105807.005002 (Series 2) – PCTl Application MUTANT PI3K-ALPHA INHIBITORS AND THEIR USE AS PHARMACEUTICALS [0001] This application claims the benefit of priority of United States Provisional Applications No.63/380,270, filed October 20, 2022, the disclosure of which is hereby incorporated by reference in its entirety. TECHNICAL FIELD [0002] The disclosure is directed to mutant PI3Kα inhibitors and methods of their use. BACKGROUND [0003] Class I PI3Ks consist of a p85 regulatory subunit in complex with a p110 catalytic subunit (p110α, β, γ or δ) (1). p110α, coded by the PIK3CA gene shows a broad tissue distribution and the binding of a phosphorylated receptor tyrosine kinase (RTK) activates p110a through the release of a subset of inhibitory contacts with p85. P110α generate phosphatidylinositol3,4,5-trisphosphate (PtdIns(3,4,5)P3; also known as PIP3), which interact with 3-phosphoinositide-binding Pleckstrin homology (PH) domains found in diverse proteins, including protein kinases such as AKT resulting in its phosphorylation at Thr308 and Ser473 triggering a cascade of mitogenic signaling (2). This signaling results in a multitude of cellular effects including proliferation, survival, chemotaxis, cellular trafficking, motility, metabolism, inflammatory and allergic responses, transcription and translation (3). [0004] PIK3CA hotspot mutations are one of the most frequent oncogenic mutations in cancer. Common hotspot mutations in PIK3CA helical (E542K, E545K) and kinase (H1047R) domains function by perturbing local interfaces between p85 and p110α and increasing dynamic events required for catalysis on membranes (1,4). Oncogenic mutations in the PIK3CA gene increase lipid kinase activity and transform cells and are the drivers of the pathology. These mutations are observed in a broad range of cancers including breast, colon, uterine, bladder, cervical, and lung cancer (5,6,7). [0005] Given its key role in cancer PI3Ks have been the focus of extensive drug development. In 2017, the pan-class I PI3K inhibitor copanlisib (Aliqopa/BAY 80-6946; Bayer) was approved for follicular lymphoma and in 2019, the PI3Kα inhibitor alpelisib (Piqray/NVP-BYL719; Novartis) was approved for the treatment of advanced breast cancer, in combination with the estrogen receptor (ER) downregulator fulvestrant (1,8). There are a number of PI3Kα selective inhibitors that are in late stage clinical trials (1). 105807.005002 (Series 2) – PCTl Application [0006] Although these approvals and early clinical data have validated the pathway as a viable drug target, the development of PI3K inhibitors has proved challenging, with progress hampered by poor drug tolerance (9). The lack of Clinical benefit and poor tolerability of pan-class I PI3K and dual PI3Kα/PI3Kδ, or even PI3Kα selective inhibitors have impacted the realization of full clinical utility of these compounds. The toxicity of PI3K inhibitors is dependent on their isoform selectivity profile. Inhibition of PI3Kα is associated with hyperglycemia and rash, whereas inhibition of PI3Kδ or RI3Kγ is associated with diarrhea, myelosuppression, and transaminitis (1). A recent study reported that while progression of disease is the largest contributor to Alpelisib discontinuation, adverse events are the leading cause for early drug cessation (10). Shorter Alpelisib exposure is associated with greater cancer progression. Therefore, selective inhibitors of PI3Kα mutants H1047R and/or E545K/E543K while sparing wild type PI3Kα, β, γ or δ could enhance the therapeutic margin and result in therapies that benefit cancer patients that carry these mutations. [0007] Additional small molecule mutant PI3Kα selective inhibitors are needed. [0008] (1) PI3K inhibitors are finally coming of age. Vanhaesebroeck B, Perry MWD, Brown JR, André F, Okkenhaug K. Nat Rev Drug Discov.2021 Oct;20(10):741-769. doi: 10.1038/s41573-021-00209-1. Epub 2021 Jun 14. PMID: 34127844. [0009] (2) AKT/PKB Signaling: Navigating the Network. Manning BD, Toker A. Cell.2017 Apr 20;169(3):381-405. doi: 10.1016/j.cell.2017.04.001. PMID: 28431241. [0010] (3) Fruman, D. A. et al. The PI3K pathway in human disease. Cell 170, 605–635 (2017). PMID: 28802037 PMCID: PMC5726441 DOI: 10.1016/j.cell.2017.07.029. [0011] (4) PIK3CA mutations in advanced cancers: characteristics and outcomes. Janku F, Wheler JJ, Naing A, Stepanek VM, Falchook GS, Fu S, Garrido-Laguna I, Tsimberidou AM, Piha-Paul SA, Moulder SL, Lee JJ, Luthra R, Hong DS, Kurzrock R. Oncotarget.2012 Dec;3(12):1566-75. doi: 10.18632/oncotarget.716. PMID: 23248156. [0012] (5) Frequency and spectrum of PIK3CA somatic mutations in breast cancer. Martínez-Sáez O, Chic N, Pascual T, Adamo B, Vidal M, González-Farré B, Sanfeliu E, Schettini F, Conte B, Brasó-Maristany F, Rodríguez A, Martínez D, Galván P, Rodríguez AB, Martinez A, Muñoz M, Prat A. Breast Cancer Res.2020 May 13;22(1):45. doi: 10.1186/s13058- 020-01284-9. PMID: 32404150. [0013] (6) Cancer-specific mutations in PIK3CA are oncogenic in vivo. Bader AG, Kang S, Vogt PK. Proc Natl Acad Sci U S A.2006 Jan 31;103(5):1475-9. doi: 10.1073/pnas.0510857103. Epub 2006 Jan 23. PMID: 16432179. - 2 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application [0014] (7) Oncogenic Signaling Pathways in The Cancer Genome Atlas. Sanchez-Vega F, Mina M, Armenia J, Chatila WK, Luna A, La KC, Dimitriadoy S, Liu DL, Kantheti HS, Saghafinia S, Chakravarty D, Daian F, Gao Q, Bailey MH, Liang WW, Foltz SM, Shmulevich I, Ding L, Heins Z, Ochoa A, Gross B, Gao J, Zhang H, Kundra R, Kandoth C, Bahceci I, Dervishi L, Dogrusoz U, Zhou W, Shen H, Laird PW, Way GP, Greene CS, Liang H, Xiao Y, Wang C, Iavarone A, Berger AH, Bivona TG, Lazar AJ, Hammer GD, Giordano T, Kwong LN, McArthur G, Huang C, Tward AD, Frederick MJ, McCormick F, Meyerson M; Cancer Genome Atlas Research Network, Van Allen EM, Cherniack AD, Ciriello G, Sander C, Schultz N. Cell.2018 Apr 5;173(2):321-337.e10. doi: 10.1016/j.cell.2018.03.035. PMID: 29625050. [0015] (8) Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer. André F, Ciruelos E, Rubovszky G, Campone M, Loibl S, Rugo HS, Iwata H, Conte P, Mayer IA, Kaufman B, Yamashita T, Lu YS, Inoue K, Takahashi M, Pápai Z, Longin AS, Mills D, Wilke C, Hirawat S, Juric D; SOLAR-1 Study Group. N Engl J Med.2019 May 16;380(20):1929-1940. doi: 10.1056/NEJMoa1813904. PMID: 31091374. [0016] (9) A multidisciplinary approach to optimizing care of patients treated with alpelisib. Rugo HS, Lacouture ME, Goncalves MD, Masharani U, Aapro MS, O'Shaughnessy JA. Breast. 2022 Feb;61:156-167. doi: 10.1016/j.breast.2021.12.016. Epub 2021 Dec 27. PMID: 35016012. [0017] (10) Factors leading to alpelisib discontinuation in patients with hormone receptor positive, human epidermal growth factor receptor-2 negative breast cancer. Cheung YM, Cromwell GE, Tolaney SM, Min L, McDonnell ME. Breast Cancer Res Treat.2022 Apr;192(2):303-311. doi: 10.1007/s10549-021-06476-1. Epub 2022 Jan 9. PMID: 35000092. SUMMARY OF THE INVENTION [0018] The disclosure is directed to compounds of Formula I: or a pharmaceutically acceptable salt thereof, wherein ring A is aryl, a 3-8 membered cycloalkyl ring, a 5-7 membered heteroaryl ring comprising 1-4 heteroatoms selected from N, O, and S, or a 5-7 membered heterocyclic group comprising 1-4 heteroatoms selected from N, O, and S; - 3 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application W is a 5-10 membered heteroaryl ring comprising 1-4 heteroatoms selected from N, O, and S, or a 5-12 membered heterocyclic group comprising 1-4 heteroatoms selected from N, O, and S, C1-C8 alkyl, haloalkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkenyl, NR ^c R ^d , OR ^b , or SR ^b ; wherein each group is optionally substituted by 1-6 R ^f groups; Y is CR ² or N; n is 1, 2, 3, 4 or 5; m is 1, 2 or 3; L is a bond, S, NR ^a or C ₁ -C ₆ alkylene; R ¹ is heterocycloalkyl, heterocycloalkenyl or (C1-C6-alkyl)-R ^e ; wherein each group is optionally substituted by 1-6 R ^f groups; each R ² and R ⁵ is independently H, D, halogen, C ₁ -C ₈ alkoxide, C ₁ -C ₈ alkyl, haloalkyl, - OH, -CN, -NO2, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, -OR ^a , -SR ^a , -NR ^c R ^d , -NR ^a R ^c , -C(O)R ^b , -OC(O)R ^b , - C(O)OR ^b , -C(O)NR ^c R ^d , -S(O)R ^b , -S(O)2NR ^c R ^d , -S(O)(=NR ^b )R ^b , -SF5, -P(O)R ^b R ^b , - P(O)(OR ^b )(OR ^b ), -B(OR ^c )(OR ^d ), -S(O)2R ^b , -C(O)NR ^b OR ^b , -S(O) ₂ OR ^b , -OS(O) ₂ OR ^b , or - OPO(OR ^b )(OR ^b ); wherein said C1-C8 alkyl is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR ^a , -SR ^a , -NR ^a R ^d , or NR ^c R ^d ; each R ³ and R ⁴ is independently H, D, halogen, C ₁ -C ₈ alkoxide, C ₁ -C ₈ alkyl, haloalkyl, or CN; wherein said C1-C8 alkyl is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR ^a , -SR ^a , -NR ^a R ^d , or NR ^c R ^d ; or R ³ and R ⁴ together with the atom to which they are attached are combined to form a C ₃ -C ₇ cycloalkyl or C ₄ -C ₈ heterocycloalkyl; each R ^a is independently H, D, -C(O)R ^b , -C(O)OR ^c , -C(O)NR ^c R ^d , -C(=NR ^b )NR ^b R ^c , - C(=NOR ^b )NR ^b R ^c _, -C(=NCN)NR ^b R ^c _, -P(OR ^c ) ₂ , -P(O)R ^c R ^b , -P(O)OR ^c OR ^b , -S(O)R ^b , -S(O)NR ^c R ^d , -S(O) ₂ R ^b , -S(O) ₂ NR ^c R ^d , SiR ^b ₃ , -C ₁ -C ₁₀ alkyl, -C ₂ -C ₁₀ alkenyl, -C ₂ -C ₁₀ alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl; each R ^b , is independently H, D, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl; each R ^c or R ^d is independently H, D, -C ₁ -C ₁₀ alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -OC ₁ - C6alkyl, -O-cycloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; - 4 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application or R ^c and R ^d , together with the atom to which they are both attached, form a monocyclic or multicyclic heterocycloalkyl, or a monocyclic or multicyclic heterocyclo-alkenyl group; R ^e is C3-C8 cycloalkyl, heterocycloalkyl wherein the heterocycloalkyl is attached to (C1- C6-alkyl) through a carbon atom or a sulfur atom of the heterocycloalkyl group, cycloalkenyl, heterocycloalkenyl wherein the heterocycloalkenyl is attached to (C ₁ -C ₆ -alkyl) through a carbon atom or a sulfur atom of the heterocycloalkenyl group, aryl, or heteroaryl, and each C ₃ -C ₈ cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl is optionally substituted by 1-6 R ^f groups; each R ^f is independently H, D, oxo,halogen, C ₁ -C ₈ alkoxide, C ₁ -C ₈ alkyl, haloalkyl, -OH, -CN, -NO2, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, -OR ^a , -SR ^a , -NR ^c R ^d , -NR ^a R ^c , -C(O)R ^b , -OC(O)R ^b , - C(O)OR ^b , -C(O)NR ^c R ^d , -S(O)R ^b , -S(O)2NR ^c R ^d , -S(O)(=NR ^b )R ^b , -SF5, -P(O)R ^b R ^b , - P(O)(OR ^b )(OR ^b ), -B(OR ^c )(OR ^d ), -S(O)2R ^b , -C(O)NR ^b OR ^b , -S(O) ₂ OR ^b , -OS(O) ₂ OR ^b , or - OPO(OR ^b )(OR ^b ); wherein said C1-C8 alkyl is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR ^a , -SR ^a , -NR ^a R ^d , or NR ^c R ^d . [0019] Stereoisomers of the compounds of Formula I, and the pharmaceutical salts and stereoisomers thereof, are also contemplated, described, and encompassed herein. Methods of using compounds of Formula I are described, as well as pharmaceutical compositions including the compounds of Formula I. DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS [0020] The disclosure may be more fully appreciated by reference to the following description, including the following definitions and examples. Certain features of the disclosed compositions and methods which are described herein in the context of separate aspects, may also be provided in combination in a single aspect. Alternatively, various features of the disclosed compositions and methods that are, for brevity, described in the context of a single aspect, may also be provided separately or in any subcombination. [0021] At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges. For example, the term “C1-C6 alkyl” is specifically intended to individually disclose methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, and C ₆ alkyl. “C ₀ alkyl” refers to a covalent bond. - 5 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application [0022] It is further intended that the compounds of the invention are stable. As used herein “stable” refers to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and preferably capable of formulation into an efficacious therapeutic agent. [0023] It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable sub-combination. [0024] The term “alkyl,” when used alone or as part of a substituent group, refers to a straight- or branched-chain hydrocarbon group having from 1 to 12 carbon atoms (“C1-C12”), preferably 1 to 6 carbons atoms (“C ₁ -C ₆ ”), in the group. Examples of alkyl groups include methyl (Me, C ₁ alkyl), ethyl (Et, C ₂ alkyl), n-propyl (C ₃ alkyl), isopropyl (C ₃ alkyl), butyl (C ₄ alkyl), isobutyl (C4alkyl), sec-butyl (C4alkyl), tert-butyl (C4alkyl), pentyl (C5alkyl), isopentyl (C5alkyl), tert- pentyl (C ₅ alkyl), hexyl (C ₆ alkyl), isohexyl (C ₆ alkyl), and the like. Alkyl groups of the are optionally substituted. Unless otherwise specified, in those embodiments wherein the alkyl group is substituted, the alkyl group can be substituted with 1, 2, or 3 substituents independently selected from -OH, -CN, amino, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1- C ₆ haloalkoxy, -C(O)NH(C ₁ -C ₆ alkyl), -C(O)N(C ₁ -C ₆ alkyl) ₂ , -OC(O)NH(C ₁ -C ₆ alkyl), - OC(O)N(C1-C6alkyl)2, -S(O)2NH(C1-C6alkyl), and -S(O)2N(C1-C6alkyl)2. In other embodiments, the alkyl group is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR ^a , -SR ^a , -NR ^a R ^d , or NR ^c R ^d ; or the alkyl group is optionally substituted by 1-6 R ^f groups. [0025] The term “halo” or halogen refers to chloro, fluoro, bromo, or iodo. [0026] The term “cycloalkyl” when used alone or as part of a substituent group refers to cyclic- containing, non-aromatic hydrocarbon groups having from 3 to 10 carbon atoms (“C _3- C ₁₀ ”), preferably from 3 to 6 carbon atoms (“C _3- C ₆ ”). Cycloalkyl groups of the disclosure include monocyclic groups, as well as multicyclic groups such as bicyclic and tricyclic groups. In those embodiments having at least one multicyclic cycloalkyl group, the cyclic groups can share one common atom (i.e., spirocyclic). In other embodiments having at least one multicyclic cycloalkyl group, the cyclic groups share two common atoms (e.g., fused or bridged). Examples of cycloalkyl groups include, for example, cyclopropyl (C3), cyclobutyl (C4), cyclopropylmethyl (C ₄ ), cyclopentyl (C ₅ ), cyclohexyl (C ₆ ), 1-methylcyclopropyl (C ₄ ), 2-methylcyclopentyl (C ₄ ), adamantanyl (C ₁₀ ), spiro[3.3]heptanyl, bicyclo[3.3.0]octanyl, and the like. Cycloalkyl groups of - 6 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application the disclosure are optionally substituted. Unless otherwise specified, in those embodiments wherein the cycloalkyl group is substituted, the cycloalkyl group can be substituted with 1, 2, or 3 substituents independently selected from -OH, -CN, amino, halo, C1-C6alkyl, C1-C6alkoxy, C1- C6haloalkyl, and C1-C6haloalkoxy, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -OC(O)NH(C1- C ₆ alkyl), -OC(O)N(C ₁ -C ₆ alkyl) ₂ , -S(O) ₂ NH(C ₁ -C ₆ alkyl), and -S(O) ₂ N(C ₁ -C ₆ alkyl) ₂ . In other embodiments, the cycloalkyl group is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR ^a , -SR ^a , -NR ^a R ^d , or NR ^c R ^d ; or the cycloalkyl group is optionally substituted by 1-6 R ^f groups. [0027] The term “heterocycloalkyl” when used alone or as part of a substituent group refers to any three to twelve membered monocyclic or multicyclic, saturated ring structure containing at least one heteroatom selected from the group consisting of O, N and S. Heterocycloalkyl groups of the disclosure include monocyclic groups, as well as multicyclic groups such as bicyclic and tricyclic groups. In those embodiments having at least one multicyclic heterocycloalkyl group, the cyclic groups can share one common atom (i.e., spirocyclic). In other embodiments having at least one multicyclic heterocycloalkyl group, the cyclic groups share two common atoms (e.g., fused or bridged). The term -C ₃ -C ₆ heterocycloalkyl refers to a heterocycloalkyl group having between three and six carbon ring atoms. The heterocycloalkyl group may be attached at any heteroatom or carbon atom of the group such that the result is a stable structure. Examples of heterocycloalkyl groups include, but are not limited to, azepanyl, aziridinyl, azetidinyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, piperazinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, oxazepanyl, oxiranyl, oxetanyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, azepanyl, diazepanyl, oxepanyl, dioxepanyl, azocanyl diazocanyl, oxocanyl, dioxocanyl, azaspiro[2.2]pentanyl, oxaazaspiro[3.3]heptanyl, oxaspiro[3.3]heptanyl, dioxaspiro[3.3]heptanyl, , and the like. Heteroycloalkyl groups of the disclosure are optionally substituted. Unless otherwise specified, in those embodiments wherein the heterocycloalkyl group is substituted, the heterocycloalkyl group can be substituted with 1, 2, or 3 substituents independently selected from -OH, -CN, amino, halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, and C ₁ -C ₆ haloalkoxy, -C(O)NH(C ₁ -C ₆ alkyl), - C(O)N(C1-C6alkyl)2, -OC(O)NH(C1-C6alkyl), -OC(O)N(C1-C6alkyl)2, -S(O)2NH(C1-C6alkyl), and -S(O)2N(C1-C6alkyl)2. In other embodiments, the heterocycloalkyl group is optionally - 7 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR ^a , -SR ^a , -NR ^a R ^d , or NR ^c R ^d ; or the heterocycloalkyl group is optionally substituted by 1-6 R ^f groups. [0028] The term “heterocycloalkenyl” when used alone or as part of a substituent group refers to any three to twelve membered monocyclic or multicyclic, partially saturated ring structure containing at least one heteroatom selected from the group consisting of O, N and S. Heterocycloalkenyl groups of the disclosure include monocyclic groups, as well as multicyclic groups such as bicyclic and tricyclic groups. In those embodiments having at least one multicyclic heterocycloalkyenyl group, the cyclic groups can share one common atom (i.e., spirocyclic). In other embodiments having at least one multicyclic heterocycloalkenyl group, the cyclic groups share two common atoms (e.g., fused or bridged). The term -C3-C6 heterocycloalkenyl refers to a heterocycloalkenyl group having between three and six carbon atoms. The heterocycloalkenyl group may be attached at any heteroatom or carbon atom of the partially saturated ring such that the result is a stable structure. Heterocycloalkenyl groups include groups in which the partially saturated ring is fused to an aryl group, such as, for example isoindoline, , or in which the partially saturated ring is fused to a heteroaryl group, such as, for example, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine, . Heteroycloalkenyl groups of the disclosure are optionally substituted. Unless otherwise specified, in those embodiments wherein the heterocycloalkenyl group is substituted, the heterocycloalkenyl group can be substituted with 1, 2, or 3 substituents independently selected from -OH, -CN, amino, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy, - C(O)NH(C ₁ -C ₆ alkyl), -C(O)N(C ₁ -C ₆ alkyl) ₂ , -OC(O)NH(C ₁ -C ₆ alkyl), -OC(O)N(C ₁ -C ₆ alkyl) ₂ , - S(O) ₂ NH(C ₁ -C ₆ alkyl), and -S(O) ₂ N(C ₁ -C ₆ alkyl) ₂ . In other embodiments, the heterocycloalkenyl group is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR ^a , - SR ^a , -NR ^a R ^d , or NR ^c R ^d ; or the heterocycloalkenyl group is optionally substituted by 1-6 R ^f groups. [0029] The term “heterocyclic group,” when used alone or as part of a substituent group, refers to a heterocycloalkyl group or a heterocycloalkenyl group. [0030] The term “heteroaryl” when used alone or as part of a substituent group refers to a mono- or bicyclic- aromatic ring structure including carbon atoms as well as up to five heteroatoms selected from nitrogen, oxygen, and sulfur. Heteroaryl rings can include a total of 5, 6, 7, 8, 9, or 10 ring atoms. Examples of heteroaryl groups include but are not limited to, - 8 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application pyrrolyl, furyl, thiophenyl (thienyl), oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl, and the like. Heteroaryl groups of the disclosure are optionally substituted. Unless otherwise specified, in those embodiments wherein the heteroaryl group is substituted, the heteroaryl group can be substituted with 1, 2, or 3 substituents independently selected from -OH, -CN, amino, halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, and C ₁ - C6haloalkoxy, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -OC(O)NH(C1-C6alkyl), - OC(O)N(C1-C6alkyl)2, -S(O)2NH(C1-C6alkyl), and -S(O)2N(C1-C6alkyl)2. In other embodiments, the heteroaryl group is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR ^a , -SR ^a , -NR ^a R ^d , or NR ^c R ^d ; or the heteroaryl group is optionally substituted by 1-6 R ^f groups. [0031] The term “aryl” when used alone or as part of a substituent group refers to a mono- or bicyclic- aromatic carbon ring structure. Aryl rings can include a total of 5, 6, 7, 8, 9, or 10 ring atoms. Examples of aryl groups include but are not limited to, phenyl, napthyl, and the like. Aryl groups of the disclosure are optionally substituted. Unless otherwise specified, in those embodiments wherein the aryl group is substituted, the aryl group can be substituted with 1, 2, or 3 substituents independently selected from -OH, -CN, amino, halo, C1-C6alkyl, C1-C6alkoxy, C1- C6haloalkyl, and C1-C6haloalkoxy, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -OC(O)NH(C1- C ₆ alkyl), -OC(O)N(C ₁ -C ₆ alkyl) ₂ , -S(O) ₂ NH(C ₁ -C ₆ alkyl), and -S(O) ₂ N(C ₁ -C ₆ alkyl) ₂ . In other embodiments, the aryl group is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR ^a , -SR ^a , -NR ^a R ^d , or NR ^c R ^d ; or the aryl group is optionally substituted by 1-6 R ^f groups. [0032] When a range of carbon atoms is used herein, for example, C ₁ -C ₆ , all ranges, as well as individual numbers of carbon atoms are encompassed, for example, “C1-3” includes C1-3, C1-2, C2- ₃ , C ₁ , C ₂ , and C ₃ . The term “C _1-6 alk” refers to an aliphatic linker having 1, 2, 3, 4, 5, or 6 carbon atoms and includes, for example, –CH ₂ -, –CH(CH ₃ )-, -CH(CH ₃ )-CH ₂ -, and –C(CH ₃ ) ₂ -. The term “-C0alk-” refers to a bond. [0033] The term “C0-C6alk” when used alone or as part of a substituent group refers to an aliphatic linker having 0, 1, 2, 3, 4, 5 or 6 carbon atoms. The term “-C ₁ alk-”, for example, refers to a -CH ₂ -. The term “-C ₀ alk-” refers to a bond. [0034] Unless otherwise specified, in those embodiments wherein the -C1-C6alkyl, -C1-C10 alkyl, -C ₁ -C ₈ alkoxide, -C ₂ -C ₆ alkenyl, -C ₂ -C ₁₀ alkenyl, -C ₂ -C ₆ alkynyl, -C ₂ -C ₁₀ alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkenyl, and heterocycloalkyl groups are - 9 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application substituted, they can be optionally substituted with 1, 2, or 3 substituents independently selected from -OH, -CN, amino, halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, and C ₁ -C ₆ haloalkoxy, - C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -OC(O)NH(C1-C6alkyl), -OC(O)N(C1-C6alkyl)2, - S(O)2NH(C1-C6alkyl), and -S(O)2N(C1-C6alkyl)2. In other embodiments, the -C1-C6alkyl, -C1- C ₁₀ alkyl, -C ₁ -C ₈ alkoxide, -C ₂ -C ₆ alkenyl, -C ₂ -C ₁₀ alkenyl, -C ₂ -C ₆ alkynyl, -C ₂ -C ₁₀ alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkenyl, and heterocycloalkyl groups are optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR ^a , -SR ^a , - NR ^a R ^d , or NR ^c R ^d ; or the -C1-C6alkyl, -C1-C10 alkyl, -C1-C8 alkoxide, -C2-C6alkenyl, -C2- C ₁₀ alkenyl, -C ₂ -C ₆ alkynyl, -C ₂ -C ₁₀ alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkenyl, and heterocycloalkyl groups are optionally substituted by 1-6 R ^f groups. [0035] As used herein, “alkoxy” refers to an –O-alkyl group. Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like. [0036] As used herein, “hydroxylalkyl” refers to an alkyl group substituted by OH. [0037] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. [0038] Compounds of the invention may also include tautomeric forms. All tautomeric forms are encompassed. [0039] In some embodiments, the compounds of the present invention may exist as rotational isomers. In some embodiments, the compounds of the present invention exist as mixtures of rotational isomers in any proportion. In other embodiments, the compounds of the present invention exist as particular rotational isomers, substantially free of other rotational isomers. [0040] Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. - 10 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application [0041] In some embodiments, the compounds of the invention, and salts thereof, are substantially isolated. By “substantially isolated” is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the compound of the invention. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound of the invention, or salt thereof. Methods for isolating compounds and their salts are routine in the art. [0042] The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, “pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 17 ^th ed., Mack Publishing Company, Easton, Pa., 1985, p.1418 and Journal of Pharmaceutical Science, 66, 1 (1977) p.1–19, each of which is incorporated herein by reference in its entirety. [0043] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. [0044] A “pharmaceutically acceptable excipient” refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of an agent and that is compatible therewith. - 11 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols. [0045] A “solvate” refers to a physical association of a compound of Formula I with one or more solvent molecules. [0046] “Subject” includes humans. The terms “human,” “patient,” and “subject” are used interchangeably herein. [0047] “Treating” or “treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, “treating” or “treatment” refers to delaying the onset of the disease or disorder. [0048] “Compounds of the present disclosure,” and equivalent expressions, are meant to embrace compounds of Formula I as described herein, as well as its subgenera, which expression includes the stereoisomers (e.g., entaniomers, diastereomers) and constitutional isomers (e.g., tautomers) of compounds of Formula I as well as the pharmaceutically acceptable salts, where the context so permits. [0049] As used herein, the term “isotopic variant” refers to a compound that contains proportions of isotopes at one or more of the atoms that constitute such compound that is greater than natural abundance. For example, an “isotopic variant” of a compound can be radiolabeled, that is, contain one or more radioactive isotopes, or can be labeled with non-radioactive isotopes such as for example, deuterium ( ² H or D), carbon-13 ( ¹³ C), nitrogen-15 ( ¹⁵ N), or the like. It will be understood that, in a compound where such isotopic substitution is made, the following atoms, where present, may vary, so that for example, any hydrogen may be ² H/D, any carbon may be ¹³ C, or any nitrogen may be ¹⁵ N, and that the presence and placement of such atoms may be determined within the skill of the art. [0050] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers,” for example, diastereomers, enantiomers, and atropisomers. The compounds of this disclosure may possess one or more asymmetric centers; such compounds can - 12 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application therefore be produced as individual (R)- or (S)-stereoisomers at each asymmetric center, or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include all stereoisomers and mixtures, racemic or otherwise, thereof. Where one chiral center exists in a structure, but no specific stereochemistry is shown for that center, both enantiomers, individually or as a mixture of enantiomers, are encompassed by that structure. Where more than one chiral center exists in a structure, but no specific stereochemistry is shown for the centers, all enantiomers and diastereomers, individually or as a mixture, are encompassed by that structure. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art. [0051] The disclosure is directed to compounds of Formula I: or a pharmaceutically acceptable salt thereof, wherein ring A is aryl, a 3-8 membered cycloalkyl ring, a 5-7 membered heteroaryl ring comprising 1-4 heteroatoms selected from N, O, and S, or a 5-7 membered heterocyclic group comprising 1-4 heteroatoms selected from N, O, and S; W is a 5-10 membered heteroaryl ring comprising 1-4 heteroatoms selected from N, O, and S, a 5-12 membered heterocyclic group comprising 1-4 heteroatoms selected from N, O, and S, C1-C8 alkyl, haloalkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkenyl, NR ^c R ^d , OR ^b , or SR ^b ; wherein each group is optionally substituted by 1-6 R ^f groups; Y is CR ² or N; n is 1, 2, 3, 4 or 5; m is 1, 2 or 3; L is a bond, S, NR ^a or C ₁ -C ₆ alkylene; R ¹ is heterocycloalkyl, heterocycloalkenyl or (C1-C6-alkyl)-R ^e ; wherein each group is optionally substituted by 1-6 R ^f groups; each R ² and R ⁵ is independently H, D, halogen, C ₁ -C ₈ alkoxide, C ₁ -C ₈ alkyl, haloalkyl, - OH, -CN, -NO2, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, - 13 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application heterocycloalkyl, heterocycloalkenyl, -OR ^a , -SR ^a , -NR ^c R ^d , -NR ^a R ^c , -C(O)R ^b , -OC(O)R ^b , - C(O)OR ^b , -C(O)NR ^c R ^d , -S(O)R ^b , -S(O)2NR ^c R ^d , -S(O)(=NR ^b )R ^b , -SF5, -P(O)R ^b R ^b , - P(O)(OR ^b )(OR ^b ), -B(OR ^c )(OR ^d ), -S(O)2R ^b , -C(O)NR ^b OR ^b , -S(O)2OR ^b , -OS(O)2OR ^b , or - OPO(OR ^b )(OR ^b ); wherein said C1-C8 alkyl is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR ^a , -SR ^a , -NR ^a R ^d , or NR ^c R ^d ; each R ³ and R ⁴ is independently H, D, halogen, C ₁ -C ₈ alkoxide, C ₁ -C ₈ alkyl, haloalkyl, or CN; wherein said C1-C8 alkyl is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR ^a , -SR ^a , -NR ^a R ^d , or NR ^c R ^d ; or R ³ and R ⁴ together with the atom to which they are attached are combined to form a C3-C7 cycloalkyl or C4-C8 heterocycloalkyl; each R ^a is independently H, D, -C(O)R ^b , -C(O)OR ^c , -C(O)NR ^c R ^d , -C(=NR ^b )NR ^b R ^c , - C(=NOR ^b )NR ^b R ^c _, -C(=NCN)NR ^b R ^c _, -P(OR ^c ) ₂ , -P(O)R ^c R ^b , -P(O)OR ^c OR ^b , -S(O)R ^b , -S(O)NR ^c R ^d , -S(O) ₂ R ^b , -S(O) ₂ NR ^c R ^d , SiR ^b ₃ , -C ₁ -C ₁₀ alkyl, -C ₂ -C ₁₀ alkenyl, -C ₂ -C ₁₀ alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl; each R ^b , is independently H, D, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl; each R ^c or R ^d is independently H, D, -C1-C10 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -OC1- C6alkyl, -O-cycloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; or R ^c and R ^d , together with the atom to which they are both attached, form a monocyclic or multicyclic heterocycloalkyl, or a monocyclic or multicyclic heterocyclo-alkenyl group. R ^e is C ₃ -C ₈ cycloalkyl, heterocycloalkyl wherein the heterocycloalkyl is attached to (C ₁ - C ₆ -alkyl) through a carbon atom or a sulfur atom of the heterocycloalkyl group, cycloalkenyl, heterocycloalkenyl wherein the heterocycloalkenyl is attached to (C1-C6-alkyl) through a carbon atom or a sulfur atom of the heterocycloalkenyl group, aryl, or heteroaryl, and each C ₃ -C ₈ cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl is optionally substituted by 1-6 R ^f groups; each R ^f is independently H, D, oxo, halogen, C1-C8 alkoxide, C1-C8 alkyl, haloalkyl, -OH, -CN, -NO2, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, -OR ^a , -SR ^a , -NR ^c R ^d , -NR ^a R ^c , -C(O)R ^b , -OC(O)R ^b , - C(O)OR ^b , -C(O)NR ^c R ^d , -S(O)R ^b , -S(O) ² NR ^c R ^d , -S(O)(=NR ^b )R ^b , -SF ⁵ , -P(O)R ^b R ^b , - P(O)(OR ^b )(OR ^b ), -B(OR ^c )(OR ^d ), -S(O)2R ^b , -C(O)NR ^b OR ^b , -S(O) ₂ OR ^b , -OS(O) ₂ OR ^b , or - - 14 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application OPO(OR ^b )(OR ^b ); wherein said C1-C8 alkyl is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR ^a , -SR ^a , -NR ^a R ^d , or NR ^c R ^d . [0052] In some embodiments, ring A in Formula (I) is a 5-7-membered heteroaryl. In some embodiments, ring A is a 5-membered heteroaryl. In other embodiments, ring A is a 6- membered heteroaryl. In yet other embodiments, ring A is a 7-membered heteroaryl. [0053] In some embodiments, ring A in Formula (I) is aryl, a 3-8 membered cycloalkyl ring, a 5-7 membered heteroaryl ring comprising 1-4 heteroatoms selected from N, O, and S, or a 5-7 membered heterocyclic group comprising 1-4 heteroatoms selected from N, O, and S. [0054] In some embodiments, ring A in Formula (I) is aryl. In some embodiments, ring A in Formula (I) is a phenyl ring. In other embodiments, ring A in Formula (I) is a 3-8 membered cycloalkyl ring. In other embodiments, ring A in Formula (I) is a 5-7 membered heteroaryl ring comprising 1-4 heteroatoms selected from N, O, and S. In other embodiments, ring A in Formula (I) is a 5-7 membered heterocyclic group comprising 1-4 heteroatoms selected from N, O, and S. [0055] In some embodiments, W in Formula (I) is a 5-10 membered heteroaryl ring comprising 1-4 heteroatoms selected from N, O, and S, a 5-12 membered heterocyclic group comprising 1-4 heteroatoms selected from N, O, and S, C1-C8 alkyl, haloalkyl, -C ² -C ⁶ alkenyl, -C ² -C ⁶ alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkenyl, NR ^c R ^d , OR ^b , or SR ^b , wherein each group is optionally substituted by 1-6 R ^f groups. [0056] In some embodiments, W in Formula (I) is a 5-12 membered heterocyclic group comprising 1-4 heteroatoms selected from N, O, and S. In some embodiments, the 5-12 membered heterocyclic group is an isoindoline group or a piperidine group. In some embodiments, the 5-12 membered heterocyclic group is an isoindoline group. In some embodiments, the 5-12 membered heterocyclic group is a piperidine group. In some embodiments, W in Formula (I) is NR ^c R ^d . In some embodiments, W in Formula (I) is substituted by 1-6 R ^f groups. [0057] In other embodiments, W in Formula (I) is a 5-10 membered heteroaryl ring comprising 1-4 heteroatoms selected from N, O, and S. In other embodiments, W in Formula (I) is C1-C8 alkyl. In other embodiments, W in Formula (I) is haloalkyl. In other embodiments, W in Formula (I) is -C2-C6 alkenyl. In other embodiments, W in Formula (I) is -C2-C6 alkynyl. In other embodiments, W in Formula (I) is aryl. In other embodiments, W in Formula (I) is heteroaryl. In other embodiments, W in Formula (I) is cycloalkyl. In other embodiments, W in Formula (I) is cycloalkenyl. In other embodiments, W in Formula (I) is heterocycloalkenyl. In - 15 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application other embodiments, W in Formula (I) is NR ^c R ^d . In other embodiments, W in Formula (I) is NR ^c R ^d . In other embodiments, W in Formula (I) is OR ^b . In other embodiments, W in Formula (I) is SR ^b . In some embodiments, W in Formula (I) is substituted by 1 or 2 R ^f groups. [0058] In some embodiments, Y in Formula (I) is CR ² or N. In some embodiments, Y in Formula (I) is N. In other embodiments, Y in Formula (I) is CR ² . In other embodiments, Y in Formula (I) is CH. [0059] In some embodiments, n in Formula (I) is 1, 2, 3, 4 or 5. In some embodiments, n in Formula (I) is 1. In other embodiments, n in Formula (I) is 2. In yet other embodiments, n in Formula (I) is 3. In yet other embodiments, n in Formula (I) is 4. In yet other embodiments, n in Formula (I) is 5. [0060] In some embodiments, m in Formula (I) is 1, 2 or 3. In some embodiments, m in Formula (I) is 1. In other embodiments, m in Formula (I) is 2. In yet other embodiments, m in Formula (I) is 3. [0061] In some embodiments, L in Formula I is a bond, S, NR ^a or C1-C6 alkylene. In some embodiments, L in Formula (I) is NR ^a . In some embodiments, L in Formula (I) is NH. In some embodiments, L in Formula (I) is NC ₁ -C ₈ alkyl. In some embodiments, L in Formula (I) is N- methyl. In other embodiments, L in Formula (I) is a bond. In other embodiments, L in Formula (I) is S. In other embodiments, L in Formula (I) is C1-C6 alkylene. In other embodiments, L in Formula (I) is methylene. [0062] In some embodiments, R ¹ in Formula I is heterocycloalkyl, heterocycloalkenyl or (C1- C6-alkyl)-R ^e ; wherein each group is optionally substituted by 1-6 R ^f groups. In some embodiments, R ¹ in Formula I is heterocycloalkyl optionally substituted by 1-6 R ^f groups. In some embodiments, R ¹ in Formula I is tetrahydro-2H-pyran optionally substituted by 1-6 R ^f groups. In other embodiments, R ¹ in Formula I is tetrahydrothiophene optionally substituted by 1-6 R ^f groups. In other embodiments, R ¹ in Formula I is tetrahydrothiophene-1,1-dioxide optionally substituted by 1-6 R ^f groups. In yet other embodiments, R ¹ in Formula I is tetrahydrofuran optionally substituted by 1-6 R ^f groups. In yet other embodiments, R ¹ in Formula I is oxetane optionally substituted by 1-6 R ^f groups. In yet other embodiments, R ¹ in Formula I is pyrrolidine optionally substituted by 1-6 R ^f groups. [0063] In some embodiments, R ¹ in Formula I is heterocycloalkenyl optionally substituted by 1-6 R ^f groups. In some embodiments, R ¹ in Formula I is (C1-C6-alkyl)-R ^e optionally substituted by 1-6 R ^f groups. In some embodiments, R ^e is azetidine optionally substituted by 1-6 R ^f groups, pyrazole optionally substituted by 1-6 R ^f groups, p-methoxybenzene or propyl. In some - 16 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application embodiments, R ^e is pyrazole optionally substituted by 1-6 R ^f groups. In other embodiments, R ^e is p-methoxybenzene. In other embodiments, R ^e is propyl. [0064] In some embodiments, each R ² in Formula I is independently H, D, halogen, C1-C8 alkoxide, C1-C8 alkyl, haloalkyl, -OH, -CN, -NO ² , -C ² -C ⁶ alkenyl, -C ² -C ⁶ alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, -OR ^a , -SR ^a , -NR ^c R ^d , -NR ^a R ^c , -C(O)R ^b , -OC(O)R ^b , -C(O)OR ^b , -C(O)NR ^c R ^d , -S(O)R ^b , -S(O)2NR ^c R ^d , -S(O)(=NR ^b )R ^b , - SF ⁵ , -P(O)R ^b R ^b , -P(O)(OR ^b )(OR ^b ), -B(OR ^c )(OR ^d ) or -S(O) ² R ^b , -C(O)NR ^b OR ^b , -S(O)2OR ^b , - OS(O)2OR ^b , or -OPO(OR ^b )(OR ^b ); wherein said C1-C8 alkyl is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR ^a , -SR ^a , -NR ^a R ^d , or NR ^c R ^d . [0065] In some embodiments, at least one R ² in Formula I is H. In some embodiments, at least one R ² in Formula I is D. In some embodiments, at least one R ² in Formula I is halogen. In some embodiments, at least one R ² in Formula I is C ₁ -C ₈ alkoxide. In some embodiments, at least one R ² in Formula I is C ₁ -C ₈ alkyl. In some embodiments, the C ₁ -C ₈ alkyl is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR ^a , -SR ^a , -NR ^a R ^d , or NR ^c R ^d . [0066] In other embodiments, at least one R ² in Formula I is haloalkyl. In other embodiments, at least one R ² in Formula I is -OH. In other embodiments, at least one R ² in Formula I is -CN. In other embodiments, at least one R ² in Formula I is -NO ² . In other embodiments, at least one R ² in Formula I is -C2-C6 alkenyl. In other embodiments, at least one R ² in Formula I is -C2-C6 alkynyl. In other embodiments, at least one R ² in Formula I is aryl. In other embodiments, at least one R ² in Formula I is hetereoaryl. In other embodiments, at least one R ² in Formula I is cycloalkyl. In other embodiments, at least one R ² in Formula I is cycloalkenyl. In other embodiments, at least one R ² in Formula I is heterocycloalkyl. In some embodiments, at least one R ² in Formula I is heterocycloalkenyl. In other embodiments, at least one R ² in Formula I is -OR ^a . In other embodiments, at least one R ² in Formula I is -SR ^a . In other embodiments, at least one R ² in Formula I is -NR ^c R ^d . In other embodiments, at least one R ² in Formula I is -NR ^a R ^c . In other embodiments, at least one R ² in Formula I is -C(O)R ^b . In other embodiments, at least one R ² in Formula I is -OC(O)R ^b . In other embodiments, at least one R ² in Formula I is -C(O)OR ^b . In other embodiments, at least one R ² in Formula I is -C(O)NR ^c R ^d . In other embodiments, at least one R ² in Formula I is -S(O)R ^b . In other embodiments, at least one R ² in Formula I is - S(O) ² NR ^c R ^d . In other embodiments, at least one R ² in Formula I is -S(O)(=NR ^b )R ^b . In other embodiments, at least one R ² in Formula I is -SF5. In other embodiments, at least one R ² in Formula I is -P(O)R ^b R ^b . In other embodiments, at least one R ² in Formula I is -P(O)(OR ^b )(OR ^b ). - 17 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application In other embodiments, at least one R ² in Formula I is -B(OR ^c )(OR ^d ). In other embodiments, at least one R ² in Formula I is -S(O)2R ^b . In other embodiments, at least one R ² in Formula I is - C(O)NR ^b OR ^b . In other embodiments, at least one R ² in Formula I is -S(O)2OR ^b . In other embodiments, at least one R ² in Formula I is -OS(O)2OR ^b . In other embodiments, at least one R ² in Formula I is -OPO(OR ^b )(OR ^b ). [0067] In some embodiments, at least one R ² in Formula I is H, C ₁ -C ₈ alkyl, CF ₃ , Br, F, CN or CHF2. In some embodiments, at least one R ² in Formula I is H. In some embodiments, at least one R ² in Formula I is C1-C8alkyl. In some embodiments, at least one R ² in Formula I is methyl. In some embodiments, at least one R ² in Formula I is CF ₃ . In some embodiments, at least one R ² in Formula I is Br. In some embodiments, at least one R ² in Formula I is F. In some embodiments, at least one R ² in Formula I is CN. In some embodiments, at least one R ² in Formula I is CHF ₂ . [0068] In some embodiments, R ³ in Formula I is H, D, halogen, C ₁ -C ₈ alkoxide C ₁ -C ₈ alkyl, haloalkyl, or CN; wherein said C1-C8 alkyl is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR ^a , -SR ^a , -NR ^a R ^d , or NR ^c R ^d . [0069] In some embodiments, R ³ in Formula I is H. In some embodiments, R ³ in Formula I is D. In some embodiments, R ³ in Formula I is halogen. In some embodiments, R ³ in Formula I is C1-C8 alkoxide. In some embodiments, R ³ in Formula I is C1-C8 alkyl. In some embodiments, the C ₁ -C ₈ alkyl is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR ^a , -SR ^a , -NR ^a R ^d , or NR ^c R ^d . In some embodiments, R ³ in Formula I is haloalkyl. In some embodiments, R ³ in Formula I is CN. [0070] In other embodiments, R ³ in Formula I is H or C ₁ -C ₈ alkyl. In other embodiments, R ³ in Formula I is H. In other embodiments, R ³ in Formula I is C ₁ -C ₈ alkyl. In other embodiments, R ³ in Formula I is methyl. [0071] In some embodiments, R ⁴ in Formula I is H, D, halogen, C ₁ -C ₈ alkoxide C ₁ -C ₈ alkyl, haloalkyl, or CN; wherein said C ₁ -C ₈ alkyl is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR ^a , -SR ^a , -NR ^a R ^d , or NR ^c R ^d . [0072] In some embodiments, R ⁴ in Formula I is H. In some embodiments, R ⁴ in Formula I is D. In some embodiments, R ⁴ in Formula I is halogen. In some embodiments, R ⁴ in Formula I is C ₁ -C ₈ alkoxide. In some embodiments, R ⁴ in Formula I is C ₁ -C ₈ alkyl. In some embodiments, the C1-C8 alkyl is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR ^a , -SR ^a , -NR ^a R ^d , or NR ^c R ^d . In some embodiments, R ⁴ in Formula I is haloalkyl. In some embodiments, R ⁴ in Formula I is CN. - 18 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application [0073] In other embodiments, R ⁴ in Formula I is H or C1-C8 alkyl. In other embodiments, R ⁴ in Formula I is H. In other embodiments, R ⁴ in Formula I is C ₁ -C ₈ alkyl. In other embodiments, R ⁴ in Formula I is methyl. [0074] In some embodiments, R ³ and R ⁴ in Formula I together with the atom to which they are attached are combined to form a C ₃ -C ₇ cycloalkyl or C ₄ -C ₈ heterocycloalkyl. In some embodiments, R ³ and R ⁴ in Formula I together with the atom to which they are attached are combined to form a C3-C7 cycloalkyl. In some embodiments, R ³ and R ⁴ in Formula I together with the atom to which they are attached are combined to form a C4-C8 heterocycloalkyl. [0075] In some embodiments, each R ⁵ in Formula I is independently H, D, halogen, C ₁ -C ₈ alkoxide, C1-C8 alkyl, haloalkyl, -OH, -CN, -NO2, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, -OR ^a , -SR ^a , -NR ^c R ^d , -NR ^a R ^c , -C(O)R ^b , -OC(O)R ^b , -C(O)OR ^b , -C(O)NR ^c R ^d , -S(O)R ^b , -S(O)2NR ^c R ^d , -S(O)(=NR ^b )R ^b , - SF5, -P(O)R ^b R ^b , -P(O)(OR ^b )(OR ^b ), -B(OR ^c )(OR ^d ) or -S(O)2R ^b , -C(O)NR ^b OR ^b , -S(O) ₂ OR ^b , - OS(O)2OR ^b , or -OPO(OR ^b )(OR ^b ); wherein said C1-C8 alkyl is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR ^a , -SR ^a , -NR ^a R ^d , or NR ^c R ^d . [0076] In some embodiments, at least one R ⁵ in Formula I is H. In some embodiments, at least one R ⁵ in Formula I is D. In some embodiments, at least one R ⁵ in Formula I is halogen. In some embodiments, at least one R ⁵ in Formula I is C1-C8 alkoxide. In some embodiments, at least one R ⁵ in Formula I is C ₁ -C ₈ alkyl. In some embodiments, the C ₁ -C ₈ alkyl is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR ^a , -SR ^a , -NR ^a R ^d , or NR ^c R ^d . [0077] In other embodiments, at least one R ⁵ in Formula I is haloalkyl. In other embodiments, at least one R ⁵ in Formula I is -OH. In other embodiments, at least one R ⁵ in Formula I is -CN. In other embodiments, at least one R ⁵ in Formula I is -NO ² . In other embodiments, at least one R ⁵ in Formula I is -C2-C6 alkenyl. In other embodiments, at least one R ⁵ in Formula I is -C2-C6 alkynyl. In other embodiments, at least one R ⁵ in Formula I is aryl. In other embodiments, at least one R ⁵ in Formula I is hetereoaryl. In other embodiments, at least one R ⁵ in Formula I is cycloalkyl. In other embodiments, at least one R ⁵ in Formula I is cycloalkenyl. In other embodiments, at least one R ⁵ in Formula I is heterocycloalkyl. In some embodiments, at least one R ⁵ in Formula I is heterocycloalkenyl. In other embodiments, at least one R ⁵ in Formula I is -OR ^a . In other embodiments, at least one R ⁵ in Formula I is -SR ^a . In other embodiments, at least one R ⁵ in Formula I is -NR ^c R ^d . In other embodiments, at least one R ⁵ in Formula I is -NR ^a R ^c . In other embodiments, at least one R ⁵ in Formula I is -C(O)R ^b . In other embodiments, at least one - 19 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application R ⁵ in Formula I is -OC(O)R ^b . In other embodiments, at least one R ⁵ in Formula I is -C(O)OR ^b . In other embodiments, at least one R ⁵ in Formula I is -C(O)NR ^c R ^d . In other embodiments, at least one R ⁵ in Formula I is -S(O)R ^b . In other embodiments, at least one R ⁵ in Formula I is - S(O) ² NR ^c R ^d . In other embodiments, at least one R ⁵ in Formula I is -S(O)(=NR ^b )R ^b . In other embodiments, at least one R ⁵ in Formula I is -SF5. In other embodiments, at least one R ⁵ in Formula I is -P(O)R ^b R ^b . In other embodiments, at least one R ⁵ in Formula I is -P(O)(OR ^b )(OR ^b ). In other embodiments, at least one R ⁵ in Formula I is -B(OR ^c )(OR ^d ). In other embodiments, at least one R ⁵ in Formula I is -S(O) ² R ^b . In other embodiments, at least one R ⁵ in Formula I is - C(O)NR ^b OR ^b . In other embodiments, at least one R ⁵ in Formula I is -S(O) ₂ OR ^b . In other embodiments, at least one R ⁵ in Formula I is -OS(O)2OR ^b . In other embodiments, at least one R ⁵ in Formula I is -OPO(OR ^b )(OR ^b ). [0078] In some embodiments, , at least one R ⁵ in Formula I is a carboxylic acid group or isostere thereof. In some embodiments, , at least one R ⁵ in Formula I is a carboxylic acid group. In some embodiments, , at least one R ⁵ in Formula I is -CO2H. In other embodiments, , at least one R ⁵ in Formula I is an isostere of a carboxylic acid group. [0079] In some embodiments, each R ^a in Formula I is independently H, D, -C(O)R ^b , - C(O)OR ^c , -C(O)NR ^c R ^d , -C(=NR ^b )NR ^b R ^c , -C(=NOR ^b )NR ^b R ^c , -C(=NCN)NR ^b R ^c , -P(OR ^c )2, - P(O)R ^c R ^b , -P(O)OR ^c OR ^b , -S(O)R ^b , -S(O)NR ^c R ^d , -S(O)2R ^b , -S(O)2NR ^c R ^d , SiR ^b 3, -C1-C10alkyl, - C ₂ -C ₁₀ alkenyl, -C ₂ -C ₁₀ alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl. [0080] In some embodiments, R ^a in Formula I is H. In some embodiments, R ^a in Formula I is D. In some embodiments, R ^a in Formula I is -C(O)R ^b . In some embodiments, R ^a in Formula I is -C(O)OR ^c . In some embodiments, R ^a in Formula I is -C(O)NR ^c R ^d . In some embodiments, R ^a in Formula I is -C(=NR ^b )NR ^b R ^c . In some embodiments, R ^a in Formula I is C(=NOR ^b )NR ^b R ^c . In some embodiments, R ^a in Formula I is -C(=NCN)NR ^b R ^c . [0081] In other embodiments, R ^a in Formula I is -P(OR ^c ) ₂ , -P(O)R ^c R ^b , -P(O)OR ^c OR ^b , -S(O)R ^b , -S(O)NR ^c R ^d , -S(O)2R ^b , -S(O)2NR ^c R ^d , SiR ^b 3, and the like. In yet other embodiments, R ^a in Formula I is -C1-C10alkyl, -C2-C10 alkenyl, -C2-C10 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, and the like. [0082] In some embodiments, each R ^b in Formula I is independently H, D, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C2-C6 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl. - 20 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application [0083] In some embodiments, R ^b in Formula I is H. In some embodiments, R ^b in Formula I is D. In some embodiments, R ^b in Formula I is -C ₁ -C ₆ alkyl. In some embodiments, R ^b in Formula I is -C2-C6 alkenyl. In some embodiments, R ^b in Formula I is -C2-C6 alkynyl. In other embodiments, R ^b in Formula I is aryl. In other embodiments, R ^b in Formula I is cycloalkyl. In other embodiments, R ^b in Formula I is cycloalkenyl. In other embodiments, R ^b in Formula I is heteroaryl. In other embodiments, R ^b in Formula I is heterocycloalkyl. In other embodiments, R ^b in Formula I is heterocycloalkenyl. [0084] In some embodiments, each R ^c or R ^d in Formula I is independently H, D, -C1-C6 alkyl, - C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl. [0085] In some embodiments, R ^c or R ^d in Formula I is H. In some embodiments, R ^c or R ^d in Formula I is D. In some embodiments, R ^c or R ^d in Formula I is -C ₁ -C ₁₀ alkyl. In some embodiments, R ^c or R ^d in Formula I is -C ₂ -C ₆ alkenyl. In some embodiments, R ^c or R ^d in Formula I is -C2-C6 alkynyl. In other embodiments, R ^c or R ^d in Formula I is -OC1-C6alkyl. In other embodiments, R ^c or R ^d in Formula I is -O-cycloalkyl. In other embodiments, R ^c or R ^d in Formula I is aryl. In other embodiments, R ^c or R ^d in Formula I is cycloalkyl. In other embodiments, R ^c or R ^d in Formula I is cycloalkenyl. In other embodiments, R ^c or R ^d in Formula I is heteroaryl. In other embodiments, R ^c or R ^d in Formula I is heterocycloalkyl. In other embodiments, R ^c or R ^d in Formula I is heterocycloalkenyl. [0086] In yet other embodiments, R ^c and R ^d in Formula I, together with the atom to which they are both attached, form a monocyclic or multicyclic heterocycloalkyl, or a monocyclic or multicyclic heterocyclo-alkenyl group. In yet other embodiments, R ^c and R ^d in Formula I form a monocyclic heterocycloalkyl. In yet other embodiments, R ^c and R ^d in Formula I form a multicyclic heterocycloalkyl. In yet other embodiments, R ^c and R ^d in Formula I form a monocyclic heterocyclo-alkenyl group. In yet other embodiments, R ^c and R ^d in Formula I form a multicyclic heterocyclo-alkenyl group. [0087] In some embodiments, R ^e in Formula I is C3-C8 cycloalkyl, heterocycloalkyl wherein the heterocycloalkyl is attached to (C1-C6-alkyl) through a carbon atom or a sulfur atom of the heterocycloalkyl group, cycloalkenyl, heterocycloalkenyl wherein the heterocycloalkenyl is attached to (C ₁ -C ₆ -alkyl) through a carbon atom or a sulfur atom of the heterocycloalkenyl group, aryl, or heteroaryl, and each C3-C8 cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl is optionally substituted by 1-6 R ^f groups. - 21 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application [0088] In some embodiments, R ^e in Formula I is C3-C8 cycloalkyl optionally substituted by 1-6 R ^f groups. In some embodiments, R ^e in Formula I is heterocycloalkyl optionally substituted by 1-6 R ^f groups. In some embodiments, the heterocycloalkyl is attached to (C1-C6-alkyl) through a carbon atom of the heterocycloalkyl group. In some embodiments, the heterocycloalkyl is attached to (C ₁ -C ₆ -alkyl) through a sulfur atom of the heterocycloalkyl group. In other embodiments, R ^e in Formula I is cycloalkenyl optionally substituted by 1-6 R ^f groups. In other embodiments, R ^e in Formula I is heterocycloalkenyl optionally substituted by 1-6 R ^f groups. In other embodiments, the heterocycloalkenyl is attached to (C1-C6-alkyl) through a carbon atom of the heterocycloalkenyl group. In other embodiments, the heterocycloalkenyl is attached to (C ₁ - C6-alkyl) through a sulfur atom of the heterocycloalkenyl group. In yet other embodiments, R ^e in Formula I is aryl optionally substituted by 1-6 R ^f groups. In yet other embodiments, R ^e in Formula I is heteroaryl optionally substituted by 1-6 R ^f groups. [0089] In some embodiments, R ^e in Formula I is azetidine or piperidine optionally substituted by 1-6 R ^f groups, pyrazole optionally substituted by 1-6 R ^f groups, phenyl optionally substituted by 1-6 R ^f groups or cycloalkyl optionally substituted by 1-6 R ^f groups. In some embodiments, R ^e in Formula I is azetidine optionally substituted by 1-6 R ^f groups. In some embodiments, R ^e in Formula I is piperidine optionally substituted by 1-6 R ^f groups. In some embodiments, R ^e in Formula I is phenyl optionally substituted by 1-6 R ^f groups. In some embodiments, R ^e in Formula I is cycloalkyl optionally substituted by 1-6 R ^f groups. [0090] In some embodiments, each R ^f in Formula I is independently H, D, oxo, halogen, C1-C8 alkoxide, C1-C8 alkyl, haloalkyl, -OH, -CN, -NO ² , -C ² -C ⁶ alkenyl, -C ² -C ⁶ alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, -OR ^a , -SR ^a , -NR ^c R ^d , -NR ^a R ^c , -C(O)R ^b , -OC(O)R ^b , -C(O)OR ^b , -C(O)NR ^c R ^d , -S(O)R ^b , -S(O)2NR ^c R ^d , -S(O)(=NR ^b )R ^b , - SF ⁵ , -P(O)R ^b R ^b , -P(O)(OR ^b )(OR ^b ), -B(OR ^c )(OR ^d ), -S(O) ² R ^b , -C(O)NR ^b OR ^b , -S(O)2OR ^b , - OS(O) ₂ OR ^b , or -OPO(OR ^b )(OR ^b ); wherein said C ₁ -C ₈ alkyl is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR ^a , -SR ^a , -NR ^a R ^d , or NR ^c R ^d . [0091] In some embodiments, R ^f in Formula I is H. In some embodiments, R ^f in Formula I is D. In some embodiments, R ^f in Formula I is oxo. In some embodiments, R ^f in Formula I is halogen. In some embodiments, R ^f in Formula I is C ₁ -C ₈ alkoxide. In some embodiments, R ^f in Formula I is C ₁ -C ₈ alkyl. In some embodiments, the C ₁ -C ₈ alkyl is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR ^a , -SR ^a , -NR ^a R ^d , or NR ^c R ^d . In some embodiments, R ^f in Formula I is haloalkyl. In some embodiments, R ^f in Formula I is -OH. In some embodiments, R ^f in Formula I is -CN. In some embodiments, R ^f in Formula I is -NO2. In - 22 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application some embodiments, R ^f in Formula I is -C ² -C ⁶ alkenyl. In some embodiments, R ^f in Formula I is - C2-C6 alkynyl. In some embodiments, R ^f in Formula I is aryl. In some embodiments, R ^f in Formula I is heteroaryl. In some embodiments, R ^f in Formula I is cycloalkyl. In other embodiments, R ^f in Formula I is cycloalkenyl. In other embodiments, R ^f in Formula I is heterocycloalkyl. In other embodiments, R ^f in Formula I is heterocycloalkenyl. In other embodiments, R ^f in Formula I is -OR ^a . In other embodiments, R ^f in Formula I is -SR ^a . In other embodiments, R ^f in Formula I is -NR ^c R ^d . In other embodiments, R ^f in Formula I is -NR ^a R ^c . In other embodiments, R ^f in Formula I is -C(O)R ^b . In other embodiments, R ^f in Formula I is - OC(O)R ^b . In other embodiments, R ^f in Formula I is -C(O)OR ^b . In other embodiments, R ^f in Formula I is -C(O)NR ^c R ^d . In yet other embodiments, R ^f in Formula I is -S(O)R ^b . In yet other embodiments, R ^f in Formula I is -S(O) ² NR ^c R ^d . In yet other embodiments, R ^f in Formula I is - S(O)(=NR ^b )R ^b . In yet other embodiments, R ^f in Formula I is -SF5. In yet other embodiments, R ^f in Formula I is -P(O)R ^b R ^b . In yet other embodiments, R ^f in Formula I is -P(O)(OR ^b )(OR ^b ). In yet other embodiments, R ^f in Formula I is -B(OR ^c )(OR ^d ). In yet other embodiments, R ^f in Formula I is -S(O)2R ^b . In yet other embodiments, R ^f in Formula I is -C(O)NR ^b OR ^b . In yet other embodiments, R ^f in Formula I is -S(O) ₂ OR ^b . In yet other embodiments, R ^f in Formula I is - OS(O)2OR ^b . In yet other embodiments, R ^f in Formula I is -OPO(OR ^b )(OR ^b ). [0092] In some embodiments, the compounds of Formula (I) are the pharmaceutically acceptable salts. In some embodiments, the compounds of Formula (I) are solvates. In some embodiments, the compounds of Formula (I) are N-oxides. In some embodiments, the compounds of Formula (I) are stereoisomers. [0093] In some embodiments, the compounds of Formula (I) are represented by compounds of Formula II or a pharmaceutically acceptable salt or stereoisomer thereof; wherein each R ¹ , R ² , R ³ , R ⁴ , R ⁵ , m, n, W, L, and ring A are defined with respect to Formula (I). [0094] In some embodiments, the compounds of Formula (I) are represented by compounds of Formula III - 23 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application or a pharmaceutically acceptable salt or stereoisomer thereof; wherein each R ¹ , R ² , R ³ , R ⁴ , R ⁵ , m, n, W and ring A are defined with respect to Formula (I). [0095] In some embodiments, the compounds of Formula (I) are represented by compounds of Formula IV or a pharmaceutically acceptable salt or stereoisomer thereof; wherein each R ¹ , R ² , R ³ , R ⁴ , R ⁵ , m, n, and W are defined with respect to Formula (I). [0096] In some embodiments, the compounds of Formula (I) are represented by compounds of Formula V or a pharmaceutically acceptable salt or stereoisomer thereof; wherein each R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^c , R ^d , m, and n are defined with respect to Formula (I). [0097] In some embodiments, the compounds of Formula (I) are represented by compounds of Formula VI or a pharmaceutically acceptable salt or stereoisomer thereof; wherein each R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^c , R ^d , m, and n are defined with respect to Formula (I). [0098] In yet further embodiments, the compounds of Formula (I) are: - 24 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application 2-((1-(2-(Isoindolin-2-yl)-6-methyl-4-oxo-3-(tetrahydro-2H-p yran-4-yl)-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(2-(3-Azabicyclo[3.1.0]hexan-3-yl)-6-methyl-4-oxo-3-(t etrahydro-2H-pyran-4-yl)- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(2-(Isoindolin-2-yl)-6-methyl-4-oxo-3-((S)-tetrahydro- 2H-pyran-3-yl)-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(3-((R)-1,1-Dioxidotetrahydrothiophen-3-yl)-2-(isoindo lin-2-yl)-6-methyl-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(3-((1-Acetylazetidin-3-yl)methyl)-2-(isoindolin-2-yl) -6-methyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(2-(Isoindolin-2-yl)-6-methyl-3-((R)-1-(methylsulfonyl )pyrrolidin-3-yl)-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(2-(Isoindolin-2-yl)-6-methyl-4-oxo-3-((S)-tetrahydrof uran-3-yl)-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(2-(Isoindolin-2-yl)-3-(4-methoxybenzyl)-6-methyl-4-ox o-3,4-dihydroquinazolin- 8-yl)ethyl)amino)benzoic acid; 2-((1-(2-(Isoindolin-2-yl)-6-methyl-3-((1-methyl-1H-pyrazol- 4-yl)methyl)-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(3-(Cyclopropylmethyl)-2-(isoindolin-2-yl)-6-methyl-4- oxo-3,4-dihydroquinazolin- 8-yl)ethyl)amino)benzoic acid; 2-((1-(3-(2,2-Dimethyltetrahydro-2H-pyran-4-yl)-2-(isoindoli n-2-yl)-6-methyl-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic; 2-[1-[2-(5-Fluoro-1,3-dihydroisoindol-2-yl)-6-methyl-3-(oxan -4-yl)-4-oxoquinazolin-8- yl]ethylamino]benzoic acid; 2-[1-[2-(5-Azaspiro[2.4]heptan-5-yl)-6-methyl-3-(oxan-4-yl)- 4-oxoquinazolin-8- yl]ethylamino]benzoic acid; 2-[1-[2-(4,4-Difluoropiperidin-1-yl)-6-methyl-3-(oxan-4-yl)- 4-oxoquinazolin-8- yl]ethylamino]benzoic acid; 2-[1-[2-(5,7-Dihydropyrrolo[3,4-b]pyridin-6-yl)-6-methyl-3-( oxan-4-yl)-4- oxoquinazolin-8-yl]ethylamino]benzoic acid; 2-[1-[6-Methyl-2-(1-methyl-4,6-dihydropyrrolo[3,4-c]pyrazol- 5-yl)-3-(oxan-4-yl)-4- oxoquinazolin-8-yl]ethylamino]benzoic acid; - 25 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application 6-((1-(2-(3-Azabicyclo[3.1.0]hexan-3-yl)-6-methyl-4-oxo-3-(t etrahydro-2H-pyran-4-yl)- 3,4-dihydroquinazolin-8-yl)ethyl)amino)-2,3-difluorobenzoic acid; 2-((1-(2-(Isoindolin-2-yl)-4-oxo-3-(tetrahydro-2H-pyran-4-yl )-6-(trifluoromethyl)-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; or a pharmaceutically acceptable salt thereof. [0099] It will be apparent that the compounds of Formula I, including all subgenera described herein, may have multiple stereogenic centers. As a result, there exist multiple stereoisomers (enantiomers and diastereomers) of the compounds of Formula I (and subgenera described herein). The present disclosure contemplates and encompasses each stereoisomer of any compound of Formula I (and subgenera described herein), as well as mixtures of said stereoisomers. [00100] Pharmaceutically acceptable salts and solvates of the compounds of Formula I (including all subgenera described herein) are also within the scope of the disclosure. [00101] Isotopic variants of the compounds of Formula I (including all subgenera described herein) are also contemplated by the present disclosure. Pharmaceutical Compositions and Methods of Administration [00102] In some embodiments, the disclosure is directed to pharmaceutical compositions comprising compounds of Formula I, or a pharmaceutically acceptable salt or solvate thereof. [00103] The subject pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of a compound of the present disclosure as the active ingredient, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. Where desired, the pharmaceutical compositions contain pharmaceutically acceptable salt and/or coordination complex thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. [00104] The subject pharmaceutical compositions can be administered alone or in combination with one or more other agents, which are also typically administered in the form of pharmaceutical compositions. Where desired, the one or more compounds of the invention and other agent(s) may be mixed into a preparation or both components may be formulated into separate preparations to use them in combination separately or at the same time. [00105] In some embodiments, the concentration of one or more compounds provided in the pharmaceutical compositions of the present invention is less than 100%, 90%, 80%, 70%, 60%, - 26 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% (or a number in the range defined by and including any two numbers above) w/w, w/v or v/v. [00106] In some embodiments, the concentration of one or more compounds of the invention is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 1.25% , 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% (or a number in the range defined by and including any two numbers above) w/w, w/v, or v/v. [00107] In some embodiments, the concentration of one or more compounds of the invention is in the range from approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40%, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, approximately 1% to approximately 10% w/w, w/v or v/v. [00108] In some embodiments, the concentration of one or more compounds of the invention is in the range from approximately 0.001% to approximately 10%, approximately 0.01% to approximately 5%, approximately 0.02% to approximately 4.5%, approximately 0.03% to - 27 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application approximately 4%, approximately 0.04% to approximately 3.5%, approximately 0.05% to approximately 3%, approximately 0.06% to approximately 2.5%, approximately 0.07% to approximately 2%, approximately 0.08% to approximately 1.5%, approximately 0.09% to approximately 1%, approximately 0.1% to approximately 0.9% w/w, w/v or v/v. [00109] In some embodiments, the amount of one or more compounds of the invention is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g (or a number in the range defined by and including any two numbers above). [00110] In some embodiments, the amount of one or more compounds of the invention is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g, , 0.15 g, 0.2 g, , 0.25 g, 0.3 g, , 0.35 g, 0.4 g, , 0.45 g, 0.5 g, 0.55 g, 0.6 g, , 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5g, 7 g, 7.5g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g (or a number in the range defined by and including any two numbers above). [00111] In some embodiments, the amount of one or more compounds of the invention is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g. [00112] The compounds according to the invention are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used. An exemplary dosage is 10 to 30 mg per day. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician. [00113] A pharmaceutical composition of the invention typically contains an active ingredient (i.e., a compound of the disclosure) of the present invention or a pharmaceutically acceptable salt and/or coordination complex thereof, and one or more pharmaceutically acceptable excipients, - 28 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application carriers, including but not limited to inert solid diluents and fillers, diluents, sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. [00114] Described below are non- limiting exemplary pharmaceutical compositions and methods for preparing the same. Pharmaceutical Compositions for Oral Administration. [00115] In some embodiments, the invention provides a pharmaceutical composition for oral administration containing a compound of the invention, and a pharmaceutical excipient suitable for oral administration. [00116] In some embodiments, the invention provides a solid pharmaceutical composition for oral administration containing: (i) an effective amount of a compound of the invention; optionally (ii) an effective amount of a second agent; and (iii) a pharmaceutical excipient suitable for oral administration. In some embodiments, the composition further contains: (iv) an effective amount of a third agent. [00117] In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral consumption. Pharmaceutical compositions of the invention suitable for oral administration can be presented as discrete dosage forms, such as capsules, cachets, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in- water emulsion, or a water-in-oil liquid emulsion. Such dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free- flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. [00118] This invention further encompasses anhydrous pharmaceutical compositions and dosage forms comprising an active ingredient, since water can facilitate the degradation of some - 29 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application compounds. For example, water may be added (e.g., 5%) in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf- life or the stability of formulations over time. Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms of the invention which contain lactose can be made anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected. An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions may be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, and strip packs. [00119] An active ingredient can be combined in an intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration. In preparing the compositions for an oral dosage form, any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro- crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose. For example, suitable carriers include powders, capsules, and tablets, with the solid oral preparations. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. [00120] Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxy-propyl methyl cellulose, microcrystalline cellulose, and mixtures thereof. [00121] Examples of suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or - 30 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof. [00122] Disintegrants may be used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Too much of a disintegrant may produce tablets which may disintegrate in the bottle. Too little may be insufficient for disintegration to occur and may thus alter the rate and extent of release of the active ingredient(s) from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) may be used to form the dosage forms of the compounds disclosed herein. The amount of disintegrant used may vary based upon the type of formulation and mode of administration, and may be readily discernible to those of ordinary skill in the art. About 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant, may be used in the pharmaceutical composition. Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof. [00123] Lubricants which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, or mixtures thereof. Additional lubricants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, or mixtures thereof. A lubricant can optionally be added, in an amount of less than about 1 weight percent of the pharmaceutical composition. [00124] When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof. [00125] The tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can also be presented as hard gelatin capsules - 31 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil. [00126] Surfactant which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be employed, a mixture of lipophilic surfactants may be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed. [00127] A suitable hydrophilic surfactant may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of or less than about 10. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance (“HLB” value). Surfactants with lower HLB values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions. [00128] Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10. However, HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions. [00129] Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acyl lactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof. [00130] Within the aforementioned group, ionic surfactants include, by way of example: lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and - 32 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di- glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof. [00131] Ionic surfactants may be the ionized forms of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG- phosphatidylethanolamine, PVP -phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholylsarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate, lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, and salts and mixtures thereof. [00132] Hydrophilic non-ionic surfactants may include, but are not limited to, alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters and hydrophilic transesterification products of a polyol with at least one member of the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide. [00133] Other hydrophilic-non-ionic surfactants include, without limitation, PEG- 10 laurate, PEG- 12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG- 12 oleate, PEG- 15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG- 15 stearate, PEG-32 distearate, PEG-40 stearate, PEG- 100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, - 33 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application PEG-40 glyceryl laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30 soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG- 100 succinate, PEG-24 cholesterol, polyglyceryl-lOoleate, Tween 40, Tween 60, sucrose monostearate, sucrose mono laurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octyl phenol series, and poloxamers. [00134] Suitable lipophilic surfactants include, by way of example only: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins/vitamin derivatives; and mixtures thereof. Within this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of a polyol with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides. [00135] In one embodiment, the composition may include a solubilizer to ensure good solubilization and/or dissolution of the compound of the present invention and to minimize precipitation of the compound of the present invention. This can be especially important for compositions for non-oral use, e.g., compositions for injection. A solubilizer may also be added to increase the solubility of the hydrophilic drug and/or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion. [00136] Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin - 34 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application derivatives; ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG ; amides and other nitrogen-containing compounds such as 2-pyrrolidone, 2-piperidone, ε-caprolactam, N- alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and isomers thereof, δ-valerolactone and isomers thereof, β-butyrolactone and isomers thereof; and other solubilizers known in the art, such as dimethyl acetamide, dimethyl isosorbide, N-methyl pyrrolidones, monooctanoin, diethylene glycol monoethyl ether, and water. [00137] Mixtures of solubilizers may also be used. Examples include, but not limited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol. [00138] The amount of solubilizer that can be included is not particularly limited. The amount of a given solubilizer may be limited to a bioacceptable amount, which may be readily determined by one of skill in the art. In some circumstances, it may be advantageous to include amounts of solubilizers far in excess of bioacceptable amounts, for example to maximize the concentration of the drug, with excess solubilizer removed prior to providing the composition to a subject using conventional techniques, such as distillation or evaporation. Thus, if present, the solubilizer can be in a weight ratio of 10%, 25%o, 50%), 100%o, or up to about 200%> by weight, based on the combined weight of the drug, and other excipients. If desired, very small amounts of solubilizer may also be used, such as 5%>, 2%>, 1%) or even less. Typically, the solubilizer may be present in an amount of about 1%> to about 100%, more typically about 5%> to about 25%> by weight. [00139] The composition can further include one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, without limitation, detackifiers, anti-foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof. - 35 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application [00140] In addition, an acid or a base may be incorporated into the composition to facilitate processing, to enhance stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)-aminomethane (TRIS) and the like. Also suitable are bases that are salts of a pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like. Salts of polyprotic acids, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used. When the base is a salt, the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, and the like. Example may include, but not limited to, sodium, potassium, lithium, magnesium, calcium and ammonium. [00141] Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p- toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid and the like. Pharmaceutical Compositions for Injection. [00142] In some embodiments, the invention provides a pharmaceutical composition for injection containing a compound of the present invention and a pharmaceutical excipient suitable for injection. Components and amounts of agents in the compositions are as described herein. - 36 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application [00143] The forms in which the novel compositions of the present invention may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles. [00144] Aqueous solutions in saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, for the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. [00145] Sterile injectable solutions are prepared by incorporating the compound of the present invention in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, certain desirable methods of preparation are vacuum-drying and freeze- drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile- filtered solution thereof. Pharmaceutical Compositions for Topical (e.g., Transdermal) Delivery. [00146] In some embodiments, the invention provides a pharmaceutical composition for transdermal delivery containing a compound of the present invention and a pharmaceutical excipient suitable for transdermal delivery. [00147] Compositions of the present invention can be formulated into preparations in solid, semisolid, or liquid forms suitable for local or topical administration, such as gels, water soluble jellies, creams, lotions, suspensions, foams, powders, slurries, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, dimethylsulfoxide (DMSO)-based solutions. In general, carriers with higher densities are capable of providing an area with a prolonged exposure to the active ingredients. In contrast, a solution formulation may provide more immediate exposure of the active ingredient to the chosen area. - 37 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application [00148] The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients, which are compounds that allow increased penetration of, or assist in the delivery of, therapeutic molecules across the stratum corneum permeability barrier of the skin. There are many of these penetration- enhancing molecules known to those trained in the art of topical formulation. [00149] Examples of such carriers and excipients include, but are not limited to, humectants (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols. [00150] Another exemplary formulation for use in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of a compound of the present invention in controlled amounts, either with or without another agent. [00151] The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. Nos.5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. Pharmaceutical Compositions for Inhalation. [00152] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner. Other Pharmaceutical Compositions. - 38 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application [00153] Pharmaceutical compositions may also be prepared from compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. Preparations for such pharmaceutical compositions are well-known in the art. See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 20037ybg; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001 ; Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty- Second Edition (The Pharmaceutical Press, London, 1999); all of which are incorporated by reference herein in their entirety. [00154] Administration of the compounds or pharmaceutical composition of the present invention can be affected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical (e.g., transdermal application), rectal administration, via local delivery by catheter or stent or through inhalation. Compounds can also be administered intraadiposally or intrathecally. [00155] The amount of the compound administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to 7 g/day, preferably about 0.05 to about 2.5 g/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, e.g., by dividing such larger doses into several small doses for administration throughout the day. [00156] In some embodiments, a compound of the invention is administered in a single dose. [00157] Typically, such administration will be by injection, e.g., intravenous injection, in order to introduce the agent quickly. However, other routes may be used as appropriate. A single dose of a compound of the invention may also be used for treatment of an acute condition. [00158] In some embodiments, a compound of the invention is administered in multiple doses. Dosing may be about once, twice, three times, four times, five times, six times, or more than six - 39 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application times per day. Dosing may be about once a month, once every two weeks, once a week, or once every other day. In another embodiment a compound of the invention and another agent are administered together about once per day to about 6 times per day. In another embodiment the administration of a compound of the invention and an agent continues for less than about 7 days. In yet another embodiment the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary. [00159] Administration of the compounds of the invention may continue as long as necessary. In some embodiments, a compound of the invention is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, a compound of the invention is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, a compound of the invention is administered chronically on an ongoing basis, e.g., for the treatment of chronic effects. [00160] An effective amount of a compound of the invention may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant. [00161] The compositions of the invention may also be delivered via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer. Such a method of administration may, for example, aid in the prevention or amelioration of restenosis following procedures such as balloon angioplasty. Without being bound by theory, compounds of the invention may slow or inhibit the migration and proliferation of smooth muscle cells in the arterial wall which contribute to restenosis. A compound of the invention may be administered, for example, by local delivery from the struts of a stent, from a stent graft, from grafts, or from the cover or sheath of a stent. In some embodiments, a compound of the invention is admixed with a matrix. Such a matrix may be a polymeric matrix and may serve to bond the compound to the stent. Polymeric matrices suitable for such use, include, for example, lactone-based polyesters or copolyesters such as polylactide, polycaprolactonglycolide, polyorthoesters, polyanhydrides, polyaminoacids, polysaccharides, polyphosphazenes, poly (ether-ester) copolymers (e.g. PEO-PLLA); polydimethylsiloxane, poly(ethylene-vinylacetate), acrylate-based polymers or copolymers (e.g. polyhydroxyethyl methylmethacrylate, polyvinyl pyrrolidinone), fluorinated polymers such as polytetrafluoroethylene and cellulose esters. Suitable matrices may be nondegrading or may degrade with time, releasing the compound or compounds. Compounds - 40 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application of the invention may be applied to the surface of the stent by various methods such as dip/spin coating, spray coating, dip-coating, and/or brush-coating. The compounds may be applied in a solvent and the solvent may be allowed to evaporate, thus forming a layer of compound onto the stent. Alternatively, the compound may be located in the body of the stent or graft, for example in microchannels or micropores. When implanted, the compound diffuses out of the body of the stent to contact the arterial wall. Such stents may be prepared by dipping a stent manufactured to contain such micropores or microchannels into a solution of the compound of the invention in a suitable solvent, followed by evaporation of the solvent. Excess drug on the surface of the stent may be removed via an additional brief solvent wash. In yet other embodiments, compounds of the invention may be covalently linked to a stent or graft. A covalent linker may be used which degrades in vivo, leading to the release of the compound of the invention. Any bio-labile linkage may be used for such a purpose, such as ester, amide or anhydride linkages. Compounds of the invention may additionally be administered intravascularly from a balloon used during angioplasty. Extravascular administration of the compounds via the pericard or via advential application of formulations of the invention may also be performed to decrease restenosis. [00162] A variety of stent devices which may be used as described are disclosed, for example, in the following references, all of which are hereby incorporated by reference: U.S. Pat. No. 5451233; U.S. Pat. No.5040548; U.S. Pat. No.5061273; U.S. Pat. No.5496346; U.S. Pat. No. 5292331; U.S. Pat. No.5674278; U.S. Pat. No.3657744; U.S. Pat. No.4739762; U.S. Pat. No. 5195984; U.S. Pat. No.5292331 ; U.S. Pat. No.5674278; U.S. Pat. No.5879382; U.S. Pat. No. 6344053. [00163] The compounds of the invention may be administered in dosages. It is known in the art that due to intersubject variability in compound pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. Dosing for a compound of the invention may be found by routine experimentation in light of the instant disclosure. [00164] When a compound of the invention is administered in a composition that comprises one or more agents, and the agent has a shorter half- life than the compound of the invention unit dose forms of the agent and the compound of the invention may be adjusted accordingly. [00165] The subject pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository. The pharmaceutical composition may be in unit dosage forms suitable for single administration of - 41 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application precise dosages. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc. [00166] Exemplary parenteral administration forms include solutions or suspensions of active compound in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired. Methods of Use [00167] The method typically comprises administering to a subject a therapeutically effective amount of a compound of the invention. The therapeutically effective amount of the subject combination of compounds may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells, e.g., reduction of proliferation or downregulation of activity of a target protein. The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried. [00168] As used herein, the term "IC50" refers to the half maximal inhibitory concentration of an inhibitor in inhibiting biological or biochemical function. This quantitative measure indicates how much of a particular inhibitor is needed to inhibit a given biological process (or component of a process, i.e., an enzyme, cell, cell receptor or microorganism) by half. In other words, it is the half maximal (50%) inhibitory concentration (IC) of a substance (50% IC, or IC50). EC50 refers to the plasma concentration required for obtaining 50% of a maximum effect in vivo. [00169] In some aspects, the present disclosure provides a method of modulating PI3K (e.g., PI3Kα) activity (e.g., in vitro or in vivo), comprising contacting a cell with a therapeutically effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof. [00170] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound as described herein or a - 42 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. [00171] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. [00172] In some embodiments, the disease or disorder is associated with an implicated PI3K activity. In some embodiments, the disease or disorder is a disease or disorder in which PI3K activity is implicated. [00173] In some embodiments, the disease or disorder is a cancer. [00174] In some embodiments, the cancer is selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, aids-related cancers, aids- related lymphoma, anal cancer, astrocytoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, osteosarcoma, malignant fibrous histiocytoma, brain tumors, breast cancer, bronchial tumors, Burkitt lymphoma, carcinoid tumor, cancer of unknown primary, cardiac (heart) tumors, atypical teratoid/rhabdoid tumor, primary CNS lymphoma, cervical cancer, cholangiocarcinoma, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), colorectal cancer, craniopharyngioma, cutaneous t-cell lymphoma, mycosis fungoides, Sezary syndrome, ductal carcinoma in situ (DCIS), embryonal tumors, medulloblastoma, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, malignant gastrointestinal stromal tumors (GIST), germ cell tumors, gestational trophoblastic disease, hairy cell leukemia, head and neck cancer, hepatocellular cancer, Langerhans cell histiocytosis, Hodgkin lymphoma, islet cell tumors, pancreatic neuroendocrine tumors, Kaposi sarcoma, kidney cancer, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, male breast cancer, intraocular melanoma, Merkel cell carcinoma, malignant mesothelioma, metastatic cancer, metastatic squamous neck cancer, midline tract carcinoma with nut gene changes, mouth cancer, multiple endocrine neoplasia syndromes, multiple myeloma/plasma cell neoplasms, myelodysplastic syndromes, myelodysplastic neoplasms, myeloproliferative neoplasms, chronic myeloproliferative neoplasm, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, lip and oral cavity cancer, oropharyngeal cancer, malignant fibrous histiocytoma of bone, ovarian cancer, - 43 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application pancreatic cancer, pancreatic neuroendocrine tumors (islet cell tumors), papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumor, plasma cell neoplasm, multiple myeloma, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, recurrent cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, childhood vascular tumors, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma of the skin, testicular cancer, oropharyngeal cancer, hypopharyngeal cancer, thymoma, thymic carcinoma, thyroid cancer, tracheobronchial tumors, transitional cell cancer of the renal pelvis and ureter, urethral cancer, uterine sarcoma, vaginal cancer, vascular tumors, vulvar cancer, and Wilms tumor. [00175] In some embodiments, the cancer is Endometrial cancer, Breast cancer, Oesophageal squamous-cell cancer, Cervical squamous-cell carcinoma, Cervical adenocarcinoma, Colorectal adenocarcinoma, Bladder Urothelial Carcinoma, Glioblastoma, Ovarian cancer, Non-small-cell Lung cancer, Esophagogastric cancer, Nerve-sheath tumor, Head and neck squamous-cell carcinoma, Melanoma, Esophagogastric adenocarcinoma, Soft-tissue sarcoma, Prostate cancer, Fibrolamellar carcinoma, Hepatocellular carcinoma, Diffuse glioma, Colorectal cancer, Pancreatic cancer, Cholangiocarcinoma, B-cell lymphoma, Mesothelioma, Adrenocortical carcinoma, Renal non-clear-cell carcinoma, Renal clear-cell carcinoma, Germ-cell carcinoma, Thymic tumor, Pheochromocytoma, Miscellaneous neuroepithelial tumor, thyroid cancer, leukemia, or encapsulated glioma. [00176] In some embodiments, the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, cervical cancer, bladder cancer, esophageal cancer, pancreatic cancer, bone cancer, hepatobiliary cancer, medulloblastoma, kidney cancer or prostate cancer. [00177] In some embodiments, the cancer is a breast cancer, a prostate cancer, or a brain cancer. In some embodiments, the cancer is a breast cancer. In some embodiments, the cancer is a prostate cancer. In some embodiments, the cancer is a brain cancer. [00178] In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, the breast cancer is ductal carcinoma in situ (DCIS). In some embodiments, the breast cancer is invasive ductal carcinoma. In some embodiments, the breast cancer is triple negative breast cancer. In some embodiments, the breast cancer is medullary carcinoma. In some - 44 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application embodiments, the breast cancer is tubular carcinoma. In some embodiments, the breast cancer is mucinous carcinoma. In some embodiments, the breast cancer is Paget disease of the breast or nipple. In some embodiments, the breast cancer is inflammatory breast cancer (IBC). [00179] In some embodiments, the prostate cancer is an adenocarcinoma. In some embodiments, the prostate cancer is a small cell carcinoma. In some embodiments, the prostate cancer is a neuroendocrine tumor. In some embodiments, the prostate cancer is a transitional cell carcinoma. In some embodiments, the prostate cancer is a sarcoma. [00180] In some embodiments, the brain cancer is an acoustic neuroma. In some embodiments, the brain cancer is an astrocytoma. In some embodiments, the brain cancer is a brain metastasis. In some embodiments, the brain cancer is choroid plexus carcinoma. In some embodiments, the brain cancer is craniopharyngioma. In some embodiments, the brain cancer is an embryonal tumor. In some embodiments, the brain cancer is an ependymoma. In some embodiments, the brain cancer is a glioblastoma. In some embodiments, the brain cancer is a glioma. In some embodiments, the brain cancer is a medulloblastoma. In some embodiments, the brain cancer is a meningioma. In some embodiments, the brain cancer is an oligodendroglioma. In some embodiments, the brain cancer is a pediatric brain tumor. In some embodiments, the brain cancer is a pineoblastoma. In some embodiments, the brain cancer is a pituitary tumor. [00181] In some embodiments, the disease or disorder associated with PI3K includes, but is not limited to, CLOVES syndrome (congenial lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome), PIK3CA-related overgrowth syndrome (PROS), breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer. [00182] In some embodiments, the diseases or disorder associated with PI3K is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome). [00183] In some embodiments, the disease or disorder associated with PI3K is PIK3CA-related overgrowth syndrome (PROS). [00184] In some embodiments, the disease or disorder associated with PI3K is breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer. - 45 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application [00185] In some embodiments, the disease or disorder associated with PI3K is breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer. [00186] In some embodiments, the disease or disorder associated with PI3K is leukemia, lymphoma, or sarcoma. [00187] In some embodiments, the cancer is endometrial cancer, head and neck cancer, or a sarcoma. [00188] In some embodiments, the cancer is endometrial cancer. In some embodiments the cancer is head and neck cancer. In some embodiments, the cancer is a sarcoma. [00189] In some embodiments, the sarcoma is soft tissue sarcoma, osteosarcoma, chondrosarcoma, Ewing sarcoma, hemangioendothelioma, angiosarcoma, fibrosarcoma, myofibrosarcoma, chordoma, adamantinoma, liposarcoma, leiomyosarcoma, malignant peripheral nerve sheath tumor, rhabdomyosarcoma, synovial sarcoma, or malignant solitary fibrous tumor. [00190] In some embodiments, the sarcoma is soft tissue sarcoma. In some embodiments the soft tissue sarcoma is liposarcoma, atypical lipomatous tumor, dermatofibrosarcoma protuberans, malignant solitary fibrous tumor, inflammatory myofibroblastic tumor, low-grade myofibroblastic sarcoma, fibrosarcoma, myxofibrosarcoma, low-grade fibromyxoid sarcoma, giant cell tumor of soft tissues, leiomyosarcoma, malignant glomus tumor, rhabdomyosarcoma, hemangioendothelioma, angiosarcoma of soft tissue, extraskeletal osteosarcoma, gastrointestinal stromal tumor, malignant gastrointestinal stromal tumor (GIST), malignant peripheral nerve sheath tumor, malignant Triton tumor, malignant granular cell tumor, malignant ossifying fibromyxoid tumor, stromal sarcoma, myoepithelial carcinoma, malignant phosphaturic mesenchymal tumor, synovial sarcoma, epithelioid sarcoma, alveolar soft part sarcoma, clear cell sarcoma of soft tissue, extraskeletal myxoid chondrosarcoma, extraskeletal Ewing sarcoma, desmoplastic small round cell tumor, extrarenal rhabdoid tumor, perivascular epithelioid cell tumor, intimal sarcoma, undifferentiated spindle cell sarcoma, undifferentiated pleomorphic sarcoma, undifferentiated round cell sarcoma, undifferentiated epithelioid sarcoma, or undifferentiated sarcoma, not otherwise specified. [00191] In some aspects, the present disclosure provides a method of treating or preventing a cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. - 46 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application [00192] In some aspects, the present disclosure provides a method of treating a cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. [00193] In some aspects, the present disclosure provides a method of treating or preventing a breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. [00194] In some aspects, the present disclosure provides a method of treating a breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. [00195] In some aspects, the present disclosure provides a method of treating or preventing a prostate cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. [00196] In some aspects, the present disclosure provides a method of treating a prostate cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. [00197] In some aspects, the present disclosure provides a method of treating or preventing a brain cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. [00198] In some aspects, the present disclosure provides a method of treating a brain cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. [00199] In some aspects, the present disclosure provides a compound as described herein or a pharmaceutically acceptable salt thereof for use in modulating PI3K (e.g., PI3Kα) activity (e.g., in vitro or in vivo). - 47 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application [00200] In some aspects, the present disclosure provides a compound as described herein or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease or disorder disclosed herein. [00201] In some aspects, the present disclosure provides a compound as described herein or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder disclosed herein. [00202] In some aspects, the present disclosure provides a compound as described herein or a pharmaceutically acceptable salt thereof for use in treating or preventing a cancer in a subject in need thereof. [00203] In some aspects, the present disclosure provides a compound as described herein or a pharmaceutically acceptable salt thereof for use in treating a cancer in a subject in need thereof. [00204] In some aspects, the present disclosure provides a compound as described herein or a pharmaceutically acceptable salt thereof for use in treating or preventing a breast cancer in a subject in need thereof. [00205] In some aspects, the present disclosure provides a compound as described herein or a pharmaceutically acceptable salt thereof for use in treating a breast cancer in a subject in need thereof. [00206] In some aspects, the present disclosure provides a compound as described herein or a pharmaceutically acceptable salt thereof for use in treating or preventing a prostate cancer in a subject in need thereof. [00207] In some aspects, the present disclosure provides a compound as described herein or a pharmaceutically acceptable salt thereof for use in treating a prostate cancer in a subject in need thereof. [00208] In some aspects, the present disclosure provides a compound as described herein or a pharmaceutically acceptable salt thereof for use in treating or preventing a brain cancer in a subject in need thereof. [00209] In some aspects, the present disclosure provides a compound as described herein or a pharmaceutically acceptable salt thereof for use in treating a brain cancer in a subject in need thereof. [00210] In some aspects, the present disclosure provides use of a compound as described herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for modulating PI3K (e.g., PI3Kα) activity (e.g., in vitro or in vivo). - 48 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application [00211] In some aspects, the present disclosure provides use of a compound as described herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein. [00212] In some aspects, the present disclosure provides use of a compound as described herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein. [00213] In some aspects, the present disclosure provides use of a compound as described herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a cancer in a subject in need thereof. [00214] In some aspects, the present disclosure provides use of a compound as described herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a cancer in a subject in need thereof. [00215] In some aspects, the present disclosure provides use of a compound as described herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a breast cancer in a subject in need thereof. [00216] In some aspects, the present disclosure provides use of a compound as described herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a breast cancer in a subject in need thereof. [00217] In some aspects, the present disclosure provides use of a compound as described herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a prostate cancer in a subject in need thereof. [00218] In some aspects, the present disclosure provides use of a compound as described herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a prostate cancer in a subject in need thereof. [00219] In some aspects, the present disclosure provides use of a compound as described herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a brain cancer in a subject in need thereof. [00220] In some aspects, the present disclosure provides use of a compound as described herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a brain cancer in a subject in need thereof. [00221] The present disclosure provides compounds that function as modulators of PI3K activity. The present disclosure therefore provides a method of modulating PI3K activity in vitro - 49 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application or in vivo, said method comprising contacting a cell with a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, as defined herein. [00222] In some embodiments, PI3K is modulation is inhibition of PI3K. [00223] In some embodiments, the PI3K inhibitor is a compound as described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the PI3K inhibitor is a PI3Kα inhibitor. In some embodiments, the PI3K inhibitor is a PI3Kα H1047R mutant inhibitor. In some embodiments, the PI3K inhibitor is alpha/beta non-selective. In some embodiments, the PI3K inhibitor is alpha selective. In some embodiments, the PI3K inhibitor is beta selective. [00224] Effectiveness of compounds of the disclosure can be determined by industry-accepted assays/disease models according to standard practices of elucidating the same as described in the art and are found in the current general knowledge. [00225] The present disclosure also provides a method of treating a disease or disorder in which PI3K activity is implicated in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein. [00226] The disclosure provides a method of modulating the activity of the PI3Kα allosteric active site, wherein the modulation is induced through peripheral site targeting. In some embodiments, the peripheral site is targeted with an agent selected from a small molecule, a peptide, a peptidomimetic, a protein, a protein mimetic, a nucleic acid, an antibody, an antibody- drug conjugate, a nucleoprotein complex, an immunotherapy, or a combination thereof. Synthesis [00227] Compounds of the invention, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes. [00228] The reactions for preparing compounds of the invention can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan. - 50 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application [00229] Preparation of compounds of the invention can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety. [00230] Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., ¹ H or ¹³ C), infrared spectroscopy, spectrophotometry (e.g., UV- visible), or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography. [00231] The expressions, “ambient temperature,” “room temperature,” and “r.t.” as used herein, are understood in the art, and refer generally to a temperature, e.g., a reaction temperature, that is about the temperature of the room in which the reaction is carried out, for example, a temperature from about 20 ^o C to about 30 ^o C. [00232] Compounds of the invention can be prepared using numerous preparatory reactions known in the literature. The Schemes below provide general guidance in connection with preparing the compounds of the invention. One skilled in the art would understand that the preparations shown in the Schemes can be modified or optimized using general knowledge of organic chemistry to prepare various compounds of the invention. Example synthetic methods for preparing compounds of the invention are provided in the Schemes below. [00233] The following Examples are provided to illustrate some of the concepts described within this disclosure. While the Examples are considered to provide an embodiment, it should not be considered to limit the more general embodiments described herein. EXAMPLES General Synthetic Procedures [00234] Compounds of Formula (I) can be prepared from optionally protected 1-1 as shown in Scheme I. Compounds 1-1 where Lg is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf, OTs, or OMs) can be transformed into compounds 1-2 under standard Stille conditions (e.g., palladium(0) catalyst, such as bis(triphenylphosphine)palladium(II) dichloride and an appropriate stannane, such as tri-n-butyl(1-ethoxyvinyl)tin), or Heck conditions (e.g., palladium catalyst, such as palladium(II) acetate, a ligand, such as 1,3-bis(diphenylphosphino)propane, and - 51 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application an appropriate olefin, such as butyl vinyl ether), or carbonylation coupling conditions (e.g., palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0), a carbonyl source, such as carbon monoxide, and suitable boronic acid, such as phenylboronic acid). Compounds 1-2 can be converted to compounds 1-4 under either reductive conditions (e.g., in the presence of a suitable reducing agent such as sodium borohydride) or nucleophilic addition conditions with nucleophiles 1-3 where M ¹ is a metal (e.g., Li, MgCl, MgBr, ZnCl, or ZnBr). Alcohols 1-4 can be transformed to compounds 1-5 where Lg ¹ is halogen (e.g., Cl, Br, or I) under standard deoxygenative halogenation conditions (e.g., thionyl chloride, phosphorous tribromide, or triphenylphosphine and iodine) or a pseudohalogen (e.g., OTf, OTs, or OMs) under standard sulfonylation conditions (e.g., in the presence of a sulfonylating agent, such as methanesulfonyl chloride, p-toluenesulfonyl chloride, or trifluoromethanesulfonic anhydride, and a base, such as triethylamine). Alkylation of compounds 1-5 with nucleophiles 1-6 optionally in the presence of a base (e.g., triethylamine) can provide compound of Formula (I). Alternatively, reaction of compounds 1-5 with compounds 1-7 where the ring A contains an NH, or SH, or OH group) under standard alkylation conditions optionally in the presence of a base (e.g., sodium hydride) can provide compound 1-8. Scheme I - 52 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application [00235] Compounds of Formula (I) can be prepared from optionally protected compounds 1-2 as shown in Scheme II. Reaction of compounds 1-2 with compounds 2-1 under standard reductive amination conditions (e.g., reducing agent such as, sodium triacetoxyborohydride and optionally an acid, such as acetic acid) can provide compounds 2-2. Alternatively, compounds 2-2 can be converted to compounds 2-5 under reductive condition (e.g., in the presence of a suitable reducing agent, such as sodium borohydride). Alcohols 2-5 can be transformed to compounds 2-6 where Lg ² is halogen (e.g., Cl, Br, or I) under standard deoxygenative halogenation conditions (e.g., thionyl chloride, phosphorous tribromide, or triphenylphosphine and iodine) or a pseudohalogen (e.g., OTf, OTs, or OMs) under sulfonylation standard conditions (e.g., in the presence of a sulfonylating agent, such as methanesulfonyl chloride, p- toluenesulfonyl chloride, or trifluoromethanesulfonic anhydride, and a base, such as triethylamine). Alkylation of compounds 2-6 with nucleophiles 2-1 optionally in the presence of a base (e.g., triethylamine) can provide compounds 2-2. Alternatively, compounds 1-2 can be reacted with compounds 2-3 under standard reductive amination conditions (e.g., reducing agent - 53 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application such as, sodium triacetoxyborohydride and optionally an acid, such as acetic acid) to provide compounds 2-4. Scheme II [00236] Intermediates for the synthesis of compounds of Formula (I) can be prepared as shown in Scheme III. Compounds 3-1 where Lg ³ is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can be coupled with an amine 3-2 under standard amide bond formation conditions such as in the presence of an amide coupling reagent (e.g., N,N’-cabonyldiimidazole or HATU and a base (e.g., diisopropylethylamine) to provide compounds 3-3. Anilines 3-3 can be converted to heterocycles 3-4 under standard acylation conditions (e.g., in the presence of N,N’- cabonyldiimidazole or triphosgene and a suitable base, such as 1,8-diazabicyclo[5.4.0]undec-7- ene). Diones 3-4 can be halogenated with suitable reagents, such as phosphoryl chloride or phosphoryl bromide, to provide compounds 3-5 where X ² is halogen (e.g., Cl or Br). Reaction of halides 3-5 with a compounds 3-6 under standard nucleophilic aromatic substitution conditions, such as in the presence of a suitable base (e.g., N,N-diisoproylethylamine), or under standard Buchwald-Hartwig coupling conditions (e.g., palladium catalyst such as, XPhos Pd G3, and a base, such as Cs2CO3 or K3PO4) can afford compounds 3-7. Scheme III - 54 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application [00237] Intermediates for the synthesis of compounds of Formula (I) can be prepared as shown in Scheme IV. Reaction of compounds 4-1 where Lg ⁴ is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) with nitrites 4-2 where R ^e is C ₃ -C ₈ alkyl in the presence of an acid (e.g., HCl) can provide oximes 4-3. Acylation of oximes 4-3 with an acyl chloride 4-4 where R ^f is C1-C8 alkyl, such as acetyl chloride, optionally in the presence of a base, such as triethylamine can afford compounds 4-5. Compounds 4-5 can be converted to an ester 4-6 where R ^g is C1-C8 alkyl by Beckmann fragmentation in the presence of a base (e.g., diethylamine) in a suitable solvent (e.g., methanol). Treatment of compounds 4-6 with an amine 3-2 can afford compounds 4-7. Alkylation of compounds 4-7 with an electrophile 4-8 where Lg ⁵ is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) in the presence of a base (e.g.triethylamine or K2CO3) can afford compounds 4-9 where R ^h is H, D, -C1-C10 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl or two R ^h , together with the atom to which they are both attached, form a monocyclic or multicyclic heterocycloalkyl, or a monocyclic or multicyclic heterocyclo-alkenyl group. Scheme IV - 55 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application [00238] Intermediates for the synthesis of compounds of Formula (I) can be prepared as shown in Scheme V. Beckmann rearrangement of compounds 4-5 in the presence of an activating reagent (e.g., phosphorous pentachloride) can provide compounds 5-1. Reaction of compounds 5-1 with electrophiles 5-2 where Lg ⁶ is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) under standard conditions (e.g., base, such as triethylamine or K2CO3) can afford compounds 5-3. Reaction of compounds 5-3 with a compound 5-4 under standard nucleophilic aromatic substitution conditions in the presence of a suitable base (e.g., N,N- diisopropylethylamine, K ₂ CO ₃ , KHMDS, or NaH) or Buchwald-Hartwig coupling under standard conditions (e.g., palladium catalyst such as, XPhos Pd G3, and a base, such as Cs2CO3 or K3PO4) can afford compounds 5-5. Scheme V - 56 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application [00239] Compounds of Formula (I) can be prepared from optionally protected 2-6 as shown in Scheme VI. Alkylation of compounds 2-6 with compounds 6-1 optionally in the presence of a base (e.g., triethylamine) can provide compounds 6-2. Scheme VI [00240] Intermediates for the synthesis of compounds of Formula (I) can be prepared as shown in Scheme VII. Reaction of heterocycles 3-4 with amines 3-6 in the presence of an amide coupling reagent (e.g., (benzotriazol-1-yl-oxy)tri-pyrrolidinophosphonium hexafluorophosphate or bromotripyrrolidinophosphonium hexafluorophosphate) and a base (e.g., 1,8- diazabicyclo[5.4.0] undec-7-ene) can provide compound 3-7. Scheme VII - 57 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application [00241] Intermediates for the synthesis of compounds of Formula (I) can be prepared as shown in Scheme VIII. Anilines 3-3 can be converted to heterocycles 8-1 under standard conditions (e.g., in the presence of 1,1-thiocarbonyldiimidazole or carbon disulfide and a base (e.g., potassium tert-butoxide or KOH)). Reaction of heterocycles 8-1 with electrophiles 8-2 where Lg ⁷ is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) and R ⁱ is C ₁ -C ₈ alkyl under standard conditions (e.g., base, such as triethylamine or K ₂ CO ₃ ) can afford compounds 8- 3. Oxidation of compounds 8-3 using a standard oxidant (e.g., m-chloroperoxybenzoic acid) can provide sulfones 8-4. Reaction of sulfones 8-4 with nucleophiles 5-4 under standard nucleophilic aromatic substitution conditions in the presence of a suitable base (e.g., N,N- diisopropylethylamine, K2CO3, KHMDS, or NaH) can afford compounds 1-1. Scheme VIII Example 1. 2-((1-(2-(Isoindolin-2-yl)-6-methyl-4-oxo-3-(tetrahydro-2H-p yran-4-yl)-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (isomer 1) [00242] Step 1.2-Amino-3-bromo-5-methyl-N-(tetrahydro-2H-pyran-4-yl)benza mide - 58 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application [00243] To a solution of 2-amino-3-bromo-5-methylbenzoic acid (2.0 g, 8.7 mmol) in THF (60 mL) was added 1,1'-carbonyldiimidazole (1.70 g, 10.4 mmol), and the resulting reaction mixture was stirred for 3 h.4-Aminotetrahydropyran (1.90 mL, 18.3 mmol) was added, and the reaction mixture stirred for another 4 h. The reaction was quenched by addition of water, and the reaction mixture was concentrated. The residue was diluted with water and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The crude material was used for the next step without further purifications. LC-MS calc. for C ₁₃ H ₁₈ BrN ₂ O ₂ [M+H] ⁺ : m/z = 313.1, 315.1; Found: 313.1, 315.1. [00244] Step 2.8-Bromo-6-methyl-3-(tetrahydro-2H-pyran-4-yl)quinazoline-2 ,4(1H,3H)-dione [00245] To a solution of crude 2-amino-3-bromo-5-methyl-N-(tetrahydro-2H-pyran-4- yl)benzamide (600 mg) in THF (15 mL) was added 1,1'-carbonyldiimidazole (620 mg, 3.83 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.86 mL, 5.7 mmol), and the resulting reaction mixture was stirred at 75 °C overnight. The reaction mixture was cooled to room temperature, poured into ice-cold sat. NH4Cl (aq.), and was stirred for 30 min, upon which solid precipitation was observed. The solid was filtered, washed with a minimal amount of water, and collected. The solid was dissolved in DCM and washed with water. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The crude material was used for the next step without further purification. LC-MS calc. for C14H16BrN2O3 [M+H] ⁺ : m/z = 339.0, 341.0; Found: 339.1, 341.1. [00246] Step 3.8-Bromo-2-chloro-6-methyl-3-(tetrahydro-2H-pyran-4-yl)quin azolin-4(3H)- one - 59 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application [00247] To the crude 8-bromo-6-methyl-3-(tetrahydro-2H-pyran-4-yl)quinazoline-2,4 (1H,3H)- dione (500.0 mg) was added phosphorous oxychloride (6.90 mL, 73.7 mmol). The resulting solution was treated with N,N-diisopropylethylamine (1.28 mL, 7.37 mmol), and the reaction mixture was heated at 95 °C for 16 h. Then the reaction mixture was cooled to room temperature and concentrated. The brown sticky residue was cooled with an ice bath, and ice was added to the flask, 5 N NaOH (aq.) was added until pH >9. The mixture was diluted with water and extracted with EtOAc (30 mL × 3) The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The concentrated material was used without further purification. LC-MS calc. for C ₁₄ H ₁₆ BrN ₂ O ₃ [M+H] ⁺ : m/z = 357.1, 359.1; Found: 357.1, 359.1. [00248] Step 4.8-Bromo-2-(isoindolin-2-yl)-6-methyl-3-(tetrahydro-2H-pyra n-4- yl)quinazolin-4(3H)-one [00249] A mixture of crude 8-bromo-2-chloro-6-methyl-3-(tetrahydro-2H-pyran-4- yl)quinazolin-4(3H)-one (500.0 mg), isoindoline hydrochloride (653 mg, 4.20 mmol), N, N- diisopropylethylamine (1.2 mL, 7.0 mmol) in THF (6 mL) and MeCN (2 mL) was heated at 70 °C for 4 h. Then the reaction mixture was cooled to room temperature and concentrated. The mixture was diluted with water and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0–100% EtOAc/hexanes) to afford the title compound (450.0 mg, 1.022 mmol). LC-MS calc. for C ₂₂ H ₂₃ BrN ₃ O ₂ [M+H] ⁺ : m/z = 440.1, 442.1; Found: 440.1, 442.1. [00250] Step 5.8-Acetyl-2-(isoindolin-2-yl)-6-methyl-3-(tetrahydro-2H-pyr an-4-yl)quinazolin- 4(3H)-one - 60 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application [00251] 8-Bromo-2-(isoindolin-2-yl)-6-methyl-3-(tetrahydro-2H-pyran- 4-yl)quinazolin-4(3H)- one (570 mg, 1.3 mmol), tributyl(1-ethoxyvinyl)tin (0.66 mL, 1.9 mmol), and bis(triphenylphosphine) palladium(II) dichloride (136 mg, 0.194 mmol) were dissolved in 1,4-dioxane (10 mL). Then the reaction mixture was heated at 100°C for 12 h. The reaction mixture was cooled to room temperature, 4 N HCl (~0.2 mL in 1,4-dioxane/water) (Acros, 366521000) was added, and then the reaction mixture was heated to 50 °C for 1 h. The reaction mixture was cooled to room temperature, neutralized with NaHCO3, concentrated, diluted with water, and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The crude residue was purified by silica gel chromatography (0–100% EtOAc/hexanes) to afford the title compound (400 mg, 1.0 mmol, 77%). LC-MS calc. for C24H26N3O3 [M+H] ⁺ : m/z = 404.2; Found: 404.1. [00252] Step 6.8-(1-Hydroxyethyl)-2-(isoindolin-2-yl)-6-methyl-3-(tetrahy dro-2H-pyran-4- yl)quinazolin-4(3H)-one [00253] To 8-acetyl-2-(isoindolin-2-yl)-6-methyl-3-(tetrahydro-2H-pyran -4-yl)quinazolin- 4(3H)-one (400.0 mg, 0.991 mmol) was added methanol (30 mL). NaBH4 (375 mg, 9.91 mmol) was added in small portions. After stirring for 4 h, the reaction was quenched by the addition of water. The reaction mixture was concentrated, diluted with water, and extracted with DCM (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0–100% EtOAc/hexanes) to afford the title compound (340.0 mg, 0.840 mmol, 84.7%). LC-MS calc. for C24H28N3O3 [M+H] ⁺ : m/z = 406.2; Found: 406.1. [00254] Step 7.2-((1-(2-(Isoindolin-2-yl)-6-methyl-4-oxo-3-(tetrahydro-2H -pyran-4-yl)-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (isomer 1) - 61 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application [00255] To a solution of 8-(1-hydroxyethyl)-2-(isoindolin-2-yl)-6-methyl-3-(tetrahydr o-2H- pyran-4-yl)quinazolin-4(3H)-one (340.0 mg, 0.8380 mmol) in DCM (1.0 mL) was added phosphorus tribromide (0.05 mL, 0.5 mmol) dropwise at 0 °C. The mixture was then stirred for 1 h. The reaction mixture was diluted with water (5.0 mL), and the two phases were separated. The organic layer was washed with brine (10.0 mL), dried over Na ₂ SO ₄ , filtered, and concentrated. To the crude residue was added a solution of anthranilic acid (287 mg, 2.10 mmol) in DMF (6.0 mL). The mixture was stirred at 60 °C overnight. The reaction mixture was cooled to room temperature, and the crude reaction was purified by prep-HPLC on a CSH Fluoro-Phenyl column (14–30% MeCN/0.1% NH ₃ (aq.)). Fractions were combined and concentrated. The mixture was acidified to pH ~ 4 with AcOH and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to afford the title compound as free base (125 mg). [00256] The isomers were separated using chiral prep-HPLC on an i-Amylose-3 column (30 mL/min, 90:5:5 hexanes/IPA/MeOH) to afford two isomers: isomer 1 (tR = 2.88 min, 39 mg, 0.074 mmol, 8.9%) and isomer 2 (t _R = 3.19 min). Isomer 1: ¹ H NMR (400 MHz, DMSO) δ 8.49 (s, 1H), 7.77 (dd, J = 7.9, 1.7 Hz, 1H), 7.68 (dd, J = 2.1, 1.0 Hz, 1H), 7.45 – 7.35 (m, 3H), 7.31 (dd, J = 5.6, 3.1 Hz, 2H), 7.10 (ddd, J = 8.6, 7.1, 1.7 Hz, 1H), 6.50 – 6.39 (m, 2H), 5.39 (m, J = 7.1 Hz, 1H), 5.09 – 4.89 (m, 4H), 4.60 – 4.50 (m, 1H), 3.96 (dt, J = 11.7, 6.5 Hz, 2H), 3.50 (q, J = 11.1 Hz, 2H), 3.03 – 2.81 (m, 2H), 2.30 (s, 3H), 1.84 (d, J = 12.5 Hz, 1H), 1.68 (d, J = 12.4 Hz, 1H), 1.55 (d, J = 6.6 Hz, 3H). LC-MS calc. for C31H33N4O4 [M+H] ⁺ : m/z = 525.2; Found: 525.1. Example 2.2-((1-(2-(3-Azabicyclo[3.1.0]hexan-3-yl)-6-methyl-4-oxo-3- (tetrahydro-2H- pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (isomer 1) [00257] The title compound was synthesized by procedures analogous to those outlined in Example 1. The isomers were separated using chiral prep-HPLC on an i-Amylose-3 column (30 mL/min, 90:10 hexanes/EtOH) to afford two isomers: isomer 1 (t _R = 7.77 min) and isomer 2 (t _{R =} 8.41 min). Isomer 1: LC-MS calc. for C28H33N4O4 [M+H] ⁺ : m/z = 489.2; Found: 489.1. - 62 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application Example 3. 2-((1-(2-(Isoindolin-2-yl)-6-methyl-4-oxo-3-((S)-tetrahydro- 2H-pyran-3-yl)-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [00258] The title compound was synthesized by procedures analogous to those outlined in Example 1, substituting (S)-tetrahydro-2H-pyran-3-amine hydrochloride for 4- aminotetrahydropyran in Step 1, to obtain the title compound as an acetate salt. LC-MS calc. for C ₃₁ H ₃₃ N ₄ O ₄ [M+H] ⁺ : m/z = 525.2; Found: 525.1. Example 4. 2-((1-(3-((R)-1,1-Dioxidotetrahydrothiophen-3-yl)-2-(isoindo lin-2-yl)-6-methyl- 4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [00259] The title compound was synthesized by procedures analogous to those outlined in Example 1, substituting (R)-3-aminotetrahydrothiophene 1,1-dioxide hydrochloride for 4- aminotetrahydropyran in Step 1, to obtain the title compound as an acetate salt. ¹ H NMR (400 MHz, DMSO) δ 12.70 (s, 1H), δ 8.44 (s, 1H), 7.77 (dd, J = 7.9, 1.7 Hz, 1H), 7.72 (d, J = 2.4 Hz, 1H), 7.46 (t, J = 1.9 Hz, 1H), 7.41 (ddd, J = 4.9, 3.2, 1.4 Hz, 2H), 7.31 (dd, J = 5.6, 3.1 Hz, 2H), 7.14 – 7.05 (m, 1H), 6.47 (t, J = 7.5 Hz, 1H), 6.41 (dd, J = 8.6, 3.2 Hz, 1H), 5.41 (dd, J = 14.7, 8.2 Hz, 2H), 5.09 (dd, J = 13.1, 3.6 Hz, 2H), 4.94 (dd, J = 13.4, 6.8 Hz, 2H), 3.95 – 3.56 (m, 4H), 2.88 – 2.55 (m, 2H), 2.31 (s, 3H), 1.55 (dd, J = 6.7, 1.9 Hz, 3H).LC-MS calc. for C30H31N4O5S [M+H] ⁺ : m/z = 559.2; Found: 559.1. Example 5. 2-((1-(3-((1-Acetylazetidin-3-yl)methyl)-2-(isoindolin-2-yl) -6-methyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid - 63 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application [00260] Step 1. tert-Butyl 3-((2-amino-3-bromo-5-methylbenzamido)methyl)azetidine-1- carboxylate [00261] The title compound was synthesized by procedures analogous to those outlined in Example 1, Step 1 substituting tert-butyl 3-(aminomethyl) azetidine-1-carboxylate for 4- aminotetrahydropyran. LC-MS calc. for C ₁₇ H ₂₅ BrN ₃ O ₃ [M+H] ⁺ : m/z = 398.1, 400.1; Found: 398.1, 400.1. [00262] Step 2. tert-Butyl 3-((8-bromo-6-methyl-4-oxo-2-thioxo-1,4-dihydroquinazolin-3( 2H)- yl)methyl)azetidine-1-carboxylate [00263] To a solution of carbon disulfide (0.30 mL, 5.0 mmol) in ethanol (15 mL) was added KOH (560 mg, 10 mmol), and the solution was left to stir at 30 °C for 1 h. To this solution was added tert-butyl 3-((2-amino-3-bromo-5-methylbenzamido)methyl)azetidine-1-car boxylate (400.0 mg, 1.000 mmol), and the reaction mixture was heated at 95 °C overnight. The reaction was then cooled, concentrated, and acidified with AcOH until pH ~5. The mixture was extracted - 64 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application with EtOAc (30 mL × 3) and water. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude material was advanced to the next step without further purification. LC-MS calc. for C13H18BrN2O2 [M+H] ⁺ : m/z = 440.1, 442.1; Found: 440.1, 442.1. [00264] Step 3. tert-Butyl 3-((8-bromo-6-methyl-4-oxo-2-(propylthio)quinazolin-3(4H)- yl)methyl)azetidine-1-carboxylate [00265] To a solution of crude tert-butyl 3-((8-bromo-6-methyl-4-oxo-2-thioxo-1,4- dihydroquinazolin-3(2H)-yl)methyl)azetidine-1-carboxylate (300.0 mg) in acetone (10 mL) was added anhydrous K2CO3 (282 mg, 2.04 mmol) and 1-iodopropane (0.199 mL, 2.04 mmol). After stirring for 3 h, the reaction mixture was concentrated and extracted with EtOAc (30 mL × 3) and water. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The crude material was advanced to the next step without further purification. LC-MS calc. for C21H29BrN3O3S [M+H] ⁺ : m/z = 482.1, 484.1; Found: 482.1, 484.1. [00266] Step 4.3-((1-Acetylazetidin-3-yl)methyl)-8-bromo-6-methyl-2-(prop ylthio)quinazolin- 4(3H)-one [00267] To a solution of crude tert-butyl 3-((8-bromo-6-methyl-4-oxo-2- (propylthio)quinazolin-3(4H)-yl)methyl)azetidine-1-carboxyla te (125 mg) in DCM (10 mL) was added TFA (0.30 mL, 3.9 mmol). After stirring 4 h, the reaction mixture was concentrated, neutralized with sat. NaHCO3 (aq.), and extracted with DCM (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude material was dissolved in DCM (3 mL). To this solution were added acetyl chloride (0.26 mL, 0.26 - 65 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application mmol) and triethylamine (0.055 mL, 0.39 mmol). After stirring for 4 h, the reaction mixture was extracted with DCM (30 mL × 3) and water. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude material was advanced to the next step without further purification. LC-MS calc. for C18H23BrN3O2S [M+H] ⁺ : m/z = 424.1, 426.1; Found: 424.1, 426.1. [00268] Step 5.3-((1-Acetylazetidin-3-yl)methyl)-8-bromo-2-(isoindolin-2- yl)-6- methylquinazolin-4(3H)-one [00269] To a solution of crude 3-((1-acetylazetidin-3-yl)methyl)-8-bromo-6-methyl-2- (propylthio)quinazolin-4(3H)-one (50.0 mg, 0.118 mmol) in DCM (3 mL) at 0 °C was added m- chloroperbenzoic acid (61 mg, 0.35 mmol). The reaction gradually warmed to room temperature. After stirring for 3 h, the reaction was quenched by addition of sat. Na2S2O3 (aq.) and was extracted with DCM (30 mL × 3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The crude material was dissolved in MeCN, and to this solution was added isoindoline hydrolchloride (38 mg, 0.24 mmol) and N, N-diisopropylamine (0.07 mL, 0.4 mmol). After heating at 70 °C for 3 h, the reaction was cooled, concentrated, and extracted with extracted with EtOAc (30 mL × 3) and water. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude material was purified by silica gel chromatography (0–30% MeOH/DCM) to afford the title compound (25.0 mg, 0.0535 mmol). LC-MS calc. for C ₂₃ H ₂₄ BrN ₄ O ₂ [M+H] ⁺ : m/z = 467.1, 469.1; Found: 467.1, 469.1. [00270] Step 6.2-((1-(3-((1-Acetylazetidin-3-yl)methyl)-2-(isoindolin-2-y l)-6-methyl-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [00271] The title compound was synthesized by procedures analogous to those outlined in Example 1, Steps 5–7 to obtain the title compound as a free base. LC-MS calc. for C32H34N5O4 [M+H] ⁺ : m/z = 552.1; Found: 552.1. - 66 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application Example 6. 2-((1-(2-(Isoindolin-2-yl)-6-methyl-3-((R)-1-(methylsulfonyl )pyrrolidin-3-yl)-4- oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [00272] Step 1. tert-Butyl (R)-3-(8-bromo-6-methyl-4-oxo-2-(propylthio)quinazolin-3(4H) - yl)pyrrolidine-1-carboxylate [00273] The title compound was synthesized by procedures analogous to those outlined in Example 5, Steps 1-3. LC-MS calc. for C17H25BrN3O3 [M+H] ⁺ : m/z = 398.1, 400.1; Found: 398.1, 400.1. [00274] Step 2. (R)-8-Bromo-2-(isoindolin-2-yl)-6-methyl-3-(1-(methylsulfony l)pyrrolidin-3- yl)quinazolin-4(3H)-one [00275] The title compound was synthesized by procedures analogous to those outlined in Example 5, Step 4 utilizing methane sulfonyl chloride instead of acetyl chloride. LC-MS calc. for C17H23BrN3O3S2 [M+H] ⁺ : m/z = 460.0, 462.0; Found: 460.1, 462.1. [00276] Step 3.2-((1-(2-(Isoindolin-2-yl)-6-methyl-3-((R)-1-(methylsulfon yl)pyrrolidin-3-yl)-4- oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [00277] The title compound was synthesized by procedures analogous to those outlined in Example 5, Steps 5-6 to obtain the title compound as an acetate salt. LC-MS calc. for C ₃₁ H ₃₄ N ₅ O ₅ S [M+H] ⁺ : m/z = 588.2; Found: 588.1. - 67 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application Example 7. 2-((1-(2-(Isoindolin-2-yl)-6-methyl-4-oxo-3-((S)-tetrahydrof uran-3-yl)-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (isomer 1) [00278] The title compound was synthesized by procedures analogous to those outlined in Example 1 substituting (S)-tetrahydrofuran-3-amine for 4-aminotetrahydropyran in Step 1. The isomers were separated using chiral prep HPLC on a Lux iA3 column (30 mL/min, 66:17:17 hexane/IPA/MeOH) to afford two isomers: isomer 1 (t _R = 2.28 min) and isomer 2 (t _R = 2.82 min). Isomer 1: ¹ H NMR (400 MHz, DMSO) δ 12.63 (s, 1H), 8.39 (s, 1H), 7.77 (dd, J = 7.9, 1.7 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.45 – 7.35 (m, 3H), 7.30 (dd, J = 5.6, 3.1 Hz, 2H), 7.12 (ddd, J = 8.7, 7.1, 1.8 Hz, 1H), 6.52 – 6.42 (m, 2H), 5.39 (s, 1H), 5.22 (s, 1H), 5.10 (d, J = 13.6 Hz, 2H), 4.97 (d, J = 13.6 Hz, 2H), 4.24 (q, J = 7.6 Hz, 1H), 4.09 (t, J = 8.4 Hz, 1H), 4.02 – 3.88 (m, 2H), 2.50 – 2.36 (m, 2H), 2.30 (s, 3H), 1.55 (d, J = 6.7 Hz, 3H). LC-MS calc. for C30H31N4O4 [M+H] ⁺ : m/z = 511.2; Found: 511.1. Examples 8-10 [00279] Examples 8-10 listed in Tables 1 and 2 were synthesized according to procedures analogous to Example 1. All examples in this table were prepared as the TFA salt unless otherwise noted. Table 1. Examples 8-10 - 68 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application + Table 2. Examples 8-10 Example 11.2-((1-(3-(2,2-Dimethyltetrahydro-2H-pyran-4-yl)-2-(isoind olin-2-yl)-6-methyl- 4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic - 69 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application [00280] Step 1: 2-Amino-3-bromo-N-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-5- methylbenzamide [00281] To a solution of 2-amino-3-bromo-5-methylbenzoic acid (1.0 g, 4.4 mmol) in THF (50 mL) was added 1,1'-carbonyldiimidazole (0.78 g, 4.8 mmol). The reaction was stirred for 16 h.2,2-Dimethyloxan-4-amine (0.84 g, 6.5 mmol) was added. The reaction was stirred for an additional 16 h. The reaction was diluted with water (50 mL). The layers were separated, and the aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to afford the title compound (0.95 g, 2.8 mmol, 64% yield) as a colorless solid, which was used directly in the next step without any further purification. LC-MS calc. for C ₁₅ H ₂₂ BrN ₂ O ₂ [M+H] ⁺ : m/z= 341.0; Found 341.0. [00282] Step 2: 8-Bromo-3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-6-methylqui nazoline- 2,4(1H,3H)-dione [00283] To a solution of 2-amino-3-bromo-N-(2,2-dimethyloxan-4-yl)-5-methylbenzamide (916 mg, 2.69 mmol) in THF (30 mL) was added triphosgene (637 mg, 2.15 mmol). The resulting mixture was stirred at 60 °C for 0.5 h. The mixture was cooled to 0 °C. Water (30 mL) was added, and the mixture was stirred for 1 h. The solid was collected by filtration to afford the title compound (0.9 g, 2 mmol, 90% yield) as a colorless solid. LC-MS calc. for C16H20BrN2O3 [M+H] ⁺ : m/z= 367.0; Found 367.1. - 70 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application [00284] Step 3: 8-Bromo-2-chloro-3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-6- methylquinazolin-4(3H)-one [00285] To a solution of 8-bromo-3-(2,2-dimethyloxan-4-yl)-6-methyl-1H-quinazoline-2, 4- dione (850 mg, 2.31 mmol) in phosphoryl chloride (10.0 mL, 106 mmol) was added N,N- diisopropyl-ethylamine (1.01 mL, 5.79 mmol). The mixture was heated to 105 °C for 6 h. To the mixture was added an additional portion of N,N-diisopropylethylamine (1.01 mL, 5.79 mmol). The mixture was stirred overnight. To the mixture was added an additional portion of N,N- Diisopropylethylamine (1.01 mL, 5.79 mmol). The mixture was stirred overnight. The reaction mixture was concentrated, and the resulting residue was poured into water (100 mL). The resulting suspension was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over Na2SO4, concentrated, and purified by silica column chromatography (0–30% EtOAc/heptane) to afford the title compound (600 mg, 1.56 mmol, 67.2% yield) as a colorless solid. LCMS calc. for C ₁₆ H ₁₉ BrClN ₂ O ₂ [M+H] ⁺ : m/z= 385.0; Found 384.9. [00286] Step 4: 8-Bromo-3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(isoindol in-2-yl)-6- methylquinazolin-4(3H)-one [00287] To a suspension of 8-bromo-2-chloro-3-(2,2-dimethyloxan-4-yl)-6-methylquinazoli n- 4-one (540 mg, 1.40 mmol) and isoindoline hydrochloride (545 mg, 3.50 mmol) in THF (8 mL) was added diisopropylethylamine (1.22 mL, 7.00 mmol). The mixture was stirred at 60 °C for 4 h. The mixture was cooled to room temperature and diluted with water (8 mL) and EtOAc (10 mL). The organic phase was separated, and the aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic phases were dried over Na ₂ SO ₄ , concentrated, and purified by silica column chromatography (0–40% EtOAc/heptane) to afford the title compound (623 mg, 1.33 mmol, 95.0% yield) as a beige solid. LC-MS calc. for C24H27BrN3O2 [M+H] ⁺ : m/z= 468.1; Found 468.0. - 71 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application [00288] Step 5: 8-Acetyl-3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(isoindo lin-2-yl)-6- methylquinazolin-4(3H)-one [00289] To a solution of 8-bromo-2-(1,3-dihydroisoindol-2-yl)-3-(2,2-dimethyloxan-4-y l)-6- methylquinazolin-4-one (334 mg, 0.712 mmol) and bis(triphenylphosphine)palladium(II) dichloride (49.9 mg, 0.0712 mmol) in 1,4-dioxane (5 mL) was added tributyl(1-ethoxyvinyl)tin (289 μL, 0.855 mmol). The mixture was heated at 100 °C. The mixture was cooled to room temperature and sat. KF (aq.) (10 mL) and EtOAc (10 mL) were added. The mixture was stirred vigorously for 4 h. The mixture was filtered through Celite®. The layers were separated, and the aqueous layer was extracted with EtOAc (3 x 10 mL). To the combined organic layers was added 2 N HCl (30 mL). The mixture was stirred for 1 h. The aqueous layer was separated, and the organic layer was extracted with 3 N HCl (2 x 30 mL). The aqueous layers were combined and basified to pH >12 using 4 N NaOH. The solid was collected by filtration, washed with water, and recrystallized in EtOH to afford the title compound (186 mg, 0.431 mmol, 60.5% yield) as a colorless solid. LC-MS calc. for C ₂₆ H ₃₀ N ₃ O ₃ [M+H] ⁺ : m/z= 432.2; Found 432.2. [00290] Step 6: 3-(2,2-Dimethyltetrahydro-2H-pyran-4-yl)-8-(1-hydroxyethyl)- 2-(isoindolin-2- yl)-6-methylquinazolin-4(3H)-one [00291] To a suspension of 8-acetyl-2-(1,3-dihydroisoindol-2-yl)-3-(2,2-dimethyloxan-4- yl)-6- methylquinazolin-4-one (176 mg, 0.408 mmol) in methanol (2 mL) and DCM (1 mL) was added sodium borohydride (15.4 mg, 0.408 mmol). The mixture was stirred for 0.5 h. The reaction was quenched with water (2 mL). The mixture was concentrated, and the resulting residue was diluted with DCM (10 mL) and water (10 mL). The organic phase was separated, and the aqueous phase was extracted with DCM (2 x 10 mL). The combined organic phases were dried over Na ₂ SO ₄ , concentrated, and purified by silica column chromatography (0–50% - 72 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application EtOAc/heptane) to afford the title compound (160 mg, 0.369 mmol, 90.5% yield) as a colorless solid. LC-MS calc. for C ₂₆ H ₃₂ N ₃ O ₃ [M+H] ⁺ : m/z= 434.2; Found 434.3. [00292] Step 7: 1-(3-(2,2-Dimethyltetrahydro-2H-pyran-4-yl)-2-(isoindolin-2- yl)-6-methyl-4- oxo-3,4-dihydroquinazolin-8-yl)ethyl methanesulfonate [00293] To a solution of 2-(1,3-dihydroisoindol-2-yl)-3-(2,2-dimethyloxan-4-yl)-8-(1- hydroxyethyl)-6-methylquinazolin-4-one (20.5 mg, 0.0473 mmol) in DCM (1 mL) was added methanesulfonyl chloride (7.32 uL, 0.0946 mmol) and triethylamine (19.8 uL, 0.142 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 0.5 h. The reaction was quenched with water (1 mL), and the reaction mixture diluted with DCM (3 mL). The layers were separated, and the aqueous layer was extracted with DCM (2 x 3 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated to afford the title compound (24.2 mg) as a clear oil. The crude product was used in the next step directly without further purification. [00294] Step 8: 2-((1-(3-(2,2-Dimethyltetrahydro-2H-pyran-4-yl)-2-(isoindoli n-2-yl)-6-methyl- 4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [00295] To a solution of 1-[2-(1,3-dihydroisoindol-2-yl)-3-(2,2-dimethyloxan-4-yl)-6- methyl- 4-oxoquinazolin-8-yl]ethyl methanesulfonate (24.2 mg) in DCM (2 mL) was added anthranilic acid (32.4 mg, 0.237 mmol) and triethylamine (6.59 μL, 0.0473 mmol). The mixture was heated to 45 °C overnight. The mixture was cooled to room temperature, concentrated, and purified by prep-HPLC on C18 column (10–90% MeCN/0.1% TFA (aq)) to afford the title compound (11.5 mg, 0.0208 mmol, 44.0% yield over two steps) as a colorless solid. ¹ H NMR (300 MHz, DMSO- d6) δ 12.60 (br, 1H), 8.38 (br, 1H), 7.77 (dd, J = 7.9, 1.7 Hz, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.45 – 7.37 (m, 3H), 7.36 – 7.26 (m, 2H), 7.19 – 7.06 (m, 1H), 6.53 – 6.39 (m, 2H), 5.39 (q, J = 6.6 Hz, 1H), 5.11 – 4.80 (m, 4H), 4.68 (t, J = 12.4 Hz, 1H), 2.82 (dt, J = 29.5, 12.6 Hz, 2H), 2.29 (s, 3H), 2.05 – 1.67 (m, 2H), 1.66 – 1.42 (m, 4H), 1.31 – 1.20 (m, 7H). LCMS calc. for C33H37N4O4 [M+H] ⁺ : m/z= 553.2; Found 553.2. - 73 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application Example 12.2-[1-[2-(5-Fluoro-1,3-dihydroisoindol-2-yl)-6-methyl-3-(o xan-4-yl)-4- oxoquinazolin-8-yl]ethylamino]benzoic acid [00296] Step 1: 2-(5-Fluoro-1,3-dihydroisoindol-2-yl)-8-(1-hydroxyethyl)-6-m ethyl-3-(oxan-4- yl)quinazolin-4-one [00297] The title compound was synthesized by procedures analogous to Example 1, Steps 1– 5. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.87 (dd, J = 2.1, 1.0 Hz, 1H), 7.37 (d, J = 2.1 Hz, 1H), 7.32 - 7.26 (m, 1H), 7.10 – 6.99 (m, 2H), 5.21 (s, 1H), 5.05 (s, 1H), 4.85 (d, J = 15.0 Hz, 4H), 4.48 (tt, J = 11.7, 3.6 Hz, 1H), 4.16 (dd, J = 11.4, 4.3 Hz, 2H), 3.58 – 3.36 (m, 2H), 3.20 (qd, J = 12.4, 4.5 Hz, 2H), 2.42 (s, 3H), 1.73 (d, J = 12.8 Hz, 2H), 1.64 (d, J = 6.6 Hz, 3H). LC-MS calc. for C24H27FN3O3 [M+H] ⁺ : m/z= 424.2; Found 424.2 [00298] Step 2: 8-(1-Bromoethyl)-2-(5-fluoro-1,3-dihydroisoindol-2-yl)-6-met hyl-3-(oxan-4- yl)quinazolin-4-one [00299] To a solution of 2-(5-fluoro-1,3-dihydroisoindol-2-yl)-8-(1-hydroxyethyl)-6-m ethyl-3- (oxan-4-yl)quinazolin-4-one (35.0 mg, 0.0826 mmol) in DCM (1 mL) was added phosphorus tribromide (0.0235 mL, 0.248 mmol). The resulting mixture was stirred at 35 °C for 1 h. The reaction was quenched with sat. NaHCO3 (10 mL), and the reaction mixture diluted with EtOAc (10 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (10 mL x 2). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated to afford the - 74 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application title compound (40.2 mg, 0.0826 mmol) as a colorless oil. The crude product was used in next step directly without further purification. [00300] Step 3: 2-[1-[2-(5-Fluoro-1,3-dihydroisoindol-2-yl)-6-methyl-3-(oxan -4-yl)-4- oxoquinazolin-8-yl]ethylamino]benzoic acid [00301] To a solution of 8-(1-bromoethyl)-2-(5-fluoro-1,3-dihydroisoindol-2-yl)-6-met hyl-3- (oxan-4-yl)quinazolin-4-one (crude from Step 2) in DCM (1 mL) was added anthranilic acid (22.6 mg, 0.164 mmol) followed by N,N-diisopropylethylamine (0.0716 mL, 0.411 mmol). The reaction was stirred at 35 °C overnight. The reaction mixture was directly purified by prep- HPLC on a C18-column (20–100% MeCN/0.1% TFA (aq.)) to the title compound as a TFA salt (17.3 mg, 0.0312 mmol, 37.9% yield over two steps) as a white solid. ¹ H NMR (300 MHz, DMSO-d6) δ 8.39 (s, 1H), 7.77 (dd, J = 8.0, 1.7 Hz, 1H), 7.68 (dd, J = 2.1, 0.9 Hz, 1H), 7.49 – 7.38 (m, 2H), 7.27 (dd, J = 9.1, 2.5 Hz, 1H), 7.13 (ddt, J = 10.1, 7.0, 2.0 Hz, 2H), 6.52 – 6.41 (m, 2H), 5.39 (d, J = 6.8 Hz, 1H), 4.97 (dt, J = 34.3, 14.6 Hz, 4H), 4.63 – 4.44 (m, 1H), 3.95 (q, J = 7.2, 3.7 Hz, 2H), 3.50 (q, J = 10.7 Hz, 2H), 2.91 (dtd, J = 24.4, 12.2, 7.9 Hz, 2H), 2.30 (s, 3H), 1.83 (d, J = 12.4 Hz, 1H), 1.67 (d, J = 12.2 Hz, 1H), 1.55 (d, J = 6.6 Hz, 3H). LC-MS calc. for C ₁₃ H ₃₂ FN ₄ O ₄ [M+H] ⁺ : m/z= 543.2; Found 543.2. Examples 13 – 16 [00302] Examples 13 – 16 listed in Tables 3 and 4 were synthesized according to procedures analogous to Example 11, Steps 6–8 (Method A) or Example 12 (Method B). The appropriate starting materials for these sequences can be synthesized according to procedures analogous to Example 1, Steps 1–5. All examples in this table were prepared as the TFA salt unless otherwise noted. Table 3. Examples 13-16 + - 75 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application + Table 4. Examples 13-16 - 76 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application Example 17.6-((1-(2-(3-Azabicyclo[3.1.0]hexan-3-yl)-6-methyl-4-oxo-3 -(tetrahydro-2H- pyran-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)-2,3-difl uorobenzoic acid - 77 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application [00303] The title compound was synthesized by procedures analogous to those outlined in Example 1. ¹ H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.65 (dd, J = 2.1, 1.0 Hz, 1H), 7.41 (d, J = 2.1 Hz, 1H), 7.21 (q, J = 9.4 Hz, 1H), 6.21 – 6.13 (m, 1H), 5.25 (q, J = 6.6 Hz, 1H), 4.31 (t, J = 11.8 Hz, 1H), 3.96 (td, J = 11.6, 4.2 Hz, 2H), 3.88 (d, J = 10.3 Hz, 1H), 3.67 (d, J = 10.3 Hz, 1H), 3.61 – 3.56 (m, 1H), 3.50 (d, J = 10.1 Hz, 1H), 3.44 – 3.34 (m, 2H), 2.96 – 2.74 (m, 2H), 2.29 (s, 3H), 1.75 – 1.53 (m, 4H), 1.51 (d, J = 6.6 Hz, 3H), 0.59 (td, J = 7.6, 4.6 Hz, 1H), 0.40 (q, J = 4.1 Hz, 1H). LC-MS calc. for C ₂₈ H ₃₁ F ₂ N ₄ O ₄ [M+H] ⁺ : m/z = 525.2; Found: 525.1. Example 18.2-((1-(2-(Isoindolin-2-yl)-4-oxo-3-(tetrahydro-2H-pyran-4 -yl)-6- (trifluoromethyl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)ben zoic acid [00304] Step 1: Methyl 2-amino-3-bromo-5-(trifluoromethyl)benzoate [00305] To a solution of methyl 2-amino-5-(trifluoromethyl) benzoate (5.00 g, 22.8 mmol) in acetic acid (50.0 mL, 22.8 mmol) was added N-bromosuccinimide (3.86 g, 21.7 mmol). The mixture was stirred at 120 °C for 2 h under a nitrogen atmosphere. The reaction was quenched with water (100 mL), extracted with EtOAc (3 x 50 mL), washed with water (50 mL x 3), and dried over Na2SO4. The combined organic layers were concentrated and purified by silica gel chromatography (0–5 % EtOAc/hexanes) to afford the title compound (6.40 g, 21.0 mmol, 42.0%) as a yellow solid. LC-MS calc. for C ₉ H ₈ BrF ₃ NO ₂ [M+H] ⁺ : m/z= 297.9; Found 297.4. [00306] Step 2: 2-Amino-3-bromo-5-(trifluoromethyl)benzoic acid - 78 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application [00307] To a solution of methyl 2-amino-3-bromo-5-(trifluoromethyl)benzoate (6.40 g, 21.5 mmol) in water (10 mL) was added lithium hydroxide (1.54 g, 64.4 mmol), and the reaction mixture was stirred for 24 h. The mixture was extracted with EtOAc (100 mL x 3), washed with water (100 mL x 3), dried over Na2SO4. The combined organic layer was concentrated to afford the title compound (14.0 g, 54.7 mmol, 90.2% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.06 (d, J = 4.0 Hz, 1H), 7.60 (d, J = 2.4 Hz, 1H). LC-MS calc. for C ₈ H ₆ BrF ₃ NO ₂ [M+H] ⁺ : m/z= 283.9; Found 282.5. [00308] Step 3: 2-Amino-3-bromo-N-(tetrahydro-2H-pyran-4-yl)-5-(trifluoromet hyl)benzamide [00309] The title compound was synthesized by procedures analogous to those outlined in Example 1, Step 1. LC-MS calc. for C ₁₃ H ₁₅ BrF ₃ N ₂ O ₂ [M+H] ⁺ : m/z= 367.0; Found 365.5. [00310] Step 4: 8-Bromo-3-(tetrahydro-2H-pyran-4-yl)-6-(trifluoromethyl)quin azoline- 2,4(1H,3H)-dione [00311] The title compound was synthesized by procedures analogous to those outlined in Example 1, Step 2. Rf = 0.3 (3:1 hexane/EtOAc). [00312] Step 5: 8-Bromo-2-chloro-3-(tetrahydro-2H-pyran-4-yl)-6-(trifluorome thyl) quinazolin-4(3H)-one [00313] The title compound was synthesized by procedures analogous to those outlined in Example 1, Step 3. Rf =0.3 (3:1 hexanes/EtOAc). - 79 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application [00314] Step 6: 8-Bromo-2-(isoindolin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)-6- (trifluoromethyl)quinazolin-4(3H)-one [00315] The title compound was synthesized by procedures analogous to those outlined in Example 1, Step 4. ¹ H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 1H), 8.15 (s, 1H), 7.40 (s, 2H), 7.30 (s, 2H), 5.10 (s, 4H), 4.40 (t, J = 1.6 Hz, 1H), 3.91 (d, J = 2.0 Hz, 2H), 3.45 (t, J = 1.6 Hz, 2H), 2.81 – 2.78 (m, 2H), 1.78 (d, J = 2.0 Hz, 2H). LCMS calc. for C22H20BrF3N3O2 [M+H] ⁺ : m/z= 494.1; Found 410.4. [00316] Step 7: 8-Acetyl-2-(isoindolin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)-6- (trifluoromethyl) quinazolin-4(3H)-one [00317] The title compound was synthesized by procedures analogous to those outlined in Example 1, Steps 5. LC-MS calc. for C ₂₄ H ₂₃ F ₃ N ₃ O ₃ [M+H] ⁺ : m/z= 458.2; Found 458.7. [00318] Step 8: 8-(1-Hydroxyethyl)-2-(isoindolin-2-yl)-3-(tetrahydro-2H-pyra n-4-yl)-6- (trifluoromethyl)quinazolin-4(3H)-one [00319] The title compound was synthesized by procedures analogous to those outlined in Example 1, Step 6. LC-MS calc. for C ₂₄ H ₂₃ F ₃ N ₃ O ₂ [M-OH] ⁺ : m/z= 442.2; Found 442.7. [00320] Step 9: 1-(2-(Isoindolin-2-yl)-4-oxo-3-(tetrahydro-2H-pyran-4-yl)-6- (trifluoromethyl)- 3,4-dihydroquinazolin-8-yl)ethyl methanesulfonate - 80 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application [00321] To a solution of 2-(1,3-dihydroisoindol-2-yl)-8-(1-hydroxyethyl)-3-(oxan-4-yl )-6- (trifluoromethyl)quinazolin-4-one (40.0 mg, 0.0896 mmol) in DCM (5 mL) was added N,N- diisopropylethylamine (22.5 mg, 0.167 mmol) and methanesulfonyl chloride (15.0 mg, 0.130 mmol) at 0 °C. The reaction mixture was stirred at 20 °C for 14 h. The mixture was used directly in the next step without workup and purification. Rf = 0.3 (3:1 hexanes/EtOAc). [00322] Step 10: Methyl 2-((1-(2-(isoindolin-2-yl)-4-oxo-3-(tetrahydro-2H-pyran-4-yl )-6- (trifluoromethyl)-3,4-dihydroquinazolin-8-yl ethyl)amino)benzoate [00323] To a solution of 1-[2-(1,3-dihydroisoindol-2-yl)-3-(oxan-4-yl)-4-oxo-6- (trifluoromethyl) quinazolin-8-yl]ethyl methanesulfonate (40.0 mg, 0.0744 mmol) in DCM (5 mL) was added N,N-diisopropylethylamine (28.9 mg, 0.223 mmol) and methyl anthranilate (11.3 mg, 0.0744 mmol). The mixture was stirred for 24 h. The reaction mixture was diluted with water (15 mL) and extracted with DCM (5 mL x 3). The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified by prep-HPLC on a C18 column (10–80% MeCN/0.1% TFA (aq)) to afford the title compound (20.0 mg, 0.0337 mmol, 45.4% yield) as a yellow oil. LC-MS calc. for C ₃₂ H ₃₂ F ₃ N ₄ O ₄ [M+H] ⁺ : m/z= 593.2; Found 593.9. [00324] Step 11: 2-((1-(2-(Isoindolin-2-yl)-4-oxo-3-(tetrahydro-2H-pyran-4-yl )-6- (trifluoromethyl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)ben zoic acid - 81 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application [00325] To a solution of methyl 2-[1-[2-(1,3-dihydroisoindol-2-yl)-3-(oxan-4-yl)-4-oxo-6- (trifluoromethyl)quinazolin-8-yl]ethylamino]benzoate (21.0 mg, 0.0345 mmol) in methanol (0.5 mL), THF (0.5 mL), and water (0.2 mL) was added sodium hydroxide (5.52 mg, 0.138 mmol). The mixture was stirred at 45 °C for 14 h. The mixture was cooled to room temperature, and the reaction mixture was acidified to pH 5-6 with 1 N HCl. The crude material was purified by prep-HPLC on a C18 column (30–60% MeCN/0.1% TFA (aq)) to afford the title compound (5.2 mg, 0.0090 mmol, 26% yield) as a yellow solid. LC-MS calc. for C31H30F3N4O4 [M+H] ⁺ : m/z= 579.2; Found 579.2. Example A: PI3K Pathway Activation Assay [00326] The inhibitory activity of compounds was evaluated by measuring phosphorylation of AKT on Ser473 as a readout of the PI3K pathway using HTRF (CisBio catalog number: 64AKSPE). These studies were conducted in the T-47D cell line. These cell lines were chosen as T-47D contains the PIK3CA H1047R oncogenic mutation. Cells were maintained in a 37°C incubator at 5% CO ₂ in the following media: RPMI 1640, ATCC© Modification (Gibco, A10491-01) supplemented with 10% v/v FBS (Gibco, 26140-079), 1% penicillin streptomycin (Gibco, 15140-122), and 7.4 ug/mL insulin (MilliporeSigma, I9278); Cells were seeded in 384- well plates at a density of 4,000 cells/well. Compounds dissolved in DMSO were added using a digital dispense (D300E, Tecan) 10-point serial dilution. After two hours of treatment, cells were lysed for thirty minutes and then incubated with detection reagents per HTRF kit material and manufacturer’s instructions. Fluorescence signal was measured with a multimode plate reader (Envision 2105, Perkin Elmer). Fluorescent signal was normalized to background and DMSO controls to obtain percent inhibition/activity for each compound. The results are summarized in Table A. Table A – IC50 Values - 82 - ^{4868-3881-1526.1} 105807.005002 (Series 2) – PCTl Application [00327] In Table A, a “+” denotes an IC50 value of > 10000 nM; a “++” denotes an IC50 value of 500 nM < IC ₅₀ ≤ 10000 nM; a “+++” denotes an IC ₅₀ value of < 500 nM. [00328] While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example. - 83 - ^{4868-3881-1526.1}