 2H).Step 5: Preparation of 2-(3-hydroxy-3-methylcyclobutyl)acetonitrile:

[0299] To a stirred solution of 2-(3-oxocyclobutyl)acetonitrile (10.00 g, 91.64 mmol, 1.00 equiv.) in THF (200 mL) was added chloro(methyl)magnesium (91.64 mL, 274.91 mmol, 3 equiv., 3M in THF) dropwise at -78°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for Ih, quenched with sat. NH4CI (aq.) at 0°C and diluted with water (500 mL). The resulting mixture was extracted with CH2CI2 (3x500 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (2: 1) to afford 2-(3 -hydroxy-3 -methylcyclobutyl)acetonitrile (9.20 g, 80.2%) as a yellow liquid. ’H NMR (400 MHz, DMSO-d6) 5 4.93 (s, IH), 2.63 - 2.54 (m, 2H), 2.15 - 2.00 (m, 3H), 1.80 - 1.69 (m, 2H), 1.22 (s, 3H).Step 6: Preparation of 2-((ls,3r)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutyl)acetonitrile:

[0300] To a stirred solution of 2-(3-hydroxy-3-methylcyclobutyl)acetonitrile (9.20 g, 73.50 mmol, 1.00 equiv.) and imidazole (15.01 g, 220.50 mmol, 3.00 equiv.) in CH2CI2 (100 mL) was added tert- butyl(chloro)dimethylsilane (22.16 g, 147.00 mmol, 2.00 equiv.) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16h, diluted with water (200 mL) and extracted with CH2Q2 (3 x 200 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (10: 1) to afford 2- ((ls,3r)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutyl)acetonitrile (11.00 g, 62.5%) as a yellow liquid. 'H NMR (400 MHz, CDCh) 5 2.38 (d, J= 6.6 Hz, 2H), 2.24 - 2.15 (m, 2H), 2.13 - 2.00 (m, IH), 1.85 (td, J= 9.0, 2.8 Hz, 2H), 1.30 (d, J= 1.0 Hz, 3H), 0.81 (s, 9H), 0.00 (s, 6H).Step 7: Preparation of (R)-2-((ls,3S)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutyl)-3- oxopropanenitrile:

[0301] To a stirred solution of 2-((ls,3r)-3-((tert-butyldimethylsilyl)oxy)-3- methylcyclobutyl)acetonitrile (6.00 g, 25.06 mmol, 1.00 equiv.) in THF (120 mL) was added LDA (12.53 mL, 25.06 mmol, 1.00 equiv.) dropwise at -78°C under nitrogen atmosphere. The resulting mixture was stirred at -78°C for 30min and treated with ethylformate (2.42 mL, 30.07 mmol, 1.20 equiv.) dropwise at -78°C. The resulting mixture was stirred at -78°C for 30min, slowly warmed to 25°C andWSGR Docket No. 67898-706.601 stirred for 16h. The mixture was acidified to pH 3 with HC1 aq. (3N). The resulting mixture was diluted with water (200 mL) and extracted with CH2Q2 (3x200 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (3: 1) to afford (R)-2-((ls,3S)-3-((tert-butyldimethylsilyl)oxy)-3- methylcyclobutyl) -3 -oxopropanenitrile (4.00 g, 59.6%) as a yellow oil. LC-MS: (ES-H, m / z): [M-H]' = 266.2. 'H NMR (400 MHz, DMSO-6) 5 10.93 (s, 1H), 7.25 - 7.01 (m, 1H), 2.89 - 2.48 (m, 1H), 2.17 - 2.02 (m, 2H), 1.93 (d, J = 4.5 Hz, 2H), 1.32 - 1.22 (m, 3H), 0.79 (d, J= 1.1Hz, 9H), -0.00 (d, J= 1.0 Hz, 6H).Intermediate 45Step 1: Preparation of l-(2-amino-4-chloro-6-fluorophenyl)ethan-l-one:

[0302] To a stirred solution of 3 -chloro-5 -fluoroaniline (5 g, 34.35 mmol, 1.0 equiv.) in 1,4- dimethylbenzene (10 mL) were added BCEQ.O M in methylene chloride) (50 mL, 85.35 mmol, 1.3 equiv.) dropwise over 30 min at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C for 2h and allowed to warm to room temperature for 10 min. To the above mixture was added MeCN (15 mL, 274.80 mmol, 8.0 equiv.) dropwise over 20 min at room temperature. The reaction mixture was stirred at room temperature for 10 min, then treated with 1,4-dimethylbenzene (10 mL) and AlCh (2.3 g, 17.17 mmol, 0.50 equiv.) in portions over 10 min at room temperature. The resulting mixture was stirred at room temperature for Ih, then heated to 80°C for 16h under nitrogen atmosphere. The reaction mixture was cooled to room temperature and treated with HC1 (4N, 50 mL) dropwise over 20 min. The resulting mixture was stirred at 80°C for 4h, poured into ice water (400 mL) at 0°C and extracted with EtOAc (3 x 300 mL). The organic phase was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (0-20% gradient in 30 min) to afford l-(2-amino-4-chloro-6- fluorophenyl)ethan-l-one (1.3 g, 16.1%) as a yellow solid and l-(2-amino-6-chloro-4- fhrorophenyl)ethan-l-one(800 mg, crude) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+=188.2. ’HNMR (400 MHz, CDCI3) 5 6.92 - 6.38 (m, 2H), 6.35 (d, J= 2.0 Hz, 2H), 2.58 (d, J= 8.4 Hz, 3H).Step 2: Preparation of N-(2-acetyl-5-chloro-3-fluorophenyl)-7-oxabicyclo[2.2.1]heptane-l- carboxamide:WSGR Docket No. 67898-706.601

[0303] To a stirred solution of l-(2-amino-4-chloro-6-fluorophenyl)ethan-l-one (500 mg, 2.67 mmol, 1.0 equiv.) and 7-oxabicyclo[2.2.1]heptane-l-carboxylic acid (417 mg, 2.93 mmol, 1.1 equiv.) in MeCN (15 mb) were added TCFH (1.5 g, 5.35 mmol, 2.0 equiv.) and 1 -methyl- IH-imidazole (1.09 g, 13.33 mmol, 5.0 equiv.) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight and diluted with EtOAc (150 mb). The organic layer was washed with 3x50 mb of water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (0-20% gradient in 30 min) to afford N-(2-acetyl-5-chloro-3-fluorophenyl)-7- oxabicyclo[2.2.1] heptane -1 -carboxamide (500 mg, 56.8%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+=312.1. 'HNMR (400 MHz, DMSO-6) 5 11.36 (s, 1H), 8.33 - 8.30 (m, 1H), 7.38 (dd, J= 11.4, 2.1 Hz, 1H), 4.75 (t, J= 5.0 Hz, 1H), 2.57 (d, J= 6.8 Hz, 3H), 1.95 - 1.88 (m, 2H), 1.82 - 1.76 (m, 2H), 1.74 - 1.69 (m, 2H), 1.67 - 1.61 (m, 2H).Step 3: Preparation of 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-7-chloro-5-fluoroquinolin-4-ol:

[0304] To a stirred solution of N-(2-acetyl-5-chloro-3-fluorophenyl)-7-oxabicyclo[2.2.1]heptane-l- carboxamide (500 mg, 1.40 mmol, 1.0 equiv.) and NaOH (168 mg, 4.21 mmol, 3.0 equiv.) in dioxane (15 mL) was stirred at 80°C for 3h under nitrogen atmosphere. The resulting mixture was diluted with EtOAc (100 mL). The organic layer was washed with water (3 x 40 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Q2 / MeOH (0-10% gradient in 20 min) to afford 2-(7- oxabicyclo[2.2.1]heptan-l-yl)-7-chloro-5-fluoroquinolin-4-ol (260 mg, 38.3%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+= 294.0. ’HNMR (400 MHz, DMSO-6) 5 11.47 (s, 1H), 7.73 (t, J= 1.6 Hz, 1H), 7.17 (dd, J= 11.5, 2.0 Hz, 1H), 6.02 (s, 1H), 4.77 (t, J= 5.1 Hz, 1H), 2.12 - 2.05 (m, 2H), 1.90 - 1.82 (m, 2H), 1.72 (ddt, J= 14.1, 9.6, 4.6 Hz, 4H).Step 4: Preparation of 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-4,7-dichloro-5-fluoroquinoline:

[0305] To a stirred solution of 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-7-chloro-5-fluoroquinolin-4-ol (250 mg, 0.85 mmol, 1.0 equiv.) in toluene (6 mL) were added phosphoryl trichloride (261 mg, 1.70 mmol, 2.0 equiv.) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100°C for 2h, cooled to room temperature, poured into ice water (100 mL), and basified to pH 8 with saturated Na2COs (aq.). The resulting mixture was extracted with EtOAc (3 x 50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (0- 30% gradient in 30 min) to afford 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-4,7-dichloro-5-fluoroquinoline (260 mg, 68.5%) as a brown solid. LC-MS: (ES+H, m / z): [M+H]+= 312.0. ’HNMR (400 MHz, DMSO- d6) 5 8.00 (t, J= 1.7 Hz, 1H), 7.80 (s, 1H), 7.75 (dd, J= 12.0, 2.1 Hz, 1H), 4.77 (t, J= 5.0 Hz, 1H), 2.16 - 2.09 (m, 2H), 1.90 - 1.82 (m, 2H), 1.82 - 1.76 (m, 2H), 1.75 - 1.69 (m, 2H).Step 5: Preparation of 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-7-chloro-5-fluoroquinoline:

[0306] To a stirred solution of 4,7-dichloro-5-fluoro-2-{7-oxabicyclo[2.2.1]heptan-l-yl}quinoline (140 mg, 0.45 mmol, 1.0 equiv.) and Pd(dppf)Ch CH2Q2 (35 mg, 0.04 mmol, 0.1 equiv.) in THF (6 mL)WSGR Docket No. 67898-706.601 were added N,N,N',N'-Tetramethylethylenediamine (105 mg, 0.89 mmol, 2.0 equiv.) and NaBH (25 mg, 0.67 mmol, 1.5 equiv.) in portions at 0°C. The resulting mixture was stirred at room temperature for Ih, quenched with ice water (100 mL) and extracted with EtOAc (3 x 40 mL). The organic layer was dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (0-30% gradient in 30 min) to afford 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-7-chloro-5-fluoroquinoline (100 mg, 56.2%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+= 278.1.1HNMR (400 MHz, DMSO-6) 5 8.50 (dd, J= 8.8, 0.8 Hz, IH), 7.94 (dd, J= 2.0, 1.1 Hz, IH), 7.80 (d, J= 8.7 Hz, IH), 7.66 (dd,J= 9.8, 1.9 Hz, IH), 4.77 (t, J = 5.0 Hz, IH), 2.17 - 2.10 (m, 2H), 1.90 - 1.82 (m, 2H), 1.81 - 1.75 (m, 2H), 1.72 (dd, J= 10.9, 7.3 Hz, 2H).Step 6: Preparation of 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-5-fluoro-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoline:

[0307] To a stirred solution of 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-7-chloro-5-fluoroquinoline (40 mg, 0.16 mmol, 1.0 equiv.) and EEPim (58 mg, 0.27 mmol, 1.3 equiv.) in dioxane (3 mL) were added Pd2(dba)s (15 mg, 0.02 mmol, 0.1 equiv.), XPhos (15 mg, 0.03 mmol, 0.2 equiv.), and AcOK (52 mg, 0.54 mmol, 3.0 equiv.) in portions at room temperature, The resulting mixture was stirred at 80°C for 2h under nitrogen atmosphere. The crude product was used in the next step directly without further purification.LC-MS: (ES+H, m / z): [M+H]+= 370.2.Intermediate 46Step 1: Preparation of 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-7-chloroquinoline-4-d:

[0308] To a stirred mixture of 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-4,7-dichloroquinoline (50 mg, 0.17 mmol, 1.00 equiv.) and Pd(dppf)C12 CH2CI2 (7 mg, 0.01 mmol, 0.05 equiv.) in THF (2 mL) was added N,N,N',N'-Tetramethylethylenediamine (40 mg, 0.34 mmol, 2.00 equiv.) and sodium tetrahydroborate -d4 (14 mg, 0.34 mmol, 2.00 equiv.) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2h, quenched with D2O at 0°C and diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3 x lOmL). The combined organic layers were concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 5: 1) to afford 2-(7- oxabicyclo[2.2.1]heptan-l-yl)-7-chloroquinoline-4-d (25 mg, 56.4%, 94% deuterium purity) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+=294.0. 'H NMR (400 MHz, DMSO-6) 5 8.07 - 8.01 (m, 2H), 7.72 (s, IH), 7.63 (dd, J= 8.8, 2.1 Hz, IH), 4.75 (t, J= 5.0 Hz, IH), 2.13 (td, J= 10.0, 3.6 Hz, 2H), 1.92 - 1.67 (m, 6H).WSGR Docket No. 67898-706.601Step 2: Preparation of 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoline-4-d:

[0309] To a stirred mixture of 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-7-chloroquinoline-4-d (20 mg, 0.08 mmol, 1.00 equiv.) and 4,4,5,5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (29 mg, 0.12 mmol, 1.50 equiv.) in dioxane (1 mL) were added AcOK (23 mg, 0.23 mmol, 3.00 equiv.), XPhos (7 mg, 0.02 mmol, 0.20 equiv.) and Pd2(dba)s (7 mg, 0.01 mmol, 0.10 equiv.). The resulting mixture was stirred at 100°C for Ih under nitrogen atmosphere. The resulting mixture was used in the next step directly without further purification. LC-MS: (ES+H, m / z): [M+H]+=353.1.Intermediate 47Step 1: Preparation of 4-chloro-N-methoxy-N-methyl-2-oxabicyclo[2.1.1]hexane-l-carboxamide:

[0310] A mixture of 4-chloro-2-oxabicyclo[2.1.1]hexane-l-carboxylic acid (500 mg, 3.07 mmol, 1.00 equiv.), propanephosphonic acid cyclic anhydride(50% in ethyl acetate) (1.96 g, 6.15 mmol, 2.00 equiv.) and EtsN (933 mg, 9.22 mmol, 3.00 equiv.) in THF (5 mL) was stirred at room temperature for 30 min. To the above mixture was added N,O-dimethylhydroxylamine hydrochloride (449 mg, 4.61 mmol, 1.50 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 2 h, diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CfLCL / McOH (50: 1) to afford 4-chloro-N-methoxy-N-methyl-2-oxabicyclo[2.1.1]hexane-l- carboxamide (350 mg, 55.3%) as a brown liquid. LC-MS: (ES+H, m / z): [M+H]+=205.85. 'H NMR (400 MHz, DMSO-d6) 5 3.80 (s, 2H), 3.68 (s, 3H), 3.15 (s, 3H), 2.40 (dd, J= 4.5, 1.8 Hz, 2H), 2.21 (dd, J = 4.5, 1.8 Hz, 2H).Step 2: Preparation of l-{4-chloro-2-oxabicyclo[2.1.1]hexan-l-yl}ethanone:

[0311] To a stirred mixture of 4-chloro-N-methoxy-N-methyl-2-oxabicyclo[2.1.1]hexane-l- carboxamide (330 mg, 1.60 mmol, 1.00 equiv.) in THF (8 mL) was added MeMgBr (3 mol / L) (1.0 mL, 3.21 mmol, 2.00 equiv.) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 2 h, quenched by the addition of sat. NH4CI (aq.) (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford l-{4-chloro-2-WSGR Docket No. 67898-706.601 oxabicyclo[2.1.1]hexan-l-yl}ethanone (180 mg, crude) as a brown oil. 'HNMR (400 MHz, DMSO-t / e) 5 3.84 (s, 2H), 2.47 (dd, J= 4.3, 1.7 Hz, 2H), 2.22 (s, 3H), 2.16 (dd, J= 4.3, 1.7 Hz, 2H).Step 3: Preparation of 7-bromo-2-{4-chloro-2-oxabicyclo[2.1.1]hexan-l-yl}quinoline:

[0312] A mixture of l-{4-chloro-2-oxabicyclo[2.1.1]hexan-l-yl}ethanone (180 mg, 1.12 mmol, 1.00 equiv.), 2-amino-4-bromobenzaldehyde (224 mg, 1.12 mmol, 1.00 equiv.) and NaOH (44 mg, 1.12 mmol, 1.00 equiv.) in EtOH (3 m ) was stirred at 80 °C for 2 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / EtOAc (9: 1) to afford 7- bromo-2-{4-chloro-2-oxabicyclo[2.1.1]hexan-l-yl}quinoline (130 mg, 35.7%) as a light yellow solid. LC-MS: (ES+H, m / z): [M+H]+=325.80 'HNMR (400 MHz, DMSO-6) 5 8.48 (d, 1H), 8.22 (d, J= 2.0 Hz, 1H), 8.00 (d, J= 8.7 Hz, 1H), 7.78 (dd, J= 8.7, 2.0 Hz, 1H), 7.71 (d, J= 8.5 Hz, 1H), 3.99 (s, 2H), 2.66 (dd, J= 4.4, 1.8 Hz, 2H), 2.40 (dd, J= 4.4, 1.7 Hz, 2H).Step 4: Preparation of 2-{4-chloro-2-oxabicyclo[2.1.1]hexan-l-yl}-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoline:

[0313] A mixture of 7-bromo-2-{4-chloro-2-oxabicyclo[2.1.1]hexan-l-yl}quinoline (50 mg, 0.15 mmol, 1.00 equiv.), PimEE (58 mg, 0.23 mmol, 1.50 equiv.), Pd2(dba)s (14 mg, 0.01 mmol, 0.10 equiv.), XPhos (14 mg, 0.03 mmol, 0.20 equiv.) and AcOK (30 mg, 0.30 mmol, 2.00 equiv.) in 1,4-dioxane (1 mb) was stirred at 100 °C for 1 h under nitrogen atmosphere. The resulting mixture was used in the next step directly without further purification. LC-MS: (ES+H, m / z): [M+H]+=372.00.Intermediate 48Step 1: Preparation of 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-7-chloro-5-fluoro-4-methoxyquinoline:

[0314] To a stirred solution of 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-4,7-dichloro-5-fluoroquinoline (200 mg, 0.64 mmol, 1.0 equiv.) in methanol (8 mb) were added sodium methoxide(30% in methanol) (1.15 g, 6.38 mmol, 10 equiv., 30%) dropwise at 25°C under nitrogen atmosphere. The resulting mixture was stirred at 50°C for 6h, cooled to room temperature and diluted with EtOAc (100 mb). The organic layer was washed with 2 x 20 mb of water and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (0% to 40% gradient in 30 min) to afford 2-(7- oxabicyclo[2.2.1]heptan-l-yl)-7-chloro-5-fluoro-4-methoxyquinoline (150 mg, 53.2%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+= 308.1 ’HNMR (400 MHz, DMSO-6) 57.79 (t, J= 1.6 Hz, 1H), 7.47 (dd, J= 11.8, 2.1 Hz, 1H), 7.17 (s, 1H), 4.75 (t, J= 5.0 Hz, 1H), 4.03 (s, 3H), 2.15 - 2.08 (m, 2H), 1.89 - 1.82 (m, 2H),1.80 - 1.74 (m, 2H), 1.73 - 1.69 (m, 2H).WSGR Docket No. 67898-706.601Step 2: Preparation of 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-5-fluoro-4-methoxy-7-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline:

[0315] To a stirred solution of 7-chloro-5-fluoro-4-methoxy-2-{7-oxabicyclo[2.2.1]heptan-l- yl}quinoline (40 mg, 0.16 mmol, 1.0 equiv.) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2- dioxaborolane) (53 mg, 0.21 mmol, 1.3 equiv.) in dioxane (2 mL) were added Pd2(dba)s (15 mg, 0.02 mmol, 0.1 equiv.) and XPhos (15 mg, 0.03 mmol, 0.2 equiv.), AcOK (47 mg, 0.48 mmol, 3.0 equiv.) in portions at 25°C, The resulting mixture was stirred at 80°C for 2h under nitrogen atmosphere. The crude product was used in the next step directly without further purification. LC-MS: (ES+H, m / z): [M+H]+= 400.2.Intermediate 49Step 1: Preparation of N-(2-acetyl-5-bromophenyl)-7-oxabicyclo[2.2.1]heptane-l-carboxamide:

[0316] To a stirred solution of l-(2-amino-4-bromophenyl)ethanone (500 mg, 2.33 mmol, 1.00 equiv.) and 7-oxabicyclo[2.2.1]heptane-l-carboxylic acid (332 mg, 2.33 mmol, 1 equiv.) in MeCN (15 mL) were added TCFH (1310 mg, 4.67 mmol, 2.00 equiv.) and 1 -methyl- IH-imidazole (956 mg, 11.68 mmol, 5.00 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (5: 1) to afford N-(2-acetyl- 5-bromophenyl)-7-oxabicyclo[2.2.1]heptane-l-carboxamide (600 mg, 75.9%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+=337.95. ’H NMR (400 MHz, DMSO-6) 5 12.07 (s, 1H), 8.92 (d, J= 2.0 Hz, 1H), 8.03 (d, J= 8.6 Hz, 1H), 7.45 (dd, J= 8.6, 2.1 Hz, 1H), 4.76 (t, J= 5.0 Hz, 1H), 2.63 (s, 3H), 2.00 - 1.88 (m, 2H), 1.86 - 1.52 (m, 6H).Step 2: Preparation of 7-bromo-2-{7-oxabicyclo[2.2.1]heptan-l-yl}quinolin-4-ol:

[0317] A solution of N-(2-acetyl-5-bromophenyl)-7-oxabicyclo[2.2.1]heptane-l-carboxamide (500 mg, 1.48 mmol, 1.00 equiv.) and NaOH (118 mg, 2.96 mmol, 2.00 equiv.) in 1,4-dioxane (8 mL) was stirred at 110 °C for 2 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and diluted with water (20 mL). The aqueous layer was extracted with EtOAc (3 x 30 mL). The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with QLCL / MeOH (10: 1) to afford 7-bromo-2-{7- oxabicyclo[2.2.1]heptan-l-yl}quinolin-4-ol (300 mg, 63.3%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+=320.10. ’H NMR (400 MHz, DMSO-6) 5 11.42 (s, 1H), 8.06 (d, J= 1.9 Hz, 1H), 7.97 (d, J =WSGR Docket No. 67898-706.6018.6 Hz, 1H), 7.45 (dd, J= 8.6, 1.9 Hz, 1H), 6.09 (d, J= 1.7 Hz, 1H), 4.78 (t, J= 5.1 Hz, 1H), 2.17 - 2.05 (m, 2H), 1.97 - 1.81 (m, 2H), 1.80 - 1.62 (m, 4H).Step 3: Preparation of 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-7-bromo-4-chloroquinoline:

[0318] To a stirred solution of 7-bromo-2-{ 7-oxabicyclo [2.2.1 ]heptan-l-yl}quinolin-4-ol (100 mg, 0.31 mmol, 1.00 equiv.) was added phosphoryl trichloride (5 mL) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 4 h, cooled to room temperature and quenched by the addition of sodium hyposulfite (aq.) (30 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (1 x 20 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure to afford 2-(7- oxabicyclo[2.2.1]heptan-l-yl)-7-bromo-4-chloroquinoline (100 mg, crude) as a yellow oil. LC-MS: (ES+H, m / z): [M+H]+=337.85. 'HNMR (400 MHz, DMSO-tL) 5 8.29 (d, J= 2.0 Hz, 1H), 8.13 (d, J = 8.9 Hz, 1H), 7.89 (dd, J= 8.9, 2.0 Hz, 1H), 7.84 (s, 1H), 4.76 (t, J= 5.0 Hz, 1H), 2.17 - 2.06 (m, 2H), 1.87 - 1.69(m, 6H).Step 4: Preparation of 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-4-chloro-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoline:

[0319] To a stirred mixture of 4,4,5,5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2- dioxaborolane (30 mg, 0.12 mmol, 0.80 equiv.) and 7-bromo-4-chloro-2-{7-oxabicyclo[2.2.1]heptan-l- yl}quinoline (50 mg, 0.15 mmol, 1.00 equiv.) in 1,4-dioxane (5 mL) was added PC , (8 mg, 0.03 mmol, 0.20 equiv.), AcOK (36 mg, 0.37 mmol, 2.50 equiv.) at room temperature. To the above mixture was added Pd(dppf)C12 (11 mg, 0.02 mmol, 0.10 equiv.) at room temperature. The resulting mixture was stirred at 80 °C for 3 h under nitrogen atmosphere. The resulting mixture was used in the next step directly without further purification. LC-MS: (ES+H, m / z): [M+H]+=386.30.Intermediate 50Step 1: Preparation of N-methoxy-N,3-dimethyl-2-oxabicyclo[2.1.1]hexane-l-carboxamide:

[0320] A solution of 3-methyl-2-oxabicyclo[2.1.1]hexane-l-carboxylic acid (400 mg, 2.81 mmol, 1.00 equiv.) and EtsN (1.42 g, 14.07 mmol, 5.00 equiv.) in DMF (10 mL) was treated with HATU (1.93 g, 5.07 mmol, 1.80 equiv.) at 25°C for 10 min under nitrogen atmosphere followed by the addition of methoxy(methyl)aminehydrochloride (412 mg, 4.22 mmol, 1.50 equiv.) in portions at 25°C. The resulting mixture was stirred at 25 °C for 1 h, diluted with H2O (100 mL) and extracted with EtOAc (3 x 60 mL). The combined organic layers were washed with brine (3 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purifiedWSGR Docket No. 67898-706.601 by silica gel column chromatography, eluted with EtOAc in petroleum ether (0% to 30% gradient in 20 min) to afford N-methoxy-N,3-dimethyl-2-oxabicyclo[2.1.1]hexane-l-carboxamide (500 mg, 95.9%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+=186.10. 'HNMR (400 MHz, CDC13) 54.29 - 4.17 (m, 1H), 3.75 (s, 3H), 3.24 (s, 3H), 2.62 (t, J= 3.1 Hz, 1H), 2.16 (dd, J= 6.3, 3.3 Hz, 1H), 1.98 (t, J= 4.5 Hz, 1H), 1.89 (t, J = 5.4 Hz, 2H), 1.29 (d, J = 6.2 Hz, 3H).Step 2: Preparation of (ls,3s)-3-[4-amino-3-(l-oxo-2-phenylisoquinolin-7-yl)pyrazolo[4,3-c]pyridin- l-yl]cyclobutane-l-carbaldehyde:

[0321] To a stirred solution ofN-methoxy-N,3-dimethyl-2-oxabicyclo[2.1.1]hexane-l-carboxamide (500 mg, 2.699 mmol, 1.00 equiv.) in THF (10 mL) was added methylmagnesium bromide(3 M in 2- MeTHF, 1.00 mL, 3.00 mmol, 1.10 equiv.) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C for an additional 2 h. The reaction was quenched by the addition of NH4CI aq. (10 mL) at 0°C. The resulting mixture was diluted with H2O (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford l-{3-methyl-2- oxabicyclo[2.1.1]hexan-l-yl}ethanone (260 mg, 68.7%) as a colorless oil.Step 3: Preparation of 7-bromo-2-{3-methyl-2-oxabicyclo[2.1.1]hexan-l-yl}quinoline:

[0322] A mixture of l-{3-methyl-2-oxabicyclo[2.1.1]hexan-l-yl}ethanone (200 mg, 1.43 mmol, 1.00 equiv.), 2-amino-4-bromobenzaldehyde (285 mg, 1.43 mmol, 1.00 equiv.) and NaOH (57 mg, 1.43 mmol, 1.00 equiv.) in EtOH (5 mL) was stirred at 80°C for 2 h. The resulting mixture was diluted with H2O (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2x50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc in petroleum ether (0% to 10% gradient in 20 min) to afford 7-bromo-2-{3-methyl-2- oxabicyclo[2.1.1]hexan-l-yl}quinoline (140 mg, 32.3%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+=304.00. 'H NMR (400 MHz, DMSO-6) 5 8.41 (d, J= 8.5 Hz, 1H), 8.21 (d, J= 2.0 Hz, 1H), 7.97 (d, J= 8.7 Hz, 1H), 7.75 (dd, J= 8.7, 2.0 Hz, 1H), 7.69 (d, J= 8.5 Hz, 1H), 4.37 - 4.25 (m, 1H), 2.77 (t, J = 3.1 Hz, 1H), 2.38 - 2.30 (m, 1H), 2.24 - 2.14 (m, 1H), 1.97 - 1.80 (m, 2H), 1.29 (d, J= 6.2 Hz, 3H).Step 4: Preparation of 2-{3-methyl-2-oxabicyclo[2.1.1]hexan-l-yl}-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoline:

[0323] A mixture of 7-bromo-2-{ 3 -methyl -2 -oxabicyclo [2.1. l]hexan-l-yl} quinoline (120 mg, 0.39 mmol, 1.00 equiv.), PimEL (110 mg, 0.43 mmol, 1.10 equiv.), AcOK (116 mg, 1.18 mmol, 3.00 equiv.), XPhos (38 mg, 0.08 mmol, 0.20 equiv.) and Pd2(dba)s (36 mg, 0.04 mmol, 0.10 equiv.) in 1,4-dioxane (5 mL) was stirred at 80°C for 3 h under nitrogen atmosphere. The resulting mixture was used in the next step directly without further purification. LC-MS: (ES+H, m / z): [M+H]+=352.15.Intermediate 51WSGR Docket No. 67898-706.601Step 1: Preparation of 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-7-bromo-4-(difluoromethoxy)quinoline:

[0324] A solution of 7-bromo-2-{7-oxabicyclo[2.2.1]heptan-l-yl}quinolin-4-ol (150 mg, 0.47 mmol, 1.00 equiv.) and K2CO3 (129 mg, 0.94 mmol, 2.00 equiv.) in bromodifluoromethane(10% in DMF) (5 mL) was stirred at room temperature for 2 h under nitrogen atmosphere. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (7: 1) to afford 7-bromo-4-(difluoromethoxy)-2-{7- oxabicyclo[2.2.1]heptan-l-yl}quinoline (100 mg, 57.6%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+=369.95.1H NMR (400 MHz, DMSO-tL) 5 8.24 (d, J= 1.9 Hz, 1H), 8.05 (d, J= 8.9 Hz, 1H), 7.96 - 7.55 (m, 2H), 7.41 (s, 1H), 4.77 (t, J= 5.0 Hz, 1H), 2.20 - 2.05 (m, 2H), 1.98 - 1.63 (m, 6H).Step 2: Preparation of 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-4-(difluoromethoxy)-7-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline:

[0325] To a stirred solution of 7-bromo-4-(difluoromethoxy)-2-{7-oxabicyclo[2.2.1]heptan-l- yl}quinoline (70 mg, 0.19 mmol, 1.00 equiv.) and bis(pinacolato)diboron (57 mg, 0.22 mmol, 1.20 equiv.) in 1,4-dioxane (3 mL) were added AcOK (46 mg, 0.47 mmol, 2.50 equiv.), XPhos (9 mg, 0.02 mmol, 0.10 equiv.) and Pd2(dba)s (9 mg, 0.01 mmol, 0.05 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for2 h under nitrogen atmosphere. The crude product was used in the next step directly without further purification. LC-MS: (ES+H, m / z): [M+H]+= 417.80.Intermediate 52Step 1: Preparation of l-(6-amino-4-chloro-2,3-difluorophenyl)ethan-l-one:

[0326] To a stirred solution of 3-chloro-4,5-difluoroaniline (9.50 g, 58.09 mmol, 1.00 equiv.) in p- xylene (15 mL) was added BCE (1.0 M in CH2CI2) (75 mL, 75.51 mmol, 1.30 equiv.) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C for 2h then allowed to warm to roomWSGR Docket No. 67898-706.601 temperature. To the above mixture was added MeCN (19.08 g, 464.69 mmol, 8.00 equiv.) dropwise over 20 min at room temperature. The resulting mixture was stirred at room temperature for an additional 20 min and then treated with added -xylene (15 mL) and Aids (3.87 g, 29.04 mmol, 0.50 equiv., portion wise). The resulting mixture was stirred at room temperature for Ih and then heated to 80°C for overnight under nitrogen atmosphere. The mixture cooled to room temperature and treated with HC1 aq. (4N, 70 mL) dropwise. The resulting mixture was stirred at 80°C for 4h, cooled to room temperature, poured into water (400 mL), and extracted with EtOAc (700 mL). The organic phase was washed with brine (100 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (0%-10% gradient in 30 min) to afford l-(6-amino-4-chloro-2,3-difluorophenyl)ethan-l-one (490 mg, 4.1%) as a yellow solid and l-(6-amino-2-chloro-3,4-difluorophenyl)ethan-l-one (890 mg, 7.4%) as an off-white solid. LC-MS: (ES+H, m / z): [M+H]+= 206.1. 'HNMR (400 MHz, DMSO-tL) 5 7.24 (s, 2H), 6.77 (dd, J = 6.0, 2.3 Hz, IH), 2.53 (s, 3H).19FNMR (376 MHz, DMSO-tL) 5 -130.27, - 130.34, -158.86, -158.92.Step 2: Preparation of N-(2-acetyl-5-chloro-3,4-difluorophenyl)-7-oxabicyclo[2.2.1]heptane-l- carboxamide:

[0327] To a stirred mixture of l-(6-amino-2-chloro-3,4-difluorophenyl)ethan-l-one (440 mg, 2.14 mmol, 1.00 equiv.) and 7-oxabicyclo[2.2.1]heptane-l-carboxylic acid (304 mg, 2.14 mmol, 1.00 equiv.) in MeCN (10 mL) were added TCFH (1201 mg, 4.28 mmol, 2.00 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 0°C for 15 min then treated with 1 -methyl- 1H- imidazole (879 mg, 10.70 mmol, 5.00 equiv.) dropwise at 0°C. The resulting mixture was stirred at room temperature for 4h and diluted with EtOAc (160 mL). The organic layer was washed with 3 x 40 mL of water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (0%-20% gradient in 30 min) to afford N-(2-acetyl-5-chloro-3,4-difluorophenyl)-7- oxabicyclo[2.2.1]heptane-l-carboxamide (420 mg, 59.5%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+= 330.1. ’HNMR (400 MHz, DMSO-tL) 5 11.01 (s, IH), 8.24 (dd, J= 6.4, 2.3 Hz, IH), 4.74 (t, J = 5.0 Hz, IH), 2.59 (d, J= 6.1 Hz, 3H), 1.94 - 1.86 (m, 2H), 1.83 - 1.74 (m, 2H), 1.73 - 1.67 (m,2H), 1.66 - 1.58 (m, 2H)19FNMR (376 MHz, DMSO-tL) 5 -130.97, -131.03, -144.29, -144.35.Step 3: Preparation of 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-7-chloro-5,6-difluoroquinolin-4-ol:

[0328] To a stirred solution of N-(2-acetyl-5-chloro-3,4-difluorophenyl)-7-oxabicyclo[2.2.1]heptane- 1-carboxamide (360 mg, 1.09 mmol, 1.00 equiv.) in dioxane (8 mL) was added NaOH (87 mg, 2.18 mmol, 2.00 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100°C for 4h, cooled to room temperature and diluted with EtOAc (130 mL). The organic layer was washed with 3 x 30 mL of water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (0%-50% gradient in 30 min) to afford 2-(7-oxabicyclo[2.2.1]heptan- l-yl)-7-chloro-5,6-difluoroquinolin-4-ol (215 mg, 63.1%) as a light brown solid. LC-MS: (ES+H, m / z):WSGR Docket No. 67898-706.601[M+H]+= 312.0. ’HNMR (400 MHz, DMSO-6) 5 11.53 (s, 1H), 7.87 (dd, J= 6.1, 2.0 Hz, 1H), 6.02 (s, 1H), 4.78 (t, J= 5.0 Hz, 1H), 2.13 - 2.05 (m, 2H), 1.92 - 1.81 (m, 2H), 1.78 - 1.67 (m, 4H).19FNMR (376 MHz, DMSO-d6) 5 -139.21, -139.26, -147.65, -147.71.Step 4: Preparation of 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-4,7-dichloro-5,6-difluoroquinoline:

[0329] To a stirred solution of 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-7-chloro-5,6-difluoroquinolin-4-ol (200 mg, 0.64 mmol, 1.00 equiv.) in toluene (7 mL) was added phosphoryl trichloride (197 mg, 1.28 mmol, 2.00 equiv.) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100°C for 2h, cooled to room temperature and quenched with ice water (20 mL) at 0°C. The mixture was basified to pH 8 with saturated Na2COs (aq.) (3 mL). The aqueous layer was extracted with CH2CI2 (3 x 50 mL). The organic layer was dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (0%-20% gradient in 30 min) to afford 2-(7-oxabicyclo[2.2.1]heptan- l-yl)-4,7-dichloro-5,6-difluoroquinoline (180 mg, 84.9%) as a brown solid. LC-MS: (ES+H, m / z): [M+H]+= 330.11HNMR (400 MHz, DMSO-6) 5 8.23 (dd, J = 6.8, 2.3 Hz, 1H), 7.86 (s, 1H), 4.77 (t, J = 5.0 Hz, 1H), 2.16 - 2.08 (m, 2H), 1.87 - 1.69 (m, 6H).19FNMR (376 MHz, DMSO-tL) 5 -137.01, - 137.06, -139.36, -139.41.Step 5: Preparation of 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-7-chloro-5,6-difluoroquinoline:

[0330] To a stirred mixture of 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-4,7-dichloro-5,6-difluoroquinoline (130 mg, 0.39 mmol, 1.00 equiv.) and Pd(dppf)CL (14 mg, 0.02 mmol, 0.05 equiv.) in THF (7 mL) were added N,N,N',N'-tetramethylethylenediamine (92 mg, 0.79 mmol, 2.00 equiv.) and NaBFL (24 mg, 0.63 mmol, 1.60 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for Ih and quenched by the addition of saturated Na2COs (aq.) (4 mL) at 0°C. The resulting mixture was diluted with EtOAc (100 mL). The organic layer was washed with 3 x 30 mL of water and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (Petroleum ether / EtOAc 10: 1) to afford 2-(7- oxabicyclo[2.2.1]heptan-l-yl)-7-chloro-5,6-difluoroquinoline (60 mg, 51.5%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+= 296.1. 'HNMR (400 MHz, DMSO-tL) 5 8.55 (d, J= 8.8 Hz, IH), 8.16 (dd, J = 6.4, 2.1 Hz, IH), 7.85 (d, J = 8.8 Hz, IH), 4.77 (t, J= 5.0 Hz, IH), 2.17 - 2.10 (m, 2H), 1.90 - 1.82 (m, 2H), 1.82 -1.70 (m, 4H)19FNMR (376 MHz, DMSO-tL) 5 -142.25, -142.30, -144.69, -144.74.Step 6: Preparation of 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-5,6-difluoro-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoline:

[0331] To a stirred mixture of 2-(7-oxabicyclo[2.2.1]heptan-l-yl)-7-chloro-5,6-difluoroquinoline (40 mg, 0.14 mmol, 1.00 equiv.) and bis(pinacolato)diboron (52 mg, 0.20 mmol, 1.50 equiv.) in Dioxane (3 mL) were added Pd2(dba)s (12 mg, 0.01 mmol, 0.10 equiv.), XPhos (13 mg, 0.03 mmol, 0.20 equiv.) and AcOK (40 mg, 0.41 mmol, 3.00 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C for 3h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was used in the next step directly without further purification. LC-MS: (ES+H, m / z): [M+H]+= 388.1.WSGR Docket No. 67898-706.601Intermediate 53Step 1: Preparation of 4-(difluoromethyl)-N-methoxy-N-methyl-2-oxabicyclo[2.1.1]hexane-l- carboxamide:

[0332] To a stirred solution of 4-(difluoromethyl)-2-oxabicyclo[2.1.1]hexane-l-carboxylic acid (400 mg, 2.25 mmol, 1.00 equiv.) and EtsN (2.27 g, 22.45 mmol, 10.00 equiv.) in THF (5 mL) was added propanephosphonic acid cyclic anhydride (2.86 g, 4.49 mmol, 2.00 equiv., 50% in ethyl acetate) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was warmed 25°C for Ih, then treated with methoxy(methyl)amine hydrochloride (0.66 g, 6.74 mmol, 3.00 equiv.) in portions. The resulting mixture was stirred at 25 °C for 16 h, diluted with water (30 mL) and extracted with CH2CI2 (3 x 150 mL). The combined organic layers were washed with brine (2 x 30 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure to get a residue. The residue was purified by silica gel column chromatography, eluted with CH2Q2 / MeOH (30: 1) to afford 4- (difluoromethyl)-N-methoxy-N-methyl-2-oxabicyclo[2.1.1]hexane-l-carboxamide (400 mg, 80.5%) as a light yellow oil. LC-MS: (ES+H, m / z): [M+H]+=222.1. ’H NMR (400 MHz, CDCI3) 5 6.05 (t, J= 55.8 Hz, IH), 3.91 (s, 2H), 3.76 (s, 3H), 3.24 (s, 3H), 2.27 - 2.18 (m, 2H), 2.06 - 1.97 (m, 2H).Step 2: Preparation of l-(4-(difluoromethyl)-2-oxabicyclo[2.1.1]hexan-l-yl)ethan-l-one:

[0333] To a stirred solution of 4-(difluoromethyl)-N-methoxy-N-methyl-2-oxabicyclo[2.1.1]hexane-l- carboxamide (300 mg, 1.36 mmol, 1.00 equiv.) in THF (3 mL) was added MeMgBr (0.7 mL, 2.03 mmol, 1.50 equiv., 3M in THF) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was warmed to 25°C for 2 h, quenched with sat. NH4CI (aq.) (40 mL) at 0°C and extracted with CH2Q2 (3 x 100 mL). The combined organic layers were washed with brine (2 x 30 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure to afford l-(4-(difluoromethyl)-2- oxabicyclo[2.1.1]hexan-l-yl)ethan-l-one (150 mg, crude) as a yellow solid. ’H NMR (400 MHz, CDCI3) 5 6.03 (t, J = 55.8 Hz, IH), 3.94 (s, 2H), 2.30 (s, 3H), 2.25 (dd, J= 4.6, 1.7 Hz, 2H), 1.92 (dd, J= 4.7, 1.8 Hz, 2H).Step 3: Preparation of 7-bromo-2-(4-(difluoromethyl)-2-oxabicyclo[2.1.1]hexan-l-yl)quinoline:

[0334] A solution of l-(4-(difluoromethyl)-2-oxabicyclo[2.1.1]hexan-l-yl)ethan-l-one (150 mg, 0.85 mmol, 1.00 equiv.), 2-amino-4-bromobenzaldehyde (341 mg, 1.70 mmol, 2.00 equiv.) and NaOH (34 mg, 0.85 mmol, 1 .00 equiv.) in dioxane (4 mL) was stirred at 80°C for 1 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (50 mL) and extracted with CH2CI2 (3 x 100 mL). The combined organic layers were washed withWSGR Docket No. 67898-706.601 brine (2 x 30 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure to get a residue. The residue was purified by silica gel column chromatography, eluted with PE / EA (10: 1) to afford 7-bromo-2-(4-(difluoromethyl)-2-oxabicyclo[2.1.1]hexan-l-yl)quinoline (100 mg, 34.5%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+=340.1. ’H NMR (400 MHz, CDC13) 5 8.35 (s, 1H), 8.17 (d, J= 8.5 Hz, 1H), 7.73 - 7.66 (m, 2H), 7.63 (dd, J= 8.7, 1.9 Hz, 1H), 6.15 (t, J = 55.9 Hz, 1H), 4.08 (s, 2H), 2.63 - 2.54 (m, 2H), 2.11 (dd, J= 4.7, 1.8 Hz, 2H).Step 4: Preparation of 2-(4-(difluoromethyl)-2-oxabicyclo[2.1.1]hexan-l-yl)-7-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)quinoline:

[0335] To a stirred solution of 7-bromo-2-(4-(difluoromethyl)-2-oxabicyclo[2.1.1]hexan-l- yl)quinoline (60 mg, 0.18 mmol, 1.00 equiv.) and PimEE (67 mg, 0.27 mmol, 1.50 equiv.) in dioxane (2 mL) were added Pd(dppf)C12CH2C12 (14 mg, 0.02 mmol, 0.10 equiv.) and AcOK (52 mg, 0.53 mmol, 3.00 equiv.) in portions at 25°C under nitrogen atmosphere. The resulting mixture was stirred at 100°C for 3 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered and the filter cake was washed with CH2Q2 (2 x 30 mL). The filtrate was concentrated under reduced pressure to afford 2-(4-(difluoromethyl)-2-oxabicyclo[2.1. l]hexan-l-yl)-7- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (60 mg, crude) as a brown solid. LC-MS: (ES+H, m / z): [M+H]+=388.0.Intermediates 54 and 55Step 1: Preparation of ((Is, 3s)-3-aminocyclobutyl)m ethanol hydrochloride salt:

[0336] To a stirred solution of tert-butyl ((ls,3s)-3-(hydroxymethyl)cyclobutyl)carbamate (9.00 g, 44.72 mmol, 1.00 equiv.) in CH2Q2 (100 mL) was added HC1 in 1,4-dioxane (4.0 M) (72 mL) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3h then concentrated under reduced pressure to afford ((ls,3s)-3-aminocyclobutyl)methanol hydrochloride salt (8.06 g, crude) as an off-white solid. LC-MS: (ES+H, m / z): [M+H]+= 102.1.Step 2: Preparation of ((ls,3s)-3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclobutyl)methanol:WSGR Docket No. 67898-706.601

[0337] To a stirred mixture of 2-(4,6-dichloropyrimidin-5-yl)acetaldehyde (4.50 g, 23.56 mmol, 1.00 equiv.) and ((ls,3s)-3-aminocyclobutyl)methanol hydrochloride salt (4.86 g, 35.34 mmol, 1.50 equiv.) in EtOH (70 mL) were added DIEA (12.18 g, 94.24 mmol, 4.00 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C for 6h, cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in EtOAc (300 mL), washed with 3 x 50 mL of water, and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Q2 / MeOH (0%-10% gradient in 30 min) to afford ((ls,3s)-3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)cyclobutyl)methanol (3.00 g, 53.6%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+=238.0.'HNMR (400 MHz, DMSO-6) 5 8.63 (s, 1H), 7.95 (d, J= 3.6 Hz, 1H), 6.68 (d, J= 3.3 Hz, 1H), 5.22 - 5.08 (m, 1H), 4.63 (t, J= 5.3 Hz, 1H), 3.52 (d, J= 9.5 Hz, 2H), 2.59 - 2.52 (m, 2H), 2.35 - 2.29 (m, 3H).Step 3: Preparation of ((ls,3s)-3-(5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)cyclobutyl)methanol:

[0338] To a stirred solution of ((ls,3s)-3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)cyclobutyl)methanol (2.80 g, 11.78 mmol, 1.00 equiv.) in DMF (45 mL) was added NBS (2.31 g, 12.96 mmol, 1.10 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for Ih and diluted with EtOAc (600 mL). The organic layer was washed with 3 x 300 mL of water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / MeOH (0% -10% gradient in 30 min) to afford ((ls,3s)-3-(5-bromo-4-chloro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)cyclobutyl)methanol (3.02 g, 80.4%) as a grey solid. LC-MS: (ES+H, m / z): [M+H]+= 316.0.1HNMR (400 MHz, DMSO-6) 5 8.66 (s, IH), 8.24 (s, IH), 5.22 - 5.09 (m, IH), 4.62 (t, J= 5.1 Hz, IH), 3.50 (d, J= 4.8 Hz, 2H), 2.49 - 2.44 (m, 2H), 2.31 - 2.24 (m, 3H).Step 4: Preparation of ((ls,3s)-3-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7- yl)cyclobutyl)methanol:

[0339] To a stirred solution of ((ls,3s)-3-(5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)cyclobutyl)methanol (3.00 g, 9.48 mmol, 1.00 equiv.) in dioxane (40 mL) was added NH3.H2O (40 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100°C for overnight, cooled to room temperature and concentrated under reduced pressure to afford ((ls,3s)-3-(4- amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclobutyl)methanol (2.8 g, crude) as a brown oil. LC- MS: (ES+H, m / z): [M+H]+= 297.1. 'HNMR (400 MHz, DMSO-6) 5 8.08 (s, IH), 7.63 (s, IH), 6.70 (s, 2H), 5.08 - 4.94 (m, IH), 4.63 (s, IH), 3.47 (d, J= 4.6 Hz, 2H), 2.44 - 2.38 (m, 2H), 2.23 - 2.16 (m, 3H).Step 5: Preparation of 5-bromo-7-((ls,3s)-3-(iodomethyl)cyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine:

[0340] To a stirred mixture of [(ls,3s)-3-{4-amino-5-bromopyrrolo[2,3-d]pyrimidin-7- yl}cyclobutyl]methanol (700 mg, 2.35 mmol, 1.00 equiv.), imidazole (240 mg, 3.53 mmol, 1.50 equiv.) and PPhs (926 mg, 3.53 mmol, 1.50 equiv.) in CH2Q2 (35 mL) were added iodine (896 mg, 3.53 mmol,WSGR Docket No. 67898-706.6011.50 equiv.) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight and quenched with sat. Na2S20s (aq.) at room temperature. The resulting mixture was extracted with CH2Q2 (200 mL). The organic layer was washed with 2x30 mL of water, brine (l x 30 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / EtOAc (0%-50%) to afford 5-bromo-7-((ls,3s)-3-(iodomethyl)cyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-amine (450 mg, crude) as a brown solid. LC-MS: (ES+H, m / z): [M+H]+= 406.90 'H NMR (400 MHz, DMSO-d6) 5 8.10 (s, 1H), 7.78 (s, 1H), 6.90 - 6.50 (bro, 2H), 5.03 - 4.99 (m, 1H), 3.50 (d, J= 7.2 Hz, 2H), 2.56 (d, J= 3.1 Hz, 1H), 2.51 -2.41 (m, 2H), 2.14 - 2.08 (m, 2H).Step 6: Preparation of 5-bromo-7-((ls,3s)-3-((dimethylamino)methyl)cyclobutyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine:

[0341] To a stirred solution of 5-bromo-7-[(ls,3s)-3-(iodomethyl)cyclobutyl]pyrrolo[2,3-d]pyrimidin- 4-amine (450 mg, crude) and dimethylamine hydrochloride salt (901 mg, 11.06 mmol, 10 equiv.) in MeCN (20 mL) were added K2CO3 (1527 mg, 11.06 mmol, 10 e...

Claims

1. WSGR Docket No. 67898-706.601CLAIMSWHAT IS CLAIMED IS:

1. A compound of Formula (I) or (II), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof:X1is N or CRX1;RX1is hydrogen, deuterium, halogen, -CN, -ORa, -SF5, -SRa, -NRcRd, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci- Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl;X2is N or CRX2;RX2is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -SF5, -SRa, -NRcRd, Ci-Cealkyl, Ci- Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl;U is N or C;T is N or C; provided that U and T are not both N;V is N or C;Y is N or CRY;RYis hydrogen, deuterium, halogen, -CN, -ORa, -SF5, -SRa, -NRcRd, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci- Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, or cycloalkyl;W is N or C;L1is absent or -[C(R’)2]q-; q is 1, 2, or 3; each R1is independently hydrogen, deuterium, halogen, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, or cycloalkyl; or two R1are taken together to form a cycloalkyl or heterocycloalkyl;Ring A is cycloalkyl or heterocycloalkyl; each R2is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)NRcRd, -OC(=O)Ra, - OC(=O)ORb, -SF5, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=NRb)(=O)Ra, -S(=O)2NRcRd, -NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -NRbS(=O)2NRcRd, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-C6deuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci- Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, orWSGR Docket No. 67898-706.601 heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R2a; and / or two R2on the same atom are taken together to form an oxo; each R2ais independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)NRcRd, -OC(=O)Ra, - OC(=O)ORb, -SF5, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=NRb)(=O)Ra, -S(=O)2NRcRd, -NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -NRbS(=O)2NRcRd, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-C6deuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci- Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R; and / or two R2aon the same atom are taken together to form an oxo; m is 0, 1, 2, 3, or 4; each R3is independently deuterium, halogen, -CN, -NO2, -ORa, -SF5, -NRcRd, -C(=O)Ra, C(=O)ORb, - C(=O)NRcRd, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R; n is 0, 1, 2, or 3;R4is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)NRcRd, -OC(=O)Ra, -OC(=O)ORb, -SF5, -SRa, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, - NRbS(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6deuteroalkyl, Ci- Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R;Ring B is polycyclic cycloalkyl or polycyclic heterocycloalkyl; each R5is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)NRcRd, -OC(=O)Ra, - OC(=O)ORb, -SF5, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=NRb)(=O)Ra, -S(=O)2NRcRd, -NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -NRbS(=O)2NRcRd, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-C6deuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci- Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; and / or two R5on the same atom are taken together to form an oxo; p is 0, 1, 2, 3, 4, or 5;R6is hydrogen, deuterium, halogen, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; wherein the alkyl and heteroalkyl is independently optionally substituted with one or more R;WSGR Docket No. 67898-706.601R7is hydrogen, deuterium, halogen, -CN, -NO2, -ORa, -SF5, -NRcRd, -C(=O)Ra, C(=O)ORb, - C(=O)NRcRd, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R; each Rais independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rcand Rdare independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl independently optionally substituted with one or more R;L is absent or Ci-C3alkylene optionally substituted with one or more R; and each R is independently deuterium, halogen, -CN, -OH, -OCi-C3alkyl, -OCi-C3haloalkyl, - OC(=O)NHCi-C3alkyl, -OC(=O)N(Ci-C3alkyl)2, -SF5, -SCi-C3alkyl, -S(=O)Ci-C3alkyl, -S(=O)2Ci- C3alkyl, -S(=NH)(=O)Ci-C3alkyl, -S(=NCi-C3alkyl)(=O)Ci-C3alkyl, -S(=O)2NH2, -S(=O)2NHCI- C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, -NHC(=O)NHCi-C3alkyl, NHC(=O)N(Ci-C3alkyl)2, -NHC(=O)Ci-C3alkyl, -NHC(=O)OCi-C3alkyl, -NHS(=O)2Ci-C3alkyl, - C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, -C(=O)NHCi-C3alkyl, -C(=O)N(Ci- C3alkyl)3, Ci-C3alkyl, Ci-C3haloalkyl, Ci-C3deuteroalkyl, Ci-C3hydroxyalkyl, Ci-C3aminoalkyl, Ci- C3heteroalkyl, C3-Cecycloalkyl, or heterocycloalkyl; and / or two R on the same atom are taken together to form an oxo.

2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:U is C and T is C.

3. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:U is N and T is C.

4. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:U is C and T is N.WSGR Docket No. 67898-706.6015. The compound of any one of claims 1 -4, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:V is N.

6. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:V is C.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:W is N.

8. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:W is C.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:Y is CRY.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:RYis hydrogen.

11. The compound of any one of claims 1 -8, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:Y is N.

12. A compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof:X1is N or CRX1;RX1is hydrogen, deuterium, halogen, -CN, -ORa, -SF5, -SRa, -NRcRd, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl;X2is N or CRX2;WSGR Docket No. 67898-706.601RX2is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -SF5, -SRa, -NRcRd, Ci-Cealkyl, Ci- Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl;L1is absent or -[(CR1)^-; q is 1, 2, or 3; each R1is independently hydrogen, deuterium, halogen, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, or cycloalkyl; or two R1are taken together to form a cycloalkyl or heterocycloalkyl;Ring A is cycloalkyl or heterocycloalkyl; each R2is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)NRcRd, -OC(=O)Ra, - OC(=O)ORb, -SF5, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=NRb)(=O)Ra, -S(=O)2NRcRd, -NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -NRbS(=O)2NRcRd, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-C6deuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci- Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R2a; and / or two R2on the same atom are taken together to form an oxo; each R2ais independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)NRcRd, -OC(=O)Ra, - OC(=O)ORb, -SF5, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=NRb)(=O)Ra, -S(=O)2NRcRd, -NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -NRbS(=O)2NRcRd, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-C6deuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci- Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R; and / or two R2aon the same atom are taken together to form an oxo; m is 0, 1, 2, 3, or 4; each R3is independently deuterium, halogen, -CN, -NO2, -ORa, -SF5, -NRcRd, -C(=O)Ra, C(=O)ORb, - C(=O)NRcRd, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R; n is 0, 1, 2, or 3;R4is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)NRcRd, -OC(=O)Ra, -OC(=O)ORb, -SF5, -SRa, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, - NRbS(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6deuteroalkyl, Ci- Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R;WSGR Docket No. 67898-706.601Ring B is polycyclic cycloalkyl or polycyclic heterocycloalkyl; each R5is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)NRcRd, -OC(=O)Ra, - OC(=O)ORb, -SF5, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=NRb)(=O)Ra, -S(=O)2NRcRd, -NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -NRbS(=O)2NRcRd, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-C6deuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci- Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; and / or two R5on the same atom are taken together to form an oxo; p is 0, 1, 2, 3, 4, or 5;R6is hydrogen, deuterium, halogen, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; wherein the alkyl and heteroalkyl is independently optionally substituted with one or more R;R7is hydrogen, deuterium, halogen, -CN, -NO2, -ORa, -SF5, -NRcRd, -C(=O)Ra, C(=O)ORb, - C(=O)NRcRd, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R; each Rais independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rcand Rdare independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl independently optionally substituted with one or more R;L is absent or Ci-C3alkylene optionally substituted with one or more R; and each R is independently deuterium, halogen, -CN, -OH, -OCi-C3alkyl, -OCi-C3haloalkyl, - OC(=O)NHCi-C3alkyl, -OC(=O)N(Ci-C3alkyl)2, -SF5, -SCi-C3alkyl, -S(=O)Ci-C3alkyl, -S(=O)2Ci- C3alkyl, -S(=NH)(=O)Ci-C3alkyl, -S(=NCi-C3alkyl)(=O)Ci-C3alkyl, -S(=O)2NH2, -S(=O)2NHCI- C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, -NHC(=O)NHCi-C3alkyl, NHC(=O)N(Ci-C3alkyl)2, -NHC(=O)Ci-C3alkyl, -NHC(=O)OCi-C3alkyl, -NHS(=O)2Ci-C3alkyl, -WSGR Docket No. 67898-706.601C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, -C(=O)NHCi-C3alkyl, -C(=O)N(Ci- C3alkyl)2, Ci-C3alkyl, Ci-C3haloalkyl, Ci-C3deuteroalkyl, Ci-C3hydroxyalkyl, Ci-C3aminoalkyl, Ci- C3heteroalkyl, C3-Cecycloalkyl, or heterocycloalkyl; and / or two R on the same atom are taken together to form an oxo.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:X1is CRX1.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:RX1is hydrogen.

15. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:X1is N.

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:X2is CRX2.

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:RX2is hydrogen or -OH.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:RX2is hydrogen.

19. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:RX2is -OH.

20. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:X2is N.

21. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:WSGR Docket No. 67898-706.601l. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

23. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:WSGR Docket No. 67898-706.60124. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

25. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

26. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

27. The compound of claim 12, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

28. The compound of claim 12, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:WSGR Docket No. 67898-706.60129. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:L1is absent.

30. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:L1is -[C(R1)2]q-.

31. The compound of any one of claims 1 -28 or 30, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: q is 1.

32. The compound of any one of claims 1-28 or 30, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: q is 2.

33. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:Ring A is cycloalkyl.

34. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: each R2is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci- Cehaloalkyl, or Ci-Cehydroxyalkyl; wherein each alkyl is independently optionally substituted with one or more R2a.

35. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: each R2is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci- Cedeuteroalkyl, or Ci-Cehaloalkyl.

36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: each R2is independently -OH or Ci-Cealkyl.

37. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: each R2ais independently deuterium, halogen, -NRcRd, Ci-Cealkyl, or heterocycloalkyl; wherein each alkyl and heterocycloalkyl is independently optionally substituted with one or more R.

38. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:WSGR Docket No. 67898-706.601 each R2ais independently -NRcRd, or heterocycloalkyl independently optionally substituted with one or more R.

39. The compound of any one of claims 1-38, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: m is 0, 1, or 2.

40. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: m is 1 or 2.

41. The compound of any one of claims 1 -40, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: m is 2.

42. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

43. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:WSGR Docket No. 67898-706.60144. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: each R3is independently deuterium, halogen, -CN, -ORa, -NRcRd, -C(=O)NRcRd, Ci-Cealkyl, Ci- Cedeuteroalkyl, or Ci-Cehaloalkyl.

45. The compound of any one of claims 1 -44, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: each R3is independently deuterium, halogen, or Ci-Cealkyl.

46. The compound of any one of claims 1-45, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: each R3is independently halogen or Ci-Cealkyl.

47. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: each R3is independently halogen.

48. The compound of any one of claims 1-47, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: n is 0, 1, or 2.

49. The compound of any one of claims 1-48, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: n is 0 or 1.

50. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:R7is hydrogen, deuterium, halogen, -CN, -ORa, -NRcRd, -C(=O)NRcRd, Ci-Cealkyl, Ci- Cedeuteroalkyl, or Ci-Cehaloalkyl.

51. The compound of any one of claims 1 -43 or 50, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:R7is hydrogen, deuterium, or halogen.

52. The compound of any one of claims 1-43 or 50 or 51, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:R7is hydrogen or halogen.

53. The compound of any one of claims 1-43 or 50-52, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:WSGR Docket No. 67898-706.601R7is halogen.

54. The compound of any one of claims 1-42 or 49-53, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:R7is hydrogen.

55. The compound of any one of claims 1-54, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:R4is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cedeuteroalkyl, or Ci-Cehaloalkyl.

56. The compound of any one of claims 1-55, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:R4is hydrogen, deuterium, halogen, -ORa, or Ci-Cealkyl.

57. The compound of any one of claims 1-56, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:R4is -ORa.

58. The compound of any one of claims 1-57, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:R4is hydrogen.

59. The compound of any one of claims 1-58, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:R6is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cedeuteroalkyl, or Ci-Cehaloalkyl.

60. The compound of any one of claims 1-59, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:R6is hydrogen or Ci-Cealkyl.

61. The compound of any one of claims 1-60, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:R6is hydrogen.

62. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:WSGR Docket No. 67898-706.60163. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

64. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:Ring B is polycyclic cycloalkyl.

65. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:Ring B is bicyclic cycloalkyl.

66. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:Ring B is polycyclic heterocycloalkyl.

67. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:Ring B is bicyclic heterocycloalkyl.

68. The compound of any one of claims 1 -67, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: each R5is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci- Cedeuteroalkyl, or Ci-Cehaloalkyl.

69. The compound of any one of claims 1-68, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: each R5is independently deuterium, halogen, -CN, Ci-Cealkyl, or Ci-Cehaloalkyl.WSGR Docket No. 67898-706.60170. The compound of any one of claims 1 -69, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: each R5is independently halogen, Ci-Cealkyl, or Ci-Cehaloalkyl.

71. The compound of any one of claims 1-70, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: each R5is independently halogen.

72. The compound of any one of claims 1-71, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: p is 0, 1, or 2.

73. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: p is 0 or 1.

74. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

75. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

76. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:WSGR Docket No. 67898-706.60177. The compound of any one of claims 1-76, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, selected from a compound found in table 1 and in the specification.

78. A pharmaceutical composition comprising a compound of any one of claims 1-76, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

79. A method of inhibiting IGF-1R activity in a subject in need thereof, comprising administering to the subject in need thereof a compound of any one of claims 1-76, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

80. A method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject in need thereof a compound of any one of claims 1-76, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

81. The method of claim 80, wherein the disease or disorder is thyroid eye disease (TED).

82. The method of claim 80, wherein the disease or disorder is AMD (Age-related MacularDegeneration).

83. The method of claim 80, wherein the disease or disorder is Idiopathic orbital inflammation (IOI).

84. The method of claim 80, wherein the disease or disorder is an inflammatory disease.

85. The method of claim 80, wherein the disease or disorder is cancer.

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