PI3k inhibitors, compositions, and uses thereof

Abstract

The present disclosure provides phosphatidylinositol 3‑kinase (PI3K) inhibitors, and compositions, and methods for treating diseases or disorders (e.g., cancer and autoimmune diseases and disorders) with PI3K inhibitors or compositions thereof.

Description

Atty. Docket No. UM-43981.601Client Ref No. 2025-184PI3K INHIBITORS, COMPOSITIONS, AND USES THEREOFFIELD

[0001] The present disclosure provides phosphatidylinositol 3-kinase (PI3K) inhibitors, and compositions, and methods for treating diseases or disorders (e.g., cancer and autoimmune diseases and disorders) with PI3K inhibitors or compositions thereof.CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application Nos. 63 / 713,881, filed October 30, 2024, and 63 / 825.297, filed June 17, 2025, the contents of which are herein incorporated by reference in their entirety.BACKGROUND

[0003] Phosphoinositide 3-kinases (PI3Ks) are a family of enzymes involved in multiple cellular functions, including growth, survival, and metabolism. Dysregulated activation of the phosphoinositide 3-kinase (PI3K) pathway is observed in various human cancers, playing a key role in tumor progression and survival. The PI3K family consists of four isoforms, PI3Ka, PI3K0, PI3K5, and PI3Ky, classified based on their catalytic and regulatory subunits. Among the PI3K isoforms, PI3Ka and PI3K.[3 are not only expressed on tumor cells but are also found in various normal tissues, which presents a significant challenge due to the potential for off-target toxicity. PI3K5, although it has been successfully targeted in therapies and was previously approved by the FDA, was later withdrawn from the market due to its association with decreased overall survival in treated patients. There are currently no approved PI3Ky inhibitors on the market, and its selective expression suggests that targeting PI3Ky may modulate the tumor microenvironment with potentially less toxicity compared to PI3Ka, PI3K0, or PI3K5 inhibitors. IPI-549, a PI3Ky inhibitor that has completed a Phase II clinical trial, demonstrated only modest efficacy, with intolerant hepatic side effects at low doses. These dose-limiting toxicities may be related to the drug's affinity for other PI3K isoforms, such as PI3Ka. PI3K(3. and PI3K5, as in vivo concentrations of IPI-549 can reach levels comparable to their IC50 values.SUMMARY

[0004] In one aspect, disclosed herein is a compound of formula (I):Atty. Docket No. UM-43981.601Client Ref No. 2025-184or a pharmaceutically acceptable salt thereof, wherein:R1is selected from phenyl, C1-C4 aminoalkyl, ferrocenyl, adamantyl, and a group:, wherein R2is an amino acid side chain and R3is hydrogen or a nitrogen protecting group; wherein the phenyl is substituted with 1. 2, 3, 4, or 5 substituents independently selected from halo, C1-C4 haloalkyl, and C1-C4 hydroxyalkyl.10005] In some embodiments, R1is phenyl substituted with 1, 2, or 3 substituents independently selected from halo, C1-C2 haloalkyl, and C1-C4 hydroxyalkyl. In some embodiments, R1is phenyl substituted with 1, 2. or 3 substituents independently selected from fluoro, trifluoromethyl. hydroxymethyl, and hydroxy propyl. In some embodiments, at least one of the substituents is hydroxymethyl.R2H10006] In some embodiments, R1is a groupR’ 0Y , wherein R2is a tryptophan side chain and R3is selected from hydrogen and a tert-butyloxy carbonyl group.

[0007] In some embodiments, the compound is selected from:Atty. Docket No. UM-43981.601Client Ref No. 2025-184Atty. Docket No. UM-43981.601Client Ref No. 2025-184

[0008] In another aspect, disclosed herein is a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the compositions further comprise an albumin nanoparticle.

[0009] In a further aspect, disclosed herein are methods for treating or preventing a disease or disorder in a subject (e.g., a human) comprising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a composition as disclosed herein.

[0010] In some embodiments, the disease or disorder comprises cancer, an autoimmune disease or disorder, or an inflammatory disease or disorder.

[0011] In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer comprises a solid tumor or hematological cancer. In some embodiments, the cancer is metastatic cancer. In select embodiments, the disease or disorder is breast cancer, pancreatic cancer, lung cancer, or lymphoma. In some embodiments, the methods suppress or eliminate cancer metastasis, decrease tumor growth, prevent tumor recurrences, or any combination thereof. In some embodiments, the compound or the composition is administered by subcutaneous injection.Atty. Docket No. UM-43981.601Client Ref No. 2025-184

[0012] In some embodiments, the disease or disorder is lupus.

[0013] Other aspects and embodiments of the disclosure will be apparent in light of the following detailed description and accompanying figures.BRIEF DESCRIPTION OF THE DRAWINGS

[0014] FIGS. 1A-1D show AKT phosphorylation. FIGS. 1 A-1B show AKT (Ser 473) phosphorylation of M-CSF (PI3K class IA agonist) stimulated bone-marrow derived macrophages (BMDM) after adding TGR-1202 (PI3K5-selective inhibitor), IPI-549, SH-327 and SH-315 at 5gM or 1 / rM. FIG. 1A is BMDM to simulate macrophages at steady state; FIG. IB is IL -4 and IL-13 treated BMDM to simulate macrophages in tumor (M2 -like macrophages). FIG. 1C is AKT phosphorylation on N-formylmethionyl-leucyl-phenylalanine (fMLP)-activated neutrophils ( PI3 Ky highly expressed) after adding Wortmannin (pan-PI3K inhibitor), TGR-1202, IPI-549, SH-327 and SH-315 at 5 / zM. FIG. ID is AKT phosphorylation on M-CSF and C5a (PI3K class IB agonist) stimulated BMDM after adding SH-327, SH-315, IPI-549 and TGR-1202 at 1 / zM.

[0015] FIGS. 2A-2D show AKT (Ser 473 and Thr 308) phosphorylation of MC38 (FIG. 2A), Py230 (FIG. 2B), B16F10 (FIG. 2C), and 4T1 breast tumor cells (FIG. 2D) after adding BYL-719 (PI3Ka inhibitor), TGX-221 (PI3K inhibitor), SH-327, SH-315 and IPI-549 at 5 / rM or 1 / zM.

[0016] FIG. 3 shows M2-like macrophages (pre-treated with IL-4 and IL- 13, pro-tumor) polarization to Ml -like macrophages (anti-tumor, CD86 is Ml -like FACS marker) following addition of PI3K inhibitors at 5 / rM (left) or at I pM (right). LPS and IFNy group is positive control, which can strongly polarize M2-like to Ml -like macrophages.

[0017] FIG. 4 shows BMDM polarization to Ml-like macrophages (pro-inflammatory, CD86 is also activation FACS marker) following addition of PI3K inhibitors at 10 / rM (left); 5 / rM (middle); I pM (right).

[0018] FIG. 5 is a summary' of anti-tumor efficacy on MC38 xenograft model.

[0019] FIG. 6 is individual data of anti-tumor efficacy on MC38 xenograft model. CR: complete response, tumor completely disappear. There are 5 mice in each group. 3 mice in SH-315+PTX+aPD-l treated group achieved CR for over 120 days and 2 mice in IPI-549+PTX+aPD-l treated group achieved CR for over 120 days, but no mouse in SH-327+PTX+aPD-l treated group achieved CR.

[0020] FIG. 7 is survival curves on MC38 xenograft model.

[0021] FIG. 8 is a summary7of anti-tumor efficacy on MMTV-PyMT transgenic model.

[0022] FIG. 9 is pharmacokinetic profiles of PI3Ky inhibitors in MMTV-PyMT mice. SH-327,SH-315, and IPI-549 were orally administered to mice at a single dose of lOmg / kg. DrugAtty. Docket No. UM-43981.601Client Ref No. 2025-184 concentrations were measured in plasma, blood, liver, tumor, tumor-draining lymph node (TDLN), spleen, lung, heart, and kidney at 0.5h, 2h, 6h and 24h post-administration.

[0023] FIG. 10 is size distribution of albumin nano-formulations NP-315 (left, average diameter 126.7d.nm, PDI 0.182) and NP-327 (right, average diameter 122d.nm, PDI 0.153).

[0024] FIG. 11 is individual data of anti-tumor efficacy for albumin nano-formulations on MMTV-PyMT transgenic model.

[0025] FIG. 12 shows anti -tumor efficacy on MMTV-PyMT transgenic model. SH-327 (20mg / kg, p.o., daily), SH-315 (20mg / kg, p.o., daily) or IPI-549 (20mg / kg, p.o., daily) were administered alone (upper) or combined with paclitaxel (PTX, lOmg / kg, i.p., every' three days) and anti-PD-1 antibody (aPD-1, 100 / zg / mouse, i.p., every three days) (lower) on MMTV-PyMT mice starting at 10-week of age and to indicated timepoint.

[0026] FIGS. 13A-13D show anti-tumor efficacy on MC38 xenograft model. SH-327 (20mg / kg, p.o., daily), SH-315 (20mg / kg, p.o., daily) or IPI-549 (20mg / kg, p.o., daily) combined with paclitaxel (PTX, lOmg / kg, i.p., every' three days) and anti-PD-1 antibody (aPD-1, 100 / zg / mouse, i.p., every three days) were administered in MC38 mice model for 2 weeks or 1 week. FIG. 13A is the tumor growth curves after 2-week treatment. FIG. 13B is survival curves after 2-week treatment. FIG. 13C is tumor growth curves after 1-week treatment. FIG. 13D is survival curves after 1-week treatment.

[0027] FIG. 14 shows survival curve of mice over treatment period. C57BL / 6 mice were treated with low (20mg / kg, p.o., daily) or high (60mg / kg, p.o., daily) doses of SH-327 or IPI-549 for one month.

[0028] FIGS. 15A-15B show' high-dose IPI-549 reduced circulating white blood cell populations in normal C57BL / 6 mice. FIG. 15A is complete blood count (CBC) analysis showing the number of white blood cells (WBC), neutrophils (NEU), lymphocytes (LYM). basophils (BAS), monocytes (MONO), and eosinophils (EOS) in peripheral blood at baseline (day 0), and 2 and 4 weeks after treatment. FIG. 15B is CBC results at 4 w eeks post-treatment.

[0029] FIG. 16 shows high-dose IPI-549 induced extramedullary' hematopoiesis (EMH) in the mouse spleen. Histological analysis of spleen from mice treated with 60 mg / kg IPI-549 revealed extensive EMH characterized by the accumulation of EMH precursor cells in the red pulp of spleen. In contrast, few mature myeloid cells were observed compared to the vehicle control group (highlighted with orange circles).

[0030] FIGS. 17A-17D show altered immune cell composition in MMTV-PyMT tumors and tumor-draining lymph nodes (TDLNs) compared to normal mammary fat pads and lymph nodes in FVB / NJ mice. FIG. 17A is a comparison of myeloid cell populations (total myeloid cells.Atty. Docket No. UM-43981.601Client Ref No. 2025-184 neutrophils, and monocytes) in the tumor of MMTV-PyMT mice versus mammary fat pad from FVB / NJ mice. FIG. 17B is a comparison of T cell populations (total T cells, CD4+. and CD8+T cells) in the tumor of MMTV-PyMT mice versus mammary fat pad from FVB / NJ mice. FIG. 17C is a comparison of myeloid cell populations (total myeloid cells, neutrophils, and monocytes) in the lymph nodes of MMTV-PyMT mice versus lymph nodes from FVB / NJ mice. FIG. 17D is a comparison of T cell populations (total T cells, CD4+, and CD8+T cells) in lymph nodes of MMTV- PyMT mice versus lymph nodes from FVB / NJ mice.

[0031] FIGS. 18A-18D show immune microenvironment remodeling in MC38 tumors and tumordraining lymph nodes (TDLNs) following PI3Ky inhibitor-based combination therapy. FIG. 18A shows the percentage of total myeloid cells, neutrophils, and monocytes in MC38 tumors from mice treated with vehicle control, PTX + aPD-1, SH-327 + PTX + aPD-1, SH-315 + PTX + aPD-1. or IPI- 549 + PTX + aPD-1. SH-327, SH-315, and IPI-549 were administered daily by oral gavage (10 mg / kg) for one week. Paclitaxel (PTX, 10 mg / kg) and anti-PD-1 antibody (aPD-1, 100 pg / mouse) were administered intraperitoneally every three days for total 2 doses. FIG. 18B shows the percentage of total T cells, CD4+T cells, CD8+T cells, and natural killer (NK) cells in MC38 tumors after 1-week treatment. FIG. 18C are graphs of the total myeloid cells and monocytes in the TDLNs of treated MC38-bearing mice. FIG. 18D are graphs of the total T cells, CD4+T cells, and CD8+T cells in the TDLNs of MC38-bearing mice.

[0032] FIG. 19 shows size distribution ofNP-344-1 in mouse serum albumin (left, blue, average diameter 137. Id.nm. PDI 0. 165), NP-315 / itraconazole in mouse serum albumin (middle, violet, average diameter 124.5d.nm, PDI 0. 138) and NP-327 in human serum albumin (right, red, average diameter 124.3d.nm, PDI 0.145).

[0033] FIGS. 20 A and 20B show SH-315 significantly reduced ly mphadenopathy and splenomegaly in MRL-lpr mice. FIG. 20A is the quantification of lymph node (LN) volume and number in MRL-lpr mice at 17 weeks of age, showing a significant reduction following treatment with SH-315. FIG. 20B is the quantification of weights of lymph nodes and spleens collected at 18 weeks. Treatment with SH-315 markedly decreased LN and spleen size, indicating attenuation of autoimmune lymphoproliferation.

[0034] FIG. 21 shows SH-315 significantly reduced anti-dsDNA antibody in transgenic MRL-lpr lupus mouse model. The MRL-lpr mice were treated with SH-315 (15 mg / kg). Serum was collected at 17 and 18 weeks, as indicated. The auto-antibody was measured using ELISA kits.

[0035] FIGS. 22A and 22B show SH-315 alleviated renal dysfunction in MRL / lpr mice. FIG. 22A is the quantification of urine protein level in MRL-lpr mice, measured as an indicator of proteinuria. Treatment with SH-315 significantly reduced proteinuria. FIG. 22B is the quantification of serumAtty. Docket No. UM-43981.601Client Ref No. 2025-184 concentrations of blood urea nitrogen (BUN) and creatinine in MRL-lpr mice. SH-315 prevented elevations in BUN and creatinine, indicating improved kidney function. The dotted line denotes the upper limit of the normal reference range for BUN and creatinine in healthy mice.

[0036] FIG. 23 A and 23B show SH-315 prevents ear skin lesions in MRL / lpr mice. FIG. 23 A is representative images showing ear skin wounds and inflammation in vehicle-treated control mice (left) and SH-315-treated mice (right). FIG. 23B is the quantification of incidence of ear skin lesions: 37.5% of mice in the control group (3 out of 8) developed visible lesions, whereas no lesions were observed in the SH-315-treated group (0 out of 10).

[0037] FIGS. 24A-24E show SH-315 reduced antibody-secreting plasma cells, germinal center B cells, and double-negative T cells in the spleen of MRL-lpr mice. FIG. 24A shows the percentage of total B cells (CD19+B220+) and plasma cells (CD138+) within the CD45+immune cell population and the distribution of B cell subpopulations — germinal center B cells (GL7+CD38 ), transitional B cells (CD21 CD23 ), marginal zone B cells (CD21 CD23 ), and follicular B cells (CD23~CD21int) — within the total B cell pool. SH-315 treatment significantly reduced germinal center B cells, plasma cells, transitional B cells and increased marginal zone B cells while did not influence follicular B cells. FIG. 24B shows absolute cell numbers of total B cells and individual B cell subsets in the spleen. FIG. 24C is representative flow cytometry plots comparing B cell subpopulations between control and SH-315-treated groups: plasma cells (left), transitional / marginal zone / follicular B cells (middle), and germinal center B cells (right) in the spleen. FIG. 24D is representative flow cytometryplots showing plasma cells (CD138+) in lymph nodes from control and SH-315-treated mice. FIG. 24E is the percentage (left) and absolute number (right) of plasma cells in the lymph nodes.

[0038] FIGS. 25A-25B show SH-315 decreased T cells in MRL-lpr lupus mice. FIG. 25A is percentages of total CD3+T cells and T cell subsets (CD4+, CD8+, and double-negative CD4 CD8 B220+T cells) in the spleen. FIG. 25B is absolute cell numbers of total T cells and individual T cell subsets in the spleen; SH-315 treatment significantly reduced total T cell, CD4+T cell and double negative T cell numbers.

[0039] FIGS. 26A-26G show SH-315 reduced inflammatory- myeloid subsets and plasmacytoid dendritic cells in the spleen and lymph nodes of MRL-lpr mice. FIGS. 26A shows the percentage (upper) and absolute number (lower) of total myeloid cells (CD1 lb+), neutrophils (Ly6G+), monocytes (Ly6C+), and macrophages (F4 / 80+) in the spleen. FIG. 26B shows the percentage (upper) and number (lower) of activated neutrophils (CXCR4 CD62L Ly 6G ) and monocytes (CXCR4 CD62L Ly6C ). as well as migratory- macrophages (CXCR4+F4 / 80+). Treatment with SH- 315 significantly reduced all three inflammatory- populations. FIG. 26C is representative flow cytometry plots showing activated neutrophils, activated monocytes, and migratory- macrophages inAtty. Docket No. UM-43981.601Client Ref No. 2025-184 control versus SH-315-treated groups. FIG. 26D is the percentage (left) and absolute number (right) of plasmacytoid dendritic cells (pDCs, B220+PDCA-1+) and conventional dendritic cells (eDCs; CDl lc+MHC-II+). FIG. 26E is representative flow cytometry plots of pDCs in spleens of control and SH-315-treated mice. FIG. 26F is representative flow cytometry plots showing neutrophils (CD1 lb+Ly6G+) and monocytes (CD1 lb+Ly6C+) in the lymph nodes in control and SH-315-treated groups. FIG. 26G is percentage and absolute number of total myeloid cells, neutrophils, and monocytes in the lymph nodes.

[0040] FIG. 27 shows peripheral blood cell counts (white blood cell (WBC) neutrophils (NEU), lymphocytes (LYM), monocytes (MONO), eosinophils (EOS), and basophils (BAS) in MRL-lpr mice following administration of SH-315. SH-315 did not affect the cell counts, indicating no hematological toxicity.DETAILED DESCRIPTION

[0041] Described herein are phosphatidylinositol 3-kinase (PI3K) inhibitors and compositions thereof. PI3Ky inhibitor is an immunomodulator to polarize M2 tumor-associate macrophages (TAMs) to proinfl ammatory macrophages which can inhibit tumor growth. The current PI3Ky inhibitor IPI-549 (brand name Eganelisib) is in phase II clinical trial combined with Tecentriq and Abraxane to treat triple negative breast cancer (TNBC). Although the combined therapy showed prolonged patients progressive free survival period compared with Tecentriq and Abraxane patient group, IPI-549 induced severe hepatic toxicity in about 20% patients. Therefore, it is necessary to decrease toxicity of IPI-549 while maintaining its efficacy.

[0042] Section headings as used in this section and the entire disclosure herein are merely for organizational purposes and are not intended to be limiting.1. Definitions

[0043] The terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The singular forms “a,” “and” and “the” include plural references unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments “comprising,” “consisting of’ and “consisting essentially of,” the embodiments or elements presented herein, whether explicitly set forth or not.

[0044] For the recitation of numeric ranges herein, each intervening number there between with the same degree of precision is explicitly contemplated. For example, for the range of 6-9, theAtty. Docket No. UM-43981.601Client Ref No. 2025-184 numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4. 6.5, 6.6, 6.7, 6.8. 6.9, and 7.0 are explicitly contemplated.

[0045] Unless otherwise defined herein, scientific, and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. The meaning and scope of the terms should be clear; in the event, however of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0046] As used herein, “treat.” “treating” and the like means a slowing, stopping, or reversing of progression of a disease or disorder when provided a compound or composition described herein to an appropriate control subject. The term also means a reversing of the progression of such a disease or disorder to a point of eliminating or greatly reducing the symptoms. As such, “treating” means an application or administration of the compositions described herein to a subject, where the subject has a disease or a symptom of a disease, where the purpose is to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect the disease or symptoms of the disease.

[0047] A “subject” or “patient” may be human or non-human and may include, for example, animal strains or species used as “model systems” for research purposes, such a mouse model as described herein. Likewise, patient may include either adults or juveniles (e.g., children). Moreover, patient may mean any living organism, preferably a mammal (e.g., humans and non-humans) that may benefit from the administration of compositions contemplated herein. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish, and the like. In one embodiment, the mammal is a human.

[0048] As used herein, the terms “providing,” “administering,” “introducing,” are used interchangeably herein and refer to the placement of the compositions of the disclosure into a subject by a method or route which results in at least partial localization of the composition to a desired site. The compositions can be administered by any appropriate route which results in delivery to a desired location in the subject.

[0049] Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version. Handbook of Chemistry and Physics, 75thEd., insideAtty. Docket No. UM-43981.601Client Ref No. 2025-184 cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Sorrell, Organic Chemistry, 2ndedition. University Science Books, Sausalito, 2006; Smith, March's Advanced Organic Chemistry: Reactions, Mechanism, and Structure, 7thEdition, John Wiley & Sons, Inc., New York, 2013; Larock, Comprehensive Organic Transformations, 3rdEdition, John Wiley & Sons. Inc., New York, 2018; and Carruthers, Some Modem Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference.

[0050] The term "alkyl." as used herein, means a straight or branched, saturated hydrocarbon chain. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl. n-butyl, sec-butyl, iso-butyl, tent-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3- methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, 4,4-dimethylpentan-2-yL n-heptyl, n-octyl, n- nonyl, n-decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl and icosyl.

[0051] The term “amino,” as used herein, refers to an -NH2group. The term “alkylamino.” as used herein, refers to a group -NHR. wherein R is an alkyl group as defined herein. The term “dialkylamino,” as used herein, refers to a group -NR2, wherein each R is independently an alkyl group as defined herein.

[0052] The term “aminoalkyl,” as used herein, refers to an alkyl group, as defined herein, in which at least one hydrogen atom (e.g., one hydrogen atom) is replaced with an amino group, as defined herein.

[0053] The term “amino acid side chain,” as used herein, refers to a moiety attached to the a- carbon of an amino acid, preferably a naturally-occurring amino acid. For example, suitable amino acid side chains from naturally-occurring amino acids include hydrogen (as in glycine), -CH3 (as in alanine), -CH(CH3)2(as in valine), -CH2CH(CH3)2(as in leucine), -CH(CH3)CH2CH3(as in isoleucine), benzyl (as in phenylalanine), p-hydroxybenzyl (as in tyrosine). -CH2-( l / / -indol-3-yl) (as in try ptophan), -CH2-(1 / -imidazol-5-yl) (as in histidine), -CH2OH (as in serine), -CH(OH)CH3(as in threonine), -CH2SH (as in cysteine), -CH2CH2SCH3(as in methionine), -CH2COOH (as in aspartic acid), -CH2CH2COOH (as in glutamic acid), -CH2CONH2 (as in asparagine). -CH2CH2CONH2 (as in glutamine), -CH2CH2CH2CH2NH2(as in lysine), -CH2CH2CH2NHC(NH)(NH2) (as in arginine), and -CH2CH2CH2- (as in proline). Suitable amino acid side chains from non-naturally occurring amino acids include -CH2CH2CH2COOH (as in aminoadipic acid) and - CH2CH2CH2CH2COOH (as in 2- aminopimelic acid).Atty. Docket No. UM-43981.601Client Ref No. 2025-184

[0054] The term “aryl,” as used herein, refers to an aromatic carbocyclic ring system having a single ring (monocyclic) or multiple rings (bicyclic or tricyclic) including fused ring systems, and zero heteroatoms. As used herein, aryl contains 6-20 carbon atoms (C6-C20 aryl), 6 to 14 ring carbon atoms (C6-C14 aryl), 6 to 12 ring carbon atoms (C6-C12 aryl), or 6 to 10 ring carbon atoms (Ce-Cio ary l). Representative examples of ary l groups include, but are not limited to, pheny l, naphthyl, anthracenyl, and phenanthrenyl.

[0055] The term “halogen” or “halo,” as used herein, means F, Cl, Br, or I.

[0056] The term “haloalkyl,” as used herein, means an alkyl group, as defined herein, in which at least one hydrogen atom (e.g., one, two, three, four, five, six, seven or eight hydrogen atoms) is replaced with a halogen. In some embodiments, each hydrogen atom of the alky l group is replaced with a halogen. Representative examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyL trifluoromethyl, 2,2,2-trifluoroethyL and 3,3,3-trifluoropropyl.

[0057] The term “hydroxy,” as used herein, refers to an -OH group.

[0058] The term “hydroxyalkyl,” as used herein, refers to an alky l group, as defined herein, in which at least one hydrogen atom (e.g., one hydrogen atom) is replaced with a hydroxy group, as defined herein.

[0059] The term “nitrogen protecting group,” as used herein, refers to a group intended to protect an amino group against undesirable reactions during synthetic procedures. Common nitrogen protecting groups include acyl groups such as acetyl, benzoyl, 2-bromoacetyl, 4-bromobenzoyl, tert- butylacetyl, carboxaldehyde, 2-chloroacetyl, 4-chlorobenzoyl, a-chlorobutyryl, 4-nitrobenzoyl, o- nitrophenoxyacetyl, phthalyl, pivaloyl, propionyl, trichloroacetyl, and trifluoroacetyl; sulfonyl groups such as benzenesulfonyl and / 2-toluenesul fonyl; carbamate-forming groups such as benzyloxy carbonyl (Cbz), te / 7-butyloxy carbonyl (Boc), p-chlorobenzyloxy carbonylsmethoxy benzyloxycarbonyl, fluorenylmethyloxy carbonyl (Fmoc); and the like. Nitrogen protecting groups are well-known in the art and include those described in detail in Greene ’s Protective Groups in Organic Synthesis, P. G. M. Wuts, 5th edition, John Wiley & Sons, Inc., 2014, which is incorporated herein by reference.

[0060] As used herein, the term “substituent” refers to a group substituted on an atom of the indicated group.

[0061] When a group or moiety can be substituted, the term “substituted” indicates that one or more (e.g., 1, 2, 3, 4, 5, or 6; in some embodiments 1, 2, or 3; and in other embodiments 1 or 2) hydrogen atoms on the group indicated in the expression using “substituted” can be replaced with a selection of recited indicated groups or with a suitable substituent group known to those of skill in the art (e.g., one or more of the groups recited below), provided that the designated atom’s normalAtty. Docket No. UM-43981.601Client Ref No. 2025-184 valence is not exceeded. Substituent groups include, but are not limited to, alky l, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyd, cycloalkenyl, guanidino, halo, haloalkyL haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, phosphate, phosphonate, sulfonic acid, sulfonamido, thiol, thione, thioxo, or combinations thereof.

[0062] As used herein, in chemical structures the indication:“ represents a point of attachment of one moiety' to another moiety.

[0063] In some instances, the number of carbon atoms in a hydrocarbyl substituent (e.g., alkyl) is indicated by the prefix “Cx-Cy”, wherein x is the minimum and y is the maximum number of carbon atoms in the substituent. Thus, for example, “C1-C3 alkyd” refers to an alkyl substituent containing from 1 to 3 carbon atoms.

[0064] For compounds described herein, groups and substituents thereof may be selected in accordance with permitted valence of the atoms and the substituents, such that the selections and substitutions result in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.

[0065] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they optionally encompass substituents resulting from writing the structure from right to left, e.g., -CH2O- is intended to encompass -OCH2-, and -C(O)NH- is intended to encompass -NHC(O)-.

[0066] Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the present disclosure. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.2. Compounds

[0067] In one aspect, disclosed herein is a compound of formula (I):Atty. Docket No. UM-43981.601Client Ref No. 2025-184or a pharmaceutically acceptable salt thereof, wherein:R1is selected from phenyl, C1-C4 aminoalkyl, ferrocenyl, adamantyl, and a group:R2HRt. N / H n Y o wherein R2is an amino acid side chain and R3is hydrogen or a nitrogen protecting group; wherein the phenyl is substituted with 1. 2, 3, 4, or 5 substituents independently selected from halo, C1-C4 haloalkyl, and C1-C4 hydroxyalkyl.10068] In some embodiments, R1is phenyl substituted with 1, 2, or 3 substituents independently selected from halo, C1-C2 haloalkyl, and C1-C4 hydroxyalkyl. In some embodiments, R1is phenyl substituted with 1, 2. or 3 substituents independently selected from halo, C1-C2 haloalkyl, and C1-C2 hydroxyalkyl. In some embodiments, R1is phenyl substituted with 1. 2, or 3 substituents independently selected from fluoro, trifluoromethyl, hydroxymethyl, and hydroxypropyl. In some embodiments, R1is phenyl substituted with 1, 2, or 3 substituents independently selected from fluoro, trifluoromethyl, and hydroxymethyl. In some embodiments, at least one of the substituents is hydroxymethyl. In some embodiments, R1is phenyl substituted with 1 halo substituent (e.g.. fluoro) and one hydroxymethyl substituent.

[0069] In some embodiments, R1is a group, wherein R2is a tryptophan side chain and R3is selected from hydrogen and a tert-butyloxy carbonyl group.

[0070] In some embodiments, R1is C1-C4 aminoalkyl. In some embodiments, R1is C1-C2 aminoalkyl, such as 1 -aminoethyl. In some embodiments, R1is ferrocenyl. In some embodiments, R1is adamantyl.10071] In some embodiments, the compound is selected from:Atty. Docket No. UM-43981.601Client Ref No. 2025-184Atty. Docket No. UM-43981.601Client Ref No. 2025-184

[0072] In some embodiments, the compound is:Atty. Docket No. UM-43981.601Client Ref No. 2025-184, pharmaceutically acceptable salt thereof.10073] The compounds may exist as stereoisomers wherein asymmetric or chiral centers are present. The stereoisomer is “R” or “S” depending on the configuration of substituents around the chiral carbon atom. The terms “R” and “S” used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, in Pure Appl. Chem., 1976. 45: 13- 30. The disclosure contemplates various stereoisomers and mixtures thereof and these are specifically included within the scope of this disclosure. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. Individual stereoisomers of the compounds may be prepared synthetically from commercially available starting materials, which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by methods of resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and optional liberation of the optically pure product from the auxiliary as described in Fumiss, Hannaford, Smith, and Tatchell, “Vogel's Textbook of Practical Organic Chemistry,” 5th edition (1989), Longman Scientific & Technical, Essex CM20 2JE, England (or more recent versions thereof), or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns, or (3) fractional recrystallization methods.

[0074] It should be understood that the compounds may possess tautomeric forms, as well as geometric isomers, and that these also constitute embodiments of the disclosure.

[0075] The present disclosure also includes isotopically-labeled compounds, which is identical to those recited in formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes include those for hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, but not limited to2H,3H,13C,14C,15N,18O,170,31P,32P ,35S,18F, andj6Cl, respectively. Substitution with heavier isotopes such as deuterium, for example,2H,Atty. Docket No. UM-43981.601Client Ref No. 2025-184 can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. The compound may incorporate positron-emitting isotopes for medical imaging and positron-emitting tomography (PET) studies for determining the distribution of receptors. Suitable positron-emitting isotopes that can be incorporated into the compounds arenC,13N,15O, and18F. Isotopically-labeled compounds can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using appropriate isotopically-labeled reagent in place of non-isotopically-labeled reagent.

[0076] The disclosed compounds may exist as pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt'’ refers to salts or zwitterions of the compounds which are water or oil-soluble or dispersible, suitable for treatment of disorders without undue toxicity’, irritation, and allergic response, commensurate with a reasonable benefit / risk ratio and effective for their intended use. The salts may be prepared during the final isolation and purification of the compounds or separately by reacting an amino group of the compounds with a suitable acid. For example, a compound may be dissolved in a suitable solvent, such as but not limited to methanol and water and treated with at least one equivalent of an acid, like hydrochloric acid. The resulting salt may precipitate out and be isolated by filtration and dried under reduced pressure. Alternatively, the solvent and excess acid may be removed under reduced pressure to provide a salt. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, paratoluenesulfonate, undecanoate, hydrochloric, hydrobromic, sulfuric, phosphoric and the like. The amino groups of the compounds may also be quatemized with alkyl chlorides, bromides, and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl and the like.

[0077] Basic addition salts may be prepared during the final isolation and purification of the disclosed compounds by reaction of a carboxy l group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or an organic primary, secondary, or tertiary amine. Quaternary amine salts can be prepared, such as those derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethyl aniline, N-methylpiperidine, N- methylmorpholine, di cyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-Atty. Docket No. UM-43981.601Client Ref No. 2025-184 ephenamine and N,N'-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.

[0078] Compounds may be synthesized according to a variety of methods, including those illustrated in the Examples. Reaction conditions and reaction times for each individual step can vary depending on the particular reactants employed and substituents present in the reactants used. Specific procedures are provided in the Examples section. Reactions can be worked up in the conventional manner, e.g., by eliminating the solvent from the residue and further purified according to methodologies generally known in the art such as, but not limited to, crystallization, distillation, extraction, trituration, and chromatography. Unless otherwise described, the starting materials and reagents are either commercially available or can be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature. Starting materials, if not commercially available, can be prepared by procedures selected from standard organic chemical techniques, techniques that are analogous to the synthesis of known, structurally similar compounds, or techniques that are analogous to the above described schemes or the procedures described in the synthetic examples section.

[0079] Routine experimentations, including appropriate manipulation of the reaction conditions, reagents and sequence of the synthetic route, protection of any chemical functionality that cannot be compatible with the reaction conditions, and deprotection at a suitable point in the reaction sequence of the method are included in the scope of the disclosure. Suitable protecting groups and the methods for protecting and deprotecting different substituents using such suitable protecting groups are well know n to those skilled in the art; examples of which can be found in PGM Wuts and TW Greene, in Greene's book titled Protective Groups in Organic Synthesis (4th ed.), John Wiley & Sons, NY (2006), which is incorporated herein by reference in its entirety. Synthesis of the compounds of the disclosure can be accomplished by methods analogous to those described in the synthetic schemes described hereinabove and in specific examples.

[0080] When an optically active form of a disclosed compound is required, it can be obtained by carry ing out one of the procedures described herein using an optically active starting material (prepared, for example, by asymmetric induction of a suitable reaction step), or by resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization, or enzymatic resolution).

[0081] Similarly, when a pure geometric isomer of a compound is required, it can be obtained by carrying out one of the above procedures using a pure geometric isomer as a starting material, or by resolution of a mixture of the geometric isomers of the compound or intermediates using a standard procedure such as chromatographic separation.Atty. Docket No. UM-43981.601Client Ref No. 2025-184

[0082] It can be appreciated that the synthetic schemes and specific examples as described are illustrative and are not to be read as limiting the scope of the disclosure as it is defined in the appended claims. All alternatives, modifications, and equivalents of the synthetic methods and specific examples are included within the scope of the claims.3. Compositions

[0083] The disclosed compounds, along with other PI3K inhibitor compounds, may be incorporated into compositions that may be suitable for administration to a subject (such as a patient, which may be a human or non-human). a. Pharmaceutical Compositions[0084| The compounds may be incorporated into pharmaceutically acceptable compositions. The pharmaceutical compositions may include a “therapeutically effective amount” or a “prophylactically effective amount” of the compound(s). A “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary', to achieve the desired therapeutic result. A therapeutically effective amount of the composition may be determined by a person skilled in the art and may vary' according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the composition to elicit a desired response in the individual. A therapeutically' effective amount is also one in which any toxic or detrimental effects of a compound of the disclosure (e g., a compound of formula (I)) are outweighed by the therapeutically beneficial effects. A “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.

[0085] The pharmaceutical compositions and formulations may include pharmaceutically acceptable carriers. The term “pharmaceutically acceptable earner,” as used herein, means a nontoxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material, surfactant, cyclodextrins or formulation auxiliary' of any ty pe. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as. but not limited to, lactose, glucose and sucrose; starches such as, but not limited to, com starch and potato starch; cellulose and its derivatives such as, but not limited to, sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as, but not limited to, cocoa butter and suppository waxes; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil. olive oil. com oil and soybean oil; surfactants such as, but not limited to. cremophor EL. cremophor RH 60, Solutol HS 15 and polysorbate 80; cyclodextrins such as, but not limited to.Atty. Docket No. UM-43981.601Client Ref No. 2025-184 alpha-CD, beta-CD, gamma-CD, HP-beta-CD, SBE-beta-CD; glycols; such as propylene glycol: esters such as, but not limited to, ethyl oleate and ethyl laurate; agar; buffering agents such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other nontoxic compatible lubricants such as, but not limited to, sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.[0086| The route by which the disclosed compounds are administered and the form of the composition will dictate the type of carrier to be used. The composition may be in a variety' of forms, suitable, for example, for systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implants, or parenteral injections) or topical administration (e.g., dermal, pulmonary, nasal, aural, ocular, liposome delivery systems, or iontophoresis).

[0087] Carriers for systemic administration ty pically include at least one of diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, antioxidants, preservatives, glidants, solvents, suspending agents, wetting agents, surfactants, cyclodextrins combinations thereof, and others. All carriers are optional in the compositions.[0088| Suitable diluents include sugars such as glucose, lactose, dextrose, and sucrose; diols such as propylene glycol; calcium carbonate; sodium carbonate; sugar alcohols, such as glycerin; mannitol; and sorbitol. The amount of diluent(s) in a systemic or topical composition is typically about 50 to about 90%.

[0089] Suitable lubricants include silica, talc, stearic acid and its magnesium salts and calcium salts, calcium sulfate; and liquid lubricants such as polyethylene glycol and vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, com oil and oil of theobroma. The amount of lubncant(s) in a systemic or topical composition is typically about 5 to about 10%.

[0090] Suitable binders include polyvinyl pyrrolidone; magnesium aluminum silicate; starches such as com starch and potato starch; gelatin; tragacanth; and cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, methylcellulose, microcry stalline cellulose, and sodium carboxymethylcellulose. The amount of binder(s) in a systemic composition is typically about 5 to about 50%.

[0091] Suitable disintegrants include agar, alginic acid and the sodium salt thereof, effervescent mixtures, croscarmellose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clays, and ion exchange resins. The amount of disintegrant(s) in a systemic or topical composition is typically about 0.1 to about 10%.Atty. Docket No. UM-43981.601Client Ref No. 2025-184

[0092] Suitable colorants include a colorant such as an FD&C dye. When used, the amount of colorant in a systemic or topical composition is typically about 0.005 to about 0. 1%.

[0093] Suitable flavors include menthol, peppermint, and fruit flavors. The amount of flavor(s), when used, in a systemic or topical composition is typically about 0.1 to about 1.0%.

[0094] Suitable sweeteners include aspartame and saccharin. The amount of sweetener(s) in a systemic or topical composition is typically about 0.001 to about 1%.

[0095] Suitable antioxidants include butylated hydroxyanisole ("BHA”). butylated hydroxytoluene (“BHT”), and vitamin E. The amount of antioxidant(s) in a systemic or topical composition is ty pically about 0.1 to about 5%.

[0096] Suitable preservatives include benzalkonium chloride, methyl paraben, and sodium benzoate. The amount of preservative(s) in a systemic or topical composition is typically about 0.01 to about 5%.

[0097] Suitable glidants include silicon dioxide. The amount of glidant(s) in a systemic or topical composition is typically about 1 to about 5%.

[0098] Suitable solvents include water, isotonic saline, ethyl oleate, glycerine, hydroxylated castor oils, alcohols such as ethanol, dimethyl sulfoxide, N-Methyl-2-Pyrrolidone, dimethyl acetamide and phosphate (or other suitable buffer). The amount of solvent(s) in a systemic or topical composition is typically from about 0 to about 100%.

[0099] Suitable suspending agents include AVICEL RC-591 (from FMC Corporation of Philadelphia. Pa.) and sodium alginate. The amount of suspending agent(s) in a systemic or topical composition is ty pically about 1 to about 8%.

[0100] Suitable surfactants include lecithin, Polysorbate 80, and sodium lauryl sulfate, and the TWEENS from Atlas Powder Company of Wilmington, Del. Suitable surfactants include those disclosed in the C.T.F.A. Cosmetic Ingredient Handbook. 1992, pp.587-592; Remington's Pharmaceutical Sciences, 15th Ed. 1975, pp. 335-337; and McCutcheon's Volume 1, Emulsifiers & Detergents, 1994, North American Edition, pp. 236-239. The amount of surfactant(s) in the systemic or topical composition is ty pically about 0.1% to about 5%.

[0101] Suitable cyclodextrins include alpha-CD, beta-CD, gamma-CD, hydroxypropyl betadex (HP-beta-CD). sulfobutyl-ether P-cyclodextrin (SBE-beta-CD). The amount of cyclodextrins in the systemic or topical composition is typically about 0% to about 40%.

[0102] Although the amounts of components in the systemic compositions may vary depending on the type of systemic composition prepared, in general, systemic compositions include 0.01% to 50% of an active compound (e.g., a compound of formula (I)) and 50% to 99.99% of one or moreAtty. Docket No. UM-43981.601Client Ref No. 2025-184 carriers. Compositions for parenteral administration ty pically include 0.1% to 10% of actives and 90% to 99.9% of a carrier including a diluent and a solvent.

[0103] Compositions for oral administration can have various dosage forms. For example, solid forms include tablets, capsules, granules, and bulk powders. These oral dosage forms include a safe and effective amount, usually at least about 5%, and more particularly from about 25% to about 50% of actives. The oral dosage compositions include about 50% to about 95% of carriers, and more particularly, from about 50% to about 75%.

[0104] Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, fdm-coated, or multiple-compressed. Tablets typically include an active component, and a carrier comprising ingredients selected from diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, glidants, and combinations thereof. Specific diluents include calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose. Specific binders include starch, gelatin, and sucrose. Specific disintegrants include alginic acid and croscarmellose. Specific lubricants include magnesium stearate, stearic acid, and talc. Specific colorants are the FD&C dyes, which can be added for appearance. Chewable tablets preferably contain sweeteners such as aspartame and saccharin, or flavors such as menthol, peppermint, fruit flavors, or a combination thereof.

[0105] Capsules (including implants, time release, and sustained release formulations) typically include an active compound (e.g., a compound of formula (I)), and a carrier including one or more diluents disclosed above in a capsule comprising gelatin. Granules typically comprise a disclosed compound, and preferably glidants such as silicon dioxide to improve flow characteristics. Implants can be of the biodegradable or the non-biodegradable type.

[0106] The selection of ingredients in the carrier for oral compositions depends on secondary7considerations like taste, cost, and shelf stability, which are not critical for the purposes of this invention.[0107| Solid compositions may be coated by conventional methods, typically with pH or timedependent coatings, such that a disclosed compound is released in the gastrointestinal tract in the vicinity' of the desired application, or at various points and times to extend the desired action. The coatings typically include one or more components selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, EUDRAGIT® coatings (available from Evonik Industries of Essen, Germany), waxes and shellac.

[0108] Compositions for oral administration can have liquid forms. For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non- effervescent granules, suspensions reconstituted from non-effervescent granules, effervescentAtty. Docket No. UM-43981.601Client Ref No. 2025-184 preparations reconstituted from effervescent granules, elixirs, tinctures, syrups, and the like. Liquid orally administered compositions typically include a disclosed compound and a carrier, namely, a carrier selected from diluents, colorants, flavors, sweeteners, preservatives, solvents, suspending agents, and surfactants. Peroral liquid compositions preferably include one or more ingredients selected from colorants, flavors, and sweeteners.

[0109] Other compositions useful for attaining systemic delivery’ of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically include one or more of soluble filler substances such as diluents including sucrose, sorbitol, and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methylcellulose. Such compositions may further include lubricants, colorants, flavors, sweeteners, antioxidants, and glidants.

[0110] The disclosed compounds can be topically administered. Topical compositions that can be applied locally to the skin may be in any form including solids, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-on and rinse-out hair conditioners, milks, cleansers, moisturizers, sprays, skin patches, and the like. Topical compositions include: a disclosed compound (e.g., a compound of formula (1)), and a carrier. The carrier of the topical composition preferably aids penetration of the compounds into the skin. The carrier may further include one or more optional components.

[0111] The amount of the carrier employed in conjunction with a disclosed compound is sufficient to provide a practical quantity of composition for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods of this invention are described in the following references: Modem Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms. 2nd Ed., (1976).[0112| A carrier may include a single ingredient or a combination of two or more ingredients. In the topical compositions, the carrier includes a topical carrier. Suitable topical carriers include one or more ingredients selected from phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, symmetrical alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol. PPG-2 myristyl propionate, dimethyl isosorbide, castor oil. combinations thereof, and the like. More particularly, carriers for skin applications include propylene glycol, dimethyl isosorbide, and water, and even more particularly, phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, and symmetrical alcohols.Atty. Docket No. UM-43981.601Client Ref No. 2025-184

[0113] The carrier of a topical composition may further include one or more ingredients selected from emollients, propellants, solvents, humectants, thickeners, powders, fragrances, pigments, and preservatives, all of which are optional.

[0114] Suitable emollients include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane- 1,2-diol, butane-l,3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, and combinations thereof. Specific emollients for skin include stearyl alcohol and poly dimethylsiloxane. The amount of emollient(s) in a skin-based topical composition is typically about 5% to about 95%.

[0115] Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof. The amount of propellant(s) in a topical composition is typically about 0% to about 95%.

[0116] Suitable solvents include water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulfoxide, dimethyl formamide, tetrahydrofuran, and combinations thereof. Specific solvents include ethyl alcohol and homotopic alcohols. The amount of solvent(s) in a topical composition is typically about 0% to about 95%.

[0117] Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof. Specific humectants include glycerin. The amount of humectant(s) in a topical composition is typically 0% to 95%.[0118| The amount of thickener(s) in a topical composition is typically about 0% to about 95%.

[0119] Suitable powders include beta-cyclodextrins, hydroxypropyl cyclodextrins, chalk, talc, fullers earth, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetra alkyl ammonium smectites, trialkyl aryl ammonium smectites, chemically -modified magnesium aluminum silicate, organically -modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, ethylene glycol monostearate, and combinations thereof. The amount of powder(s) in a topical composition is typically 0% to 95%.

[0120] The amount of fragrance in a topical composition is typically about 0% to about 0.5%, particularly, about 0.001% to about 0.1%.Atty. Docket No. UM-43981.601Client Ref No. 2025-184

[0121] Suitable pH adjusting additives include HC1 or NaOH in amounts sufficient to adjust the pH of a topical pharmaceutical composition. b. Albumin Nanoparticle Compositions

[0122] The disclosure further provides compositions comprising an effective amount of a phosphatidylinositol 3-kinase (PI3K) inhibitor, or a pharmaceutically acceptable salt thereof, and albumin nanoparticles. A variety of PI3K inhibitors can be used in conjunction with the albumin nanoparticles to form suitable compositions. In some embodiments, the PI3K inhibitor is a compound of formula (I), as disclosed herein. The albumin nanoparticles compositions and formulations may also include pharmaceutically acceptable carriers, as described above.

[0123] In some embodiments, the albumin nanoparticle encapsulates, e.g., forms a shell surrounding, the PI3K inhibitor. In certain embodiments, the nanoparticle composition achieves a high encapsulate efficiency (>70-90%) and good stability.

[0124] Albumins include the most abundant plasma proteins in mammals and albumins from a large and diverse number of mammals have been characterized by biochemical methods and / or bysequence information. Any natural, synthetic, or engineered albumin may be used in the context of the nanoparticle compositions described herein. In some embodiments, the albumin is human serum albumin or albumin from animal species (e g., bovine serum albumin, porcine serum albumin, or the like). In some embodiments, the albumin is human serum albumin.

[0125] The compositions may contain albumin and the PI3K inhibitor in different molar ratios. The molar ratio of albumin to disclosed compounds ranges from 1 :20 to 20: 1.

[0126] In some embodiments, the diameter of each albumin nanoparticle is in the range of 50 to 200 nm. The diameter of the nanoparticle may be about 50 nm, about 75 nm, about 100 nm, about 125 nm, about 150 nm, about 175 nm, or about 200 nm. c. Additional Nanoformulations

[0127] In some embodiments, the PI3K inhibitors are incorporated into compositions comprising poly(lactic acid) (PLA) and / or poly (lactic-co-gly colic acid) (PLGA) nanoparticles, a liposome, lipid nanoparticle, or a micelle. In some embodiments, the PI3K inhibitors are encapsulated in the PLA or PLGA nanoparticle, the liposome, the lipid nanoparticle, or the micelle. The nanoformulations may also include pharmaceutically acceptable carriers, as described above.

[0128] In some embodiments, the disclosed compounds are incorporated into liposomal compositions comprising one or more vesicle forming lipids. Methods of making liposomal compositions include, for example, lipid film hydration, optionally coupled with sonication or extrusion, solvent evaporation (e.g., ethanol injection, ether injection, or reverse phase evaporation) or detergent removal methods. The disclosed compounds can be combined with the lipid(s) beforeAtty. Docket No. UM-43981.601Client Ref No. 2025-184 formation of the vesicles (passive loading) or after vesicle formation (active loading). The liposome compositions may prolong circulation time in vivo, increase stability of the compound, and prevent degradation in the bloodstream. The liposomal composition may increase the distribution of the compounds within the lung, breast, pancreas, and spleen.

[0129] Any naturally occurring or synthetic vesicle forming lipid or combinations thereof can be used. The one or more vesicle forming lipids may be selected from di-aliphatic chain lipids, such as phospholipids; diglycerides; di-aliphatic glycolipids; single lipids such as sphingomyelin or glycosphingolipid; steroidal lipids; hydrophilic polymer derivatized lipids; or mixtures thereof.

[0130] The liposomes may contain other non-vesicle forming lipids or other moieties, including but not limited to amphiphilic polymers, polyanions, sterols, and surfactants. The liposomes contained in the liposome composition can also be targeting liposomes, e.g., liposomes containing one or more targeting moieties or biodistribution modifiers on the surface of the liposomes. A targeting moiety can be any agent that is capable of specifically binding or interacting with a desired target and are generally known in the art, for example ligands such as folic acid, proteins, antibody or antibody fragments, and the like).

[0131] The liposomes can have any liposome structure, e.g., structures having an inner space sequestered from the outer medium by one or more lipid bilayers, or any microcapsule that has a semi-permeable membrane with a lipophilic central part where the membrane sequesters an interior. In some embodiments, the liposome may be a unilamellar liposome, having a single lipid layer. The disclosed compounds may be completely or partially located in the interior space of the liposome or completely or partially within the bilayer membrane of the liposome. In some embodiments, the lipids for a micelle.

[0132] In some embodiments, the disclosed compounds are incorporated into nanoformulations comprising PLA and / or PLGA. PLA or PLGA nanoformulations may be prepared by various methods known in the art such as single / double emulsion-solvent evaporation technique, spray drying, spray freeze drying, supercritical fluid drying, and nanoprecipitation. d. Additional Therapeutic Agents

[0133] The compositions disclosed herein may further comprise at least one additional therapeutic agent. In some embodiments, the at least one additional therapeutic agent comprises at least one chemotherapeutic agent. As used herein, the term '‘chemotherapeutic” or '‘anti -cancer drug” includes any small molecule or other drug used in cancer treatment or prevention. Chemotherapeutics include, but are not limited to, cyclophosphamide, methotrexate. 5-fluorouracil, doxorubicin, docetaxel, daunorubicin, bleomycin, vinblastine, dacarbazine, cisplatin, paclitaxel, raloxifene hydrochloride, tamoxifen citrate, abemacicilib, afinitor (Everolimus), alpelisib, anastrozole, pamidronate.Atty. Docket No. UM-43981.601Client Ref No. 2025-184 anastrozole, exemestane, capecitabine, epirubicin hydrochloride, eribulin mesylate, toremifene, fulvestrant. letrozole, gemcitabine, goserelin, ixabepilone, emtansine, lapatinib, olaparib, megestrol, neratinib, palbociclib, ribociclib, talazoparib, thiotepa, toremifene, methotrexate, and tucatinib. In select embodiments, the chemotherapeutic agent is paclitaxel.10134] In some embodiments, the chemotherapeutic is added to the pharmaceutical composition comprising the compounds disclosed herein. In some embodiments, the compositions of the chemotherapeutic agent are incorporated into the compositions comprising a PI3K inhibitor and an albumin nanoparticle. In some embodiments, the albumin nanoparticle encapsulates, e.g., forms a shell surrounding, both the chemotherapeutic agent and the PI3K inhibitor. In some embodiments, the chemotherapeutic agent is incorporated into the compositions comprising a PI3K inhibitor and a PLGA and / or PLA nanoparticle, a liposome, a lipid nanoparticle, or a micelle. In some embodiments, the chemotherapeutic agent is encapsulated in the PLGA and / or PLA nanoparticle, liposome, lipid nanoparticle, or micelle.4. Methods of Use

[0135] The disclosure further provides methods for treating a disease or disorder comprising administration of a PI3K inhibitor, or a composition thereof, to a subject in need thereof. In some embodiments, the PI3K inhibitor is a compound of formula (I), as disclosed herein. In some embodiments, the subject is a human.

[0136] The disease or disorder may comprise cancer, autoimmune, and inflammatory diseases.

[0137] In some embodiments, the disease or disorder is an inflammatory disease or disorder. Inflammatory diseases are characterized by activation of the immune system in a tissue or an organ to abnormal levels that may lead to abnormal function and / or disease in the tissue or organ. The inflammatory’ diseases and disorders that may be treated by the methods of the present invention include, but are not limited to, arthritis, rheumatoid arthritis, asthma, inflammatory bowel disease (Crohn's disease or ulcerative colitis), chronic obstructive pulmonary disease (COPD), allergic rhinitis, vasculitis (polyarteritis nodosa, temporal arteritis, Wegener's granulomatosis, Takayasu's arteritis, or Behcet’s syndrome), inflammatory’ neuropathy, psoriasis, systemic lupus erythematosus (SLE), chronic thyroiditis, Hashimoto's thyroiditis, Addison's disease, polymyalgia rheumatica, Sjogren's syndrome, or Churg-Strauss syndrome. In some important embodiments, the inflammatory disease is rheumatoid arthritis.

[0138] In some embodiments, the disease or disorder is an autoimmune disease or disorder. Autoimmune diseases and disorders refer to conditions in a subject characterized by cellular, tissue and / or organ injury caused by an immunologic reaction of the subject to its own cells, tissues, and / orAtty. Docket No. UM-43981.601Client Ref No. 2025-184 organs. Autoimmune diseases and disorders that may be treated by the methods of the present invention include, but are not limited to. alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, autoimmune diseases of the adrenal gland, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune oophoritis and orchitis, autoimmune thrombocytopenia, Behcets disease, bullous pemphigoid, cardiomyopathy, celiac sprue-dermatitis, chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, CREST syndrome, cold agglutinin disease, Crohn's disease, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia- fibromyositis, glomerulonephritis, Graves' disease, Guillain-Barre, Hashimoto's thyroiditis, idiopathic pulmonary' fibrosis, idiopathic thrombocytopenia purpura (ITP), irritable bowel disease (IBD), IgA neuropathy, juvenile arthritis, lichen planus, lupus erythematosus, Meniere's disease, mixed connective tissue disease, multiple sclerosis, type 1 or immune-mediated diabetes mellitus, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndromes, polymyalgia rheumatics, polymyositis and dermatomyositis, primary7agammaglobulinemia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, Raynaud's phenomenon, Reiter's syndrome. Rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, stiff-man syndrome, systemic lupus erythematosus, lupus erythematosus, takayasu arteritis, temporal arteritis / giant cell arteritis, ulcerative colitis, uveitis, vasculitides such as dermatitis herpetiformis vasculitis, vitiligo, and Wegener's granulomatosis.

[0139] Some autoimmune disorders are also associated with an inflammatory condition. Examples of inflammatory7disorders which are also autoimmune disorders that can be prevented, treated or managed in accordance with the methods of the invention include, but are not limited to, asthma, encephalitis, inflammatory7bowel disease, chronic obstructive pulmonary7disease (COPD), allergic disorders, pulmonary fibrosis, undifferentiated spondyloarthropathy, undifferentiated arthropathy, arthritis, inflammatory osteolysis, and chronic inflammation resulting from chronic viral or bacterial infections. Examples of the types of psoriasis which can be treated in accordance with the compositions and methods of the invention include, but are not limited to, plaque psoriasis, pustular psoriasis, erythrodermic psoriasis, guttate psoriasis and inverse psoriasis.

[0140] In some embodiments, the disease or disorder is lupus, including but not limited to, systemic lupus erythematosus, discoid lupus, subacute cutaneous lupus erythematosus, cutaneous lupus erythematosus (such as chilblain lupus erythematosus), drug-induced lupus, neonatal lupus, lupus nephritis. In select embodiments, the disease or disorder is systemic lupus erythematosus (SLE). SLE is a chronic and life-threatening autoimmune disease which can lead to multiple organ pathologies (including the skin, muscles, bones, lungs, kidneysAtty. Docket No. UM-43981.601Client Ref No. 2025-184(e.g., lupus nephritis), cardiovascular and central nervous systems), with renal complications, infections, myocardial infarction and central nervous system manifestations being the major causes of morbidity.

[0141] Lupus progresses in a series of flares, or periods of acute illness, followed by remissions. The symptoms of a flare, which vary considerably between patients and even within the same patient, include malaise, fever, symmetric joint pain, and photosensitivity (development of rashes after brief sun exposure). Other symptoms of lupus include hair loss, ulcers of mucous membranes and inflammation of the lining of the heart and lungs which leads to chest pain. The methods herein may reduce the recurrence (e.g., number or periodicity) of the flares, decrease the severity of the flares, decrease the length of time of the flares, or any combination thereof. The methods may further decrease or reduce any other symptoms of associated with lupus.

[0142] In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer comprises a solid tumor. In some embodiments, the cancer comprises a blood cancer or lymphoma. In some embodiments, the cancer is metastatic cancer. In some embodiments, the disclosed compounds, compositions, or methods result in suppression of elimination of metastasis. In some embodiments, the disclosed compounds, compositions, or methods result in decreased tumor growth. In some embodiments, the disclosed compounds, compositions, or methods prevent tumor recurrence.

[0143] The disclosed PI3K inhibitors may be useful to treat a wide variety of cancers including carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, or seminoma. The cancer may be a cancer of the bladder, blood, bone, brain, breast, cervix, colon / rectum, endometrium, head and neck, kidney, liver, lung, lymph nodes, muscle tissue, ovary, pancreas, prostate, skin, spleen, stomach, testicle, thyroid, or uterus. In select embodiments, the cancer may comprise breast cancer.[0144| The disclosed PI3K inhibitor, or a composition thereof may be administered to a subject by a variety of methods. In any of the uses or methods described herein, administration may be by various routes know n to those skilled in the art, including without limitation oral, inhalation, intravenous, intramuscular, topical, subcutaneous, systemic, and / or intraperitoneal administration to a subject in need thereof. In some embodiments, the disclosed PI3K inhibitor, or a composition thereof, as disclosed herein may be administered by parenteral administration (including, but not limited to, subcutaneous, intramuscular, intravenous, intraperitoneal, intracardiac and intraarticular injections). In some embodiments, the disclosed PI3K inhibitor, or a composition thereof, as disclosed herein may be administered by oral administration.Atty. Docket No. UM-43981.601Client Ref No. 2025-184

[0145] The amount of the PI3K inhibitor, or a composition thereof, of the present disclosure required for use in treatment or prevention will vary not only with the particular compound selected but also with the route of administration, the nature and / or symptoms of the disease and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician. The determination of effective dosage levels, the dosage levels necessary to achieve the desired result, can be accomplished by one skilled in the art using routine methods, for example, human clinical trials, in vivo studies, and in vitro studies. For example, useful dosages of a PI3K inhibitor, or a composition thereof, can be determined by comparing their in vitro activity, and in vivo activity in animal models.

[0146] Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vivo and / or in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, FIPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC value. Compositions should be administered using a regimen, which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.

[0147] It should be noted that the attending physician would know how to and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity ). The magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the symptoms to be treated and the route of administration. Further, the dose, and perhaps dose frequency, will also vary according to the age, body weight, and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.

[0148] PI3K inhibitors, or compositions thereof, disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology’ of a particular compound, a subset of the compounds sharing certain chemical moieties, or a composition comprising a PI3K inhibitor, may be established by determining in vitro toxicity toyvards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity' in animals, such as mammals, or more specifically, humans. Alternatively, the toxicity of particular compounds in an animal model, such as mice, rats, rabbits, dogs, or monkeys, may be determined using knownAtty. Docket No. UM-43981.601Client Ref No. 2025-184 methods. Efficacy may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to determine efficacy, the skilled artisan can be guided by the state of the art to choose an appropriate model, dose, route of administration and / or regime.10149] A therapeutically effective amount of a PI3K inhibitor disclosed herein, or compositions thereof, may be administered alone or in combination with a therapeutically effective amount of at least one additional therapeutic agent. In some embodiments, effective combination therapy is achieved with a single composition or pharmacological formulation that includes both agents, or with two distinct compositions or formulations, administered at the same time, wherein one composition includes a compound of this invention, and the other includes the second agent(s).

[0150] In some embodiments, the at least one additional therapeutic agent comprises at least one chemotherapeutic agent. As used herein, the term '‘chemotherapeutic” or '‘anti-cancer drug” includes any small molecule or other drug used in cancer treatment or prevention. Chemotherapeutics include, but are not limited to, cyclophosphamide, methotrexate, 5-fluorouracil, doxorubicin, docetaxel, daunorubicin, bleomycin, vinblastine, dacarbazine, cisplatin, paclitaxel, raloxifene hydrochloride, tamoxifen citrate, abemacichb, everolimus, alpelisib, anastrozole, pamidronate, anastrozole, exemestane, capecitabine, epirubicin hydrochloride, eribulin mesylate, toremifene, fulvestrant, letrozole, gemcitabine, goserelin, ixabepilone, emtansine, lapatinib, olaparib, megestrol, neratinib, palbociclib, ribociclib, talazoparib, thiotepa. toremifene, methotrexate, and tucatinib. In select embodiments, the chemotherapeutic agent comprises paclitaxel.

[0151] The chemotherapeutic agent (e.g., paclitaxel) may be provided separately or in a single composition with the PI3K inhibitor. In some embodiments, the single composition of the chemotherapeutic agent is simultaneously incorporated into compositions comprising an albumin nanoparticle. In some embodiments, the albumin nanoparticle encapsulates, e.g., forms a shell surrounding, both the chemotherapeutic agent and the PI3K inhibitor.

[0152] A wide range of second therapies may be used in conjunction with the compounds of the present disclosure. The second therapy may be administration of an additional therapeutic agent or may be a second therapy not connected to administration of another agent. Such second therapies include, but are not limited to. surgery, immunotherapy, radiotherapy, or an additional chemotherapeutic or anti-cancer agent.

[0153] The second therapy (e.g., an immunotherapy) may be administered at the same time as the initial therapy, either in the same composition or in a separate composition administered at substantially the same time as the first composition. In some embodiments, the second therapy may precede or follow the treatment of the first therapy by time intervals ranging from hours to months.Atty. Docket No. UM-43981.601Client Ref No. 2025-184

[0154] In some embodiments, the second therapy includes immunotherapy. Immunotherapies include chimeric antigen receptor (CAR) T-cell or T-cell transfer therapies, cytokine therapy, immunomodulators, cancer vaccines, or administration of antibodies (e.g., monoclonal antibodies).

[0155] In some embodiments, the immunotherapy comprises administration of antibodies. The antibodies may target antigens either specifically expressed by tumor cells or antigens shared with normal cells. In some embodiments, the immunotherapy may comprise an antibody targeting, for example. CD20, CD33, CD52, CD30. HER (also referred to as erbB or EGFR), VEGF, CTLA-4 (also referred to as CD152), epithelial cell adhesion molecule (EpCAM, also referred to as CD326), and PD-1 / PD-L1. Suitable antibodies include, but are not limited to, rituximab, blinatumomab, trastuzumab, gemtuzumab, alemtuzumab, ibritumomab. tositumomab, bevacizumab, cetuximab, panitumumab, ofatumumab, ipilimumab, brentuximab, pertuzumab and the like). In some embodiments, the additional therapeutic agent may comprise anti-PD-l / PD-Ll antibodies, including, but not limited to, pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, durvalumab, and ipilimumab. The antibodies may also be linked to a chemotherapeutic agent. Thus, in some embodiments, the antibody is an antibody-drug conjugate.

[0156] The immunotherapy (e.g., administration of antibodies) may be administered to a subject by a variety of methods. In any of the uses or methods described herein, administration may be by various routes known to those skilled in the art, including without limitation oral, inhalation, intravenous, intramuscular, topical, subcutaneous, systemic, and / or intraperitoneal administration to a subject in need thereof. In some embodiments, the immunotherapy may be administered in the same or different manner than the PI3K inhibitor, or composition thereof. The immunotherapy may be administered by parenteral administration (including, but not limited to, subcutaneous, intramuscular, intravenous, intraperitoneal, intracardiac and intraarticular inj ections).5. Kits

[0157] In another aspect, the disclosure provides kits comprising at least one disclosed compound or a pharmaceutically acceptable salt thereof, or a composition comprising the compound or a pharmaceutically acceptable salt thereof, and instructions for using the compound or composition.

[0158] The kits can also comprise other agents and / or products co-packaged, co-formulated, and / or co-delivered with other components. For example, a drug manufacturer, a drug reseller, a physician, a compounding shop, or a pharmacist can provide a kit comprising a disclosed compound and / or product and another agent (e.g., a chemotherapeutic, a monoclonal antibody, a pain reliever, an anti-seizure medicine, a steroid, an anti-emetic) for delivery to a patient.Atty. Docket No. UM-43981.601Client Ref No. 2025-184

[0159] The kits can also comprise instructions for using the components of the kit. The instructions are relevant materials or methodologies pertaining to the kit. The materials may include any combination of the following: background information, list of components, brief or detailed protocols for using the compositions, troubleshooting, references, technical support, and any other related documents. Instructions can be supplied with the kit or as a separate member component, either as a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation.

[0160] It is understood that the disclosed kits can be employed in connection with the disclosed methods. The kit may further contain containers or devices for use with the methods or compositions disclosed herein. The kits optionally may provide additional components such as buffers and disposable single-use equipment (e.g.. pipettes, cell culture plates, or flasks).

[0161] The kits provided herein are in suitable packaging. Suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging, and the like. Individual member components of the kits may be physically packaged together or separately.6. Examples

[0162] Abbreviations used in the schemes and examples that follow are: DCM is dichloromethane; DMAP is 4-dimethylaminopyridine; DMF is dimethylformamide; DMSO is dimethyl sulfoxide; eq is equivalent; EtOAc is ethyl acetate; MeOH is methanol; TBAF is tetra-n- butylammonium fluoride; TBSC1 is tert-butyldimethylsilyl chloride; TBDMSC1 is tert- butyldimethylsilyl chloride; THF is tetrahydrofuran; and TFA is trifluoroacetic acid.Example 1 Compound SynthesisGeneral Method IA B[0163| An oven dried sealed tube was charged with compound A (0. 1 mmol, 1 equiv), dichlorobis(acetonitrile)palladium (15 mol%), X-Phos (45 mol%), and cesium carbonate (3 equiv) followed by propionitrile (1 mL) and DMSO (0.25 mL). The mixture was bubbled with N2 for 15 min. Alkyne B (3.0 equiv) was added, and the reaction was sealed and heated to 105 °C for 4h untilAtty. Docket No. UM-43981.601Client Ref No. 2025-184 there was no more starting material as indicated by LC / MS analysis. The reaction was then partitioned between brine and ethyl acetate (x3). The organics were dried (Na2SC>4), concentrated on celite in vacuo, and purified by flash chromatography on silica gel.General Method IIAtty. Docket No. UM-43981.601Client Ref No. 2025-1848 SH-344

[0164] A mixture of benzyl alcohol (1 or 6) (1.00 g, 4.27 mmol), TBDMSC1 (0.708 g, 4.70 mmol), and imidazole (0.639 g, 9.39 mmol) in DCM (10 mL) was stirred at room temperature for 16 hours. The mixture was partitioned between saturated NH4CI and DCM (x3). The organics were washed with brine, dried (N zSCL), and concentrated. The residue was purified by column chromatography (S1O2. 0-10% EtOAc / hexane) to afford 3 or 7.

[0165] An oven dried sealed tube was charged with compound 3 or 7 (0.1 1 mmol, 1.1 equiv), Alkyne 4 (0.1 mmol, 1 equiv), dichlorobis(triphenylphosphine)palladium (3 mol%) and cuprous iodide (3 mol%) followed by tri ethylamine (1 mL). The mixture was bubbled with N2 for 10 min and heated to 65 °C for 16 hours. The reaction was then partitioned between brine and ethyl acetate (x3). The combined organics were dried over NazSCL, concentrated on celite, and purified by flash chromatography on silica gel to get compound (5 or 8).

[0166] To a solution of silyl ether 5 or 8 (1 mmol) in THF (10 mL) w as added TBAF (IM in THF, 2 mmol) in dropwise. The resulting brown solution was stirred for 6 hours. The reaction was quenched with water then extracted with sat NaHCCh / water (1: 1) and DCM (x3) or EtOAc (x3). The combined organic extracts were washed with brine, dried over NazSCL. concentrated on celite in vacuo, and purified by silica gel column chromatography to afford compound SH-342 or SH-344.Atty. Docket No. UM-43981.601Client Ref No. 2025-184

[0167] Additional compounds can be prepared by analogous methods using appropriate starting materials.SH-313

[0168] 2-amino-N-((lS)-l-(8-(3-aminobut-l-yn-l-yl)-l-oxo-2-phenyl-l,2-dihydroisoquinolin- 3-yl)ethyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (SH-313). Method I, 41.7 mg, 85% yield.JH NMR (600 MHz, CDC13) 8 8.39 (dd, J= 6.7, 1.7 Hz, 1H), 8.33 (dd, J= 4.5, 1.7 Hz, 1H). 7.85 (d, J = 7.1 Hz, 1H), 7.51 - 7.34 (m, 6H), 7.33 - 7.25 (m, 2H), 6.73 (dd, J= 6.8, 4.4 Hz, 1H), 6.54 (d, J= 3.3 Hz, 1H), 5.53 (s, 2H), 4.73 (t, J = 6.9 Hz, 1H), 3.88 (dd, J= 8.4, 6.5 Hz, 1H), 2.32 (s, 2H), 1.40 - 1.26 (m, 6H).

[0169] (S)-2-amino-N-(l-(8-((4-fluorophenyl)ethynyl)-l-oxo-2-phenyl-l,2- dihydroisoquinolin-3-yl)ethyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (SH-315). Method I,42.3 mg, 78% yield. 'H NMR (600 MHz, CDCI3) 6 8.49 (dd, J= 6.7. 1.7 Hz. 1H), 8.44 (dd, J= 4.5, 1.7 Hz, 1H), 7.96 (d, J = 7.0 Hz, 1H), 7.67 (dt, J = 7.5, 1.0 Hz, 1H), 7.60 - 7.36 (m, 8H), 7.34 - 7.29 (m, 1H), 7.12 - 7.04 (m, 2H), 6.84 (dd, J= 6.8, 4.4 Hz, 1H), 6.67 (s, 1H), 5.61 (s, 2H), 4.85 (t, J= 6.9 Hz, 1H), 1.44 (d, J= 6.8 Hz, 3H).Atty. Docket No. UM-43981.601Client Ref No. 2025-184

[0170] SH-316. Method I, 54.4 mg, 86% yield. 'H NMR (600 MHz, CDCh) 5 8.39 (dd, J= 6.7,1.7 Hz, 1H), 8.34 (dd, J= 4.4, 1.6 Hz, 1H), 7.84 (d, J= 7.2 Hz, 1H), 7.57 (dd, J= 7.5, 1.2 Hz, 1H),7.47 - 7.27 (m, 7H), 6.74 (dd, J= 6.8, 4.4 Hz, 1H), 6.54 (s, 1H), 5.51 (s, 2H), 5.23 (s, 1H), 4.77 (t, J= 6.9 Hz. 1H), 4.45 (t, J= 1.8 Hz, 2H), 4.15 (1, J= 1.8 Hz, 4H). 4.11 (dd. .7= 3.0, 1.3 Hz, 2H). 1.34(d, J = 6.8 Hz, 3H).SH-318

[0171] N-((S)-l-(8-(((3S,5S,7S)-adamantan-l-yl)ethynyl)-l-oxo-2-phenyl-l,2- dihydroisoquinoIin-3-yl)ethyl)-2-aminopyrazolo[l,5-a]pyrimidine-3-carboxamide (SH-318).Method I, 47.1 mg, 81% yield. *H NMR (600 MHz, CDCh) 8 8.47 (dd, J= 6.8, 1.7 Hz, 1H), 8.42 (dd, = 4.5, 1.7 Hz, 1H), 7.88 (d, J= 7.3 Hz, 1H), 7.54 (dt, J= 8.1. 2.8 Hz, 2H), 7.50 - 7.42 (m. 4H), 7.41 - 7.34 (m, 2H), 6.82 (dd, J= 6.7, 4.4 Hz, 1H), 6.59 (s, 1H), 5.58 (d, J= 17.4 Hz, 2H), 4.85 - 4.78 (m, 1H), 2.01 (d, .7= 2.9 Hz, 4H), 1.99 - 1.95 (m, 3H), 1.70 (d, .7= 4.0 Hz, 6H), 1.41 (d, J = 6.8 Hz, 3H), 1.28 (s, 2H).Atty. Docket No. UM-43981.601Client Ref No. 2025-184SH-320

[0172] (S)-2-amino-N-(l-(l-oxo-2-phenyl-8-((4-(trifluoromethyl)phenyl)ethynyl)-l,2- dihydroisoquinolin-3-yl)ethyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (SH-320). Method I,47.2 mg, 80% yield. 'H NMR (600 MHz, CDCh) 5 8.48 (dd, J= 6.8, 1.7 Hz. 1H), 8.44 (dd, J= 4.5, 1.7 Hz. 1H), 7.97 (d. J = 7.0 Hz. 1H), 7.70 (ddd, J = 15.2. 8.0, 4.4 Hz, 3H). 7.61 - 7.46 (m, 8H). 7.43 - 7.39 (m, 1H), 6.83 (dd, J= 6.8, 4.4 Hz, 1H), 6.68 (s, 1H), 5.62 (s, 2H), 4.85 (t, J = 6.9 Hz, 1H), 1.44 (d, J = 6.8 Hz, 3H).

[0173] (S)-2-amino-N-(l-(8-((2,3-difluorophenyl)ethynyl)-l-oxo-2-phenyl-l,2- dihydroisoquinoIin-3-yl)ethyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (SH-321). Method I, 39.2 mg, 70% yield. 'H NMR (600 MHz, CDC13) 5 8.39 (dd, J= 6.8, 1.5 Hz, 1H), 8.37 - 8.33 (m, 1H), 7.86 (d, J= 7.0 Hz, 1H), 7.65 (d, J= 7.4 Hz, 1H), 7.52 - 7.44 (m, 2H), 7.44 - 7.36 (m, 3H), 7.32 (d, J= 7.9 Hz, 1H). 7.26 (s. 1H), 7.00 (d. J= 8.2 Hz. 1H), 6.90 (s, 1H), 6.76 - 6.72 (m, 1H), 6.58 (s, 1H), 5.51 (s, 2H), 4.76 (t, J = 6.9 Hz, 1H), 1.35 (d, J= 6.8 Hz, 3H).Atty. Docket No. UM-43981.601Client Ref No. 2025-184

[0174] (S)-2-amino-N-(l-(8-((2,6-difluorophenyl)ethynyl)-l-oxo-2-phenyl-l,2- dihydroisoquinolin-3-yl)ethyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (SH-322). Method I, 42 mg, 75% yield. ^ NMR ^OO MHz, CDCh) 5 8.38 (dd, J= 6.8, 1.7 Hz, 1H), 8.34 (dd, J= 4.7, 1.7 Hz, 1H), 7.85 (d, J= 7.1 Hz, 1H), 7.66 (dt, J= 7.5, 1.0 Hz, 1H), 7.49 (t, J= 7.7 Hz, 1H), 7.46 - 7.33 (m, 5H), 7.32 (ddd, J= 7.9, 2.2, 1.1 Hz, 1H), 7.12 (ddd, J = 14.6, 8.2, 6.4 Hz, 1H), 6.82 - 6.76 (m, 2H), 6.74 (dd, 6.8, 4.4 Hz, 1H), 6.57 (s, 1H), 5.51 (s, 2H), 4.77 (p, J= 6.9 Hz, 1H). 1.34 (d, J =6.8 Hz. 3H).

[0175] (S)-2-amino-N-(l-(8-((2-fluorophenyl)ethynyl)-l-oxo-2-phenyl-l,2- dihydroisoquinolin-3-yl)ethyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (SH-324). Method I,39.8 mg, 71% yield. 'H NMR (600 MHz, CDCh) 5 8.48 (dd, J= 6.7, 1.7 Hz. 1H), 8.44 (dd, J= 4.5, 1.7 Hz. 1H), 7.95 (d. J = 7. 1 Hz. 1H), 7.74 (dd, J = 7.5. 1.2 Hz. 1H), 7.64 - 7.53 (m. 3H), 7.53 - 7.44 (m, 3H), 7.44 - 7.38 (m, 1H), 7.28 - 7.23 (m, 1H), 7.10 - 7.02 (m, 2H), 6.83 (dd, J= 6.7, 4.4 Hz, 1H), 6.67 (s, 1H), 5.61 (s, 2H), 4.86 (p, J= 6.9 Hz, 1H), 1.44 (d, J= 6.8 Hz, 3H).

[0176] (S)-2-amino-N-(l-(8-((3-fluorophenyl)ethynyl)-l-oxo-2-phenyl-l,2- dihydroisoquinolin-3-yl)ethyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (SH-325). Method I,42.8 mg, 79% yield. 'H NMR (600 MHz, CDCh) 5 8.49 (dd, J= 6.7, 1.7 Hz, 1H), 8.44 (dd, J= 4.5, 1.7 Hz, 1H), 7.96 (d, J = 7.0 Hz, 1H), 7.67 (dt, J = 1.5, 1.0 Hz, 1H), 7.60 - 7.36 (m, 8H), 7.34 - 7.29 (m, 1H), 7.12 - 7.04 (m, 2H), 6.84 (dd, J = 6.8, 4.4 Hz, 1H), 6.67 (s, 1H), 5.61 (s, 2H), 4.85 (t, J = 6.9 Hz. 1H), 1.44 (d, J= 6.8 Hz, 3H).Atty. Docket No. UM-43981.601Client Ref No. 2025-184

[0177] (S)-2-amino-N-(l-(8-((3,4-difluorophenyl)ethynyl)-l-oxo-2-phenyl-l,2- dihydroisoquinolin-3-yl)ethyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (SH-326). Method I,40.3 mg, 72% yield. 'H NMR (600 MHz, CDCh) 5 8.48 (dd, J= 6.7, 1.7 Hz. 1H), 8.44 (dd, 4.4, 1.7 Hz. 1H), 7.96 (d. J = 7.0 Hz. 1H), 7.67 (dd, J = 7.5. 1.2 Hz. 1H), 7.59 - 7.54 (m. 2H), 7.54 - 7.44 (m, 4H), 7.42 - 7.36 (m, 2H), 7.32 (ddd, J= 8.1, 4.2, 2.1 Hz, 1H), 7.12 - 7.04 (m, 1H), 6.84 (dd, J= 6.7, 4.4 Hz, 1H), 6.67 (s, 1H), 5.61 (s, 2H), 4.85 (p, J= 6.9 Hz, 1H), 1.44 (d, J= 6.8 Hz, 3H).

[0178] (S)-2-amino-N-(l-(8-((2,5-difluorophenyl)ethynyl)-l-oxo-2-phenyl-l,2- dihydroisoquinolin-3-yl)ethyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (SH-327). Method I,39.8 mg, 71% yield. 'H NMR (600 MHz, CDCh) 5 8.48 (dd, J= 6.7, 1.7 Hz. 1H), 8.45 - 8.42 (m, 1H), 7.96 (d, J = 7.0 Hz. 1H), 7.72 (dt, J = 7.5, 0.9 Hz, 1H), 7.61 - 7.53 (m, 2H). 7.53 - 7.45 (m, 4H), 7.43 - 7.39 (m, 1H), 7.00 (dd, J= 9.0, 4.1 Hz, 1H), 6.98 - 6.92 (m, 1H), 6.83 (dd, J= 6.7, 4.4 Hz, 1H), 6.67 (s, 1H), 5.61 (s, 2H), 4.86 (p, J= 6.8 Hz, 1H), 1.44 (d, J= 6.8 Hz, 3H).Atty. Docket No. UM-43981.601Client Ref No. 2025-184

[0179] (S)-2-amino-N-(l-(l-oxo-2-phenyl-8-((2,4,5-trifluorophenyl)ethynyl)-l,2- dihydroisoquinolin-3-yl)ethyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (SH-328). Method I,39.9 mg, 69% yield. 'H NMR (600 MHz, CDCh) 5 8.48 (dd, J= 6.7. 1.7 Hz. 1H), 8.44 (dd, J= 4.5, 1.7 Hz, 1H), 7.96 (d, J= 7.0 Hz, 1H), 7.71 (dt, J= 7.4, 1.0 Hz, 1H), 7.61 - 7.45 (m, 6H), 7.44 - 7.37 (m, 2H), 6.93 (ddd, J= 10.1, 8.5, 6.6 Hz, 1H), 6.84 (dd, J= 6.7, 4.4 Hz, 1H), 6.67 (s, 1H), 5.61 (s, 2H), 4.85 (p, J= 6.9 Hz, 1H), 1.44 (d, J= 6.8 Hz, 3H).

[0180] (S)-2-amino-N-(l-(8-((3,5-difluorophenyl)ethynyl)-l-oxo-2-phenyl-l,2- dihydroisoquinolin-3-yl)ethyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (SH-329). Method I.40.9 mg, 73% yield. ‘H NMR (600 MHz, CDCh) 5 8.49 (dd, J= 6.8, 1.7 Hz, 1H), 8.44 (dd, .7= 4.5, 1.7 Hz, 1H), 7.96 (d, J= 7.0 Hz, 1H), 7.68 (dd, J= 7.5, 1.2 Hz, 1H), 7.62 - 7.44 (m, 5H), 7.43 - 131 (m, 1H), 7.15 - 7.04 (m, 2H), 6.84 (dd, J= 6.8, 4.4 Hz, 1H), 6.78 - 6.71 (m, 1H), 6.67 (s, 1H), 6.67 (s, 1H), 5.60 (s, 2H). 4.85 (t. J = 6.8 Hz. 1H), 1.44 (d. J= 6.8 Hz. 3H).Atty. Docket No. UM-43981.601Client Ref No. 2025-184SH-330

[0181] (S)-2-amino-N-(l-(l-oxo-2-phenyl-8-((3,4,5-trifluorophenyl)ethynyl)-l,2- dihydroisoquinolin-3-yl)ethyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (SH-330). Method I,37.6 mg. 65% yield. 'H NMR (600 MHz, CDCh) 6 8.48 (dd, J = 6.7. 1.7 Hz. 1H), 8.44 (dd, J = 4.5.1.7 Hz, 1H), 7.96 (d, J= 6.9 Hz, 1H), 7.66 (dd, J= 7.5, 1.3 Hz, 1H), 7.62 - 7.42 (m, 6H), 7.41 - 7.37 (m, 1H), 7.23 - 7.15 (m, 2H), 6.84 (dd, J= 6.8, 4.4 Hz, 1H), 6.67 (s, 1H), 5.61 (s, 2H), 4.85 (p, J =6.8 Hz, 1H), 1.44 (d, J = 6.8 Hz, 3H).SH-331

[0182] (S)-2-amino-N-( l-(8-((2,4-difluorophenyl)ethynyl)- l-oxo-2-phenyl-l,2- dihydroisoquinolin-3-yl)ethyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (SH-331). Method I, 42 mg, 75%yield.1H NMR (600 MHz, CDC13) 8 8.48 (dd, J= 6.8, 1.7 Hz, 1H), 8.44 (dd, J= 4.4, 1.7 Hz, 1H), 7.95 (d, J= 7.1 Hz, 1H), 7.72 (dd, J= 7.5, 1.3 Hz, 1H), 7.63 - 7.43 (m, 7H), 7.43 - 7.38 (m, 1H), 6.83 (dt, J= 10.2, 6.4 Hz, 3H), 6.67 (s. 1H), 5.60 (s, 2H), 4.85 (p, J= 6.9 Hz, 1H), 1.44 (d, J= 6.8 Hz. 3H).Synthesis of SH-342Atty. Docket No. UM-43981.601Client Ref No. 2025-184

[0183] A solution of (2-fluoro-5-iodophenyl)methanol (3 g, 11.90 mmol, 1 eq), TBSCI (2. 33 g, 15.47 mmol, 1.3 eq), imidazole (1.62 g, 23.81 mmol, 2 eq), DMAP (145 mg, 1.19 mmol, 0.1 eq) in DCM (70 mL, 0.2 M) was stirred at 20°C for 18 hours. The reaction was diluted with sat. NH4CI (150 mL) and extracted with DCM (2 x 100 mL). The combined organic phases were dried (Na2SO4), concentrated in vacuo on celite, and purified by chromatography on silica gel (80 g cartridge, 0-20% EtOAc / n-Hexane) to afford tert-butyl((2-lluoro-5-iodobenzyl)oxy)dimethylsilane (3.93 g, 88% yield) as a light pink oil.JH NMR (599 MHz, DMSO) 5 7.77 - 7.72 (m, 1H), 7.69 - 7.61 (m, 1H), 7.03 (app t, 1H), 4.71 (s, 2H), 0.89 (s. 9H), 0.09 (s, 6H).

[0184] A screw cap vial was charged with (S)-2-amino-N-(l -(8-ethynyl-l-oxo-2-pheny 1-1,2- dihydroisoquinolin-3-yl)ethyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (2 g, 4.46 mmol, 1.0 equiv.), Bis(triphenylphosphine)palladium(II) dichloride (157 mg, 0.22 mmol, 0.05 eq), Copper iodide (85 mg, 0.45 mmol, 0.1 eq) triethylamine (3.61 g, 5 mL, 35.69 mmol. 8 eq), and tert-butyl((2- fluoro-5-iodobenzyl)oxy)dimethylsilane (1.63 g, 1.22 mL, 4.46 mmol, 1 eq). DMF (25 mL, 0.2 M) was added, the mixture was purged with Nitrogen for 5 min in sonic bath, and then heated at 60°C for 16 hours. The reaction was cooled down to rt. The orange solution was slowly added to an iced cold aqueous solution of sat. NH4CI (400 mL). The yellow solid was filtered off, dissolved in DCM / MeOH (1 : 1, 150 mL). concentrated on celite in vacuo and purified by chromatography onAtty. Docket No. UM-43981.601Client Ref No. 2025-184 silica gel (80 g cartridge, 0-4% MeOH / DCM) to afford (S)-2-amino-N-(l-(8-((3-(((tert- butyldimethylsilyl)oxy)methyl)-4-fluorophenyl)ethynyl)-l-oxo-2-phenyl-l,2-dihydroisoquinolin-3- yl)ethyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (1.44 g, 45% yield) as a light-yellow solid.!H NMR (599 MHz, DMSO) 8 8.87 (dd, J = 6.8, 1.6 Hz, 1H), 8.49 (dd, J= 4.5, 1.6 Hz, 1H), 7.95 (d, J =6.7 Hz, 1H), 7.65 - 7.61 (m, 2H), 7.61 - 7.58 (m, 1H), 7.53 - 7.49 (m, 2H), 7.47 - 7.37 (m, 4H), 7.35 - 7.31 (m, 1H), 7.18 - 7.10 (m. 1H), 6.98 - 6.93 (m, 1H), 6.71 (s, 1H), 6.37 (s, br, 2H), 4.67 (s, 2H), 4.50 (p. J = 6.8 Hz. 1H), 1.29 (d. J= 6.8 Hz. 3H), 0.80 (s, 9H), 0.00 (s, 6H). The residue contained 2.1wt% of DMF.

[0185] To a solution of (S)-2-amino-N-(l -(8-((3-(((tert-butyldimethylsilyl)oxy)methyl)-4- fluorophenyl)ethynyl)-l -oxo-2 -phenyl-l,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[l,5-a]pyri mi dine- 3-carboxamide (1.35 g, 1.86 mmol, 1.0 eq) in THF (37 mL. 0.05M) was added TBAF (1 M in THF,2.8 mL, 2.8 mmol, 1.5 eq). The mixture was stirred at 20°C for 6 hours. The reaction was diluted with saturated NaHCCh (150 mL) and extracted with DCM (2 x 150 mL). The organics were combined, dried (NazSO-i). concentrated in vacuo and purified by chromatography on silica gel (40 g cartridge, 0-8% MeOH / DCM) to afford (S)-2-amino-N-(l-(8-((4-fluoro-3-(hy droxy methyl)pheny l)ethynyl)- 1 -oxo-2-phenyl- 1 ,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[ 1,5- a]pyrimidine-3-carboxamide (0.99 g, 90% yield) as a light-yellow solid. 'H NMR (599 MHz, DMSO) 6 8.93 (dd, J = 6.8, 1.7 Hz, 1H), 8.55 (dd, J= 4.5, 1.6 Hz, 1H), 8.01 (d, J= 6.7 Hz, 1H), 7.71 - 7.63 (m, 3H), 7.62 - 7.55 (m, 2H), 7.55 - 7.46 (m, 3H), 7.46 - 7.37 (m, 2H), 7.21 - 7.15 (m, 1H), 7.04 - 6.98 (m, 1H), 6.77 (s, 1H), 6.43 (s, br, 2H), 4.56 (p. J= 6.8 Hz. 1H), 4.52 (s. 2H), 1.36 (d, 7= 6.8 Hz, 3H).

[0186] The product was analyzed by analytical HPLC (Sunfire® Cl 8, 5 pm, 4.6 x 150 mm column, elution conditions 0. 1% TFA in water / Methanol 80%, run time 15 min), retention time 3.18 min, purity 100% @254 nm.Synthesis of SH-344:Atty. Docket No. UM-43981.601Client Ref No. 2025-184

[0187] A solution of (2-fluoro-4-iodophenyl)methanol (3 g, 11.9 mmol, 1 eq). TBSC1 (2. 33 g, 15.47 mmol, 1.3 eq), imidazole (1.62 g, 23.81 mmol, 2 eq), DMAP (145 mg, 1.19 mmol, 0.1 eq) in DCM (70 mL, 0.2 M) was stirred at 20°C for 18 hours. The reaction was diluted with sat. NH4CI (150 mL) and extracted with DCM (2 x 100 mL). The combined organic phases were dried (NazSCL), concentrated in vacuo on celite, and purified by chromatography on silica gel (80 g cartridge, 0-20% EtOAc / n-Hexane) to afford tert-butyl((2-fluoro-4-iodobenzyl)oxy)dimethylsilane (4. 17 g, 98% yield) as a colorless oil.(599 MHz, DMSO) 5 7.62 - 7.57 (m, 2H), 7.25 - 7.19 (m, 1H), 4.69 (s, 2H), 0.88 (s, 9H), 0.08 (s, 6H).

[0188] A screw cap vial was charged with (S)-2-amino-N-(l-(8-ethynyl-l-oxo-2-phenyl-l,2- dihydroisoquinolin-3-yl)ethyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (2 g, 4.46 mmol, 1.0 equiv.), Bis(triphenylphosphine)palladium(II) dichloride (157 mg, 0.22 mmol, 0.05 eq), Copper iodide (85 mg, 0.45 mmol, 0.1 eq) triethylamine (3.61 g, 5 mL, 35.69 mmol, 8 eq), and tert-butyl((2- fluoro-4-iodobenzyl)oxy)dimethylsilane (1.63 g, 1.22 mL, 4.46 mmol, 1 eq). DMF (25 mL, 0.2 M) was added, the mixture was purged with Nitrogen for 5 min in sonic bath, and then heated at 60°C for 16 hours. The reaction was cooled down to rt. The orange solution was slowly added to an iced cold aqueous solution of sat. NH4CI (400 mL). The yellow solid was filtered off, dissolved in DCM / MeOH (1 : 1, 150 mL), concentrated on celite in vacuo and purified by chromatography on silica gel (80 g cartridge, 0-4% MeOH / DCM) to afford (S)-2-amino-N-(l-(8-((4-(((tert- butyldimethylsilyl)oxy)methyl)-3-fluorophenyl)ethynyl)-l-oxo-2-phenyl-l,2-dihydroisoquinolin-3-Atty. Docket No. UM-43981.601Client Ref No. 2025-184 yl)ethyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (1.96 g, 61% yield) as a light-yellow solid. 'H NMR (599 MHz, DMSO) 5 8.93 (dd, J= 6.8, 1.6 Hz, 1H), 8.55 (dd, J= 4.5, 1.7 Hz, 1H), 8.01 (d, J = 6.7 Hz, 1H), 7.74 - 7.66 (m, 3H), 7.61 - 7.55 (m, 1H), 7.55 - 7.42 (m, 4H), 7.42 - 7.37 (m, 1H), 7.34 (d, J= 1.6 Hz, 1H), 7.28 (d, J= 1.6 Hz, 1H), 7.02 (dd, J= 6.7, 4.6 Hz, 1H), 6.78 (s, 1H), 6.43 (s, br, 2H), 4.75 (s, 2H), 4.56 (p, J= 6.8 Hz, 1H), 1.36 (d, J = 6.8 Hz, 3H), 0.88 (s, 9H), 0.08 (s, 6H). The residue contained 3.4wt% of DMF.

[0189] To a solution of (S)-2-amino-N-(l-(8-((4-(((tert-butyldimethylsilyl)oxy)methyl)-3- fluorophenyl)ethynyl)-l -oxo-2 -phenyl-l,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[l,5-a]pyrimidine- 3-carboxamide (1.95 g, 2.69 mmol, 1.0 eq) in THF (110 mL, 0.03M) was added TBAF (1 M in THF, 4 mL, 4.04 mmol, 1.5 eq). The mixture was stirred at 20°C for 6 hours. The reaction was diluted with saturated NaHCCh (150 mL) and extracted with DCM (2 x 150 mL). The organics were combined, dried (NteSCU), concentrated in vacuo and purified by chromatography on silica gel (40 g cartridge, 0-8% MeOH / DCM) to afford (S)-2-amino-N-(l-(8-((3-fluoro-4-(hydroxymethyl)phenyl)ethynyl)-l- oxo-2-phenyl-l,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (1.2 g, 69% yield) as a light-yellow solid. 'H NMR (599 MHz, DMSO) 5 8.93 (dd, J = 6.7, 1.6 Hz, 1H).8.55 (dd. J = 4.5. 1.6 Hz. 1H). 8.01 (d. J = 6.7 Hz. 1H), 7.74 - 7.66 (m. 3H), 7.61 - 7.55 (m, 1H),7.55 - 7.45 (m, 4H), 7.42 - 7.37 (m, 1H), 7.32 (dd, J= 7.8, 1.5 Hz, 1H), 7.25 (dd, J= 10.6, 1.5 Hz, 1H), 7.06 - 6.98 (m, 1H), 6.78 (s, 1H), 6.43 (s, br, 2H), 4.55 (d, J = 7.2 Hz, 3H), 1.36 (d, J= 6.8 Hz, 3H). The residue contained DCM 1 lwt%.

[0190] The product was analyzed by analytical HPLC (Sunfire® Cl 8. 5 pm, 4.6 x 150 mm column, elution conditions 0.1% TFA in water / M ethanol 80%, run time 15 min), retention time 3.22 min, purity 100% @254 nm.Synthesis of SH-344-1Atty. Docket No. UM-43981.601Client Ref No. 2025-184

[0191] To an ice-bath cold solution of methyl 3-(4-bromo-2-fluorophenyl)propanoate (1 g, 3.83 mmol, leq), in THF / MeOH (4: 1, 25 mL, 0.15M) NaBEL (435 mg, 11.50 mmol, 3 eq) was added and the mixture was stirred at 20 °C for 16 hours. The reaction was quenched by H2O (5 mL). The solvent was removed under reduced pressure. The residue was diluted with H2O (100 mL) and extracted with EtOAc (3 x 100 mL). The organics were combined, dried (Na2SO4), concentrated on celite in vacuo, and purified by chromatography on silica gel (40 g cartridge, 0-50% EtOAc / n- Hexane) to afford 3-(4-bromo-2-fluorophenyl)propan-l-ol (714 mg, 80% yield).

[0192] A solution of 3-(4-bromo-2-fluorophenyl)propan-l-ol (705 mg, 3.02 mmol, 1 eq), TBSC1 (593 mg, 3.93 mmol, 1.3 eq), imidazole (412 mg, 6.05 mmol, 2 eq), DMAP (37 mg, 0.30 mmol, 0.1 eq) in DCM (20 mL, 0.15 M) was stirred at 20°C for 18 hours. The reaction was diluted with sat. NH4CI (50 mL) and extracted with DCM (3 x 50 mL). The combined organic phases were dried (Na2SO4), concentrated in vacuo on celite, and purified by chromatography on silica gel (24 g cartridge, 0-20% EtOAc / n-Hexane) to afford (3-(4-bromo-2-fluorophenyl)propoxy)(tert- butyl)dimethylsilane (965 mg, 92% yield).

[0193] A screw cap vial was charged with (S)-2-amino-N-(l-(8-ethynyl-l-oxo-2-phenyl-l,2- dihydroisoquinolin-3-yl)ethyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (1.23 g, 2.74 mmol, 1.0 eq), Bis(triphenylphosphine)palladium(II) dichloride (96 mg, 0.14 mmol, 0.05 eq), Copper iodide (52 mg, 0.27 mmol, 0.1 eq) triethylamine (2.23 g, 3.1 mL, 22 mmol, 8 eq), and (3-(4-bromo-2-Atty. Docket No. UM-43981.601Client Ref No. 2025-184 fluorophenyl)propoxy)(tert-butyl)dimethylsilane ( 950 mg, 2.74 mmol, 1 eq). DMF (15 mL, 0.2 M) was added. The mixture was purged with nitrogen for 5 min in a sonic bath and then heated at 50°C for 16 hours. The reaction was diluted with cold water (200 mL) and extracted with DCM (3 x 150 mL). The organics were combined, washed with brine (100 mL), concentrated on celite in vacuo, and purified by chromatography on silica gel (40 g cartridge, 0-10% MeOH / DCM) to afford (S)-2- amino-N-(l-(8-((4-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-fluorophenyl)ethynyl)-l-oxo-2 -phenyl-I,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (980 mg, 50% yield).

[0194] To a solution of (S)-2-amino-N-(l-(8-((4-(3-((tert-butyldimethylsilyl)oxy)propyl)-3- fluorophenyl)ethynyl)-l -oxo-2 -phenyl-l,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[l,5-a]pyri mi dine- 3-carboxamide (950 mg, 1.33 mmol, 1 eq) in THF (20 mL, 0.07M) was added TBAF (1 M in THF, 3.4 mL, 3.33 mmol, 2.5 eq). The mixture was stirred at 20°C for 6 hours. The reaction was diluted with saturated NFLCl (50 mL) and extracted with DCM (3 x 50 mL). The organics were combined, dried NteSCU), concentrated in vacuo and purified by chromatography on silica gel (40 g cartridge, 0-10% MeOH / DCM) to afford (S)-2-amino-N-(l-(8-((3-fluoro-4-(3-hydroxypropyl)phenyl)ethynyl)- l-oxo-2-phenyl-l,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (600 mg, 75% yield) as a light-yellow solid.

[0195] The product was analyzed by analytical HPLC (Sunfire® Cl 8, 5 pm, 4.6 x 150 mm column, elution conditions 0.03% TFA in water / acetonitrile 10-95%, runtime 15 min), retention timeI I.03 min, purity 100% @254 nm. Calc, for [CssHsoFNeOsf = 601.2, found 601.0 ’H NMR (599 MHz, DMSO) 5 8.93 (dd, J = 6.7, 1.6 Hz, 1H), 8.55 (dd, J = 4.5, 1.6 Hz, 1H), 8.01 (d, J = 6.7 Hz, 1H), 7.73 - 7.65 (m, 3H), 7.60 - 7.56 (m, 1H), 7.54 - 7.46 (m, 4H), 7.41 - 7.37 (m, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.26 - 7.21 (m, 2H), 7.05 - 6.98 (m, 1H), 6.77 (s, 1H), 6.43 (s, 2H), 4.56 (p, J = 6.8 Hz, 1H), 4.50 (t, J = 4.4 Hz, 1H), 3.40 (q, J = 6.0 Hz, 2H), 2.64 (t, J = 7.9 Hz, 2H), 1.71 - 1.65 (m, 2H), 1.35 (d, J = 7.0 Hz, 3H).Example 2 Binding affinity to PI3K isoforms

[0196] The binding affinity7to PI3K a, ft, 8, y was tested using PI3Ka (pl l0a / p85a), PI3K0 (pl lO(3 / p85a), PI3K 6 (pl 10 6 Zp85 a) and PI3Ky (pl l0y / PIK3R5) assay kits (BPS Bioscience) separately. As shown in Table 1, the 1C50 of SH-315 against P13Ky is 110 nM, while it did not inhibit other three isoforms (PI3Ka PI3K0, PI3K5) with IC50s of greater than 5,000 - 10,000 nM. Thus, SH- 315 only inhibits PI3Ky, not the other three isoforms at in vivo effective concentration for clinically relevant doses. In contrast, the reported PI3Ky inhibitor IPI-549 inhibited PI3Ky with IC50 of 5.5 nM, but it also inhibited other three PI3K isoforms (PI3KaPI3K.[L PI3K.5) with its IC50s ranging from 900Atty. Docket No. UM-43981.601Client Ref No. 2025-184 to 1500 nM, indicating that IPI-549 may inhibit all four isoforms at in vivo effective concentration for clinically relevant doses.Table 1. Chemical Structure and Biochemical IC50 of PI3K inhibitors. All listed PI3K inhibitors wereAtty. Docket No. UM-43981.601Client Ref No. 2025-184Atty. Docket No. UM-43981.601Client Ref No. 2025-184Atty. Docket No. UM-43981.601Client Ref No. 2025-184Atty. Docket No. UM-43981.601Client Ref No. 2025-184Example 3 Cellular Activity

[0197] PI3K selectivity at the cellular level is indicated by the phosphorylation of AKT at Ser473 or Thr308, which occurs as a subsequent step following PI3K activation. The experiments were conducted using cells with predominant expression of specific PI3K isoforms.

[0198] Cellular activity of PI3K gamma (IPI-549, SH-315, SH-327) and delta (TGR-1202) inhibitors in bone-marrow derived macrophages (BMDMs) indicated PI3K gamma selectivity (FIG. 1). IPI-549 showed stronger pAKT inhibition on BMDM than SH-315 and SH-327. To assess PI3Ky activity, N-formylmethionyl-leucyl-phenylalanine (fMLP)-stimulated neutrophils, where fMLP activates G protein-coupled receptor (GPCR) signaling upstream of PI3Ky were used. All three compounds, IPI-549, SH-315 and SH-327, effectively inhibited AKT phosphorylation at 5pM, confirming their ability to block PI3Ky-mediated signaling (FIG. 1C). To determine whether IPI-549 acts as a pan-PI3K inhibitor, bone marrow-derived macrophages (BMDMs) stimulated with Macrophage Colony-Stimulating Factor (M-CSF), which activates receptor tyrosine kinases (RTKs) and subsequently all class IA PI3K isoforms (a, (3, and 5) were used. AKT phosphorylation in this system is inhibited when all three isoforms are simultaneously blocked. IPI-549 inhibited AKT phosphorylation at IpM. whereas SH-315 and SH-327, and the PI3K5-selective inhibitor TGR-1202 failed to inhibit AKT phosphorylation even at 5pM, further confirming that IPI-549 functions as a pan-PI3K inhibitor, while SH-315 and SH-327 are selective for PI3Ky (FIG. ID).

[0199] Cellular activity of PI3K gamma (IPI-549, SH-315, SH-327), alpha (BYL-719) and beta (TGX-221) inhibitors in MC38 (colon tumor), Py230 (breast tumor) and B16F10 (melanoma) cells, indicated PI3K alpha and beta selectivity (FIG. 2). IPI-549 showed pAKT inhibition on MC38 and Py230, similar to PI3K alpha inhibitor BYL-719. IPI-549 showed pAKT inhibition on B16F10,Atty. Docket No. UM-43981.601Client Ref No. 2025-184 similar to PI3K beta inhibitor TGX-221. However, both SH-327 and SH-315 did not show obvious PI3K alpha or beta selectivity.

[0200] IPI-549 may exert direct anti-tumor effects by inhibiting tumor-intrinsic PI3K signaling, potentially through off-target PI3Ka inhibition. While this may contribute to its anti-tumor efficacy, it also raises concerns regarding systemic toxicity, as PI3Ka is broadly expressed in normal tissues and critical for physiological homeostasis. PI3Ky inhibitors are theoretically designed to modulate immune cells in the tumor microenvironment rather than act directly on tumor cells. Therefore, the observed pAKT inhibition by IPI-549 suggests a deviation from this intended specificity, which may underlie both its therapeutic and toxicological profile.

[0201] Macrophage repolarization was evaluated after treatment with select compounds (FIGS. 3 and 4).

[0202] To assess the pharmacokinetic (PK) and tissue distribution profiles of three PI3Ky inhibitors, MMTV-PyMT transgenic breast cancer mice were orally administered a single 10 mg / kg dose of each compound. Drug concentrations were measured in plasma, whole blood, liver, tumor, tumor-draining lymph node (TDLN), spleen, lung, heart, and kidney at 0.5. 2, 6, and 24 hours postadministration (FIG. 9).

[0203] IPI-549 exhibited a rapid absorption profile, reaching peak concentration (Cmax) at approximately 0.5 hours. Notably, the Cmax of IPI-549 was substantially higher than that of SH-327 and SH-315 in plasma, liver, heart, and kidney, which may correlate with the increased systemic toxicift (FIGS. 14-16). Despite its higher tumor accumulation at Cmax, IPI-549 demonstrated decreased anti-tumor efficacy compared to SH-327. In contrast, SH-327 showed preferential accumulation in the spleen, a key immune organ. This enhanced splenic distribution may facilitate modulation of immune cell populations, such as myeloid cells and T cells, potentially contributing to its therapeutic efficacy. SH-327 preferentially accumulated in the lung, suggesting its potential to inhibit pulmonary metastases and improve overall survival.Example 4 Anti-Cancer Activity

[0204] The MMTV-PyMT transgenic mouse model is a well-established, spontaneous breast cancer model that closely mimics the progression and immunological features of human luminal B breast cancer, including early tumor onset, metastasis, and an immunosuppressive tumor microenvironment.

[0205] In vivo anti -tumor efficacy of PI3K gamma inhibitors was evaluated in a mouse model by monitoring tumor volumes (FIGS. 5, 6, and 8) and survival (FIG. 7). Dose regimen for all mouseAtty. Docket No. UM-43981.601Client Ref No. 2025-184 models: IPI-549 / SH-315 / SH-327 every day p.o. for 14 days, lOmg / kg; paclitaxel (PTX, lOmg / kg, i.p.) and aPD-1 (100 / zg / mouse, i.p.). every three days, total 5 doses.

[0206] Using this model, the therapeutic effect of SH-327, SH-315, and IPI-549 in combination with paclitaxel and anti-PD-1 antibody, starting treatment at 10 weeks of age and continuing until the experimental endpoint. When used in combination, SH-327 markedly inhibited tumor growth compared to IPI-549 and SH-315, indicating superior efficacy in this immunologically challenging setting (FIG. 12). In contrast, SH-327 or IPI-549 used alone did not significantly reduce tumor burden, highlighting the importance of combination therapy to overcome tumor immune evasion and chemoresistance in this model (FIG. 13).

[0207] When combined with paclitaxel and anti-PD-1 antibody, SH-327 exhibited anti-tumor efficacy comparable to IPI-549 after two weeks of treatment (FIG. 13 A). Notably, SH-327 achieved greater tumor grow th inhibition than IPI-549 as early as one week into treatment (FIG. 13C). In mice that achieved a complete response, no tumor relapse was observed for over 150 days (FIGS. 13B and 13D), indicating a durable and sustained therapeutic effect.

[0208] To evaluate the systemic toxicity of IPI-549 and SH-327, complete blood count (CBC) analysis and histopathological examinations were performed on normal C57BL / 6 mice treated with either low (20mg / kg, p.o., daily) or high (60mg / kg, p.o., daily) doses of SH-327 or IPI-549 for one month. Notably, one mouse in the IPI-549 low -dose group and tw o mice in the IPI-549 high-dose group died within 10 days of treatment initiation. In contrast, no mortality was observed in either the low - or high-dose groups treated with SH-327 (FIG. 14).

[0209] In the CBC analysis, no significant changes in circulating cell populations were observed in any treatment group after 2 w eeks (FIG. 15 A). However, by w eek 4, mice treated w ith high-dose IPI-549 (60 mg / kg) exhibited a significant reduction in white blood cells (WBC), neutrophils (NEU), and lymphocytes (LYM) compared to baseline (FIGS. 15A-15B). No such reductions were observed in either the low-dose IPI-549 group or in any of the SH-327-treated groups, regardless of dose.

[0210] Histopathological analysis of spleen sections revealed that mice in the IPI-549 high-dose group exhibited markedly increased extramedullary hematopoiesis (EMH). The red pulp was densely populated with blast-like erythroid and myeloid precursor cells, as well as numerous megakaryocytes, w ith a near-complete absence of mature myeloid cells (FIG. 16). In contrast, spleens from SH-327 -treated mice displayed no such abnormalities. No histopathologic alterations were observed in the heart, lung, liver, kidney, or colon in any group.

[0211] To evaluate tumor-associated immune alterations, the immune cell composition in tumors and tumor-draining lymph nodes (TDLNs) of MMTV-PyMT transgenic mice were compared with the mammary fat pad and lymph nodes (LNs) of age- and strain-matched wild-type FVB / NJ mice,Atty. Docket No. UM-43981.601Client Ref No. 2025-184 the genetic background of the MMTV-PyMT model. The mammary' fat pad serves as the normal tissue counterpart to the tumor, enabling direct comparison of tumor-induced immune remodeling.

[0212] Flow cytometry analysis revealed a striking shift in the immune landscape of MMTV- PyMT tumors. In wild-type FVB / NJ mammary fat pads, myeloid cells comprised approximately 10% of total CD45+immune cells. In contrast, this proportion increased dramatically to approximately 90% in MMTV-PyMT tumors, with neutrophils and monocytes rising from 1-3% in normal fat pads to approximately 30% each in tumors (FIG. 17A). Conversely, T cells made up approximately 50% of immune cells in normal FVB / NJ fat pads, but were markedly reduced to approximately 8% in tumors, with both CD4+and CD8+T cell subsets significantly decreased (Fig. 6B). A similar trend was observed in the lymphoid compartments. In tumor-draining lymph nodes (TDLNs) of MMTV-PyMT mice, the proportion of total myeloid cells, neutrophils, and monocytes was approximately doubled compared to normal LNs from FVB / NJ controls, while T cell frequencies did not change a lot (FIGS. 17C-17D).

[0213] These changes reflect a myeloid-dominant and T cell-suppressed immune microenvironment in both the tumor and its draining lymph node, supporting the use of PI3Ky inhibitors to suppress immunosuppressive myeloid populations such as neutrophils and monocytes and enhance T cell-mediated anti-tumor immunity, thereby improving the immune contexture of the tumor and TDLN.

[0214] Treatment with SH-327 resulted in a more pronounced reduction of immunosuppressive myeloid populations compared to IPI-549, specifically, a significantly decreased neutrophil infiltration in MC38 tumors (FIG. 18A) and a reduction in total myeloid cell percentage in tumordraining lymph nodes (TDLNs) as compared to IPI-549 (FIG. 18C). SH-327 did not reduce neutrophil counts in the peripheral blood of normal mice (FIG. 15), suggesting that it may selectively target tumor-associated inflammatory neutrophils without broadly depleting systemic neutrophil populations. In parallel, SH-327 markedly increased intratumoral T cell infiltration, including both CD4+and CD8+T cell subsets, as well as natural killer (NK) cells (FIG. 18B). In contrast, IPI-549 treatment did not significantly elevate T cell or NK cell levels in tumor compared to the vehicle control group. These changes suggest that SH-327 enhanced the immune microenvironment by both suppressing myeloid-driven immunosuppression and promoting lymphocyte-mediated immunity, which may collectively contribute to its superior therapeutic efficacy.Atty. Docket No. UM-43981.601Client Ref No. 2025-184Example 5Albumin Nanoformulations

[0215] Albumin nanoformulations were prepared by dissolving lOmg SH-315 or SH-327 in 1ml chloroform, adding the resulting dropwise into lOOmg mouse serum albumin (MSA) dissolved in 20ml Milli-Q water to generate oil-in-water emulsion. The emulsion was run six cycles at pressure 25000-30000psi on Nano DeBEE. Chloroform was then removed by rotary evaporator to get SH-315 and SH-327 encapsulated in albumin nanoparticles (NP-315 and NP-327). The size distribution was determined by dynamic light scattering (DLS) (FIG. 10).

[0216] In vivo anti-tumor efficacy PI3K gamma inhibitors (SH-315, SH-327) in nano-formulation was monitored following intravenous injection under the following dose regimens: IPI-549 / SH- 315 / SH-327 i.v. every three days, total 5 doses. lOmg / kg; paclitaxel (PTX, lOmg / kg, i.p.) and aPD-1 (lOOjUg / mouse, i.p.), every three days, total 5 doses (FIG. 11).

[0217] SH-327 was efficiently encapsulated in human serum albumin (HSA). SH-315 was incorporated into HSA and MSA nanoparticles with the addition of a small amount of itraconazole. SH-344-1 did not significantly alter the compound's PI3K isoform selectivity, as compared to SH-315 and SH-327, but improved its compatibility with albumin, enabling successful encapsulation without auxiliary agents. The size distribution was determined by dynamic light scattering (DLS) (FIG. 19).

[0218] lOmg SH-344-1 was dissolved in the co-solvent composed of 0.8ml chloroform and 0.2ml methanol. 8mg SH-315 and 2mg itraconazole were dissolved in 1ml chloroform. lOmg SH-327 was dissolved in the co-solvent composed of 0.8ml chloroform and 0.2ml methanol and was then heat at 70°C for 5min. Then the dissolved compound was added dropwise into lOOmg mouse serum albumin (MSA) or 50mg human serum albumin (HSA) dissolved in 20ml Milli-Q w ater to generate oil-in-water emulsion. The emulsion was run six cycles at pressure 25000-30000psi on Nano DeBEE. Chloroform or methanol was then removed by rotary evaporator to get SH-344-1, SH-315 / itraconazole and SH- 327 encapsulated in albumin nanoparticles (NP-344-1, NP-315 / itraconazole and NP-327).Example 6 Activity in Lupus Model

[0219] Lupus in MRL-lpr mice is characterized by lymphadenopathy (enlarged lymph nodes) and large spleen size due to hyperactive immune system in the lymphatic system. To test the efficacy of SH-315 to reduce the size of lymph nodes and spleen in lupus model, the size and number of lymph nodes in MRL-lpr lupus mice treated with SH-315 (PO, 15 mg / kg) from week 11- week 17 was monitored (FIG. 20 A). The weight of lymph nodes and spleen at 18-weeks was also measured (FIG.Atty. Docket No. UM-43981.601Client Ref No. 2025-18420B). SH-315 treatment reduced lymph node size, lymph node weight, and spleen weight in MRL- Ipr mice.

[0220] The auto-antibody against self-antigen, such as ds-DNA or nuclear proteins, generated by hyperactive B cell immunity, is often seen in lupus and the MRL-lpr lupus mouse model. To test the efficacy of SH-315 to reduce auto-antibody, the ds-DNA autoantibody in the serum of MRL-lpr lupus mice was monitored after treatment of SH-315 (PO, 15 mg / kg for 17-20 weeks). SH-315 significantly decreased ds-DNA antibody, as shown in FIG. 21.

[0221] MRL-lpr lupus mice often develop nephritis due to damage of kidney function. To test the efficacy of SH-315 to treat lupus nephritis, proteinuria, and blood urea nitrogen (BUN) in the MRL- lpr was measured mice treated with SH-315 (PO 15 mg / kg for 17-20 weeks). The data showed that treatment of SH-315 significantly reduced urine protein level (FIG. 22A) and prevented the elevation of serum BUN and creatinine (FIG. 22B), indicating a reduction in proteinuria and improved renal function.

[0222] Cutaneous lesions are a common manifestation of systemic lupus erythematosus (SLE) in both humans and lupus-prone mice, often reflecting underlying immune activation and local inflammation. In MRL-lpr mice, spontaneous development of ear skin lesions closely models lupus- associated dermatitis seen in patients, making it a relevant endpoint for therapeutic evaluation. Treatment SH-315 markedly reduced the occurrence of ear skin lesions in MRL-lpr mice. As shown in representative images (FIG. 23 A), control mice exhibited visible ear wounds and inflammation, whereas SH-315-treated mice showed no apparent skin damage. Quantification of lesion incidence revealed that 37.5% (3 out of 8) of mice in the control group developed ear skin lesions, while no lesions were observed in the SH-315 -treated group (0 out of 10), indicating that SH-315 effectively prevented lupus-associated cutaneous manifestations (FIG. 23B).

[0223] The high level of auto-antibody against self-antigen is usually generated by hyperactive B cell immunity. The hyperactive B cells recognize self-antigen through its B cell receptor to bind and uptake these antigens resulting in presentation to CD4 T helper cells. These process-activated B cells form geminal center (GC) B cells. Upon further antigen recognition by the GC B cells in the germinal center with help of follicular T cells, these B cells will undergo clonal expansion / selection and maturation to generate long-lived plasma B cells to secrete auto-antibody against self-antigens. The reduction of plasma B cells is one of the critical goals in treatment of lupus. However, most current therapeutic regimens are ineffective to reduce antibody secreting plasma B cells.

[0224] To test the efficacy of SH-315 on the reduction of B cell immunity, plasma B cells, GC B cells, marginal zone B cells, and total B cells in the spleen and lymph nodes of MRL-lpr lupus mice w ere measured after treatment of SH-315 (PO, 15 mg / kg from week 11 to week 17). SH-315Atty. Docket No. UM-43981.601Client Ref No. 2025-184 significantly decreased antibody secreting plasma B cells by 2.4-fold in spleen (FIGS. 24A-24C) and 2.9-fold in LN (FIGS. 24D-24E). SH-315 decreased the precursor of plasma cells, germinal center B cells, by 2.8-fold in spleen (FIGS. 24A-24C), strongly suggesting that SH-315 reduced auto-antibody through reduction of plasma B cells. However, it is interesting that SH-315 did not inhibit total B cells, suggesting that SH-315 may not affect normal B cells, thereby avoiding toxicity.

[0225] The activation of T cells in lupus may also exacerbate the disease progression the tissue damage. To test the effect of SH-315 on the T cells, CD4, CD8 and CD4 CD8 B220+double negative T cells in the spleen and lymph nodes of MRL-lpr mice were measured after treatment of SH-315 (PO 15 mg / kg for 17-20 weeks). SH-315 significantly decreased double negative CD4- / CD8- cells by 2-fold in spleen (FIGS. 25A-25B).

[0226] Hyperactivation of myeloid cell-mediated innate immune system is another risk factor for lupus. To test the effect of SH-315 on the activation of myeloid cells, the activation and total number neutrophils, monocytes, dendritic cells and macrophages in the lymph nodes and spleen of MRL-lpr mice were measured after SH-315 treatment (PO 15 mg / kg from week 11 to week 17). SH-315 decreased the activation of neutrophils, monocytes and macrophages by 1.9-fold. 2.5-fold, and 1.7- fold respectively in spleen (FIGS. 26A-26C), and decreased the total number of plasmacytoid dendritic cells (pDCs) by 3.5-fold in spleen (FIGS. 26D-26E). SH-315 treatment also decreased total number of neutrophils and monocytes by 6.6-fold and 2.5-fold in lymph node (FIGS. 26 F-26G). The results suggest a beneficial effect of SH-315 to treat lupus by tempering the myeloid cell-mediated innate immunity. Interestingly, SH-315 did not alter the total number of neutrophils in blood and spleen. This may provide advantages to reduce its toxicity on normal neutrophils.

[0227] To test the toxicity of SH-315 in MRL-lpr mice, the mice were dosed with SH-315 (PO 15 mg / kg from week 11 to week 17) and complete blood counts (CBCs) (white blood cells, neutrophils, lymphocytes, monocytes, eosinophils, basophils, red blood cells, platelets, hematocrit) were monitored. Treatment with SH-315 did not alter total white blood cell (WBC) count or the counts of major leukocyte subsets, including neutrophils (NEU), lymphocytes (LYM), monocytes (MONO), eosinophils (EOS), and basophils (BAS), as determined by complete blood count (CBC) analysis at 18 weeks of age (FIG. 27), suggesting SH-315 did not induce hematological toxicity.

[0228] It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the disclosure, which is defined solely by the appended claims and their equivalents.

[0229] Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and may be made without departing from the spirit and scope thereof.

Claims

Atty. Docket No. UM-43981.601Client Ref No. 2025-184CLAIMSWhat is claimed is:

1. A compound of formula (I):or a pharmaceutically acceptable salt thereof, wherein:R1is selected from phenyl, C1-C4 aminoalkyl, ferrocenyl, adamantyl, and a group:, wherein R2is an amino acid side chain and R3is hydrogen or a nitrogen protecting group; wherein the phenyl is substituted with 1. 2, 3, 4, or 5 substituents independently selected from halo. C1-C4 haloalkyl, and C1-C4 hydroxyalkyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is phenyl substituted with 1, 2, or 3 substituents independently selected from halo, C1-C2 haloalkyl, and C1-C4 hydroxy alkyl.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is phenyl substituted with 1, 2, or 3 substituents independently selected from fluoro, trifluoromethyl, hydroxymethyl, and hydroxypropyl.

4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein at least one of the substituents is hydroxymethyl.Atty. Docket No. UM-43981.601Client Ref No. 2025-1845. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R1is a group, wherein R2is a tryptophan side chain and R3is selected from hydrogen and a tert-butyloxy carbonyl group.

6. The compound of claim 1, wherein the compound is selected from:Atty. Docket No. UM-43981.601Client Ref No. 2025-1847. A pharmaceutical composition comprising an effective amount of a compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable earner.

8. The pharmaceutical composition of claim 7, wherein the composition comprises albumin nanoparticles.Atty. Docket No. UM-43981.601Client Ref No. 2025-1849. The pharmaceutical composition of claim 7 or claim 8, wherein the composition further comprises at least one additional therapeutic agent.

10. The pharmaceutical composition of claim 9, wherein the at least one additional therapeutic agent comprises an immune modulator, a chemotherapeutic agent, a nucleic acid, a decongestant, a steroid, an analgesic, an antimicrobial agent, or a combination thereof.

11. The pharmaceutical composition of claim 9, wherein the at least one additional therapeutic agent is selected from a chemotherapeutic agent, an IDO inhibitor, a Stat3 inhibitor, a TLR agonist, and a STING agonist.

12. A method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, or a composition of any of claims 7-11.

13. The method of claim 12, wherein the disease or disorder comprises cancer, an autoimmune disease, an inflammatory disease, or an infectious disease.

14. The method of claim 13, wherein the disease or disorder is cancer.

15. The method of claim 14, wherein the subject has cancer, has had cancer, is predisposed to cancer, or has a family history of cancer.

16. The method of claim 14 or claim 15, wherein the cancer comprises a solid tumor.

17. The method of claim 14 or claim 15, wherein the cancer is metastatic cancer.

18. The method of any one of claims 14-17. wherein the method suppresses or eliminates cancer metastasis, decreases tumor growth, prevents tumor recurrences, or any combination thereof.

19. The method of claim 13, wherein the disease or disorder is lupus.Atty. Docket No. UM-43981.601Client Ref No. 2025-18420. A method of inhibiting PI3Ky in a subject in need thereof, comprising administering to the subject the composition of a compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, or a composition of any of claims 7-1 1.

21. The method of claim 20, wherein the subject is human.

22. The method of claim 20 or claim 21. further comprising administering at least one additional therapeutic agent to the subject.

23. The method of claim 22, wherein the at least one additional therapeutic agent comprises an immune modulator, a chemotherapeutic agent, a nucleic acid, a decongestant, a steroid, an analgesic, an antimicrobial agent, or a combination thereof.

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