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. 67898-707.601INSULIN GROWTH FACTOR- 1 RECEPTOR (IGF-1R) INHIBITORS AND METHODS OFUSES THEREOFCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 700,988 filed September 30, 2024; which is hereby incorporated by reference in its 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 (IGFBP 1 -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, Curr Med 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-1R 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. 67898-707.601

[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 a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof:Formula (I) as defined herein.

[0007] Also disclosed herein is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof:Formula (II) as defined herein.

[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).

[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.WSGR Docket No. 67898-707.601

[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- 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 appearsWSGR Docket No. 67898-707.601 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-Cw 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 with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments,WSGR Docket No. 67898-707.601 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 three to fifteen carbon atoms (e.g., C3-C15 fully saturated cycloalkyl or C3-C15 cycloalkenyl), from three to tenWSGR Docket No. 67898-707.601 carbon atoms (e.g., C3-C10 fully saturated cycloalkyl or C3-C10 cycloalkenyl), from three to eight carbon atoms (e.g., C3-C8 fully saturated cycloalkyl or C3-C8 cycloalkenyl), from three to six carbon atoms (e.g., C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl), from three to five carbon atoms (e.g., C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyl), or three to four carbon atoms (e.g., C3-C4 fully saturated cycloalkyl or C3-C4 cycloalkenyl). 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, for example, adamantyl, norbomyl, decalinyl, bicyclo [3.3.0] octyl, bicyclo[4.3.0]nonyl, cis-decalinyl, trans-decalinyl, bicyclo [2. l.l]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, and bicyclo[3.3.2]decyl, bicyclo [1.1. l]pentyl, bicyclo[3.1.0]hexyl, bicyclo [3. l.l]heptyl, 7,7-dimethyl- bicyclo[2.2.1]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.

[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.WSGR Docket No. 67898-707.601

[0036] “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.

[0037] “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 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 some 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. 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 nitrogenWSGR Docket No. 67898-707.601 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 fully saturated heterocycloalkyl or C2-C15 heterocycloalkenyl), from two to ten carbon atoms (e.g., C2-C10 fully saturated heterocycloalkyl or C2-C10 heterocycloalkenyl), from two to eight carbon atoms (e.g., C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), from two to seven carbon atoms (e.g., C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to six carbon atoms (e.g., C2-C6 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to five carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloalkenyl), or two to four carbon atoms (e.g., C2-C4 fully saturated heterocycloalkyl or C2-C4 heterocycloalkenyl). 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-l-yl, 3-oxo-l,3- dihydroisobenzofuran-l-yl, methyl-2-oxo-l,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 a 3- 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, -CF3, -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.WSGR Docket No. 67898-707.601

[0038] “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 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 3 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- IH-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 withWSGR Docket No. 67898-707.601 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 an oxo to form an N-oxide.

[0039] 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 ).

[0040] The term “each alkyl is independently optionally substituted with one or more R” means that any alkyl moiety is independently optionally substituted with one or more R. For example, fthe alkyl moiety in a deuteroalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, or heteroalkyl is independently optionally substituted with one or more R.

[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.

[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.WSGR Docket No. 67898-707.601Compounds

[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 a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof:wherein:X1is -N- or -CR1-;R1is 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 -CR2-;R2is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -SF5, -SRa, -NRcRd, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl;Ring A is a bicyclic heteroaryl; provided that Ring A is not phthalazin- l(2H)-one or isoquinolin- 1(2H)- one; each R3is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -O(C=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(=0)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; n is 0, 1, 2, 3, or 4;Ring B is monocyclic cycloalkyl, monocyclic heterocycloalkyl, aryl, or heteroaryl; each R4is 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;WSGR Docket No. 67898-707.601 wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R; and / or two R4on the same atom are taken together to form an oxo; m is 0, 1, 2, 3, or 4;W is absent or -[C(R5)2]q-; q is 1, 2, or 3; each R5is independently hydrogen, deuterium, halogen, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, or cycloalkyl; or two R5are taken together to form a cycloalkyl or heterocycloalkyl;Ring C is cycloalkyl or heterocycloalkyl; each R6is 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 R6a; and / or two R6on the same atom are taken together to form an oxo; each R6ais 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-C6haloalkyl, Ci-C6hydroxyalkyl, 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 R6aon the same atom are taken together to form an oxo; p is 0, 1, 2, 3, or 4; each Rais independently Ci-Cealkyl, Ci-Cedeuteroalkyl, 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; each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cedeuteroalkyl, 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; each Rcand Rdare independently hydrogen, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl,WSGR Docket No. 67898-707.601 heterocycloalkyl, aryl, or 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 optionally substituted with one or more R; and each R is independently deuterium, halogen, -CN, -OH, -OCi-C3alkyl, -OCi-C3haloalkyl, -0(C=0)NH2, - O(C=O)NHCi-C3alkyl, -O(C=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-C3deuteroalkyl, Ci-C3haloalkyl, 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), X1is -CR1-. In some embodiments of a compound of Formula (I), X1is -N-.

[0049] In some embodiments of a compound of Formula (I), X2is -CR2-. In some embodiments of a compound of Formula (I), X2is -N-.

[0050] In some embodiments of a compound of Formulasome embodiments of a compound of Formulaembodiments of a compound of Formula

[0051] In some embodiments of a compound of Formula (I), R1is hydrogen, deuterium, halogen, Ci- Cealkyl, Ci-Cedeuteroalkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (I), R1is hydrogen, deuterium, halogen, Ci-Cealkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (I), R1is hydrogen, deuterium, or Ci-Cealkyl. In some embodiments of a compound of Formula (I), R1is hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (I), R1is hydrogen.

[0052] In some embodiments of a compound of Formula (I), R2is hydrogen, deuterium, halogen, -OH, Ci-Cealkyl, Ci-Cedeuteroalkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (I),WSGR Docket No. 67898-707.601R2is hydrogen, deuterium, halogen, -OH, or Ci-Cealkyl. In some embodiments of a compound of Formula (I), R2is hydrogen, deuterium, -OH, or Ci-Cealkyl. In some embodiments of a compound of Formula (I), R2is hydrogen, -OH, or Ci-Cealkyl. In some embodiments of a compound of Formula (I), R2is hydrogen or -OH. In some embodiments of a compound of Formula (I), R2is hydrogen. In some embodiments of a compound of Formula (I), R2is -OH.

[0053] In some embodiments of a compound of Formula

[0054] Also disclosed herein is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof:wherein:U is N or C;T is N or C; provided that U and T are not both N;Y1is N or C;Y2is N or CR7;R7is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -SF5, -SRa, -NRcRd, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, or cycloalkyl;Y3is N or C;Ring A is a bicyclic heteroaryl; provided that Ring A is not phthalazin- l(2H)-one or isoquinolin- 1(2H)- one; each R3is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -O(C=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-C6haloalkyl, 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; n is 0, 1, 2, 3, or 4;Ring B is monocyclic cycloalkyl, monocyclic heterocycloalkyl, aryl, or heteroaryl;WSGR Docket No. 67898-707.601 each R4is 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-C6alkyl, Ci-C6deuteroalkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, 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 R4on the same atom are taken together to form an oxo; m is 0, 1, 2, 3, or 4;W is absent or -[C(R5)2]q-; q is 1, 2, or 3; each R5is independently hydrogen, deuterium, halogen, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, or cycloalkyl; or two R5are taken together to form a cycloalkyl or heterocycloalkyl;Ring C is cycloalkyl or heterocycloalkyl; each R6is 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-C6haloalkyl, Ci-C6hydroxyalkyl, 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 R6a; and / or two R6on the same atom are taken together to form an oxo; each R6ais 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 R6aon the same atom are taken together to form an oxo; p is 0, 1, 2, 3, or 4; each Rais independently Ci-Cealkyl, Ci-Cedeuteroalkyl, 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; each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl,WSGR Docket No. 67898-707.601 or 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-Cedeuteroalkyl, 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; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently deuterium, halogen, -CN, -OH, -OCi-C3alkyl, -OCi-C3haloalkyl, -0(C=0)NH2, - O(C=O)NHCi-C3alkyl, -O(C=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-C3deuteroalkyl, Ci-C3haloalkyl, 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;

[0055] In some embodiments of a compound of Formula (II), U is N and T is C. In some embodiments of a compound of Formula (II), U is C and T is N. In some embodiments of a compound of Formula (II), U is C and T is C.

[0056] In some embodiments of a compound of Formula (II), Y1is N. In some embodiments of a compound of Formula (II), Y1is C.

[0057] In some embodiments of a compound of Formula (II), Y2is CR7. In some embodiments of a compound of Formula (II), Y2is N.

[0058] In some embodiments of a compound of Formula (II), Y3is N. In some embodiments of a compound of Formula (II), Y3is C.WSGR Docket No. 67898-707.601

[0059] In some embodiments of a compound of Formulaembodiments of a compound of Formulaof a compound of Formula

[0060] In some embodiments of a compound of Formula (II), R7is hydrogen, deuterium, halogen, Ci- Cealkyl, Ci-Cedeuteroalkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (II), R7is hydrogen, deuterium, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (II), R7is hydrogen, deuterium, or Ci-Cealkyl. In some embodiments of a compound of Formula (II), R7is hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (II), R7is hydrogen.

[0061] In some embodiments of a compound of Formula (I) or (II), Ring A is a bicyclic heteroaryl comprising two 6-membered rings.

[0062] In some embodiments of a compound of Formula (I) or (II), Ring A is a bicyclic heteroaryl comprising two 5 -membered rings.

[0063] In some embodiments of a compound of Formula (I) or (II), Ring A is a bicyclic heteroaryl comprising one 6-membered ring and 5 -membered ring.

[0064] In some embodiments of a compound of Formula (I) or (II), Ring A is a quinolinyl, thienopyridinyl, thiazolopyridinyl, or benzothiazolyl. In some embodiments of a compound of Formula (I) or (II), Ring A is a quinolinyl.

[0065] In some embodiments of a compound of Formula (I) or (II), each R3is independently deuterium, halogen, -CN, -OH, -ORa, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-WSGR Docket No. 67898-707.601Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, or cycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, and cycloalkyl, is independently optionally substituted with one or more R.

[0066] In some embodiments of a compound of Formula (I) or (II), each R3is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cedeuteroalkyl, or Ci-Cehaloalkyl.

[0067] In some embodiments of a compound of Formula (I) or (II), each R3is independently deuterium, halogen, -CN, -OH, -ORa, or -NRcRd.

[0068] In some embodiments of a compound of Formula (I) or (II), each R3is independently halogen or -ORa.

[0069] In some embodiments of a compound of Formula (I) or (II), n is 0, 1, 2, or 3. In some embodiments of a compound of Formula (I) or (II), n is 0, 1, or 2. In some embodiments of a compound of Formula (I) or (II), n is 0 or 1. In some embodiments of a compound of Formula (I) or (II), n is 1 or 2. In some embodiments of a compound of Formula (I) or (II), n is 1, 2, or 3. In some embodiments of a compound of Formula (I) or (II), n is 2 or 3. In some embodiments of a compound of Formula (I) or (II), n is 2, 3, or 4. In some embodiments of a compound of Formula (I) or (II), n is 3 or 4. In some embodiments of a compound of Formula (I) or (II), n is 1. In some embodiments of a compound of Formula (I) or (II), n is 2.

[0071] In some embodiments of a compound of Formula (I) or (II), Ring B is aryl or heteroaryl.

[0072] In some embodiments of a compound of Formula (I) or (II), Ring B is phenyl.

[0073] In some embodiments of a compound of Formula (I) or (II), Ring B is 5- to 6-membered heteroaryl. In some embodiments of a compound of Formula (I) or (II), Ring B is 6-memberedWSGR Docket No. 67898-707.601 heteroaryl. In some embodiments of a compound of Formula (I) or (II), Ring B is pyridinyl. In some embodiments of a compound of Formula (I) or (II), Ring B is 5-membered heteroaryl. In some embodiments of a compound of Formula (I) or (II), Ring B is thiophenyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, or triazolyl.

[0074] In some embodiments of a compound of Formula (I) or (II), Ring B is monocyclic cycloalkyl or monocyclic heterocycloalkyl. In some embodiments of a compound of Formula (I) or (II), Ring B is monocyclic Cs-Cs cycloalkyl. In some embodiments of a compound of Formula (I) or (II), Ring B is monocyclic Cs-Ce cycloalkyl. In some embodiments of a compound of Formula (I) or (II), Ring B is cyclobutyl, cyclopentyl, or cyclohexyl.

[0075] In some embodiments of a compound of Formula (I) or (II), Ring B is monocyclic 4- to 8- membered heterocycloalkyl. In some embodiments of a compound of Formula (I) or (II), Ring B is monocyclic 4- to 8-membered heterocycloalkyl comprising one or two heteroatoms selected from O, S, and N. In some embodiments of a compound of Formula (I) or (II), Ring B is monocyclic 4- to 6- membered heterocycloalkyl. In some embodiments of a compound of Formula (I) or (II), Ring B is monocyclic 4- to 6-membered heterocycloalkyl comprising one or two heteroatoms selected from O, S, and N. In some embodiments of a compound of Formula (I) or (II), Ring B is monocyclic 4- to 5- membered heterocycloalkyl. In some embodiments of a compound of Formula (I) or (II), Ring B is monocyclic 4- to 5-membered heterocycloalkyl comprising one or two heteroatoms selected from O, S, and N.

[0076] In some embodiments of a compound of Formula (I) or (II), each R4is independently deuterium, halogen, -CN, -OH, -ORa, -SF5, -NRcRd, Ci-Cealkyl, Ci-Cedeuteroalkyl, 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.

[0077] In some embodiments of a compound of Formula (I) or (II), each R4is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cedeuteroalkyl, or Ci-Cehaloalkyl.

[0078] In some embodiments of a compound of Formula (I) or (II), each R4is independently halogen, - OH, Ci-Cealkyl, or Ci-Cehaloalkyl.

[0079] In some embodiments of a compound of Formula (I) or (II), each R4is independently halogen or Ci-Cealkyl.

[0080] In some embodiments of a compound of Formula (I) or (II), m is 0, 1, 2, or 3. In some embodiments of a compound of Formula (I) or (II), m is 1, 2, or 3. In some embodiments of a compound of Formula (I) or (II), m is 2 or 3. In some embodiments of a compound of Formula (I) or (II), m is 0, 1, or 2. In some embodiments of a compound of Formula (I) or (II), m is 0 or 1. In some embodiments of a compound of Formula (I) or (II), m is 1 or 2. In some embodiments of a compound of Formula (I) or (II), m is 0. In some embodiments of a compound of Formula (I) or (II), m is 1. In some embodiments of a compound of Formula (I) or (II), m is 2.WSGR Docket No. 67898-707.601

[0082] In some embodiments of a compound of Formula (I) or (II), Ring C is cycloalkyl.

[0083] In some embodiments of a compound of Formula (I) or (II), Ring C is Cs-Cecycloalkyl.

[0084] In some embodiments of a compound of Formula (I) or (II), Ring C is cyclobutyl or cyclopentyl.

[0085] In some embodiments of a compound of Formula (I) or (II), Ring C is cyclobutyl.

[0086] In some embodiments of a compound of Formula (I) or (II), each R6is 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) or (II), each R6is 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) or (II), each R6is independently deuterium, halogen, -OH, Ci-Cealkyl, Ci-Cedeuteroalkyl, or Ci- Cehaloalkyl. In some embodiments of a compound of Formula (I) or (II), each R6is independently deuterium, halogen, -OH, or Ci-Cealkyl. In some embodiments of a compound of Formula (I) or (II), each R6is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cedeuteroalkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (I) or (II), each R6is independently - OH or Ci-Cealkyl. In some embodiments of a compound of Formula (I) or (II), each R6is independently - OH, -ORa, or Ci-Cealkyl. In some embodiments of a compound of Formula (I) or (II), each R6is independently -ORaor Ci-Cealkyl.

[0087] In some embodiments of a compound of Formula (I) or (II), each R6ais independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cedeuteroalkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (I) or (II), each R6ais independently deuterium, halogen, -CN, - OH, -ORa, -NRcRd, or Ci-C6alkyl.

[0088] In some embodiments of a compound of Formula (I) or (II), p is 0, 1, or 2. In some embodiments of a compound of Formula (I) or (II), p is 1 or 2. In some embodiments of a compound of Formula (I) or (II), p is 2 or 3. In some embodiments of a compound of Formula (I) or (II), p is 0. In some embodimentsWSGR Docket No. 67898-707.601 of a compound of Formula (I) or (II), p is 1. In some embodiments of a compound of Formula (I) or (II), p is 2. In some embodiments of a compound of Formula (I) or (II), p is 3.

[0089] In some embodiments of a compound of Formula (I) or (II), W is absent. In some embodiments of a compound of Formula (I) or (II), W is -[C(R1)2]q-. In some embodiments of a compound of Formula(I) or (II), W is -CH2-. In some embodiments of a compound of Formula (I) or (II), W is -CH2CH2-. In some embodiments of a compound of Formula (I) or (II), W is -CH2CH2CH2-.

[0090] In some embodiments of a compound of Formula (I) or (II), q is 1 or 2. In some embodiments of a compound of Formula (I) or (II), q is 2 or 3. In some embodiments of a compound of Formula (I) or(II), q is 1. In some embodiments of a compound of Formula (I) or (II), q is 2. In some embodiments of a compound of Formula (I) or (II), q is 3.

[0091] In some embodiments of a compound of Formula (I) or (II), each R5is independently hydrogen, deuterium, or Ci-Cealkyl. In some embodiments of a compound of Formula (I) or (II), each R5is independently hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (I) or (II), each R5is independently hydrogen. In some embodiments of a compound of Formula (I) or (II), two R5are taken together to form a cycloalkyl or heterocycloalkyl.

[0092] In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl, Ci- Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or 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 Rais independently Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl. In some embodiments of a compound disclosed herein, each Rais independently 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 disclosed herein, each Rais independently Ci-Cealkyl, Ci-Cedeuteroalkyl, or Ci-Cehaloalkyl. 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.

[0093] In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or 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-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, 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 disclosed herein, each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cedeuteroalkyl, or Ci-Cehaloalkyl. 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 or Ci-Cealkyl. In some embodiments of a compoundWSGR Docket No. 67898-707.601 disclosed herein, each Rbis independently hydrogen or Ci-Cehaloalkyl. In some embodiments of a compound disclosed herein, each Rbis hydrogen. In some embodiments of a compound disclosed herein, each Rbis independently Ci-Cealkyl. In some embodiments of a compound disclosed herein, each Rbis independently Ci-Cehaloalkyl.

[0094] In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or 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-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, 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 disclosed herein, each Rcand Rdare independently hydrogen, Ci-Cealkyl, Ci-Cedeuteroalkyl, or Ci-Cehaloalkyl. 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 or Ci-Cealkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen or Ci-Cehaloalkyl. 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. In some embodiments of a compound disclosed herein, each Rcand Rdare independently Ci-Cehaloalkyl.

[0095] In some embodiments of a compound disclosed herein, Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R.

[0096] In some embodiments of a compound disclosed herein, each R is independently deuterium, halogen, -CN, -OH, -OCi-C3alkyl, -OCi-C3haloalkyl, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, -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-C3deuteroalkyl, Ci-C3haloalkyl, Ci-C3hydroxyalkyl, Ci-C3aminoalkyl, Ci-C3heteroalkyl, or C3-Cecycloalkyl; 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 deuterium, halogen, -CN, -OH, - OCi-C3alkyl, -OCi-C3haloalkyl, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, Ci-C3alkyl, Ci-C3deuteroalkyl, Ci-C3haloalkyl, Ci-C3hydroxyalkyl, Ci-C3aminoalkyl, Ci-C3heteroalkyl, or C3-Cecycloalkyl; 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 deuterium, halogen, -CN, -OH, -OCi-C3alkyl, -OCi-C3haloalkyl, -NH2, Ci-C3alkyl, Ci-C3deuteroalkyl, 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 deuterium, halogen, -OH, -NH2, Ci-C3alkyl, Ci-C3deuteroalkyl, 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 isWSGR Docket No. 67898-707.601 independently deuterium, halogen, or Ci-Csalkyl; and / or two R on the same atom are taken together to form an oxo.

[0097] 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.

[0098] 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. 67898-707.601

[0099] In some embodiments the compound disclosed herein is selected from the group consisting of:WSGR Docket No. 67898-707.601WSGR Docket No. 67898-707.601a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0100] In some embodiments the compound disclosed herein is selected from the group consisting of:WSGR Docket No. 67898-707.601WSGR Docket No. 67898-707.601WSGR Docket No. 67898-707.601WSGR Docket No. 67898-707.601WSGR Docket No. 67898-707.601or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0101] In some embodiments the compound disclosed herein is selected from the group consisting of:WSGR Docket No. 67898-707.601or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0102] In some embodiments the compound disclosed herein is selected from the group consisting of:thereof.WSGR Docket No. 67898-707.601Further Forms of Compounds Disclosed HereinIsomers / Stereoisomers

[0103] 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 some 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

[0104] 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 fortheir 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 exampleWSGR Docket No. 67898-707.601 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 -CH3in a compound disclosed herein has been replaced by a -CD3.

[0105] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.Pharmaceutically acceptable salts

[0106] 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.

[0107] 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.

[0108] 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, benzene sulfonate, 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-napthalene sulfonate, 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 xylene sulfonate.

[0109] 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, lacticWSGR Docket No. 67898-707.601 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-naphthalenesulfonic acid, 4-methylbicyclo- [2.2.2]oct-2-ene-l-carboxylic acid, glucoheptonic acid, 4,4 ’-methylenebis-(3-hydroxy-2-ene-l -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.

[0110] 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, 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 alky 1)4 hydroxide, and the like.

[0111] 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

[0112] 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.

[0113] 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.WSGR Docket No. 67898-707.601Tautomers

[0114] 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):Method of Treatment

[0115] 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.

[0116] 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.

[0117] In some embodiments, the disease or disorder is thyroid eye disease (TED).

[0118] In some embodiments, the disease or disorder is AMD (Age-related Macular Degeneration).

[0119] In some embodiments, the disease or disorder is Idiopathic orbital inflammation (IOI).

[0120] In some embodiments, the disease or disorder is an inflammatory disease.

[0121] In some embodiments, the disease or disorder is cancer.Dosing

[0122] 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.WSGR Docket No. 67898-707.601Routes of Administration

[0123] 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.

[0124] 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.Pharmaceutical Compositions / Formulations

[0125] 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.

[0126] 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 & Wilkins 1999), herein incorporated by reference for such disclosure.Combination

[0127] 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.WSGR Docket No. 67898-707.601

[0128] 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

[0129] 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.

[0130] 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 by 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 1Step 1: Preparation of 6-chloro-N,N-bis[(4-methoxyphenyl)methyl]-5-nitropyrimidin-4-amine:

[0131] To a stirred solution of 4,6-dichloro-5-nitropyrimidine (25.00 g, 128.88 mmol, 1.00 equiv.) in MeCN (200 mb) 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 mixtureWSGR Docket No. 67898-707.601 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:

[0132] 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- 1-methylcyclobutan-l-ol hydrochloride (6.52 g, 48.21 mmol, 1.00 equiv.) in MeCN (200 mb) 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]- 1-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, CDCh) 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:

[0133] To a stirred mixture of ammonium chloride (37.14 g, 694.42 mmol, 16.65 equiv.), water (100 mb), Zinc (21.51 g, 329.06 mmol, 7.89 equiv.) and EtOH (200 mb), was added (ls,3r)-3-[(6-{bis[(4- methoxyphenyl)methyl] amino} -5 -nitropyrimidin-4-yl)amino]- 1-methylcyclobutan-l-ol (20.00 g, 41.70 mmol, 1.00 equiv.) in THF (200 mb) dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for Ih. The reaction was monitored by LCMS. The resulting mixture was fdtered and the filter cake was washed with EtOAc (3x100 mb). The combined filtrate was concentrated under reduced pressure, diluted with water (400 mb), and extracted with EtOAc (3 x 400 mb). The combined organic layers were washed with brine (1 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. ’H NMR (300 MHz, CDCI3) 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:

[0134] 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 CH2Q2 (240 mL) was addedWSGR Docket No. 67898-707.601 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 monitored by TLC (PE / EA=1 : 1, Rf=0.5). 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 x300 mb) and the combined organic layers were washed with brine (1x500 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. 'HNMR (400 MHz, CDCh) 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:

[0135] 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 CH2CI2 (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 (Column: 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) 59.48 (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). Intermediate 2-

[0136] To a stirred mixture of 2-phenyl-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) quinoline (1.00 g, 3.01 mmol, 1.00 equiv.) in THF (16 mL) and H2O (4 mL) were added NalCE (1.94 g, 9.05 mmol, 3.00 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 4h under nitrogen atmosphere. The mixture was acidified to pH 4 with 2M HC1 (aq.). and extracted with 3x50 mL of EtOAc. The organic layer was concentrated under reduced pressure and purified by trituration with methyl tert-butyl ether (30 mL). This resulted in 2-phenylquinolin-7- ylboronic acid (0.70 g, crude) as a white solid. LC-MS: (ES+H, m / z): [M+H]+=250.20. 'H NMR (400 MHz, DMSO-d6) 5 8.69 (d, J= 8.7 Hz, IH), 8.65 (s, IH), 8.36 - 8.27 (m, IH), 8.30 - 8.20 (m, 3H), 8.06 (t, J= 6.1 Hz, 2H), 7.63 (m, 4H).WSGR Docket No. 67898-707.601Intermediates 3 and 4Step 1: Preparation of (ls,3r)-3-(benzyloxy)-l-methylcyclobutan-l-ol:

[0137] To a stirred solution of 3-(benzyloxy)cyclobutan-l-one (3.00 g, 17.02 mmol, 1.00 equiv.) in THF (60 mL) was added chloro(methyl)magnesium (17 mL, 50.90 mmol, 3.00 equiv, 3mol / L) dropwise at -78°C under nitrogen atmosphere. The reaction mixture was stirred at 20°C for 1 h under nitrogen atmosphere. The reaction was quenched by the addition of sat. NH4CI (aq.) (50mL) at 0°C and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SC>4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ether: EtOAc 2: 1) to afford ( ls,3r)-3 -(benzyloxy)- 1- methylcyclobutan-l-ol (2.80 g, 85.55%) as a white oil. 'H NMR (400 MHz, DMSO-t / e) 5 7.38 - 7.23 (m, 5H), 4.98 (s, 1H), 4.33 (s, 2H), 3.71- 3.60 (m, 1H), 2.25 (m, 2H), 2.01 - 1.91 (m, 2H), 1.15 (s, 3H).Step 2: Preparation of triethyl[(ls,3r)-3-(benzyloxy)-l-methylcyclobutoxy] silane:

[0138] To a stirred solution of (ls,3r)-3-(benzyloxy)-l-methylcyclobutan-l-ol (2.00 g, 10.40 mmol, 1.00 equiv.) and EtsN (3.16 g, 31.21 mmol, 3.00 equiv.) in CH2CI2 (40 mL) was added chlorotriethylsilane (3.14 g, 20.81 mmol, 2.00 equiv.) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 40°C for 16 h under nitrogen atmosphere. The reaction mixture was diluted with water (50 mL) and extracted with CH2CI2 (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SC>4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (etherEtOAc 40: 1) to afford triethyl[(ls,3r)-3-(benzyloxy)-l-methylcyclobutoxy]silane (2.80 g, 87.81%) as a white oil. 'HNMR (400 MHz, DMSO-6) 5 7.39 - 7.23 (m, 5H), 4.34 (d, J= 5.1 Hz, 2H), 3.68 (m, 1H), 2.35 (m, 2H), 2.07 - 1.91 (m, 2H), 1.24 (t, J= 1.0 Hz, 3H),0.91 (t, J= 7.9 Hz, 9H), 0.54 (m, 6H).Step 3: Preparation of (lr,3s)-3-methyl-3-[(triethylsilyl)oxy]cyclobutan-l-ol:

[0139] A solution of triethyl[(ls,3r)-3-(benzyloxy)-l-methylcyclobutoxy]silane (2.50 g, 8.15 mmol, 1.00 equiv.) and Pd / C (1.25 g, 10%wt) in methanol (50 mL) was stirred at 25°C for 48 h under hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with MeOH (3 x 80 mL). The filtrate was concentrated under reduced pressure to afford (lr,3s)-3-methyl-3- [(triethylsilyl)oxy]cyclobutan-l-ol (1.40 g, crude) as a white oil. ’H NMR (400 MHz, DMSO-t / e) 5 4.98WSGR Docket No. 67898-707.601(s, 1H), 3.82 - 3.61 (m, 1H), 2.35 - 2.21 (m, 2H), 2.02 - 1.81 (m, 2H), 1.28 - 1.18 (m, 3H), 0.91 (t, J = 7.9 Hz, 9H), 0.54 (m, J= 7.9 Hz, 6H).Step 4: Preparation of (ls,3r)-3-methyl-3-[(triethylsilyl)oxy] cyclobutyl 4-nitrobenzoate:

[0140] To a stirred solution of (lr,3s)-3-methyl-3-[(triethylsilyl)oxy]cyclobutan-l-ol (5.00 g, 23.10 mmol, 1.00 equiv.) and 4-nitrobenzoic acid (4.25 g, 25.43 mmol, 1.10 equiv.) in THF (200 mL) was added PPhs (30.30 g, 115.52 mmol, 5.00 equiv.) and DIAD (22.43 g, 110.92 mmol, 4.80 equiv.) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C for Ih under nitrogen atmosphere, diluted with water and extracted with EtOAc (3 x lOOmL). The combined organic layers were washed with brine (3 xlOO mL), dried over anhydrous Na2SC>4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with PE / EtOAc (50: 1) to afford (ls,3r)-3-methyl-3-[(triethylsilyl)oxy]cyclobutyl 4-nitrobenzoate (5 g, crude) as a yellow solid. The crude product was purified by reversed-phase flash chromatography with the following conditions: column, C18 gel; mobile phase, MeCN in Water (0.1% HCOOH), 70% to 90% gradient in 20 min; detector, UV 254 nm to afford (ls,3r)-3-methyl-3-[(triethylsilyl)oxy]cyclobutyl 4-nitrobenzoate (1.00 g, 17.22%) as a white solid and (ls,3r)-3-hydroxy-3-methylcyclobutyl 4- nitrobenzoate (1.6 g, 27.56%) as a white solid.

[0141] (ls,3r)-3-methyl-3-[(triethylsilyl)oxy]cyclobutyl 4-nitrobenzoate: 'HNMR (400 MHz, DMSO- d6) 58.38 - 8.32 (m, 2H), 8.23 - 8.16 (m, 2H), 5.27 (m, IH), 2.64 - 2.53 (m, 2H), 2.34 - 2.22 (m, 2H), 1.48 (s, 3H), 0.94 (t, J= 7.9 Hz, 9H), 0.58(m, 6H).

[0142] (ls,3r)-3-hydroxy-3-methylcyclobutyl 4-nitrobenzoate: 'HNMR (300 MHz, DMSO-t / ,,) 5 8.40 - 8.31 (m, 2H), 8.25 - 8.13 (m, 2H), 5.28 (t, J= 7.4, 5.2 Hz, IH), 5.09 (s, IH), 2.52 - 2.40 (m, 2H), 2.25 - 2.13 (m, 2H), 1.36 (s, 3H)WSGR Docket No. 67898-707.601Intermediates 5 and 6Step 1: Preparation of (ls,3r)-3-methyl-3-[(triethylsilyl)oxy]cyclobutan-l-ol:

[0143] A solution of (ls,3r)-3-methyl-3-[(triethylsilyl)oxy]cyclobutyl 4-nitrobenzoate (1.00 g, 2.73 mmol, 1.00 equiv.) and LiOH.H2O (0.23 g, 5.47 mmol, 2.00 equiv.) in THF (40 mL) and H2O (10 mL) was stirred at 0°C for 4 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 were washed with saturated NaHCOs (aq.) (3 x 30 mL), dried over anhydrous Na2SO4and filtered. The filtrate was concentrated under reduced pressure to afford (ls,3r)-3-methyl-3-[(triethylsilyl)oxy]cyclobutan-l-ol (600 mg, crude) as a white oil. 'HNMR (300 MHz, DMSO-6) 5 4.87 (d, J= 4.8 Hz, 1H), 4.21 (m, J= 12, 4.9 Hz, 1H), 2.36 - 2.15 (m, 2H), 1.91 - 1.77 (m, 2H), 1.38 (s, 3H), 0.91 (t, J= 7.9 Hz, 9H), 0.67 - 0.46 (m, 6H)Step 2: Preparation of ethyl 4-cyano-2H-pyrazole-3-carboxylate:

[0144] A mixture of ethyl 4-iodo-2H-pyrazole-3-carboxylate (5.00 g, 18.79 mmol, 1.00 equiv.) and CuCN (3.37 g, 37.58 mmol, 2.00 equiv.) in DMF (80 mL) was stirred at 140°C under N2 atmosphere for 4h and then cooled. The resulting mixture was diluted with water and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (C LCL / MeOH 6 / 1) to afford ethyl 4-cyano-2H-pyrazole-3-carboxylate (2.6 g, 83.77%) as a grey solid. LC-MS: (ES-H, m / z): [M-H]- =164.0. ’H NMR (400 MHz, DMSO-6) 5 14.37 (s, 1H), 9.02 - 8.38 (m, 1H), 4.36 (q, J= 7.1 Hz, 2H), 1.33 (t, J= 7.1 Hz, 3H).WSGR Docket No. 67898-707.601Step 3: Preparation of 5-bromo-4-cyano-2H-pyrazole-3-carboxylate:

[0145] To a stirred mixture of ethyl 4-cyano-2H-pyrazole-3-carboxylate (1.00 g, 6.05 mmol, 1.00 equiv.) and NaOH aq. (6 mL 2mol / L) in 1,4-dioxane (30 mL) was added Br2(1.9 g, 11.88 mmol, 1.96 equiv.) in THF (10 mL) dropwise at 0°C. The resulting mixture was diluted with water and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SC>4, and filtered. The filtrate was concentrated under reduced pressure to afford ethyl 5- bromo-4-cyano-2H-pyrazole-3-carboxylate (1.5 g, crude) as a grey solid. LC-MS: (ES-H, m / z): [M-H]’ =241.9. 'HNMR (400 MHz, DMSO-6) 5 4.54 - 4.26 (m, 2H), 1.41 - 1.28 (m, 3H).Step 4: Preparation of ethyl 5-bromo-4-cyano-2-[(lr,3s)-3-methyl-3- [(triethylsilyl)oxy]cyclobutyl]pyrazole-3-carboxylate:

[0146] A solution of DIAD (1.32 g, 6.55 mmol, 4.00 equiv.) and PPh2(2.14 g, 8.19 mmol, 5.00 equiv.) in THF (50 mL) was stirred under N2at 0 °C. The reaction mixture was allowed to warm to room temperature for 30min, then cooled to 0 °C and treated with a THF (50 mL) solution of ethyl 5-bromo-4- cyano-2H-pyrazole -3 -carboxylate (400 mg, 1.63 mmol, 1.00 equiv.) and (ls,3r)-3-methyl-3- [(triethylsilyl)oxy]cyclobutan-l-ol (354 mg, 1.63 mmol, 1.00 equiv.). The reaction mixture was stirred under N2at 25 °C for 2 h. The residue was purified by silica gel column chromatography (9.4% EtOAc in petroleum ether) to afford ethyl 5-bromo-4-cyano-2-[(lr,3s)-3-methyl-3- [(triethylsilyl)oxy]cyclobutyl]pyrazole-3-carboxylate (480 mg, 66.19%) as a white solid. ’H NMR (400 MHz, DMSO- e) 5 5.28 - 5.16 (m, 1H), 4.42 - 4.32 (m, 2H), 2.71 - 2.62 (m, 2H), 2.62-2.51 (m, 2H), 1.40 (s, 3H), 1.40 - 1.29 (m, 3H), 0.93 (m, 9H), 0.63 - 0.53 (m, 6H).Step 5: Preparation of (4-amino-3-bromo-l-[(lr,3s)-3-methyl-3-[(triethylsilyl)oxy]cyclobutyl]-6H- pyrazolo[3,4-d]pyridazin-7-one):

[0147] To a stirred solution ethyl 5-bromo-4-cyano-2-[(lr,3s)-3-methyl-3- [(triethylsilyl)oxy]cyclobutyl]pyrazole-3-carboxylate (450 mg, 1.01 mmol, 1.00 equiv.) in EtOH (5 mL) was added hydrazine monohydrate (1 mL) at 25°C under N2atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product (4-amino-3-bromo-l-[(lr,3s)-3-methyl-3- [(triethylsilyl)oxy]cyclobutyl]-6H-pyrazolo[3,4-d]pyridazin-7-one (410 mg, crude) ) was used in the next step directly without further purification. LC-MS: (ES-H, m / z): [M-H]' =426. 1 Intermediate 7Step 1: Preparation of ethyl 5-bromo-4-cyano-2-cyclobutylpyrazole-3-carboxylate:

[0148] A solution of DIAD (1.65 g, 8.19 mmol, 4.00 equiv.) and PPh2(2.69g, 10.24 mmol, 5.00 equiv.) in THF (50 mL) was stirred at 0°C under N2atmosphere. The reaction mixture was warmed toWSGR Docket No. 67898-707.60125°C for 0.5h, cooled to 0°C and treated with a THF (50 mL) solution of ethyl 5-bromo-4-cyano-2H- pyrazole -3 -carboxylate (500 mg, 2.04 mmol, 1.00 equiv.) and cyclobutanol (147 mg, 2.04 mmol, 1.00 equiv.). The reaction mixture was stirred at 25°C for 2 h and extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over anhydrous Na2SO4 and fdtered. The fdtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (EtOAc / petroleum ether 1 / 6) to afford ethyl 5-bromo-4-cyano-2-cyclobutylpyrazole-3-carboxylate (160 mg, 26.10%) as a yellow solid. ’H NMR (400 MHz, DMSO-6) 5 5.58 - 5.50 (m, 1H), 4.45 - 4.33 (m, 2H), 2.61 - 2.51 (m, 2H), 2.44 - 2.32 (m, 2H), 1.91 - 1.75 (m, 2H), 1.38 - 1.30 (m, 3H).Step 2: Preparation of 4-amino-3-bromo-l-cyclobutyl-l,6-dihydro-7 / 7-pyrazolo[3,4-t / ]pyridazin-7- one:

[0149] To a stirred solution of ethyl 5-bromo-4-cyano-2-cyclobutylpyrazole-3-carboxylate (152 mg, 0.51 mmol, 1.00 equiv.) in EtOH (15 mL) was added hydrazine monohydrate (3 mL) dropwise 25°C. The resulting mixture was stirred at 80°C for 1 h, cooled to 25°C and concentrated under reduced pressure. The crude product (142 mg, crude) was used in the next step directly without further purification. LC- MS: (ES+H, m / z): [M+H]+=283.8.Intermediates 8 and 9Step 1: Preparation of 1,8-diethyl (2E,4E,6E)-3,6-dicyano-2,7-dihydroxyocta-2,4,6-trienedioate:

[0150] To a stirred mixture of sodium ethoxide (213.74 g, 565.36 mmol, 3.00 equiv., 18 wt. % in EtOH) in EtOH (400 mL) was added ethyl oxalate (82.62 g, 565.36 mmol, 3.00 equiv.) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for Ih under nitrogen atmosphere. To the above mixture was added 3 -hexenedinitrile (20.00 g, 188.45 mmol, 1.00 equiv.) at 0°C. The resulting mixture was stirred at 25°C for an additional 16 h and then cooled to 0°C. TheWSGR Docket No. 67898-707.601 precipitated solids were collected by filtration and washed with EtOH (2x50 mL). The residue was then dissolved in water (400 mL) and the mixture was acidified to pH 4 with 2N HCl(aq.). The precipitated solids were collected by filtration, washed with water (2 x 50 mL), and dried to provide 1,8-diethyl (2E,4E,6E)-3,6-dicyano-2,7-dihydroxyocta-2,4,6-trienedioate (18 g, 31%) as a yellow solid. LC-MS: (ES-H, m / z): [M-H]’ =305.2. 'HNMR (400 MHz, DMSO-6) 56.88 (s, 2H), 4.31 (q, J= 7.1 Hz, 4H), 1.30 (t, J= 7.1 Hz, 6H).Step 2: Preparation of (lr,3s)-3-methyl-3-[(triethylsilyl)oxy]cyclobutan-l-amine:

[0151] 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 (CH2CI2 / 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. ’H NMR (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 3: Preparation of ethyl 3-cyano-l-[(lr,3s)-3-methyl-3-[(triethylsilyl)oxy]cyclobutyl]pyrrole-2- carboxylate:

[0152] A mixture of 1,8-diethyl (2E,4E,6E)-3,6-dicyano-2,7-dihydroxyocta-2,4,6-trienedioate (10.00 g, 32.65 mmol, 1.00 equiv.) and (lr,3s)-3-methyl-3-[(triethylsilyl)oxy]cyclobutan-l-amine (10.55 g, 48.98 mmol, 1.50 equiv.) in ethyl acetate (200 mL) was stirred at 80°C for 16h under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was then cooled down to room temperature and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc (10:1)) to afford ethyl 3-cyano-l-[(lr,3s)-3-methyl-3-[(triethylsilyl)oxy]cyclobutyl]pyrrole-2- carboxylate (6.2 g, 52%) as a light yellow oil. LC-MS: (ES+H, m / z): [M+H]+=363.2. 7H NMR (300 MHz, DMSO-d6) 57.52 (d, J= 3.1 Hz, 1H), 6.75 (d, J= 3.0 Hz, 1H), 4.31 (q, J= 7.1 Hz, 2H), 4.22 (t, J = 7.1 Hz, 1H), 2.62 (td, J= 8.3, 7.5, 2.7 Hz, 2H), 2.41 - 2.31 (m, 2H), 1.41 (s, 3H), 1.35 - 1.30 (m, 3H), 0.94 - 0.89 (m, 9H), 0.57 (dd, J= 7.9, 1.0 Hz, 6H).Step 4: Preparation of 4-amino-l-[(lr,3s)-3-methyl-3-[(triethylsilyl)oxy]cyclobutyl]-6H-pyrrolo[2,3- d]pyridazin-7-one:

[0153] A mixture of ethyl 3-cyano-l-[(lr,3s)-3-methyl-3-[(triethylsilyl)oxy]cyclobutyl]pyrrole-2- carboxylate (6.00 g, 16.55 mmol, 1.00 equiv.) in hydrazine monohydrate (60 mL) and EtOH (60 mL) was stirred at 80°C for 4h under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature and the precipitated solids were collected by filtration and washed with water (2x10 mL) and EtOH (2x10 mL). The resulting solids were dried under vacuum to afford 4-amino- 1 -[( 1 r,3 s)-3 -methyl-3 -[(triethylsilyl)oxy]cyclobutyl] -6H-pyrrolo [2,3 -d]pyridazin-7 -one (2.4 g, 42%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+=349.3. ’H NMR (400 MHz, DMSO-6) 5WSGR Docket No. 67898-707.60111.09 (s, 1H), 7.54 (d, J= 3.0 Hz, 1H), 6.64 (d, J= 3.0 Hz, 1H), 5.64 (s, 2H), 5.51 - 5.34 (m, 1H), 2.71 - 2.57 (m, 2H), 2.39 (td, J= 9.2, 2.8 Hz, 2H), 1.42 (s, 3H), 0.94 (t, J= 7.9 Hz, 9H), 0.64 - 0.52 (m, 6H).Step 5: Preparation of 4-amino-3-bromo-l-[(lr,3s)-3-hydroxy-3-methylcyclobutyl]-6H-pyrrolo[2,3- d] pyridazin-7-one and 4-amino-3-bromo-l- [(lr,3s)-3-methyl-3- [(triethylsilyl)oxy] cyclobutyl] -6H- pyrrolo[2,3-d]pyridazin-7-one:

[0154] To a stirred mixture of 4-amino-l-[(lr,3s)-3-methyl-3-[(triethylsilyl)oxy]cyclobutyl]-6H- pyrrolo[2,3-d]pyridazin-7-one (2.40 g, 6.89 mmol, 1.00 equiv.) in CH2CI2 (25 mL) was added NBS (1.23 g, 6.89 mmol, 1.00 equiv.) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16h under nitrogen atmosphere and then, diluted with water (200 mL). The resulting mixture was extracted with CH2CI2 (3 x 200 mL) and then the combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2CI2 / MeOH (0% to 10% gradient in 30 min))to afford 4-amino-3-bromo-l-[(lr,3s)- 3-hydroxy-3-methylcyclobutyl]-6H-pyrrolo[2,3-d]pyridazin-7-one (420 mg, 19%) as yellow solid and 4- amino-3 -bromo- 1 -[( 1 r,3 s)-3 -methyl-3 - [(triethylsilyl)oxy] cyclobutyl] -6H-pyrrolo [2,3 -d]pyridazin-7 -one (1.60 g, 54%) as yellow solid.

[0155] 4-amino-3 -bromo- 1 -[( 1 r,3 s)-3 -hydroxy-3 -methylcyclobutyl] -6H-pyrrolo [2,3 -d]pyridazin-7- one: LC-MS: (ES+H, m / z): [M+H]+=313.0. ’H NMR (400 MHz, DMSO-tL) 5 11.40 (s, 1H), 7.95 (s, 1H), 5.58 (p, J= 8.5 Hz, 1H), 5.36 (s, 2H), 5.20 (s, 1H), 2.59 - 2.52 (m, 2H), 2.41 (td, J= 9.2, 2.8 Hz, 2H), 1.29 (s, 3H).

[0156] 4-amino-3-bromo-l-[(lr,3s)-3-methyl-3-[(triethylsilyl)oxy]cyclobutyl]-6H-pyrrolo[2,3- d]pyridazin-7-one : LC-MS: (ES+H, m / z): [M+H]+=427.2. ’H NMR (400 MHz, DMSO-tL) 5 11.38 (s, 1H), 7.85 (s, 1H), 5.46 - 5.38 (m, 1H), 5.36 (s, 2H), 2.60 (ddd, J= 9.0, 7.6, 2.8 Hz, 2H), 2.45 - 2.36 (m, 2H), 1.41 (s, 3H), 0.93 (t, J= 7.9 Hz, 9H), 0.58 (q, J= 8.1 Hz, 6H).Intermediate 10

[0157] To a stirred mixture of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3-benzothiazole (3.00 g, 11.48 mmol, 1.00 equiv.) and benzaldehyde (1.46 g, 13.78 mmol, 1.20 equiv.) in H2O (60 mL) was added 4-methylbenzene-l -sulfonic acid silver (6.41 g, 22.97 mmol, 2.00 equiv.) at 25°C under N2 atmosphere. The resulting mixture was stirred at 100°C for 14 h and extracted with EtOAc (3 x 60 mL). The combined organic layers were dried over anhydrous Na2SC>4and filtered. The filtrate was concentrated under reduced pressure to afford (2-phenylbenzo[aQthiazol-5-yl)boronic acid (1.30 g, 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]+=255.9.WSGR Docket No. 67898-707.601Intermediates 11 and 12Step 1: Preparation of ethyl (3E)-3-[(3-bromophenyl)imino]-3-phenylpropanoate:

[0158] To a stirred solution of 3 -bromoaniline (50.00 g, 290.65 mmol, 1.00 equiv.) and ethyl benzoylacetate (55.87 g, 290.65 mmol, 1.00 equiv.) in toluene (500 mL) was added TsOH (5.01 g, 29.06 mmol, 0.10 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 120°C for 3 h under nitrogen atmosphere and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Petroleum ether / EtOAc 5: 1) to afford ethyl (3E)-3-[(3-bromophenyl)imino]-3-phenylpropanoate (50.00 g, 49.6%) as a yellow oil. LC-MS: (ES+H, m / z): [M+H]+=346.15.Step 2: Preparation of 7-bromo-2-phenylquinolin-4-ol:

[0159] A solution of ethyl (3E)-3-[(3-bromophenyl)imino]-3-phenylpropanoate (35.00 g, 101.09 mmol, 1.00 equiv.) in PPA (80 mL) was stirred at 180 °C for 30 min under nitrogen atmosphere. The precipitated solids were collected by filtration and washed with H2O (3 x 100 mL) to afford 7-bromo-2- phenylquinolin-4-ol (40.00 g, crude) as off-white solid. LC-MS: (ES+H, m / z): [M+H]+=299.95.Step 3: Preparation of 7-bromo-4-ethoxy-2-phenylquinoline:

[0160] To a stirred solution of 7-bromo-2-phenylquinolin-4-ol (35.00 g, 116.60 mmol, 1.00 equiv.) and K2CO3 (48.35 g, 349.81 mmol, 3.00 equiv.) in DMF (350 mL) were added iodoethane (21.82 g, 139.92 mmol, 1.20 equiv.) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 4 h under nitrogen atmosphere, diluted with water and extracted with EtOAc (3x 300 mL). The organic layer was concentrated under reduced pressure and the residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 gel; mobile phase, MeCN in Water (0.1% NH3.H2O), 60% to 80% gradient in 20 min; detector, UV 254 nm to afford 7-bromo-4-ethoxy-2 -phenylquinoline (30.00 g, 78.3%) as a yellow oil.LC-MS: (ES+H, m / z): [M+H]+=328.0.Step 4: Preparation of 4-ethoxy-2-phenyl-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline:

[0161] To a stirred solution of 7-bromo-4-ethoxy-2 -phenylquinoline (3.00 g, 9.14 mmol, 1.00 equiv.) and 4,4,5,5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (2.55 g, 10.05 mmol, 1.10 equiv.) in 1,4-dioxane (30 mL) were added AcOK (2.24 g, 22.85 mmol, 2.50 equiv.), Pd2(dba)3 (0.42 g, 0.45 mmol, 0.05 equiv.) and tricyclohexylphosphine (0.26 g, 0.91 mmol, 0.10 equiv.)WSGR Docket No. 67898-707.601 in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 3 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and the residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% HCOOH), 30 % to 60 % gradient in 10 min; detector, UV 254 nm to afford 4-ethoxy-2-phenyl-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinolone (1.80 g, 52.47%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+=376.15.Intermediate 13

[0162] A solution of 6-amino-9-[(lr,3s)-3-hydroxy-3-methylcyclobutyl]-7H-purin-8-one (500 mg, 2.12 mmol, 1.00 equiv.) in DMF-DMA (15 mL) was stirred at 40°C for Ih 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 MeOH in CH2Q2 (0%-10% gradient in 30 min) to afford (E)-N,N-dimethyl-N'-{8-oxo-9-[(lr,3s)-3-hydroxy-3-methylcyclobutyl]-7H- purin-6-yl}methanimidamide (300 mg, 48.6%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+= 291.10. ’H NMR (400 MHz, DMSO-6) 511.06 (s, IH), 8.71 (s, IH), 8.22 (s, IH), 5.23 (s, IH), 4.41 - 4.35 (m, IH), 3.15 (s, 3H), 3.09 (s, 3H),3.03 - 2.98 (m, 2H), 2.33 - 2.27 (m, 2H), 1.32 (s, 3H).Intermediate 14Y=92.6%1 INT-14

[0163] To a stirred solution of 5-phenylthieno[3,2-b]pyridine (2.00 g, 9.47 mmol, 1.00 equiv.) in THF (30 mL) was added n-BuLi (5.68 mL, 14.20 mmol, 1.50 equiv., 2.5M in hexane) dropwise at -78°C under nitrogen atmosphere. The mixture stirred for 0.5 h at -78°C, then Br2 (2.27 g, 14.20 mmol, 1.50 equiv.) was added dropwise. The mixture was stirred for 2 h at -78°C, quenched with sat. Na2SOs (aq.) at -20°C- 0°C and extracted with CH2Q2 (4 x 80 mL). The organic layer was washed with brine (2 x 40 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with CH2CI2 / PE (7: 1) to afford 2- bromo-5-phenylthieno[3,2-b]pyridine (2.54 g, 92.6%) as a light yellow solid. LC-MS: (ES+H, m / z): [M+H]+=289.9. ’H NMR (400 MHz, DMSO-6) 5 8.51 (d, J= 8.6 Hz, IH), 8.17 - 8.11 (m, 2H), 7.97 (d, J= 8.6 Hz, IH), 7.84 (s, IH), 7.57 - 7.44 (m, 3H).WSGR Docket No. 67898-707.601Intermediate 15Step 1: Preparation of N-((6-chloro-3-iodopyridin-2-yl)carbamothioyl)benzamide:

[0164] A solution of 6-chloro-3-iodopyridin-2-amine (30.00 g, 117.89 mmol, 1.00 equiv.) and benzoyl isothiocyanate (23.09 g, 141.47 mmol, 1.20 equiv.) in MeCN (300 mL) was stirred at 25°C for 16 h. The resulting mixture was filtered and the filter cake was washed with MeCN (2 x 50 mL). The filtrate was concentrated under reduced pressure to afford N-((6-chloro-3-iodopyridin-2-yl)carbamothioyl)benzamide (39 g, 79.20%) as a yellow solid. The crude product was used in the next step directly without further purification. LC-MS: (ES+H, m / z): [M+H]+=417.90. 'HNMR (400 MHz, DMSO-6) 5 12.39 (s, 1H), 11.88 (s, 1H), 8.38 (d, J= 8.2 Hz, 1H), 8.05 - 7.96 (m, 2H), 7.72 - 7.63 (m, 1H), 7.60 - 7.52 (m, 2H), 7.31 (d, J= 8.2 Hz, 1H).Step 2: Preparation of N-(5-chlorothiazolo[4,5-b]pyridin-2-yl)benzamide:

[0165] A solution of N-((6-chloro-3-iodopyridin-2-yl)carbamothioyl)benzamide (39 g, 93.38 mmol, 1.00 equiv.), K2CO3 (25.81 g, 186.76 mmol, 2.00 equiv.), Cui (1.78 g, 9.34 mmol, 0.10 equiv.) and L- Proline (2.17 g, 18.67 mmol, 0.20 equiv.) in 1,4-dioxane (400 mL) was stirred at 80°C for 6 h. The reaction mixture was quenched with saturated ammonium chloride solution (500 mL) dropwise. The resulting mixture was stirred at 25°C for Ih, filtered and the filter cake was washed with saturated ammonium chloride solution (3 x 500 mL) and H2O (3 x 500 mL). The filtered solid was concentrated under reduced pressure to afford N-(5-chlorothiazolo[4,5-b]pyridin-2-yl)benzamide (40 g, crude) as a brown solid. The crude product was used in the next step directly without further purification. LC-MS: (ES+H, m / z): [M+H]+=289.95. 'HNMR (400 MHz, DMSO-6) 5 13.28 (s, IH), 8.54 (d, J= 8.2 Hz, IH), 8.20 - 8.11 (m, 2H), 7.73 - 7.65 (m, IH), 7.62 - 7.55 (m, 2H), 7.43 (d, J= 8.2 Hz, IH).Step 3: Preparation of N-(5-phenylthiazolo[4,5-b]pyridin-2-yl)benzamide:

[0166] A mixture of N-(5-chlorothiazolo[4,5-b]pyridin-2-yl)benzamide (40.00 g, 138.06 mmol, 1.00 equiv.), phenylboronic acid (16.83 g, 138.06 mmol, 1.00 equiv.), Pd(dppf)C12 CH2Q2 (11.27 g, 13.81 mmol, 0.10 equiv.) and K2CO3 (57.24 g, 414.17 mmol, 3.00 equiv.) in 1,4-dioxane (800 mL) and H2O (160 mL) was stirred at 80°C for 16 h under nitrogen atmosphere and filtered. The filter cake was washedWSGR Docket No. 67898-707.601 with EtOAc (3 x 80 mL). The resulting mixture was extracted with EtOAc (3 x 1000 mL). The combined organic layers were washed with brine (2 x 1000 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, (50% to 100% EtOAc / petroleum ether) to afford N-(5-phenylthiazolo[4,5-b]pyridin-2- yl)benzamide (16 g, 34.97%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+=332.00. ’H NMR (400 MHz, DMSO-t / e) 5 13.19 (s, 1H), 8.56 (d, J= 8.2 Hz, 1H), 8.23 - 8.11 (m, 4H), 7.94 (d, J= 8.3 Hz, 1H), 7.73 - 7.66 (m, 1H), 7.60 (dd, J= 8.2, 6.9 Hz, 2H), 7.56 - 7.51 (m, 2H), 7.49 - 7.43 (m, 1H).Step 4: Preparation of 5-phenylthiazolo[4,5-b]pyridin-2-amine:

[0167] A mixture of N-(5-phenylthiazolo[4,5-b]pyridin-2-yl)benzamide (10 g, 30.17 mmol, 1.00 equiv.) in H2SO4 (100 mL, 70%) was stirred at 120°C for 4 h. The resulting mixture was poured in ice water (500 mL). The mixture was basified to pH 11 with sodium hydroxide solution and extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (2 x 800 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with EtOAc in petroleum ether (60% to 100% gradient in 30 min) to afford 5-phenylthiazolo[4,5-b]pyridin-2-amine (3.7 g, 53.95%) as off-white solid. LC-MS: (ES+H, m / z): [M+H]+=228.05. 'HNMR (400 MHz, DMSO-6) 5 8.12 (d, J= 8.1 Hz, 1H), 8.09 - 8.03 (m, 2H), 7.96 (s, 2H), 7.57 (d, J= 8.1 Hz, 1H), 7.47 (dd, J= 8.3, 6.7 Hz, 2H), 7.43 - 7.35 (m, 1H). Step 5: Preparation of 2-bromo-5-phenyl-[l,3]thiazolo[4,5-b]pyridine:

[0168] A solution of CuBr2(2.26 g, 10.12 mmol, 2.3 equiv.) and tert-butylnitrite (1.04 g, 10.12 mmol, 2.3 equiv.) in MeCN (10 mL) was stirred at 0°C for 30 min under nitrogen atmosphere. To the above mixture was added 5-phenyl-[l,3]thiazolo[4,5-b]pyridin-2-amine (1.00 g, 4.40 mmol, 1.00 equiv.). The resulting mixture was stirred at 25°C for 2 h, diluted with H2O (100 mL) and extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with EtOAc in petroleum ether (10% to 40% gradient in 30 min) to afford 2-bromo-5-phenyl-[l,3]thiazolo[4,5-b]pyridine (800 mg, 62.45%) as off-white solid. LC- MS: (ES+H, m / z): [M+H]+=290.90. 'HNMR (400 MHz, DMSO-6) 5 8.67 (d, J= 8.5 Hz, 1H), 8.18 (dd, .7= 7.1, 1.9 Hz, 2H), 8.12 (d, J= 8.5 Hz, 1H), 7.60 - 7.45 (m, 3H).Intermediate 16Step 1: Preparation of 5-phenylthieno[3,2-b]pyridine:

[0169] A mixture of 5-chlorothieno[3,2-b]pyridine (5.00 g, 29.48 mmol, 1.00 equiv.), phenyl boronic acid (5.39 g, 44.21 mmol, 1.50 equiv.), K2CO3 (12.22 g, 88.43 mmol, 3.00 equiv.) andPd(dppf)C12.CH2C12 (0.22 g, 0.30 mmol, 0.01 equiv.) in 1,4-dioxane (60 mL) was stirred at 110°C for 5 h under nitrogen atmosphere then filtered. The filter cake was washed with DCM (3x40 mL). The filtrateWSGR Docket No. 67898-707.601 was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with PE / EtOAc (12: 1) to afford 5-phenylthieno[3,2-b]pyridine (5.96 g, 95.71%) as an off-white solid. LC-MS: (ES+H, m / z): [M+H]+=212.00.1H NMR (400 MHz, DMSO-6) 5 8.57 (dd, J= 8.6, 0.8 Hz, 1H), 8.21 - 8.13 (m, 3H), 7.96 (d, J= 8.5 Hz, 1H), 7.64 (dd, J= 5.5, 0.8 Hz, 1H), 7.57 - 7.50 (m, 2H), 7.50 - 7.42 (m, 1H).Step 2: Preparation of 5-phenylthieno[3,2-b]pyridin-2-ylboronic acid:

[0170] To a solution of 5-phenylthieno[3,2-b]pyridine (2.00 g, 9.47 mmol, 1.00 equiv.) in THF (20 mL) was added n-BuLi (4.54 mL, 11.36 mmol, 1.20 equiv, 2.5M in hexane) dropwise at -78°C under nitrogen atmosphere. The reaction mixture was stirred for 0.5 h then treated with trimethyl borate (1.38 g, 13.25 mmol, 1.40 equiv.) and stirred for 4 h at -78°C. The reaction mixture was quenched with HC1 aq. (1 M in water, 30 mL) at 0°C and extracted with CH2Q2 (5x70 mL). The organic layer was dried over anhydrous Na2SC>4 and filtered. The filtrate was concentrated under reduced pressure to afford 5- phenylthieno[3,2-b]pyridin-2-ylboronic acid (2.27 g, 94.12%) as a light yellow solid. LC-MS: (ES+H, m / z): [M+H]+=255.95. ’H NMR (400 MHz, DMSO-6) 5 8.58 (d, J= 8.6 Hz, 1H), 8.21 - 8.13 (m, 3H), 7.98 (d, J= 8.6 Hz, 1H), 7.57 - 7.44 (m, 3H).Intermediates 17 and 18Step 1: Preparation of (ls,3s)-3-((2-chloro-3-nitropyridin-4-yl)amino)-l-methylcyclobutan-l-ol:

[0171] To a stirred mixture of 2,4-dichloro-3-nitropyridine (20 g, 103.64 mmol, 1.0 equiv.) and (ls,3r)-3-amino-l-methylcyclobutan-l-ol hydrochloride (14.26 g, 103.63 mmol, 1 equiv.) in DMF (200 mL) was added EtsN (26.22 g, 259.09 mmol, 2.5 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight, filtered and the filter cake was washed with EtOAc (800 mL). The organic layer was washed with H2O (3 x 300mL), dried over anhydrous Na2SO4, and filtered. The resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with EtOAc / PE (0%-35% gradient in 35 min) to afford (ls,3s)-3-((2-chloro-3-nitropyridin-4-yl)amino)-l-methylcyclobutan-l-ol (18 g, 60.1%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+= 258.0. 'HNMR (400 MHz, DMSO-6) 5 8.01 (d, J= 6.0WSGR Docket No. 67898-707.601Hz, 1H), 7.49 (d, J= 52 Hz, 1H), 6.81 (dd, J= 62, 1.1 Hz, 1H), 5.04 (s, 1H), 3.61 (td, J= 7.8, 5.3 Hz, 1H), 2.42 (ddd, J= 11.8, 6.2, 2.6 Hz, 2H), 2.08 - 2.02 (m, 2H), 1.26 (s, 3H).Step 2: Preparation of (ls,3s)-3-((2-(bis(4-methoxybenzyl)amino)-3-nitropyridin-4-yl)amino)-l- methylcyclobutan-l-ol:

[0172] To a stirred mixture of (ls,3r)-3-[(2-chloro-3-nitropyridin-4-yl)amino]-l-methylcyclobutan-l- ol (3.8 g, 14.75 mmol, 1.0 equiv.) and EtsN (4.48 g, 44.24 mmol, 3.0 equiv.) in MeCN (80 mL) were added bis[(4-methoxyphenyl)methyl]amine (5.69 g, 22.12 mmol, 1.5 equiv.) dropwise at 80°C for overnight under nitrogen atmosphere, cooled and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc / PE (0%-70% gradient in 40 min) to afford (ls,3s)-3-((2-(bis(4-methoxybenzyl)amino)-3-nitropyridin-4-yl)amino)-l-methylcyclobutan-l-ol (5 g, 57.6%) as a yellow oil. LC-MS: (ES+H, m / z): [M+H]+= 479.2. ’H NMR (400 MHz, DMSO- 6) 5 7.85 (d, J= 5.8 Hz, 1H), 7.50 (d, J= 5.7 Hz, 1H), 7.07 -7.04 (m, 4H), 6.86 - 6.83 (m, 4H), 6.20 (d, J = 5.9 Hz, 1H), 5.06 (s, 1H), 4.35 (s, 4H), 4.03 (q, J= 7.1 Hz, 1H), 3.72 (s, 6H), 3.66 (td, J= 7.7, 5.7 Hz, 1H), 1.99 (s, 4H), 1.26 (s, 3H).Step 3: Preparation of (ls,3s)-3-((3-amino-2-(bis(4-methoxybenzyl)amino)pyridin-4-yl)amino)-l- methylcyclobutan-l-ol:

[0173] To a stirred mixture of ammonium chloride (5.58g, 104.38 mmol, 16.6 equiv.), H2O (15 mL) Zinc (3.23 g, 49.46 mmol, 7.8 equiv.) in EtOH (30 mL) was added ( 1 s,3r)-3-[(2-{bis[(4- methoxyphenyl)methyl]amino}-3-nitropyridin-4-yl)amino]-l-methylcyclobutan-l-ol (3.0 g, 6.27 mmol, 1.0 equiv.) in THF (30 mL) dropwise at 0°C. The resulting mixture was stirred at room temperature for Ih under nitrogen atmosphere, filtered, and diluted with EtOAc (300 mL). The organic layer was washed with 3xl00mL of H2O, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CTECE / MeOH (0%-10% gradient in 35 min) to afford (ls,3s)-3- ((3-amino-2-(bis(4-methoxybenzyl)amino)pyridin-4-yl)amino)-l-methylcyclobutan-l-ol (2.1 g, 74.6%) as a light brown solid. LC-MS: (ES+H, m / z): [M+H]+= 449.3. ’H NMR (400 MHz, DMSO-6) 57.39 (d, J= 5.3 Hz, IH), 7.17 (d, J= 8.3 Hz, 4H), 6.80 (d, J= 8.3 Hz, 4H), 6.10 (d, J= 5.4 Hz, IH), 5.46 (d, J = 5.6 Hz, IH), 4.96 (s, IH), 4.40 (s, 2H), 3.98 (s, 4H), 3.70 (s, 6H), 3.41 (q, J= 7.1 Hz, IH), 2.42 (ddd, J= 92, 7.1, 2.9 Hz, 2H), 1.93 (td, J= 8.6, 2.7 Hz, 2H), 1.28 (s, 3H).Step 4: Preparation of 4-(bis(4-methoxybenzyl)amino)-l-((ls,3s)-3-hydroxy-3-methylcyclobutyl)- l,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one:

[0174] To a stirred mixture of (ls,3r)-3-[(3-amino-2-{bis[(4-methoxyphenyl)methyl]amino}pyridin-4- yl)amino]-l-methylcyclobutan-l-ol (2.5 g, 6.69 mmol, 1.0 equiv.) and DIEA (1.30 g, 10.03 mmol, 1.5 equiv.) in DCM (100 mL) were added ditrichloromethyl carbonate (992 mg, 3.34 mmol, 0.50 equiv.) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C for Ih then quenched by the addition of ice water (150 mL) at 0°C. The mixture was basified to pH 9 with NaOH (2N) and extracted with CH2Q2 (3 x 200 mL). The organic layer was dried over anhydrous Na2SO4and fdtered. The fdtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with MeOH / CH2CI2 (0%-10% gradient in 35 min) to afford 4-(bis(4-WSGR Docket No. 67898-707.601 methoxybenzyl)amino)- 1 -(( 1 s, 3 s)-3 -hydroxy-3 -methylcyclobutyl)- 1 ,3 -dihydro-2H-imidazo [4,5 - c]pyridin-2-one (1.8 g, 68.6%) as a light red solid. LC-MS: (ES+H, m / z): [M+H]+= 475.3. 'HNMR (400 MHz, DMSO- e) 5 10.89 (s, 1H), 7.82 (d, J= 5.5 Hz, 1H), 7.10 - 7.05 (m, 5H), 6.85 - 6.81 (m, 4H), 5.30 (s, 1H), 4.46 (s, 4H), 4.42 (t, J= 8.6 Hz, 1H), 3.70 (s, 6H), 2.76 (td, J= 9.3, 2.7 Hz, 2H), 2.37 (ddd, J = 11.8, 6.8, 2.4 Hz, 2H), 1.34 (s, 3H).Step 5: Preparation of 4-amino-l-((ls,3s)-3-hydroxy-3-methylcyclobutyl)-l,3-dihydro-2H- imidazo [4,5-c] pyridin-2-one:

[0175] A mixture of 4-{bis[(4-methoxyphenyl)methyl]amino}-l-[(lr,3s)-3-hydroxy-3- methylcyclobutyl]-3H-imidazo[4,5-c]pyridin-2-one (1.5 g, 3.16 mmol, 1.0 equiv.) and TFA (6 m ) in DCM (7 m ) was stirred at 40°C under nitrogen atmosphere then concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 gel; mobile phase, MeCN in Water (10 mmol / E NH4HCO3) 10% to 50% gradient in 30 min to afford 4-amino-l-((ls,3s)-3-hydroxy-3-methylcyclobutyl)-l,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (700 mg, 38.6%) as a white solid. EC-MS: (ES+H, m / z): [M+H]+= 235.2. ’H NMR (400 MHz, DMSO-6) 5 10.90 - 9.81 (m, 1H), 7.64 (d, J= 5.6 Hz, 1H), 6.88 (d, J= 5.6 Hz, 1H), 5.67 (s, 2H), 5.32 (s, 1H), 4.38 (t, J= 8.6 Hz, 1H), 2.70 (td, J= 9.4, 2.8 Hz, 2H), 2.35 (td, J= 8.5, 2.9 Hz, 2H), 1.33 (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-dimethylf ormimidamide :

[0176] 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 equiv.) in dimethoxymethyldimethylamine (4 mb) was stirred at 40°C for Ih under nitrogen atmosphere then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH / CH2Q2 (0%-10% 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 (350 mg, 56.6%) as a light brown solid. LC-MS: (ES+H, m / z): [M+H]+= 290.2. ’HNMR (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 19Step 1: Preparation of N4,N4-bis(4-methoxybenzyl)-N6-((ls,3s)-3-methyl-3- ((triethylsilyl)oxy)cyclobutyl)-5-nitropyrimidine-4,6-diamine:WSGR Docket No. 67898-707.601

[0177] A solution of 6-chloro-N,N-bis(4-methoxybenzyl)-5-nitropyrimidin-4-amine (2.00 g, 4.82 mmol, 1.00 equiv.), (ls,3s)-3-methyl-3-((triethylsilyl)oxy)cyclobutan-l-amine (1.04 g, 4.82 mmol, 1.00 equiv.) and EtsN (1.46 g, 14.5 mmol, 3.00 equiv.) in MeCN (20 mb) was stirred at 80°C for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with PE / EA (5: 1) to afford N4,N4-bis(4- methoxybenzyl)-N6-((ls,3s)-3-methyl-3-((triethylsilyl)oxy)cyclobutyl)-5-nitropyrimidine-4,6-diamine (2 g, 69.8%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+=594.4. ’H NMR (400 MHz, DMSO-6) 5 8.30 (d, J= 6.5 Hz, 1H), 8.12 (s, 1H), 7.13 - 7.00 (m, 4H), 6.95 - 6.80 (m, 4H), 4.51 (s, 4H), 4.15 (h, J = 8.0 Hz, 1H), 3.72 (s, 6H), 2.44 (ddt, J= 11.4, 7.3, 2.5 Hz, 2H), 2.13 (td, J= 8.8, 2.7 Hz, 2H), 1.35 (s, 3H), 0.92 (t, J= 7.9 Hz, 9H), 0.55 (q, J= 7.9 Hz, 6H).Step 2: Preparation of N4,N4-bis(4-methoxybenzyl)-N6-((ls,3s)-3-methyl-3- ((triethylsilyl)oxy)cyclobutyl)pyrimidine-4,5,6-triamine:

[0178] To a stirred mixture of N4,N4-bis[(4-methoxyphenyl)methyl]-5-nitro-N6-[(lr,3s)-3-methyl-3- [(triethylsilyl)oxy]cyclobutyl]pyrimidine-4,6-diamine (1.40 g, 2.36 mmol, 1.00 equiv.) and ammonium chloride (1.26 g, 23.6 mmol, 10.0 equiv.) in EtOH (30 mL) was added Zinc (1.08 g, 16.51 mmol, 7.00 equiv.) in portions at 25°C under nitrogen atmosphere. The resulting mixture was stirred at 25°C for 1 h under nitrogen atmosphere, fdtered, and the fdter cake was washed with DCM (3 x 50 mL). The fdtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with PE / EA (3: 1) to afford N4,N4-bis(4-methoxybenzyl)-N6-((ls,3s)-3-methyl- 3-((triethylsilyl)oxy)cyclobutyl)pyrimidine-4,5,6-triamine (1.1 g, 82.7%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+=564.4. 'HNMR (400 MHz, DMSO-6) 5 7.70 (s, 1H), 7.21 - 7.09 (m, 4H), 6.88 - 6.75 (m, 4H), 6.46 (d, J= 6.5 Hz, 1H), 4.34 (s, 2H), 4.11 (s, 4H), 4.00 (q, J= 7.7 Hz, 1H), 3.70 (s, 6H), 2.42 (td, J= 8.5, 7.5, 2.8 Hz, 2H), 2.03 (t, J= 9.7 Hz, 2H), 1.35 (s, 3H), 0.93 (t, J= 7.9 Hz, 9H), 0.56 (q, J= 7.9 Hz, 6H).Intermediate 20Step 1: Preparation of ethyl (E)-3-((3-bromo-4-fluorophenyl)imino)-3-phenylpropanoate:

[0179] A solution of 3-bromo-4-fluoroaniline (10.00 g, 52.63 mmol, 1.00 equiv.), ethyl benzoylacetate (12.14 g, 63.15 mmol, 1.20 equiv.) and TsOH (0.91 g, 5.26 mmol, 0.10 equiv.) in toluene (160 mL) was stirred at 120°C for 16h under nitrogen atmosphere. The resulting mixture was concentrated underWSGR Docket No. 67898-707.601 reduced pressure and the residue was purified by silica gel column chromatography, eluted with PE / EA (10: 1) to afford ethyl (E)-3-((3-bromo-4-fhiorophenyl)imino)-3-phenylpropanoate (18 g, crude) as a yellow oil. LC-MS: (ES+H, m / z): [M+H]+=363.8.Step 2: Preparation of 7-bromo-6-fluoro-2-phenylquinolin-4-ol:

[0180] A mixture of ethyl (E)-3-((3-bromo-4-fluorophenyl)imino)-3-phenylpropanoate (17.00 g, 46.68 mmol, 1.00 equiv.) in PPA (180 mL) was stirred at 180°C for 0.5 h under nitrogen atmosphere. The reaction was poured into water (1.5 L) and the precipitated solids were collected by filtration and washed with water (3 x 200 mL). The resulting solid was dried under vacuum to afford 7-bromo-6-fluoro-2- phenylquinolin-4-ol (14 g, crude) as a brown solid. LC-MS: (ES+H, m / z): [M+H]+=317.9.Step 3: Preparation of 7-bromo-4-ethoxy-6-fluoro-2-phenylquinoline:

[0181] A mixture of 7-bromo-6-fluoro-2-phenylquinolin-4-ol (13.00 g, 40.86 mmol, 1.00 equiv.), iodoethane (9.56 g, 61.29 mmol, 1.50 equiv.) and K2CO3 (22.59 g, 163.45 mmol, 4.00 equiv.) in DMF (250 mL) was stirred at 25 °C for 24 h under nitrogen atmosphere. The reaction was poured into water (2 L) at room temperature and extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na2SC>4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with PE / EA (10: 1) to afford 7-bromo-4-ethoxy-6-fluoro-2 -phenylquinoline (2. 1 g, 14.8%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+=346.0. 'HNMR (400 MHz, DMSO-6) 5 8.38 (d, J= 6.6 Hz, 1H), 8.27 (dd, J= 8.0, 1.7 Hz, 2H), 7.92 (d, J= 9.4 Hz, 1H), 7.61 (s, 1H), 7.59 - 7.48 (m, 3H), 4.48 (q, J= 7.0 Hz, 2H), 1.51 (t, J= 6.9 Hz, 3H).Example 1

[0182] To a stirred solution of 6-amino-9-[(lr,3s)-3-hydroxy-3-methylcyclobutyl]-7H-purin-8-one (150 mg, 0.63 mmol, 1.00 equiv.) and 2-phenylquinolin-7-ylboronic acid (317 mg, crude) in CH2CI2 (15 mL) were added 2,2,6,6-tetramethylpiperidin-l-olate (109 mg, 0.70 mmol, 1.10 equiv.), EtsN (258 mg, 2.55 mmol, 4.00 equiv.) and Cu(OAc)2 (57 mg, 0.31 mmol, 0.50 equiv ) in portions at room temperature. The resulting mixture was stirred at 40°C for overnight under oxygen atmosphere and then filtered. The filter cake was washed with CH2Q2 (3x20 mL) and 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 the crude product (60 mg). The crude product (60 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column 30* 150 mm, 5pm; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 5% B to 5% B in 1 min, 5% B to 27% B in 2 min, 27% to 45% B in 11 min; Wave Length:WSGR Docket No. 67898-707.601254nm / 220nm nm; RTl(min): 8.63) to afford 6-amino-7-(2-phenylquinolin-7-yl)-9-[(lr,3s)-3-hydroxy-3- methylcyclobutyl]purin-8-one (20.6 mg, 7%). LC-MS: (ES+H, m / z): [M+H]+=439.20. 'H NMR (400 MHz, DMS0-d6) 5 8.58 - 8.53 (m, 1H), 8.33 - 8.29 (m, 2H), 8.25 - 8.19 (m, 2H), 8.14 (d, J= 8.7 Hz, 1H), 8.01 (d, J= 2.1 Hz, 1H), 7.64 (dd, J= 8.6, 2.2 Hz, 1H), 7.60 - 7.50 (m, 3H), 5.96 (s, 2H), 5.23 (s, 1H), 4.56 - 4.44 (m, 1H), 3.13 - 3.04 (m, 2H), 2.41 - 2.32 (m, 2H), 1.35 (s, 3H).Example 2Step 1: Preparation of 4-amino-3-(2-phenylquinolin-7-yl)-l-[(lr,3s)-3-methyl-3- [(triethylsilyl)oxy]cyclobutyl]-6H-pyrazolo[3,4-d]pyridazin-7-one:

[0183] To a stirred solution of 4-amino-3-bromo-l-[(lr,3s)-3-methyl-3-[(triethylsilyl)oxy]cyclobutyl]- 6H-pyrazolo[3,4-d]pyridazin-7-one (200 mg, 0.46 mmol, 1.00 equiv.) and 2-phenyl-7-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (154 mg, 0.46 mmol, 1.00 equiv.) in 1,4-dioxane (5 mL) and H2O (1 mL) was added Pd(dppf)C12 (68 mg, 0.09 mmol, 0.20 equiv.) and K2CO3 (193 mg, 1.40 mmol, 3.00 equiv.) at 25°C under N2 atmosphere. The resulting mixture was stirred at 110°C for 2 h, cooled, fdtered and the fdter cake was washed with THF (3 x 3 mL). The fdtrate was concentrated under reduced pressure to afford the crude product 4-amino-3-(2-phenylquinolin-7-yl)-l-[(lr,3s)-3-methyl-3- [(triethylsilyl)oxy]cyclobutyl]-6H-pyrazolo[3,4-d]pyridazin-7-one (132 mg, crude) as a black solid. LC- MS: (ES+H, m / z): [M+H]+=553.3.Step 2: Preparation of 4-amino-3-(2-phenylquinolin-7-yl)-l-[(lr,3s)-3-hydroxy-3- methylcyclobutyl]-6H-pyrazolo[3,4-d]pyridazin-7-one:

[0184] To a stirred solution of 4-amino-3-(2-phenylquinolin-7-yl)-l-[(lr,3s)-3-methyl-3- [(triethylsilyl)oxy]cyclobutyl]-6H-pyrazolo[3,4-d]pyridazin-7-one (132 mg, 0.23 mmol, 1.00 equiv.) in MeOH (2 mL) were added HC1 in 1,4-dioxane (4.0 M, 2 mL) at 0°C. The resulting mixture was stirred at 25°C for 0.5 h and concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions Column: Column: XBridge Prep OBD C18 Column 30* 150 mm, 5pm; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 5% B to 5% B in 1 min, 5% B to 25% B in 2 min, 25% to 43% B in 11 min; Wave Length: 254nm / 220nm nm; RTl(min): 9.65, to afford 4-amino-3-(2-phenylquinolin-7-yl)-l-[(lr,3s)-3-hydroxy-3- methylcyclobutyl]-6H-pyrazolo[3,4-d]pyridazin-7-one (74.6 mg, 71.24). LC-MS: (ES+H, m / z): [M+H]+=439.15. 'H NMR (400 MHz, DMSO-6) 5 11.80 (s, 1H), 8.56 (d, J= 8.6 Hz, 1H), 8.43 (d, J= 1.7 Hz, 1H), 8.32 (dd, J= 12, 2.0 Hz, 2H), 8.24 (d, J= 8.7 Hz, 1H), 8.16 (d, J= 8.4 Hz, 1H), 7.96 (dd, J= 8.3,WSGR Docket No. 67898-707.6011.7 Hz, 1H), 7.63 - 7.49 (m, 3H), 5.77-5.64 (m, 1H), 5.29 (m, 3H), 2.84 - 2.74 (m, 2H), 2.55 (m, 2H), 1.38 (s, 3H).INT-7

[0185] To a mixture of 4-amino-3-bromo- 1 -cyclobiityl-6 / / -pyrazolo|3.4 / |pyridazin-7-onc (142 mg, 0.50 mmol, 1.00 equiv.) and 2-phenyl-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (182 mg, 0.55 mmol, 1.10 equiv.) in 1,4-dioxane (5 mb) were added K2CO3 (207 mg, 1.50 mmol, 3.00 equiv.) and Pd(dppf)C12 (73 mg, 0.10 mmol, 0.20 equiv.) at 25°C. The resulting mixture was stirred at 110°C for 2 h, cooled to 25°C, fdtered, and the filter cake was washed with THF (3 x 5 mb). The filtrate was concentrated under reduced pressure to afford the crude product which was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column 30* 150 mm, 5pm; Mobile Phase A: Water (lOmmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 46% B to 56% B in 11 min; Wave Length: 254nm / 220nm nm; RTl(min): 9.58. This resulted in 4-amino-l- cyclobiityl-3-(2-phcnylqiiinolin-7-yl)-l.6-dihydro-7 / / -pyrazolo|3.4-d'|pyridazin-7-onc (40.5 mg, 19.6% over two steps). LC-MS: (ES+H, m / z): [M+H]+=409.20. ’HNMR (400 MHz, DMSO-6) 5 11.80 (s, 1H), 8.56 (d, J= 8.6 Hz, 1H), 8.44 (d, J= 1.7 Hz, 1H), 8.36 - 8.28 (m, 2H), 8.24 (d, J= 8.7 Hz, 1H), 8.16 (d, J= 8.4 Hz, 1H), 7.97 (dd, J= 8.4, 1.7 Hz, 1H), 7.61 - 7.50 (m, 3H), 6.15 - 6.02 (m, 1H), 5.26 (s, 2H), 2.80 - 2.66 (m, 2H), 2.49 - 2.43 (m, 2H), 1.95 - 1.82 (m, 2H).Example 4

[0186] To a stirred solution of 4-amino-3-bromo-l-[(lr,3s)-3-hydroxy-3-methylcyclobutyl]-6H- pyrrolo[2,3-d]pyridazin-7-one (130 mg, 0.41 mmol, 1.00 equiv.) and 2-phenyl-7-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)quinoline (137 mg, 0.41 mmol, 1.00 equiv.) in 1,4-dioxane (3 mb) and H2O (0.6WSGR Docket No. 67898-707.601 mL) was added Pd(dppf)C12 (91 mg, 0.12 mmol, 0.30 equiv.) and K2CO3 (172 mg, 1.24 mmol, 3.00 equiv.) at 25°C under N2 atmosphere. The resulting mixture was stirred at 110°C for 2h, cooled to 25°C, fdtered and the fdter cake was washed with THF (3 x 3 mL). The filtrate was concentrated under reduced pressure to afford the crude product which was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column 30* 150 mm, 5pm; Mobile Phase A: Water (lOmmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 5% B to 5% B in 1 min, 5% B to 27% B in 2 min, 27% to 43% B in 11 min; Wave Length: 254nm / 220nm nm; RTl(min): 9.25, to afford 4-amino-3-(2-phenylquinolin-7-yl)-l-[(lr,3s)-3-hydroxy-3-methylcyclobutyl]-6H-pyrrolo[2,3- d]pyridazin-7-one (26.4 mg, 14.54%). LC-MS: (ES+H, m / z): [M+H]+=438.20 'HNMR (400 MHz, DMSO- e) 5 11.45 (s, 1H), 8.51 (d, J= 8.6 Hz, 1H), 8.38 - 8.26 (m, 2H), 8.23 - 8.15 (m, 2H), 8.09 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.78 (dd, J= 8.3, 1.8 Hz, 1H), 7.62 - 7.47 (m, 3H), 5.70 - 5.75 (m, 1H), 5.22 (s, 1H), 4.86 (s, 2H), 2.68 - 2.54 (m, 4H), 1.34 (s, 3H).Example 5INT-10 Example 5

[0187] To a stirred solution of 2-phenyl-l,3-benzothiazol-5-ylboronic acid (487 mg, 1.91 mmol, 3.00 equiv.) and 6-amino-9-[(lr,3s)-3-hydroxy-3-methylcyclobutyl]-7H-purin-8-one (150 mg, 0.63 mmol, 1.00 equiv ) in DMF (3 mL) were added pyridine (100 mg, 1.27 mmol, 2.00 equiv ) and Cu(OAc)2 (231 mg, 1.27 mmol, 2.00 equiv ) in portions at room temperature. The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. The reaction mixture was diluted with EtOAc (lOOmL), washed with 3 x 20 mL of water, brine (1 x 20 mL), dried over anhydrous Na2SC>4and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (50%-100% EtOAc / Petroleum Ether gradient) to afford crude product (200 mg). The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column 30* 150 mm, 5pm; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 60 mL / min mL / min; Gradient: 28% B to 48% B in 10 min; Wave Length: 254nm / 220nm nm; RTl(min): 9.17) to afford 6-amino-7-(2-phenyl-l,3-benzothiazol-5-yl)-9-[(lr,3s)-3- hydroxy-3-methylcyclobutyl]purin-8-one (70.5 mg, 24.8%). LC-MS: (ES+H, m / z): [M+H]+=445.15. 'H NMR (400 MHz, DMSO L) 58.29 (d, J= 8.5 Hz, 1H), 8.19 (s, 1H), 8.14 (dd, J= 6.9, 2.9 Hz, 2H), 8.09 (d, J= 2.0 Hz, 1H), 7.61 (m, 3H), 7.51 (dd, J= 8.5, 2.0 Hz, 1H), 5.83 (s, 2H), 5.23 (s, 1H), 4.54 - 4.45 (m, 1H), 3.12 - 3.04 (m, 2H), 2.42 - 2.31 (m, 2H), 1.34 (s, 3H).WSGR Docket No. 67898-707.601Example 6

[0188] To a stirred mixture of 4-amino-3-bromo-l-[(lr,3s)-3-hydroxy-3-methylcyclobutyl]-6H- pyrrolo[2,3-d]pyridazin-7-one (100 mg, 0.32 mmol, 1.00 equiv.) and 4-ethoxy-2-phenyl-7-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (180 mg, 0.48 mmol, 1.50 equiv.) in 1,4-dioxane (5 mL) and H2O (2 mL) were added Pd(dppf)Cl2.CH2Cl2(26 mg, 0.032 mmol, 0.10 equiv.) and K2CC>3 (132 mg, 0.96 mmol, 3.00 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100°C for 4h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (CH2Cl2 / MeOH 10: 1) to afford crude product. The crude product (80 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column 30* 150 mm, 5pm; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 5% B to 5% B in 1 min, 5% B to 35% B in 2 min, 35% to 55% B in 11 min; Wave Length: 254nm / 220nm nm; RTl(min): 73.77) to afford 4-amino-3-(4-ethoxy-2-phenylquinolin-7-yl)-l-[(lr,3s)-3-hydroxy-3- methylcyclobutyl]-6H-pyrrolo[2,3-d]pyridazin-7-one (5.9 mg, 3.8%). LC-MS: (ES+H, m / z): [M+H]+=482.25.1H NMR (400 MHz, DMSO-tL) 5 11.44 (s, 1H), 8.35 - 8.26 (m, 2H), 8.21 (d, J= 8.5 Hz, 1H), 8.12 (d, J= 1.7 Hz, 1H), 8.03 (s, 1H), 7.71 (dd, J= 8.5, 1.8 Hz, 1H), 7.59 - 7.47 (m, 4H), 5.73 (p, J= 8.5 Hz, 1H), 5.23 (s, 1H), 4.85 (s, 2H), 4.50 (q, J= 7.0 Hz, 2H), 2.59 (dt, J= 20.8, 10.0 Hz, 4H), 1.54 (t, J= 7.0 Hz, 3H), 1.33 (s, 3H).Example 7Step 1: Preparation of (E)-N'-(7-(4-ethoxy-2-phenylquinolin-7-yl)-9-((ls,3s)-3-hydroxy-3- methylcyclobutyl)-8-oxo-8,9-dihydro-7H-purin-6-yl)-N,N-dimethylformimidamide:WSGR Docket No. 67898-707.601

[0189] To a stirred mixture of (E)-N'-(9-((ls,3s)-3-hydroxy-3-methylcyclobutyl)-8-oxo-8,9-dihydro- 7H-purin-6-yl)-N,N-dimethylformimidamide (50 mg, 0.09 mmol, 1.00 equiv.) and 7-bromo-4-ethoxy-2- phenylquinoline (28 mg, 0.09 mmol, 1.00 equiv.) in 1,4-dioxane (2 mb) were added XantPhos Pd G4 (8 mg, 0.01 mmol, 0.10 equiv.), XantPhos (10 mg, 0.02 mmol, 0.20 equiv.) and CS2CO3 (841 mg, 0.26 mmol, 3.00 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100°C overnight under nitrogen atmosphere. The mixture was allowed to cool down to room temperature, fdtered and the filter cake was washed with EtOAc (3 x 10 mL). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (0%-8% McOH / CfECE) to afford (E)-N'-(7-(4-ethoxy-2-phenylquinolin-7-yl)-9-((ls,3s)-3-hydroxy-3- methylcyclobutyl)-8-oxo-8,9-dihydro-7H-purin-6-yl)-N,N-dimethylformimidamide (30 mg, crude) as a light yellow solid. The crude product was used in the next step directly without further purification. LC- MS: (ES+H, m / z): [M+H]+= 538.3 ’H NMR (300 MHz, DMSO-6) 5 8.58 (s, 1H), 8.33 (s, 1H), 8.29 - 8.23 (m, 2H), 8.14 (d, J= 8.8 Hz, 1H), 8.04 (d, J= 2.2 Hz, 1H), 7.62 - 7.47 (m, 5H), 5.35 (s, 1H), 4.57 - 4.42 (m, 3H), 3.16 - 3.03 (m, 2H), 2.95 (s, 3H), 2.45- 2.33 (m, 2H), 2.30 (s, 3H), 1.52 (t, J= 7.0 Hz, 3H), 1.35 (s, 3H).Step 2: Preparation of 6-amino-7-(4-ethoxy-2-phenylquinolin-7-yl)-9-((ls,3s)-3-hydroxy-3- methylcyclobutyl)-7,9-dihydro-8H-purin-8-one:

[0190] To a stirred solution of (E)-N'-(7-(4-ethoxy-2-phenylquinolin-7-yl)-9-((ls,3s)-3-hydroxy-3- methylcyclobutyl)-8-oxo-8,9-dihydro-7H-purin-6-yl)-N,N-dimethylformimidamide (30 mg, 0.06 mmol, 1.00 equiv.) in MeCN (2 mL) were added hydrazine monohydrate (14 mg, 0.28 mmol, 5.00 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere, diluted with EtOAc (20 mL), washed with brine (3 x 10 mL), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0%-10% MeOH / CTECh) to afford 6-amino-7-(4-ethoxy-2-phenylquinolin-7-yl)-9-((ls,3s)-3-hydroxy-3- methylcyclobutyl)-7,9-dihydro-8H-purin-8-one (21 mg, crude) as a brown solid. The crude product (21 mg, crude) was purified by Prep-HPLC with the following conditions (Column: XB ridge Prep OBD Cl 8 Column 30* 150 mm, 5pm; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 60 mL / min mL / min; Gradient: 5% B to 5% B in 1 min, 5% B to 35% B in 2 min, 35% to 53% B in 11 min; Wave Length: 254nm / 220nm nm; RTl(min): 8.58) to afford 6-amino-7-(4-ethoxy-2- phenylquinolin-7-yl)-9-((ls,3s)-3-hydroxy-3-methylcyclobutyl)-7,9-dihydro-8H-purin-8-one (11.7 mg, 43.5%). LC-MS: (ES+H, m / z): [M+H]+= 483.25. ’HNMR (400 MHz, DMSO-6) 5 8.33 - 8.20 (m, 4H), 7.95 (d, J= 1.6 Hz, 1H), 7.63 - 7.47 (m, 5H), 5.91 (s, 2H), 5.22 (s, 1H), 4.56 - 4.42 (m, 3H), 3.13 - 3.03 (m, 2H), 2.41 - 2.30 (m, 2H), 1.54 (t, J= 6.9 Hz, 3H), 1.34 (s, 3H).WSGR Docket No. 67898-707.601Example 8Step 1: Preparation of (E)-N'-(9-((ls,3s)-3-hydroxy-3-methylcyclobutyl)-8-oxo-7-(5- phenylthieno[3,2-b]pyridin-2-yl)-8,9-dihydro-7H-purin-6-yl)-N,N-dimethylformimidamide:

[0191] A solution of (E)-N'-(9-((ls,3s)-3-hydroxy-3-methylcyclobutyl)-8-oxo-8,9-dihydro-7H-purin- 6-yl)-N,N-dimethylformimidamide (200 mg, 0.69 mmol, 1.00 equiv.), 2-bromo-5-phenylthieno[3,2- b]pyridine (400 mg, 1.38 mmol, 2.00 equiv.), (lS,2S)-cyclohexane-l,2-diamine (8 mg, 0.07 mmol, 0.10 equiv.), Cui (13 mg, 0.07mmol, 0.10 equiv.) and K3PO4 (439 mg, 2.07 mmol, 3.00 equiv.) in DMF (5 mL) was stirred at 100°C for 16 h under nitrogen atmosphere. The resulting mixture was added to water (10 mL) and extracted with EtOAc (3 x30 mL). The combined organic layers were washed with brine (2x10 mL), dried over anhydrous Na2SC>4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (CH2Q2 / MeOH 20: 1) to afford (E)-N'-(9-((ls,3s)-3-hydroxy-3-methylcyclobutyl)-8-oxo-7-(5-phenylthieno[3,2-b]pyridin-2-yl)- 8,9-dihydro-7H-purin-6-yl)-N,N-dimethylformimidamide (140 mg, 20.3%) as a brown solid. LC-MS: (ES+H, m / z): [M+H]+=500.2.Step 2: Preparation of 6-amino-9-((ls,3s)-3-hydroxy-3-methylcyclobutyl)-7-(5-phenylthieno[3,2- b]pyridin-2-yl)-7,9-dihydro-8H-purin-8-one:

[0192] A solution of (E)-N'-(9-((ls,3s)-3-hydroxy-3-methylcyclobutyl)-8-oxo-7-(5-phenylthieno[3,2- b]pyridin-2-yl)-8,9-dihydro-7H-purin-6-yl)-N,N-dimethylformimidamide (125 mg, 0.25 mmol, 1.00 equiv.) and hydrazine monohydrate (125 mg, 2.50 mmol, 10.00 equiv.) in methanol (40 mL) was stirred at 25°C for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was diluted with 30 mL water and extracted with CH2Q2 (3 x30 mL). The combined organic layers were washed with brine (2x15 mL), dried over anhydrous Na2SC>4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by trituration with acetonitrile (5 mL x 3) to afford 6-amino-7-{5-phenylthieno[3,2-b]pyridin-2-yl}-9-[(lr,3s)-3-hydroxy-3- methylcyclobutyl]purin-8-one (65.9 mg, 59.2%). LC-MS: (ES+H, m / z): [M+H]+=445.10. *HNMR (400 MHz, DMSO- e) 5 8.55 (d, J= 8.5 Hz, 1H), 8.21 (s, 1H), 8.20 - 8.15 (m, 2H), 8.01 (d, J= 8.6 Hz, 1H), 7.60 - 7.39 (m, 4H), 6.37 (s, 2H), 5.20 (s, 1H) 4.46 (q, J= 8.6 Hz, 1H), 3.05 (td, J= 9.0, 2.8 Hz, 2H), 2.38 - 2.30 (m, 2H), 1.34 (s, 3H).WSGR Docket No. 67898-707.601Example 9Step 1: Preparation of 6-nitroso-7-{5-phenyl-[l,3]thiazolo[4,5-b]pyridin-2-yl}-9-[(lr,3s)-3-hydroxy- 3-methylcyclobutyl]purin-8-one:

[0193] A mixture of 2-bromo-5-phenyl-[l,3]thiazolo[4,5-b]pyridine (250 mg, 0.86 mmol, 1.00 equiv.), (E)-N,N-dimethyl-N'-{8-oxo-9-[(lr,3s)-3-hydroxy-3-methylcyclobutyl]-7H-purin-6- yl}methanimidamide (249.28 mg, 0.86 mmol, 1.00 equiv.), CS2CO3 (699.37 mg, 2.15 mmol, 2.5 equiv.), XantPhos (99.36 mg, 0.17 mmol, 0.20 equiv.) and XantPhos Pd G4 (82.63 mg, 0.09 mmol, 0.10 equiv.) in 1,4-dioxane (10 mL) was stirred at 90°C for 16 h under nitrogen atmosphere. 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 (2 x 80 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with MeOH in CH2C12(0% to 10% gradient in 20 min) to afford 6-nitroso-7-{5-phenyl-[l,3]thiazolo[4,5- b]pyridin-2-yl}-9-[(lr,3s)-3-hydroxy-3-methylcyclobutyl]purin-8-one (270 mg, crude) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+= 474.20.Step 2: Preparation of 6-amino-7-{5-phenyl-[l,3]thiazolo[4,5-b]pyridin-2-yl}-9-[(lr,3s)-3-hydroxy- 3-methylcyclobutyl]purin-8-one:

[0194] To a stirred solution of N-(8-oxo-7-{5-phenyl-[l,3]thiazolo[4,5-b]pyridin-2-yl}-9-[(lr,3s)-3- hydroxy-3-methylcyclobutyl]purin-6-yl)formamide (200 mg, 0.30 mmol, 1.00 equiv.) in EtOH (10 mL) was added HC1 / 1,4-dioxane (3 mL, 4M) dropwise at 25°C. The resulting mixture was stirred at 25°C for 2 h, diluted with H2O (50 mL), basified to pH 11 with ammonium hydroxide and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the crude product (150 mg) was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS 30* 150 mm, 5pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Plow rate: 60 mL / min mL / min; Gradient: 41% B to61% B in 8 min; Wave Length: 254nm / 220nm nm; RTl(min): 8.57) to afford 6-amino-7-{5-phenyl-[l,3]thiazolo[4,5-b]pyridin-2-yl}-9-[(lr,3s)-3-hydroxy-3- methylcyclobutyl]purin-8-one (24.6 mg, 18.68%). LC-MS: (ES+H, m / z): [M+H]+=446.15. 'HNMR (300 MHz, DMSO- e) 5 8.55 (d, J= 8.3 Hz, 1H), 8.23 (s, 1H), 8.19 - 8.10 (m, 2H), 8.05 (s, 2H), 7.92 (d,WSGR Docket No. 67898-707.601J= 8.3 Hz, 1H), 7.60 - 7.41 (m, 3H), 4.49 - 4.45 (m, 2H), 3.19 - 3.10 (m, 2H), 2.54 (d, J= 2.8 Hz, 1H), 2.48 (d, J = 2.8 Hz, 1H), 1.41 (s, 3H).Example 10Step 1: Preparation of 4-amino-3-(2-phenyl-l,3-benzothiazol-5-yl)-l-[(lr,3s)-3-methyl-3- [(triethylsilyl)oxy]cyclobutyl]-6H-pyrrolo[2,3-d]pyridazin-7-one:

[0195] To a stirred solution of 4-amino-3-iodo-l-[(lr,3s)-3-methyl-3-[(triethylsilyl)oxy]cyclobutyl]- 6H-pyrrolo[2,3-d]pyridazin-7-one (300 mg, 0.63 mmol, 1.00 equiv.) and 2 -phenyl- l,3-benzothiazol-5- ylboronic acid (193 mg, 0.75 mmol, 1.20 equiv.) in 1,4-dioxane (30 mL) and H2O (3 mL) were added Pd(dppf)C12CH2C12 (51 mg, 0.06 mmol, 0.10 equiv.) and K2CO3 (262 mg, 1.89 mmol, 3.00 equiv.) in portions at room temperature. The resulting mixture was stirred at 110°C overnight under nitrogen atmosphere, cooled and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH / CH2Q2 (0%-10% gradient in 30 min ) to afford 4-amino-3- (2-phenyl-l,3-benzothiazol-5-yl)-l-[(lr,3s)-3-methyl-3-[(triethylsilyl)oxy]cyclobutyl]-6H-pyrrolo[2,3- d]pyridazin-7-one (190 mg, 53.8%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+= 558.30. 'HNMR (400 MHz, DMSO-d6) 511.40 (s, 1H), 8.25 - 8.18 (m, 2H), 8.15 - 8.10 (m, 2H), 7.80 (s, 1H), 7.62 - 7.59 (m, 4H),5.62 - 5.49 (m, 1H), 4.81 (s, 2H), 2.72 - 2.63 (m,2H), 2.54 (d, J= 2.6 Hz, 2H), 1.45 (s, 3H), 0.94 (t, J= 7.9 Hz, 9H), 0.62 - 0.56 (m, 6H).Step 2: Preparation of 4-amino-3-(2-phenyl-l,3-benzothiazol-5-yl)-l-[(lr,3s)-3-hydroxy-3- methyl cyclobutyl] -6H-pyrr olo [2, 3-d] pyridazin-7-one :

[0196] To a stirred solution of 4-amino-3-(2-phenyl-l,3-benzothiazol-5-yl)-l-[(lr,3s)-3-methyl-3- [(triethylsilyl)oxy]cyclobutyl]-6H-pyrrolo[2,3-d]pyridazin-7-one (170 mg, 0.30 mmol, 1.00 equiv ) in DCM (10 mL) was added HC1 in 1,4-dioxane (4.0 M) (0.15 mL, 0.61 mmol, 2.00 equiv ) dropwise at room temperature. The resulting mixture was stirred at room temperature for 2h under nitrogen atmosphere then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH / CH2CI2 (0%- 15% gradient in 30 min ) to afford crude product (110 mg). The crude product (110 mg) was purified by Prep-HPLC with the following conditions (Column: Xbridge Phenyl OBD Column, 30* 150mm 5pm; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: MeCN; Plow rate: 60 mL / min mL / min; Gradient: 29% B to 45% B in 10 min; Wave Length: 254nm / 220nm nm; RTl(min): 9.38) to afford 4-amino-3-(2-phenyl-l,3-benzothiazol-5-yl)-l-[(lr,3s)-3- hydroxy-3 -methylcyclobutyl] -6H-pyrrolo [2,3 -d]pyridazin-7-one (68.5 mg, 50.6%). LC-MS: (ES+H, m / z): [M+H]+= 444.05. ’H NMR (400 MHz, DMSO-6) 511.42 (s, 1H), 8.24 (d, J = 8.3 Hz, 1H), 8.19 (d,WSGR Docket No. 67898-707.601J= 1.6 Hz, 1H), 8.16 - 8.10 (m, 2H), 7.95 (s, 1H), 7.65 - 7.56 (m, 4H), 5.73 - 5.68 (m, 1H), 5.22 (s,lH), 4.82 (s, 2H), 2.64 - 2.56 (m, 2H), 2.55 (d, J= 2.5 Hz, 2H), 1.33 (s, 3H).Example 11INT-8 Example 11

[0197] A mixture of 4-amino-3-bromo-l-((ls,3s)-3-hydroxy-3-methylcyclobutyl)-l,6-dihydro-7H- pyrrolo[2,3-d]pyridazin-7-one (100 mg, 0.32 mmol, 1.00 equiv.), 5-phenylthieno[3,2-b]pyridin-2- ylboronic acid (163 mg, 0.64 mmol, 2.00 equiv.), Pd(dppf)C12CH2C12 (26 mg, 0.03 mmol, 0.10 equiv.) and K2CO3 (132. mg, 0.96 mmol, 3.00 equiv.) in 1,4-dioxane (1 mL) was stirred at 110°C for 16 h under nitrogen atmosphere. The resulting mixture was fdtered and the fdter cake was washed with DCM (2x30 mL). The filtrate was concentrated under reduced pressure and the residue was purified by Prep-TLC (100% EA ) followed by further purification using Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column 30* 150 mm, 5pm; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 5% B to 5% B in l min, 5% B to 27% B in 2 min, 27% to 43% B in 11 min; Wave Length: 254nm / 220nm nm; RTl(min): 9.12) to afford 4- amino-l-((ls,3s)-3-hydroxy-3-methylcyclobutyl)-3-(5-phenylthieno[3,2-b]pyridin-2-yl)-l,6-dihydro-7H- pyrrolo[2,3-d]pyridazin-7-one (26.2 mg, 18.5%). LC-MS: (ES+H, m / z): [M+H]+=444.15. 'HNMR (400 MHz, DMSO- e) 5 11.54 (s, 1H), 8.55 (d, J= 8.6 Hz, 1H), 8.22 - 8.15 (m, 2H), 8.09 (s, 1H), 7.97 (d, J= 8.5 Hz, 1H), 7.74 (d, J= 0.7 Hz, 1H), 7.57 - 7.50 (m, 2H), 7.50 - 7.43 (m, 1H), 5.67 (p, J= 8.5 Hz, 1H), 5.26 (s, 1H), 5.14 (s, 2H), 2.66 - 2.51 (m, 4H), 1.33 (s, 3H).WSGR Docket No. 67898-707.601Example 12Step 1: Preparation of (ls,3r)-3-methoxy-3-methylcyclobutyl 4-nitrobenzoate:

[0198] To a stirred solution of (ls,3r)-3-hydroxy-3-methylcyclobutyl 4-nitrobenzoate (800 mg, 3.18 mmol, 1.00 equiv.) and trimethyloxonium tetrafluoroborate (1.88 g, 12.74 mmol, 4 equiv.) in CH2CI2 (10 mL) was added N1,N1, N8,N8 -tetramethylnaphthalene -1,8 -diamine (2.73 g, 12.74 mmol, 4 equiv.) 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 layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SC>4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with EtOAc in petroleum ether (0% to 20% gradient in 20 min) to afford (ls,3r)-3-methoxy-3-methylcyclobutyl 4-nitrobenzoate (670 mg, 79.32%) as a yellow oil. ’H NMR (400 MHz, DMSO-6) 5 8.40 - 8.29 (m, 2H), 8.24 - 8.12 (m, 2H), 5.24 - 5.14 (m, 1H), 3.12 (s, 3H), 2.69 - 2.56 (m, 2H), 2.19 - 2.02 (m, 2H), 1.36 (s, 3H).Step 2: Preparation of (ls,3r)-3-methoxy-3-methylcyclobutan-l-ol:

[0199] To a stirred solution of (ls,3r)-3-methoxy-3-methylcyclobutyl 4-nitrobenzoate (530 mg, 2.00 mmol, 1.00 equiv.) in THF (10 mL) was added LiOHH2O (168 mg, 4.00 mmol, 2.00 equiv.) in H2O (5 mL) dropwise at 0°C. The resulting mixture was stirred at 25 °C for 3 h, diluted with H2O (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2x50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford (ls,3r)-3-methoxy-3-methylcyclobutan-l-ol (280 mg, crude) as a yellow oil. The crude product was used in the next step directly without further purification. 'H NMR (400 MHz, DMSO-t / e) 5 4.91 (d, J= 5.4 Hz, 1H), 4.21 - 4.00 (m, 1H), 3.03 (s, 3H), 2.37 - 2.24 (m, 2H), 1.71 - 1.60 (m, 2H), 1.26 (s, 3H).Step 3: Preparation of 5-bromo-4-cyano-2-[(lr,3s)-3-methoxy-3-methylcyclobutyl]pyrazole-3- carboxylate:

[0200] A solution of (E)-N-[[(propan-2-yloxy)carbonyl]imino](propan-2-yloxy)formamide (1.95 g, 9.64 mmol, 4.00 equiv.) and PPhs (3.16 g, 12.05 mmol, 5.00 equiv.) in THF (40 mL) was stirred at 0°CWSGR Docket No. 67898-707.601 for 30 min under nitrogen atmosphere. The mixture above was added to a solution of (ls,3r)-3-methoxy- 3-methylcyclobutan-l-ol (280 mg, 2.41 mmol, 1.00 equiv.) and ethyl 5-bromo-4-cyano-2H-pyrazole-3- carboxylate (588 mg, 2.41 mmol, 1.00 equiv.) in THF (40 mb). The resulting mixture was stirred at 50°C for 2h then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc in petroleum ether (10% to 40% gradient in 30 min) to afford ethyl 5-bromo-4-cyano-2-[(lr,3s)-3-methoxy-3-methylcyclobutyl]pyrazole-3-carboxylate (560 mg, 67.89%) as a yellow oil. LC-MS: (ES+H, m / z): [M+H]+=342.05. ’H NMR (400 MHz, DMSO-6) 5 5.35 - 5.21 (m, 1H), 4.48 - 4.25 (m, 2H), 3.11 (s, 3H), 2.66 - 2.56 (m, 2H), 2.47 - 2.36 (m, 2H), 1.38 - 1.29 (m, 6H). Step 4: Preparation of 4-amino-3-bromo-l-[(lr,3s)-3-methoxy-3-methylcyclobutyl]-6H- pyrazolo[3,4-d]pyridazin-7-one:

[0201] To a stirred solution of ethyl 5-bromo-4-cyano-2-[(lr,3s)-3-methoxy-3- methylcyclobutyl]pyrazole-3-carboxylate (560 mg, 1.64 mmol, 1.00 equiv.) in EtOH (5 mL) was added hydrazine monohydrate (1 mL) dropwise. The resulting mixture was stirred at 80°C for Ih then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in CH2CI2 (0% to 10% gradient in 20 min) to afford 4-amino-3-bromo-l-[(lr,3s)-3- methoxy-3-methylcyclobutyl]-6H-pyrazolo[3,4-d]pyridazin-7-one (260 mg, 48.41%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+=328.00. ’H NMR (400 MHz, DMSO-6) 5 11.77 (s, IH), 5.80 - 5.50 (m, 3H), 3.14 (s, 3H), 2.72 - 2.58 (m, 2H), 2.48 - 2.37 (m, 2H), 1.35 (s, 3H).Step 5: Preparation of 4-amino-3-(2-phenylquinolin-7-yl)-l-[(lr,3s)-3-methoxy-3- methylcyclobutyl]-6H-pyrazolo[3,4-d]pyridazin-7-one:

[0202] A mixture of 4-amino-3-bromo-l-[(lr,3s)-3-methoxy-3-methylcyclobutyl]-6H-pyrazolo[3,4- d]pyridazin-7-one (150 mg, 0.46 mmol, 1.00 equiv.), 2-phenyl-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoline (227 mg, 0.69 mmol, 1.50 equiv.), Pd(dppf)C12CH2C12 (34 mg, 0.05 mmol, 0.10 equiv.) and K2CO3 (126.34 mg, 0.92 mmol, 2.00 equiv.) in 1,4-dioxane (4.5 mL) and H2O (1 mL) was stirred at 100°C for 2 h under nitrogen atmosphere, diluted with H2O (40 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 60 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with MeOH in CH2CI2 (0% to 10% gradient in 15 min) to afford crude product. The crude product (240 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column 30* 150 mm, 5pm; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 5% B to 5% B in 1 min, 5% B to 40% B in 2 min, 40% to 58% B in 11 min; Wave Length: 254nm / 220nm nm; RTl(min): 10.2) to afford 4-amino-3-(2-phenylquinolin-7-yl)-l-[(lr,3s)-3-methoxy-3-methylcyclobutyl]- 6H-pyrazolo[3,4-d]pyridazin-7-one (90.4 mg, 43.71%). LC-MS: (ES+H, m / z): [M+H]+=453.20. 'H NMR (400 MHz, DMSO-6) 5 11.82 (s, IH), 8.59 - 8.51 (m, IH), 8.46 - 8.39 (m, IH), 8.35 - 8.28 (m, 2H), 8.23 (d, J= 8.6 Hz, IH), 8.15 (d, J= 8.4 Hz, IH), 7.95 (dd, J= 8.4, 1.7 Hz, IH), 7.62 - 7.47 (m, 3H), 5.91 - 5.73(m, IH), 5.27 (s, 2H), 3.16 (s, 3H), 2.90 - 2.73 (m, 2H), 2.57 - 2.51 (m, 2H), 1.40 (s, 3H).WSGR Docket No. 67898-707.601Example 13Step 1: Preparation of (E)-N'-(3-(4-ethoxy-2-phenylquinolin-7-yl)-l-((ls,3s)-3-hydroxy-3- methylcyclobutyl)-2-oxo-2,3-dihydro-lH-imidazo[4,5-c]pyridin-4-yl)-N,N-dimethylformimidamide:

[0203] A mixture of (E)-N,N-dimethyl-N'-{2-oxo-l-[(lr,3s)-3-hydroxy-3-methylcyclobutyl]-3H- imidazo[4,5-c]pyridin-4-yl}methanimidamide (350 mg, 1.21 mmol, 1.0 equiv. )7-bromo-4-ethoxy-2- phenylquinoline (476 mg, 1.45 mmol, 1.2 equiv.), XantPhos Pd G4 (146 mg, 0.15 mmol, 0.10 equiv.), XantPhos (140 mg, 0.24 mmol, 0.20 equiv.) and CS2CO3 (1.18 g, 3.63 mmol, 3.0 equiv.) in dioxane (8 mL) was stirred at 110°C for overnight 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 MeOH / CH2Q2 (0%-10% gradient in 35 min) to afford 4- amino-3-(4-ethoxy-2-phenylquinolin-7-yl)-l-[(lr,3s)-3-hydroxy-3-methylcyclobutyl]imidazo[4,5- c]pyridin-2-one (190 mg, 36.2%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+= 537.4. *HNMR (400 MHz, DMSO- e) 5 8.38 (s, 1H), 8.31 -8.26 (m, 2H), 8.13 (d, J=8.8 Hz, 1H), 7.98 -7.94 (m, 2H), 7.57 -7.49 (m, 5H), 7.29 (d, J=5.5 Hz, 1H), 5.38 (s, 1H), 4.54 -4.48 (m, 2H), 2.86 (s, 4H), 2.48 - 2.42 (m, 2H), 2.08 (s, 3H), 1.53 (t, J= 7.0 Hz, 3H), 1.37 (s, 3H), 1.23 (s, 2H).Step 2: Preparation of 4-amino-3-(4-ethoxy-2-phenylquinolin-7-yl)-l-((ls,3s)-3-hydroxy-3- methylcyclobutyl)-l,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one:

[0204] A mixture of (E)-N'-[3-(4-ethoxy-2-phenylquinolin-7-yl)-2-oxo-l-[(lr,3s)-3-hydroxy-3- methylcyclobutyl]imidazo[4,5-c]pyridin-4-yl]-N,N-dimethylmethanimidamide (150 mg, 0.34 mmol, 1.0 equiv.) and hydrazine monohydrate (2 mL) in MeCN (1 mL) was stirred at 50°C overnight under nitrogen atmosphere. The resulting mixture was diluted with water (5mL) and extracted with EtOAc (3 x 50 mL). The organic layer was dried over anhydrous Na2SC>4and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with MeOH / CH2CI2 (0%- 15% gradient in 35 min) to afford crude product (100 mg). The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column 30* 150 mm, 5pm; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Plow rate: 60 mL / min; Gradient (B%): 32% B to 52% B in 10 min; Wave Length: 254nm / 220 nm; RTl(min): 9.35 min) to afford 4-amino-3 -(4-ethoxy-2-phenylquinolin-7-yl)-l-(( Is, 3 s)-3 -hydroxy-3 - methylcyclobutyl)-l,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (42.5 mg, 31.5%). LC-MS: (ES+H, m / z): [M+H]+= 482.3. ’H NMR (400 MHz, DMSO-6) 5 8.32 - 8.28 (m, 2H), 8.26 (d, J= 8.8 Hz, 1H),WSGR Docket No. 67898-707.6017.98 (d, J= 2.1 Hz, 1H), 7.84 (d, J= 5.6 Hz, 1H), 7.61 (s, 1H), 7.58 - 7.50 (m, 4H), 7.07 (d, J = 5.6 Hz, 1H), 5.30 (s, 1H), 4.88 (s, 2H), 4.55 - 4.46 (m, 3H), 2.84 (td, J= 9.3, 2.9 Hz, 2H), 2.46 (ddd, J= 9.5, 8.1, 2.8 Hz, 2H), 1.54 (t, J= 6.9 Hz, 3H), 1.37 (s, 3H).Example 14Step 1: Preparation of N5-(4-ethoxy-6-fluoro-2-phenylquinolin-7-yl)-N4,N4-bis(4-methoxybenzyl)- N6-((ls,3s)-3-methyl-3-((triethylsilyl)oxy)cyclobutyl)pyrimidine-4,5,6-triamine:

[0205] A mixture of N4,N4-bis(4-methoxybenzyl)-N6-((ls,3s)-3-methyl-3- ((triethylsilyl)oxy)cyclobutyl)pyrimidine-4,5,6-triamine (300 mg, 0.53 mmol, 1.00 equiv.), 7-bromo-4- ethoxy-6-fluoro-2-phenylquinoline (184 mg, 0.53 mmol, 1.00 equiv.), XantPhos Pd G4 (51 mg, 0.05 mmol, 0.10 equiv.), CS2CO3 (520 mg, 1.60 mmol, 3.00 equiv.) and XantPhos (62 mg, 0.11 mmol, 0.20 equiv.) in dioxane (10 mL) was stirred at 110°C for 16 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature, fdtered and the filter cake was washed with DCM (3 x 30 mL). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with PE / EA (1: 1) to afford N5-(4-ethoxy-6-fluoro-2-phenylquinolin-7-yl)- N4,N4-bis(4-methoxybenzyl)-N6-((ls,3s)-3-methyl-3-((triethylsilyl)oxy)cyclobutyl)pyrimidine-4,5,6- triamine (450 mg, 88.3%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+=829.5. 'HNMR (400 MHz, DMSO- e) 5 8.25 - 8.17 (m, 2H), 8.11 (s, 1H), 7.56 (d, J= 12.1 Hz, 1H), 7.52 - 7.42 (m, 3H), 7.33 (s, 1H), 7.19 (d, J= 2.2 Hz, 1H), 7.01 - 6.94 (m, 4H), 6.67 (d, J= 7.0 Hz, 1H), 6.64 - 6.58 (m, 4H), 6.53 (d, J= 8.4 Hz, 1H), 4.79 (s, 2H), 4.41 (q, J= 6.9 Hz, 2H), 4.22 (s, 2H), 3.54 (s, 6H), 2.36 (s, 2H), 1.96 (s, 2H), 1.49 (t, J= 6.9 Hz, 3H), 1.31 (s, 3H), 0.79 (t, J= 7.9 Hz, 9H), 0.43 (q, J= 7.9 Hz, 6H).Step 2: Preparation of 6-(bis(4-methoxybenzyl)amino)-7-(4-ethoxy-6-fluoro-2-phenylquinolin-7-yl)- 9-((ls,3s)-3-hydroxy-3-methylcyclobutyl)-7,9-dihydro-8H-purin-8-one:WSGR Docket No. 67898-707.601

[0206] To a solution ofN5-(4-ethoxy-6-fluoro-2-phenylquinolin-7-yl)-N4,N4-bis(4-methoxybenzyl)- N6-((ls,3s)-3-methyl-3-((triethylsilyl)oxy)cyclobutyl)pyrimidine-4,5,6-triamine (440 mg, 0.46 mmol, 1.00 equiv, 86.6% purity) and DIEA (297 mg, 2.30 mmol, 5.00 equiv.) in DCM (15 mL) was added ditrichloromethyl carbonate (82 mg, 0.28 mmol, 0.60 equiv.) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0~25°C for 2 h, quenched by the addition of ice water (20 mL) at 0°C and stirred for 30 min. The resulting mixture was diluted with water (50mL) and extracted with CH2Q2 (3 x 50 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na2SC>4, and fdtered. The fdtrate was concentrated under reduced pressure to afford 6-(bis(4-methoxybenzyl) amino)-7-(4-ethoxy-6-fluoro-2-phenylquinolin-7-yl)-9-((ls,3s)-3-hydroxy-3- methylcyclobutyl)-7,9-dihydro-8H-purin-8-one (300 mg, crude) as a brown solid. LC-MS: (ES+H, m / z): [M+H]+=741.3.1H NMR (400 MHz, DMSO-6) 5 8.53 (s, 1H), 8.43 - 8.33 (m, 3H), 8.13 (dd, J= 12, 3.4 Hz, 1H), 7.92 (d, J= 10.4 Hz, 1H), 7.68 (s, 1H), 7.62 - 7.49 (m, 3H), 6.86 - 6.77 (m, 4H), 6.65 - 6.57 (m, 4H), 4.63 - 4.46 (m, 3H), 4.11 (d, J= 14.9 Hz, 2H), 3.65 (d, J= 14.9 Hz, 2H), 3.55 (s, 6H), 3.23 (dd, J= 12.7, 6.3 Hz, 2H), 2.43 (t, J= 9.3 Hz, 2H), 1.55 (t, J= 7.0 Hz, 3H), 1.22 (s, 3H).Step 3: Preparation of 6-amino-7-(4-ethoxy-6-fluoro-2-phenylquinolin-7-yl)-9-((ls,3s)-3-hydroxy-3- methylcyclobutyl)-7,9-dihydro-8H-purin-8-one

[0207] A solution of 6-(bis(4-methoxybenzyl)amino)-7-(4-ethoxy-6-fluoro-2-phenylquinolin-7-yl)-9- ((ls,3s)-3-hydroxy-3-methylcyclobutyl)-7,9-dihydro-8H-purin-8-one (200 mg, 0.27 mmol, 1.00 equiv.) in DCE (5 mL) and trifluoroacetic acid (5 mL) was stirred at 50°C for 16 h under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, diluted with DCM (50 mL) and saturated K2CO3 (aq. 50 mL) and stirred for 30 min. The mixture was extracted with CH2Q2 (2 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4, and fdtered. The fdtrate was concentrated under reduced pressure and the residue (120 mg) was purified by Prep- HPLC with the following conditions (Column: XBridge Prep OBD C18 Column 30* 150 mm, 5pm; Mobile Phase A: 10mmol / L NH4HC03+0.05%NH3H20), Mobile Phase B: MEOH; Plow rate: 60 mL / min; Gradient (B%): 20% B to 20% B in 1 min, 20% B to 50% B in 2 min, 50% to 68% B in 11 min; Wave Length: 254nm / 220 nm; RTl(min): 11.57 min) to afford 6-amino-7-(4-ethoxy-6-fluoro-2- phenylquinolin-7-yl)-9-[(lr,3s)-3-hydroxy-3-methylcyclobutyl]purin-8-one (38.4 mg, 28.4%). LC-MS: (ES+H, m / z): [M+H]+=501.25. 'HNMR (400 MHz, DMSO-6) 5 8.32 - 8.26 (m, 2H), 8.18 (s, 1H), 8.09 (d, J= 7.3 Hz, 1H), 7.95 (d, J= 10.5 Hz, 1H), 7.65 (s, 1H), 7.59 - 7.48 (m, 3H), 5.99 (s, 2H), 5.19 (s, 1H), 4.59 - 4.41 (m, 3H), 3.13 - 3.00 (m, 2H), 2.38 (td, J= 8.2, 2.7 Hz, 2H), 1.54 (t, J= 7.0 Hz, 3H), 1.34 (s, 3H).19F NMR (376 MHz, DMSO-6) 5 -122.95.Example A: Biochemical Assays

[0208] The inhibitory activity against IGF-1R and insulin receptor (IR) was measured using an ADP- Glo assay (Promega). Purified GST fusion protein containing the cytoplasmic kinase domain of human IGF-1R (CamaBio catalog number: 08-141) or IR (CamaBio catalog number: 08-142) was expressed in Sf9 cells. The peptide substrate, Axltide, was based on the mouse insulin receptor substrate 1 (amino acidWSGR Docket No. 67898-707.601979-989). The reaction buffer contained 10 mM MgCE, 0.01% Brij-35, 2 mM DTT, 0.05% BSA, 1 mM EGTA and 50 mM of HEPES (pH7.5). The kinase reaction containing 0.3 nM enzyme, 0.2mg / ml peptide substrate and compounds were pre-incubated for 30 minutes before initiating the reaction with ATP (final concentration of 100 mM) for 90 minutes at room temperature. The reaction was terminated upon addition of ADP-Glo reagent. After 1 hour, the Kinase Detection Reagent was added for an additional hour of incubation to convert ADP to ATP. Luminescence signal was collected on an Envision plate reader (PerkinElmer).

[0209] The percent (%) inhibition at each concentration of compound was calculated based on and relative to the luminescence signal in the Max and Min control wells contained within each assay plate. The Max control wells contained enzyme and substrate as 0% inhibition, and the Min control wells only contained substrate without enzyme as 100% inhibition. The concentrations and % inhibition values for tested compounds were plotted and the concentration of compound required for 50% inhibition (IC50) was determined with a four-parameter logistic dose response equation. The activity for the representative examples of the invention is shown in the following table, wherein A: 0 < IC50 < 500 nM; B: 500 nM < IC5o < 2 pM; C: 2 pM < IC5o < 10 pM; D: IC5o > 10 pM

[0210] The data from Examples A are provided in Table 2.Table 2

[0211] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims

WSGR Docket No. 67898-707.601CLAIMSWHAT IS CLAIMED IS:

1. A compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof:wherein:X1is -N- or -CR1-;R1is 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 -CR2-;R2is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -SF5, -SRa, -NRcRd, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl;Ring A is a bicyclic heteroaryl; provided that Ring A is not phthalazin- l(2H)-one or isoquinolin- 1(2H)- one; each R3is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -O(C=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; n is 0, 1, 2, 3, or 4;Ring B is monocyclic cycloalkyl, monocyclic heterocycloalkyl, aryl, or heteroaryl; each R4is 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-C6haloalkyl, Ci-C6hydroxyalkyl, 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;WSGR Docket No. 67898-707.601 and / or two R4on the same atom are taken together to form an oxo; m is 0, 1, 2, 3, or 4;W is absent or -[C(R5)2]q-; q is 1, 2, or 3; each R5is independently hydrogen, deuterium, halogen, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, or cycloalkyl; or two R5are taken together to form a cycloalkyl or heterocycloalkyl;Ring C is cycloalkyl or heterocycloalkyl; each R6is 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 R6a; and / or two R6on the same atom are taken together to form an oxo; each R6ais 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-C6haloalkyl, Ci-C6hydroxyalkyl, 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 R6aon the same atom are taken together to form an oxo; p is 0, 1, 2, 3, or 4; each Rais independently Ci-Cealkyl, Ci-Cedeuteroalkyl, 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; each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cedeuteroalkyl, 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; each Rcand Rdare independently hydrogen, Ci-Cealkyl, Ci-Cedeuteroalkyl, 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;WSGR Docket No. 67898-707.601 or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently deuterium, halogen, -CN, -OH, -OCi-C3alkyl, -OCi-C3haloalkyl, -O(C=O)NH2, - O(C=O)NHCi-C3alkyl, -O(C=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-C3deuteroalkyl, Ci-C3haloalkyl, 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:X1is -CR1-.

3. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:X1is -N-.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:X2is -CR2-.

5. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:X2is -N-.

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

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

8. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:WSGR Docket No. 67898-707.6019. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:R1is hydrogen.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:R2is hydrogen or -OH.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:R2is hydrogen.

12. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:R2is -OH.

13. A compound of Formula (II), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof:wherein:U is N or C;T is N or C; provided that U and T are not both N;Y1is N or C;Y2is N or CR7;R7is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -SF5, -SRa, -NRcRd, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, or cycloalkyl;Y3is N or C;Ring A is a bicyclic heteroaryl; provided that Ring A is not phthalazin- l(2H)-one or isoquinolin- 1(2H)- one; each R3is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -O(C=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. 67898-707.601NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -NRbS(=O)2NRcRd, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6deuteroalkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, 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; n is 0, 1, 2, 3, or 4;Ring B is monocyclic cycloalkyl, monocyclic heterocycloalkyl, aryl, or heteroaryl; each R4is 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 R4on the same atom are taken together to form an oxo; m is 0, 1, 2, 3, or 4;W is absent or -[C(R5)2]q-; q is 1, 2, or 3; each R5is independently hydrogen, deuterium, halogen, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, or cycloalkyl; or two R5are taken together to form a cycloalkyl or heterocycloalkyl;Ring C is cycloalkyl or heterocycloalkyl; each R6is 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 R6a; and / or two R6on the same atom are taken together to form an oxo; each R6ais 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 R6aon the same atom are taken together to form an oxo;WSGR Docket No. 67898-707.601 p is 0, 1, 2, 3, or 4; each Rais independently Ci-Cealkyl, Ci-Cedeuteroalkyl, 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; each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cedeuteroalkyl, 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; each Rcand Rdare independently hydrogen, Ci-Cealkyl, Ci-Cedeuteroalkyl, 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; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently deuterium, halogen, -CN, -OH, -OCi-C3alkyl, -OCi-C3haloalkyl, -O(C=O)NH2, - O(C=O)NHCi-C3alkyl, -O(C=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-C3deuteroalkyl, Ci-C3haloalkyl, Ci-C3hydroxyalkyl, Ci-C3aminoalkyl, Ci-Csheteroalkyl, C’s-Cecycloalkyl. or heterocycloalkyl; and / or two R on the same atom are taken together to form an oxo; provided that the compound is not14. The compound of claim 13, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:U is N and T is C.

15. The compound of claim 13, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:WSGR Docket No. 67898-707.601U is C and T is N.

16. The compound of claim 13, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:U is C and T is C.

17. The compound of any one of claims 13-16, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:Y1is N.

18. The compound of any one of claims 13-16, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:Y1is C.

19. The compound of any one of claims 13-18, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:Y2is CR7.

20. The compound of any one of claims 13-18, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:Y2is N.

21. The compound of any one of claims 13-20, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:Y3is N.

22. The compound of any one of claims 13-20, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:Y3is C.

23. The compound of claim 13, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

24. The compound of claim 13, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

25. The compound of claim 13, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:WSGR Docket No. 67898-707.60126. The compound of claim 13, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

27. The compound of claim 13, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

28. The compound of any one of claims 13-27, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:R7is hydrogen.

29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:Ring A is a bicyclic heteroaryl.

30. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:Ring A is a quinolinyl, thienopyridinyl, thiazolopyridinyl, or benzothiazolyl.

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

32. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: each R3is independently deuterium, halogen, -CN, -OH, -ORa, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2- Cealkynyl, or cycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, and cycloalkyl is independently optionally substituted with one or more R.

33. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:WSGR Docket No. 67898-707.601 each R3is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci- Cedeuteroalkyl, or Ci-Cehaloalkyl.

34. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: each R3is independently deuterium, halogen, -CN, -OH, -ORa, or -NRcRd.

35. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: each R3is independently halogen or -ORa.

36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: n is 0, 1, or 2.

37. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: n is 0 or 1.

38. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: n is 1 or 2.

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

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

41. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:WSGR Docket No. 67898-707.601Ring B is phenyl.

42. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:Ring B is 5- to 6-membered heteroaryl.

43. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:Ring B is 6-membered heteroaryl.

44. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:Ring B is 5-membered heteroaryl.

45. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:Ring B is monocyclic cycloalkyl or monocyclic heterocycloalkyl.

46. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:Ring B is monocyclic Cs-Cs cycloalkyl.

47. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:Ring B is monocyclic C;-C„ cycloalkyl.

48. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:Ring B is monocyclic 4- to 8-membered heterocycloalkyl.

49. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:Ring B is monocyclic 4- to 6-membered heterocycloalkyl.

50. The compound of any one of claims 1-49, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: each R4is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci- Cedeuteroalkyl, or Ci-Cehaloalkyl.

51. The compound of any one of claims 1-50, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: each R4is independently halogen or Ci-Cealkyl.

52. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: m is 0, 1, or 2.

53. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: m is 0 or 1.WSGR Docket No. 67898-707.60154. The compound of any one of claims 1-53, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: m is 1 or 2.

55. The compound of any one of claims 1-54, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:Ring C is C’s-Cecycloalkyl.

56. The compound of any one of claims 1-55, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:Ring C is cyclobutyl.

57. The compound of any one of claims 1-56, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: each R6is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci- Cedeuteroalkyl, or Ci-Cehaloalkyl.

58. The compound of any one of claims 1-57, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: each R6is independently -OH or Ci-Cealkyl.

59. The compound of any one of claims 1-58, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: p is 0, 1, or 2.

60. The compound of any one of claims 1-59, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: p is 1 or 2.

61. The compound of any one of claims 1-60, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: p is 2.

62. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:W is absent.

63. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:W is -CH2-.

64. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, selected from a compound found in the specification.

65. A pharmaceutical composition comprising a compound of any one of claims 1 -64, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable excipient.WSGR Docket No. 67898-707.60166. 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 1-64, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

67. 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 1-64, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

68. The method of claim 67, wherein the disease or disorder is thyroid eye disease (TED).

69. The method of claim 67, wherein the disease or disorder is AMD (Age-related MacularDegeneration).

70. The method of claim 67, wherein the disease or disorder is Idiopathic orbital inflammation (IOI).

71. The method of claim 67, wherein the disease or disorder is an inflammatory disease.

72. The method of claim 67, wherein the disease or disorder is cancer.

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