Multi-kinase inhibitor, PROTACs target protein ligand as well as synthesis method and application of PROTACs target protein ligand

Abstract

The invention discloses a multi-kinase inhibitor, a PROTACs target protein ligand as well as a synthesis method and application thereof, and the multi-kinase inhibitor is a compound with a structure as shown in a formula (I), and a stereoisomer or pharmaceutically acceptable salt of the compound. The invention relates to a compound which has inhibitory activity on kinases such as mixed lineage kinase 3 (MLK3, FMS-like tyrosine kinase 3 (FLT3), hematopoietic progenitor cell kinase 1 (HPK1) and the like, recruits related kinases and is used for developing protein degradation chimera (PROTACs) target heads, and a preparation method and application of the compound, and the compound can inhibit the activity of MLK3, FLT3 and HPK1 and is used for developing PROTACs, FLT3 and HPK1. The pharmaceutical composition is used for treating various diseases including cancers, immune regulation, autoimmunity and the like. (I).

Description

Technical Field

[0001] This invention relates to the field of small molecule drugs. Specifically, this invention provides a novel kinase inhibitor, particularly a compound with kinase inhibitory activities such as mixed lineage kinase 3 (MLK3), FMS-like tyrosine kinase 3 (FLT3), and hematopoietic progenitor cell kinase 1 (HPK1) and the ability to recruit related kinases for the development of protein degradation chimeric (PROTAC) targets, as well as its synthesis and application. Background Technology

[0002] Protein kinases, as core regulators of cell signal transduction, precisely regulate key biological functions such as cell proliferation, differentiation, apoptosis, and immune responses by catalyzing the phosphorylation of substrate proteins. Abnormal activation or dysregulation of their expression is closely related to a variety of major diseases, including cancer, autoimmune diseases, and chronic inflammation. Currently, small molecule kinase inhibitors have become the mainstream strategy in drug development, with representative drugs such as imatinib (for chronic myeloid leukemia) and gefitinib (for non-small cell lung cancer) successfully achieving clinical translation. However, traditional inhibitors, which only block the catalytic activity of kinases by reversibly or irreversibly binding to the ATP-binding pocket, have significant limitations: on the one hand, the target protein is not cleared, easily leading to drug resistance due to compensatory signaling pathway activation or target overexpression; on the other hand, insufficient selectivity of inhibitors easily causes off-target toxicity, limiting long-term efficacy and application scope.

[0003] Among numerous kinase targets, mixed lineage kinase 3 (MLK3), FMS-like tyrosine kinase 3 (FLT3), and hematopoietic progenitor kinase 1 (HPK1) have attracted much attention due to their crucial roles in disease. MLK3 belongs to the serine / threonine kinases of the MAPK signaling pathway and participates in the regulation of the JNK / p38 pathway, playing an important role in tumor metastasis, neurodegenerative diseases, and inflammatory responses. Studies have shown that MLK3 is highly expressed in solid tumors such as breast cancer and colorectal cancer, promoting cancer cell invasion and chemotherapy resistance, but currently no highly effective and specific inhibitors have entered clinical practice. FLT3 is a hematopoietic system-specific receptor tyrosine kinase, and its internal tandem repeat (ITD) mutation accounts for 25-30% of acute myeloid leukemia (AML) patients, which is a core driver of disease relapse and poor prognosis. Although FLT3 inhibitors such as midotulin and giglitinib have been approved for the treatment of AML, the rapid emergence of resistance mutations (such as FLT3-TKD) has significantly reduced the efficacy. HPK1, a member of the MAP4K family, is a negative regulator of the T cell receptor signaling pathway. Inhibition of its activity can relieve the suppression of T cells and enhance the anti-tumor immune response. In the tumor microenvironment, high expression of HPK1 is associated with immune escape. Inhibitors targeting HPK1 (such as HPK1i-1) have shown potential in immunotherapy, but their single-target effects are insufficient to cover complex disease mechanisms.

[0004] To address the aforementioned challenges, protein degradation-targeting chimeric (PROTACs) technology offers a revolutionary approach to kinase-targeted therapy. PROTACs employ a bifunctional molecular design, targeting a specific protein (POI) at one end and recruiting an E3 ubiquitin ligase at the other, inducing POI ubiquitination and subsequent degradation by the proteasome, thereby achieving the therapeutic goal of "clearing the target protein" rather than "inhibiting activity." Compared to traditional inhibitors, PROTACs offer advantages such as catalytic activity (a single molecule can repeatedly degrade POIs), high selectivity, and targeting "undruggable" proteins. In the field of kinases, PROTACs have been successfully applied to targets such as BTK (e.g., ARV-471) and BRD4 (e.g., AZD5153), significantly improving efficacy and overcoming drug resistance. However, the efficacy of PROTACs is highly dependent on high-quality warhead ligands, requiring the simultaneous fulfillment of: (1) high affinity binding to the target kinase; (2) preservation of chemical modification sites to ensure compatibility with linker-E3 ligand linkage; and (3) no impact on protein degradation efficiency. Currently, research on PROTAC targets for MLK3, FLT3, and HPK1 is severely lacking: Existing literature shows that MLK3 inhibitors (such as CEP-1101) lack PROTAC-compatible structures; FLT3 inhibitors (such as Quizartinib) are mostly ATP-competitive molecules, making them difficult to optimize as degradation agents; and HPK1 inhibitors (such as GSK225602) primarily focus on immune regulation, without exploring PROTAC applications. More critically, there is a lack of compounds that can simultaneously inhibit the activity of all three, hindering multi-pathway synergistic intervention—for example, in AML, FLT3 mutations are associated with MLK3-mediated metastasis, while HPK1 inhibition can enhance the immune microenvironment; combining all three could significantly improve efficacy.

[0005] Furthermore, the design of existing kinase inhibitors often neglects the chemical requirements of PROTACs. For example, some compounds contain hydrophobic groups or have excessive steric hindrance, hindering linker connection; or the active site conflicts with the binding site of PROTACs, leading to reduced degradation efficiency. This has resulted in slow progress in the development of PROTACs targeting MLK3 / FLT3 / HPK1, with related patents (such as WO2022158765A1) only reporting single-target inhibitors and failing to address the issue of multifunctional integration. Therefore, developing a novel kinase inhibitor that can efficiently inhibit the catalytic activity of MLK3, FLT3, and HPK1 while also serving as a target for PROTACs to achieve protein degradation has become an urgent scientific challenge. Summary of the Invention

[0006] This invention provides a multi-kinase inhibitor, PROTAC target protein ligands, their synthesis method, and applications. Through rational design, this compound possesses both triple kinase inhibitory activity and PROTAC target compatibility: its core structure can selectively bind to the active pockets of MLK3, FLT3, and HPK1, while retaining key functional groups for linker connection, ensuring efficient degradation capability after PROTAC construction. This design holds promise for achieving a dual mechanism in the treatment of AML, solid tumors, and autoimmune diseases (such as rheumatoid arthritis)—blocking pathogenic signaling pathways by inhibiting kinase activity and eliminating target protein accumulation effects through protein degradation, thereby overcoming the limitations of drug resistance and toxicity of traditional drugs. The synthesis method of this invention optimizes key steps, improves yield and purity, provides efficient chemical tools for subsequent drug development, and promotes the deep integration of kinase-targeted therapy and protein degradation technology.

[0007] This invention relates to the field of small molecule drugs, specifically to a novel kinase inhibitor, particularly a compound with inhibitory activity of kinases such as mixed lineage kinase 3 (MLK3), FMS-like tyrosine kinase 3 (FLT3), and hematopoietic progenitor cell kinase 1 (HPK1), and the ability to recruit related kinases for the development of protein degradation chimeric (PROTAC) targets, as well as its preparation method and application. This type of compound can inhibit the activity of MLK3, FLT3, and HPK1 and can be used to develop PROTACs for the treatment of various diseases, including cancer, immune regulation, and autoimmunity.

[0008] The technical solution of the present invention is as follows: A multi-kinase inhibitor, a PROTAC target protein ligand, is a compound with the structure shown in formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof: (I) in: X1 is an N or C atom, X2 is an N or C atom R1 is selected from the following structures: R2 is selected from the following structures: More specifically, the compound is selected from the following structures: The present invention also provides a method for preparing a compound with the structure shown in formula (I), comprising the following steps: (1) Under the catalysis of a transition metal, compound A is reacted with compound B to generate compound C; ; Formula A, Formula B, Formula C; (2) Under transition metal catalysis, compound C reacts with compound D to generate compound (I); ; Formula D; In Equations B and C, R1 is the same as R1 in Equation (I), and in Equation D, R2 is the same as R2 in Equation (I).

[0009] The MLK3 small molecule inhibitor described in this invention can be used alone, or it can be prepared as a pharmaceutically acceptable salt or used in combination with a pharmaceutically acceptable excipient or carrier.

[0010] This invention also provides a compound with the structure shown in formula (I) and its pharmaceutically acceptable salt as an inhibitor of MLK3, FLT3, and HPK1 in pharmaceutical applications. Specifically, this application is used to prepare drugs for the prevention or treatment of diseases caused by overexpression of MLK3, FLT3, and HPK1, including breast cancer, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), ovarian cancer, cervical cancer, prostate cancer, glioblastoma, and hematologic malignancies. Compared with the prior art, the beneficial effects of the present invention are as follows: This invention discloses the structures of novel compounds that exhibit kinase inhibitory activity against hybrid lineage kinase 3 (MLK3), FMS-like tyrosine kinase 3 (FLT3), and hematopoietic progenitor cell kinase 1 (HPK1), as well as the structures of compounds that recruit related kinases for the development of protein degradation chimeric (PROTAC) targets. Most of these compounds effectively inhibit the activity of MLK3, FLT3, and HPK1 kinases, indicating that these compounds, their stereoisomers, or pharmaceutically acceptable salts, as well as related drug combinations, have potential application value in the treatment of MLK3, FLT3, and HPK1-related diseases. Attached Figure Description

[0011] Figure 1 For compound 1 13 C10 NMR structural characterization diagram; Figure 2 For compound 1 1 H NMR structural characterization diagram; Figure 3 For compound 2-1 1 H NMR structural characterization diagram; Figure 4 For compound 2-1 13 C10 NMR structural characterization diagram; Figure 5 For compound 2 13 C10 NMR structural characterization diagram; Figure 6 For compound 2 1 H NMR structural characterization diagram; Figure 7 For compound 3-1 1 H NMR structural characterization diagram; Figure 8 For compound 3-1 13 C10 NMR structural characterization diagram; Figure 9 For compound 3 13 C10 NMR structural characterization diagram; Figure 10 For compound 3 1 H NMR structural characterization diagram; Figure 11 For compound 4-1 1 H NMR structural characterization diagram; Figure 12 For compound 4-1 13 C10 NMR structural characterization diagram; Figure 13 For compound 4 13 C10 NMR structural characterization diagram; Figure 14 For compound 4 1 H NMR structural characterization diagram. Detailed Implementation

[0012] Example 1: N,N-Dimethyl-4-(5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)aniline (Compound 1) Step 1: 4-(5-bromo-1H-pyrazolo[3,4-b]pyridin-3-yl)-N,N-dimethylaniline (compound 1-1) 5-Bromo-3-iodo-1H-pyrazolo[3,4-b]pyridine-1-carboxylic acid tert-butyl ester (500 mg, 1.0 eq) and N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)aniline (291.3 mg, 1.0 eq) were dissolved in a mixture of 1,4-dioxane (50 mL) and water (10 mL), followed by the addition of K₂CO₃ (488.2 mg, 3.0 eq) and Pd(dppf)Cl₂ (43.1 mg, 0.05 eq). The reaction mixture was protected under nitrogen and stirred at 110 °C for 10 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure, followed by purification by silica gel column chromatography to give compound 1-1 (127 mg, 34%).

[0013] Step 2: N,N-Dimethyl-4-(5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)aniline (Compound 1) 4-(5-bromo-1H-pyrazolo[3,4-b]pyridin-3-yl)-N,N-dimethylaniline (200 mg, 1.0 eq) and pinacol 4-(4-methyl-1-piperazinylmethyl)phenylboronic acid (199.4 mg, 1.0 eq) were dissolved in a mixture of 1,4-dioxane (25 mL) and water (5 mL), followed by the addition of K₂CO₃ (261.2 mg, 3.0 eq) and Pd(dppf)Cl₂ (23.1 mg, 0.05 eq). The reaction mixture was protected under nitrogen and stirred at 110 °C for 10 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure, followed by purification by silica gel column chromatography to give compound 1 (192 mg, 71.3%). LC-MS (M+H) + =427.96, 13 C NMR (101MHz, DMSO- D 6) δ 152.97, 150.74, 148.44, 137.91, 137.28, 130.08, 129.71,128.30, 128.05, 127.61, 121.55, 112.96, 112.53, 62.11, 55.02, 52.74, 45.91. 1 HNMR (400 MHz, DMSO- D 6) δ 8.78 (d, J = 2.1 Hz, 1H), 8.57 (d, J = 2.1 Hz, 1H), 7.89 (d, J = 8.9 Hz, 2H), 7.72 (d,J = 8.2 Hz, 2H), 7.37 (d, J = 8.2 Hz, 2H), 6.82 (d, J = 8.9 Hz, 2H), 3.47 (s, 2H), 2.94 – 2.90 (m, 6H), 2.46 – 2.25 (m,8H), 2.16 (s, 3H). Example 2: 3-(1H-indol-5-yl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazolo[3,4-b]pyridine (Compound 2) Step 1: 5-Bromo-3-(1H-indol-5-yl)-1H-pyrazolo[3,4-b]pyridine (Compound 2-1) The procedure was the same as step 1 in Example 1, where tert-butyl 5-bromo-3-iodo-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (500 mg, 1.0 eq) and pinacol 5-indoleboronic acid (286.6 mg, 1.0 eq) were reacted to generate compound 2-1 (84 mg, 22.5%). 13 C NMR (101 MHz, DMSO- D 6) δ 151.78, 149.52, 144.58, 136.48, 132.99,128.55, 126.68, 124.11, 120.69, 119.25, 114.23, 112.53, 112.30, 102.41. 1 H NMR (400 MHz, DMSO-) D 6) δ 11.20 (s, 1H), 8.79 (d, J = 2.1 Hz, 1H), 8.58 (d, J =2.2 Hz, 1H), 8.21 – 8.16 (m, 1H), 7.74 (dd, J = 8.5, 1.7 Hz, 1H), 7.53 – 7.44(m, 1H), 7.37 (t, J = 2.7 Hz, 1H), 6.53 (ddd, J = 2.9, 1.9, 0.9 Hz, 1H). The procedure was the same as step 2 in Example 1, reacting compound 2-1 (200 mg, 1.0 eq) with pinacol 4-(4-methyl-1-piperazinmethyl)phenylboronic acid (201.9 mg, 1.0 eq) to generate compound 2 (231 mg, 84.3%). LC-MS (M+H) + =423.87, 13 CNMR (101 MHz, DMSO) δ 153.01, 148.45, 137.95, 137.28, 136.36, 129.99, 129.90,128.51, 128.36, 127.62, 126.50, 124.69, 120.83, 119.20, 112.71, 112.41,102.31, 62.13, 55.13, 52.89, 46.05. 1 H NMR (400 MHz, DMSO) δ 13.70 (s, 1H), 11.24 (s, 1H), 8.85 (d, J = 2.0 Hz, 1H), 8.71 (d, J = 2.1 Hz, 1H), 8.30 (d, J = 1.6 Hz, 1H), 7.86 (dd, J = 8.5, 1.7 Hz, 1H), 7.81 – 7.72 (m, 2H), 7.57 (d, J = 8.4 Hz, 1H), 7.48 – 7.40 (m, 3H), 6.59 (t, J = 2.5 Hz, 1H), 3.67 (s, 2H), 2.50 – 2.27 (m, 8H), 2.18 (s, 3H). Example 3: N,N,2-Trimethyl-4-(5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzamide (Compound 3) Step 1: 4-(5-bromo-1H-pyrazolo[3,4-b]pyridin-3-yl)-N,N,2-trimethylbenzamide (compound 3-1) The procedure was the same as step 1 in Example 1, where tert-butyl 5-bromo-3-iodo-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (422.5 mg, 1.0 eq) and pinacol 4-(dimethylcarbamoyl)-3-methylphenylboronic acid (288 mg, 1.0 eq) were reacted to generate compound 3-1 (157 mg, 43.9%). 13 C NMR (101 MHz, DMSO- D 6) δ 170.23, 151.70, 149.92,142.35, 137.50, 135.04, 133.09, 132.89, 128.57, 126.94, 124.62, 114.10,112.97, 38.32, 34.46, 19.05. 1 H NMR (400 MHz, DMSO- D 6) δ 8.86 (d, J = 2.1 Hz, 1H), 8.61 (d, J = 2.1 Hz, 1H), 7.94 – 7.82 (m, 2H), 7.24 (d, J = 7.8 Hz, 1H), 2.99 (s, 3H), 2.77 (s, 3H), 2.27 (s, 3H). The procedure was the same as step 2 in Example 1, reacting compound 3-1 (155 mg, 1 eq) with pinacol 4-(4-methyl-1-piperazinmethyl)phenylboronic acid (136.4 mg, 1.0 eq) to generate compound 3 (79 mg, 39%). LC-MS (M+H) + =468.96, 1 H NMR (400 MHz, DMSO) δ 13.95 (s, 1H), 8.88 (d, J = 2.1 Hz, 1H), 8.72 (d, J = 2.1Hz, 1H), 8.03 – 7.96 (m, 2H), 7.79 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.4 Hz, 1H), 3.53 (s, 2H), 3.05 (s, 3H), 2.83 (s, 3H), 2.51– 2.36 (m, 8H), 2.33 (s, 3H), 2.24 (s, 3H). 13C NMR (101 MHz, DMSO) δ 170.24,152.85, 137.24, 137.10, 134.88, 133.65, 130.40, 130.00, 128.57, 128.16,127.74, 126.85, 124.70, 112.62, 62.00, 54.93, 52.59, 45.74, 38.27, 19.07. Example 4: N,N-Dimethyl-4-(5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzamide (Compound 4) Step 1: 4-(5-bromo-1H-pyrazolo[3,4-b]pyridin-3-yl)-N,N-dimethylbenzamide (compound 4-1) The procedure was the same as step 1 in Example 1, where tert-butyl 5-bromo-3-iodo-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (479 mg, 1.0 eq) and dihydroxyhexanediol 4-(dimethylcarbonyl)phenylboronic acid (218 mg, 1.0 eq) were reacted to generate compound 4-1 (201 mg, 51.2%). 13 C NMR (101 MHz, DMSO- D 6) δ 170.30, 151.72, 149.99,142.17, 136.69, 133.87, 132.84, 128.29, 126.91, 114.12, 113.07, 35.33,29.54. 1 H NMR (400 MHz, DMSO- D 6) δ 8.84 (d, J = 2.1 Hz, 1H), 8.62 (d, J = 2.1Hz, 1H), 8.14 – 7.94 (m, 2H), 7.55 – 7.40 (m, 2H), 2.96 (d, J = 14.4 Hz, 6H). The procedure was the same as step 2 in Example 1, reacting compound 4-1 (200 mg, 1.0 eq) with pinacol 4-(4-methyl-1-piperazinmethyl)phenylboronic acid (183.2 mg, 1.0 eq) to generate compound 4 (180 mg, 68%). LC-MS (M+H) + =454.93, 13CNMR (101 MHz, DMSO- D 6) δ 170.37, 152.92, 148.91, 142.76, 137.07, 136.44,134.53, 130.53, 130.07, 128.30, 128.19, 127.78, 126.95, 112.70, 62.11, 55.04,52.76, 45.94. 1 H NMR (400 MHz, DMSO- D 6) δ 8.84 (d, J = 2.1 Hz, 1H), 8.69 (d, J = 2.1 Hz, 1H), 8.14 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 8.3 Hz, 2H), 7.52 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H), 3.47 (s, 2H), 2.99 – 2.93 (m, 6H), 2.46 – 2.25 (m, 8H), 2.15 (s, 3H). In vitro kinase inhibition assay (refer to CN 113968860 A) 1. Compound preparation Weigh 1 mg of the above compound and dissolve it in 100% DMSO-d6 to prepare a 10 mM stock solution, which is then stored in a nitrogen cabinet away from light.

[0014] 2. Kinase reaction process (1) Prepare 1×Kinase buffer. (2) Preparation of compound concentration gradients: The initial test concentration of the test compound was 2400 nM, with 7 concentrations and replicate detection. The compound was diluted 100 times to a final concentration of 100% DMSO-d in a 384 source plate. 250 nL of the 100-fold final concentration of the compound was transferred to the target 3575 plate using an Echo 550 dispenser.

[0015] (3) Prepare a kinase solution with a final concentration of 2.5 times using 1×Kinase buffer.

[0016] (4) Add 10 μL of kinase solution at a final concentration of 2.5 times to the compound wells and positive control wells respectively; add 10 μL of 1×Kinase buffer to the negative control wells.

[0017] (5) Centrifuge at 1000 rpm for 30 seconds, shake the reaction plate to mix, and incubate at room temperature for 10 minutes.

[0018] (6) Prepare a mixed solution of ATP and Kinase substrate 2 at a final concentration of 5 / 3 times using 1×Kinase buffer.

[0019] (7) Add 15 μl of a mixture of ATP and substrate at 5 / 3 times the final concentration to initiate the reaction.

[0020] (8) Centrifuge the 384-well plate at 1000 rpm for 30 seconds, shake to mix, and incubate at room temperature for 30 minutes.

[0021] (9) Add 30 μL of the stop detection solution to stop the kinase reaction, centrifuge at 1000 rpm for 30 seconds, and shake to mix.

[0022] (10) Read the conversion rate using Caliper EZ Reader.

[0023] The results are shown in Table 1. Table 1. Kinase inhibition results of compounds 1-4 Note: A≤100nM, 100

Claims

1. A multi-kinase inhibitor, characterized in that, Compounds with the structure shown in formula (I), their stereoisomers, or pharmaceutically acceptable salts thereof: ； （I） in: R1 is selected from one of the following structures: ； R2 is selected from one of the following structures: 。 2. The multi-kinase inhibitor according to claim 1, characterized in that, Compounds with the following structures: 、 、 、 。 3. A PROTACs target protein ligand, characterized in that, Compounds with the following structures: 、 、 、 。 4. The method for synthesizing the multi-kinase inhibitor according to claim 1 or 2, characterized in that, Includes the following steps: (1) Under the catalysis of a transition metal, compound A is reacted with compound B to generate compound C; ； Formula A, Formula B, Formula C; (2) Under transition metal catalysis, compound C reacts with compound D to generate compound (I); ； Formula D; In Equations B and C, R1 is the same as R1 in Equation (I), and in Equation D, R2 is the same as R2 in Equation (I).

5. The use of the multi-kinase inhibitor according to claim 1 or 2 in the preparation of a medicament for the prevention or treatment of diseases caused by overexpression of MLK3, FLT3, and HPK1.

6. The application according to claim 5, characterized in that, The drug may be used alone or in combination with pharmaceutically acceptable excipients or carriers.

7. The application according to claim 5, characterized in that, The diseases caused by overexpression of MLK3, FLT3, and HPK1 include breast cancer, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, ovarian cancer, cervical cancer, prostate cancer, glioblastoma, or hematologic malignancies.

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