Methods for the treatment of hematological malignancies

Abstract

Described herein are methods of treating a hematological malignancy, including minimal residual disease in hematological malignancies, and methods of preventing relapse of hematological malignancies, the methods comprising administering an inflammasome modulator. In some embodiments the method of treatment comprises administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein the variables are as defined herein.

Description

METHODS FOR THE TREATMENT OF HEMATOLOGICAL MALIGNANCIES CROSS-REFERENCE

[0001] This application claims the benefit of U. S. Provisional Patent Application Nos. 63 / 715,435, filed November 1, 2024; 63 / 738,367 filed December 23, 2024, and 63 / 747,816 filed January 21, 2025, all of which are incorporated herein by reference in their entirety.BACKGROUND OF THE INVENTION

[0002] Despite the development of efficacious treatment for hematologic malignancies, relapse remains a major concern upon cessation of treatment. This is caused by the presence of a small population of resistant cancer cells which can evade treatment and repopulate the bone marrow upon cessation of treatment, leading to relapse. The persistence of these resistant cells has been dubbed minimal residual disease (MRD). MRD monitoring is routine in Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Chronic Lymphocytic Leukemia (CLL), Multiple Myeloma (MM), clonal hematopoiesis of indeterminate potential (CHIP), some subtypes of Non -Hodgkin Lymphoma (NHL) and Hodgkin Lymphoma (HL), and the presence of MRD is predictive of long-term outcomes and relapse risk. New methods to treat hematological malignancies, as well as MRD in hematological malignancies to prevent relapse, are needed.SUMMARY OF THE INVENTION

[0003] In one aspect, provided herein is a method of treating a hematological malignancy and / or prevent relapse of hematological malignancy in a subject. Also provided herein is a method of treating minimal residual disease of a hematological disease in a subject. In some embodiments, the methods herein comprise treatment with an inflammasome modulator. In some embodiments, the methods herein comprise treatment with a modulator of the NLRP3 inflammasome. In some embodiments, the methods herein comprise treatment with an inhibitor of NEK7 kinase. In some embodiments, the methods herein comprise treatment with an inhibitor of the NLRP3 (protein)-NEK7 (protein) interaction. In some embodiments, the methods herein comprise treatment with a compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII). In some embodiments, the methods herein comprise treatment with a compound of Formula (I). In some embodiments, the methods herein comprise administering to the subject an inflammasome modulator in conjunction with a treatment for hematological malignancies. In some embodiments, the treatment for hematological malignancies includes, withoutlimitation, induction therapy, consolidation therapy, maintenance therapy, targeted therapy, CAR-T cell therapy, cytoreductive therapy (e.g., hydroxyurea), central nervous system prophylaxis including intrathecal chemotherapy or radiation therapy, hematopoietic stem cell transplantation (HSCT), autologous stem cell transplant (ASCT), phlebotomy, administration of cytarabine, an anthracycline fludarabine, cyclophosphamide, rituximab, tyrosine kinase inhibitors (TKIs) (e.g., imatinib), Bruton’s tyrosine kinase (BTK) inhibitors (e.g., ibrutinib, acalabrutinib), BCL-2 inhibitors (e.g., venetoclax), PI3K inhibitors (e.g., idelalisib), obinutuzumab, ofatumumab, doxorubicin hydrochloride (Adriamycin), bleomycin sulfate, vinblastine sulfate, dacarbazine, ABVD, brentuximab vedotin (anti-CD30), pembrolizumab, vincristine, prednisone, R-CHOP, proteasome inhibitors (e.g., bortezomib, carfilzomib), immunomodulatory drugs (e.g., lenalidomide, thalidomide), monoclonal antibodies (e.g., daratumumab), bispecific antibodies, hypomethylating agents (e.g., azacytidine, decitabine), JAK inhibitors (e.g., ruxolitinib), or any combination thereof. The hematological malignancy may be leukemia, lymphoma, or multiple myeloma (MM). In some embodiments, the hematological malignancy is Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Chronic Lymphocytic Leukemia (CLL), Chronic Myeloid Leukemia (CML), Chronic Myelomonocytic Leukemia (CMML), Chronic Neutrophilic Leukemia (CNL), clonal hematopoiesis of indeterminate potential (CHIP), Essential Thrombocythemia (ET), Multiple Myeloma (MM), Myelodysplastic Syndromes (MDS), Non-Hodgkin Lymphoma (NHL), Hodgkin Lymphoma (HL), Polycythemia Vera (PV), Primary Myelofibrosis (PMF), Systemic Mastocytosis or a combination thereof. In some embodiments, the hematological malignancy may be, without limitation, acute lymphoblastic leukemia, acute myeloblastic leukemia in adult patients, chronic lymphocytic leukemia, chronic myeloid leukemia, diffuse large B cell lymphoma, elderly patients with malignant lymphoma, extra nodal diffuse large B-cell lymphoma and primary mediastinal B-cell lymphoma, follicular lymphoma, hairy cell leukemia, Hodgkin lymphoma, mantle cell lymphoma, marginal zone lymphomas, multiple myeloma, myelodysplastic syndromes, peripheral T-cell lymphomas, Philadelphia chromosome-negative chronic myeloproliferative neoplasms, primary central nervous system lymphomas, primary cutaneous lymphoma, mature B-cell lymphomas and chronic lymphocytic leukemia, Waldenstrom's macroglobulinemia, or any combination thereof.

[0004] Provided herein is a method of treating a hematological malignancy, comprising administering to a subject in need thereof an inflammasome modulator. In some embodiments, the inflammasome modulator is a modulator of the NLRP3 (NOD-, LRR- andpyrin domain-containing protein 3) inflammasome. In some embodiments, the inflammasome modulator inhibits the priming step of the NLRP3 inflammasome. In some embodiments, the inflammasome modulator inhibits signaling downstream of members of the TLR (toll -like receptor) family, IL-1R (interleukin 1 receptor) family, and / or TNFR1 / 2 (tumor necrosis factor receptor 1 / 2). In some embodiments, the inflammasome modulator prevents the activation of NF-kB (nuclear factor kappa-beta). In some embodiments, the administering reduces the level of TNF-a, IL-6, or the components of the NLRP3 inflammasome (e.g., NLRP3, pro-IL-ip (pro-interleukin- Ibeta), pro-IL18 (pro-interleukin- 18)), or a combination thereof, in the subject. In some embodiments, the inflammasome modulator inhibits the assembly and activation step of the NLRP3 inflammasome. In some embodiments, the inflammasome modulator inhibits the formation of a NLRP3 (protein) -NEK7 (protein) interaction. In some embodiments, the inflammasome modulator inhibits the formation of the ASC speck and the NLRP3 inflammasome. In some embodiments, the inflammasome modulator prevents caspase- 1 activation. In some embodiments, the inflammasome modulator inhibits the production of IL-ip. In some embodiments, the inflammasome modulator inhibits the production of IL- 18. In some embodiments, the inflammasome modulator inhibits the cleavage of gasdermin D. In some embodiments, the inflammasome modulator prevents pyroptotic cell death. In some embodiments, the administering comprises administering about 0.5 mg to about 10 mg of the inflammasome modulator to the subject. In some embodiments, the administering comprises administering the inflammasome modulator to the subject every day, every other day, every two days, every three days, every four days, every five days, every six days, once a week, five days on and two days off, once every two weeks, or once a month. In some embodiments, the administering comprises orally administering to the subject the inflammasome modulator. In some embodiments, the inflammasome modulator is in the form of a tablet, capsule or pill.

[0005] Provided herein is a method of treating a hematological malignancy, comprising administering to a subject having a very low risk, low risk, intermediate risk, or high risk of myelodysplastic syndrome (MDS), a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:wherein:A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6;X is CH or N;Y is NH;R1is H;R2is Ci-Ce alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl;R3is H;R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkyl cycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkyl cycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl;R5is H; andeach R6is independently halo, Ci-Ce alkyl, Ci-Ce alkoxy, cyano, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl.

[0006] In some embodiments, the subject has very low risk, low risk, or intermediate risk of MDS, wherein the very low risk, low risk, or intermediate risk of MDS is classified according to the World Health Organization (WHO) 2022 classification or Revised International Prognostic Scoring System (IPSS-R) classification. In some embodiments, the subject has very low risk or low risk MDS.

[0007] Provided herein is a method of treating a hematological malignancy, comprising administering to a subject, wherein the subject has low blast cells according to the WHO 2022 classification or IPSS-R classification, of myelodysplastic syndrome (MDS), a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:wherein:A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6;X is CH or N;Y is NH;R1is H;R2is Ci-Ce alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl;R3is H;R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkyl cycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkyl cycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl;R5is H; andeach R6is independently halo, Ci-Ce alkyl, Ci-Ce alkoxy, cyano, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl.

[0008] In some embodiments, R2is butyl, cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, pyridinyl, azetidinyl, or oxetanyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl. In some embodiments, R2is:

[0009] In some embodiments, R4is oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-triazolyl or 1, 3, 4-oxadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3-to 8-membered alkylheterocyclyl cycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-Cs halocycloalkyl, and combinations thereof. In some embodiments, R4is substituted with Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, or C3-C8 halocycloalkyl, or combinations thereof. In some embodiments, R4has one of the following

[0010] In some embodiments, A is phenyl. In some embodiments, A is unsubstituted. In some embodiments, A is substituted with one or more R6. In some embodiments, R6is chloro, fluoro, -CHF2, -CH2CH2OH, cyano, or methoxy. In some embodiments, A is:

[0011] In some embodiments, the compound is a compound of Formula (la), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:wherein:R2ais C3-C4 cycloalkyl optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl; andR4ais isoxazolyl optionally substituted with one more substituents selected from Ci-Ce haloalkyl, C3-C8 cycloalkyl or C3-C8 haloalkylcycloalkyl.

[0012] In some embodiments, R2ais cyclopropyl. In some embodiments, R4ais:

[0013] In some embodiments, the compound of Formula (I) is listed in Table 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound ofFormulapharmaceutically acceptable salt or solvate thereof.

[0014] In some embodiments, the hematological malignancy is Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Chronic Lymphocytic Leukemia (CLL), Chronic Myeloid Leukemia (CML), Chronic Myelomonocytic Leukemia (CMML), Chronic Neutrophilic Leukemia (CNL), clonal hematopoiesis of indeterminate potential (CHIP), Essential Thrombocythemia (ET), Multiple Myeloma (MM), Myelodysplastic Syndromes (MDS), Non-Hodgkin Lymphoma (NHL), Hodgkin Lymphoma (HL), Polycythemia Vera (PV), Primary Myelofibrosis (PMF), Systemic Mastocytosis or a combination thereof. In some embodiments, the subject has a positive test for minimal residual disease of the hematological malignancy as measured by flow cytometry. In some embodiments, the subject has a positive test for minimal residual disease of the hematological malignancy as measured by polymerase chain reaction (PCR). In some embodiments, the subject has a positive test for minimal residual disease of the hematological malignancy as measured by next -generation sequencing (NGS).

[0015] Provided herein is a method of treating a hematological malignancy, wherein thehematological malignancy is Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Chronic Lymphocytic Leukemia (CLL), Chronic Myeloid Leukemia (CML), Chronic Neutrophilic Leukemia (CNL), clonal hematopoiesis of indeterminate potential (CHIP), Essential Thrombocythemia (ET), Multiple Myeloma (MM), Non-Hodgkin Lymphoma (NHL), Hodgkin Lymphoma (HL), Polycythemia Vera (PV), Primary Myelofibrosis (PMF), Systemic Mastocytosis, or minimal residual disease (MRD), or a combination thereof, comprising administering to a subject in need thereof, a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:wherein:A is Ce-Cio aryl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6;X is CH or N;Y is NH;R1is H;R2is Ci-Ce alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl;R3is H;R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkyl cycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkyl cycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl;R5is H; andeach R6is independently halo, Ci-Ce alkyl, Ci-Ce alkoxy, cyano, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl.

[0016] In some embodiments, R2is butyl, cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, pyridinyl, azetidinyl, or oxetanyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl. In some embodiments, R2is:

[0017] In some embodiments, R4is oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-triazolyl or 1, 3, 4-oxadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclyl cycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof. In some embodiments, R4is substituted with Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, or C3-C8 halocycloalkyl, or combinations thereof. In some embodiments, R4has one of the following structures:

[0018] In some embodiments, A is phenyl. In some embodiments, A is unsubstituted. In some embodiments, A is substituted with one or more R6. In some embodiments, R6is chloro, fluoro, -CHF2, -CH2CH2OH, cyano, or methoxy. In some embodiments, A is:

[0019] In some embodiments, the compound is a compound of Formula (la), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:wherein:R2ais C3-C4 cycloalkyl optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl; andR4ais isoxazolyl optionally substituted with one more substituents selected from Ci-Ce haloalkyl, C3-C8 cycloalkyl or C3-C8 haloalkylcycloalkyl.

[0020] In some embodiments, R2ais cyclopropyl. In some embodiments, R4ais:

[0021] In some embodiments, the compound of Formula (I) is listed in Table 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound ofFormulapharmaceutically acceptable salt or solvate thereof.

[0022] In some embodiments, the subject has MRD, wherein the MRD is MRD in Acute Myeloid Leukemia (AML). In some embodiments, the subject has MRD, wherein the MRD is MRD in Myelodysplastic Syndromes (MDS). In some embodiments, the MRD is defined by leukemia cells not detectable in the bone marrow of the subject. In some embodiments, the MRD is defined by leukemia cells not detectable in the bone marrow of the subject using microscopy but are detectable using flow cytometry or a nucleic acid detection method. Insome embodiments, the MRD is defined by leukemia cells not detectable in the bone marrow of the subject using microscopy but are detectable using next-generation sequencing (NGS). In some embodiments, the subject has low blast cells according to the WHO 2022 classification or IPSS-R classification. In some embodiments, the blast cell percentage in bone marrow of the subject is 10% or less. In some embodiments, the blast cell percentage in bone marrow of the subject is 5% or less. In some embodiments, the blast cell is myeloblasts. In some embodiments, the subject has an isolated 5q deletion or SF3B1 mutation, or a combination thereof. In some embodiments, the administering comprises administering about 0.5 mg to about 10 mg of the compound to the subject. In some embodiments, the administering comprises administering the compound to the subject every day, every other day, every two days, every three days, every four days, every five days, every six days, once a week, five days on and two days off, once every two weeks, or once a month. In some embodiments, the administering comprises orally administering to the subject the compound. In some embodiments, the compound is in the form of a tablet, capsule or pill. In some embodiments, the subject has symptomatic anemia, optionally wherein the subject with symptomatic anemia has a hemoglobin level of less than 13.0 g / dL. In some embodiments, the subject has a hemoglobin level of less than 9.0 g / dL. In some embodiments, the subject has serum ferritin levels of greater than 50 ng / ml. In some embodiments, the subject does not have B12 or folate deficiencies, autoimmune or hereditary hemolysis, or gastrointestinal bleeding. In some embodiments, the administering prevents relapse of the hematological malignancy.DETAILED DESCRIPTION OF THE INVENTION

[0023] In one aspect, provided herein are methods of treating a hematological malignancy with a compound disclosed herein. In one aspect, provided herein are methods of treating minimal residual disease in hematological malignancies with a compound disclosed herein. The compound disclosed herein is, for example, a compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII). Terms

[0024] Unless defined otherwise, all terms of art, notations and other technical and scientific terms or terminology used herein are intended to have the same meaning as is commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. In some cases, terms with commonly understood meanings are described herein for clarity and / or for ready reference, and the inclusion of such should not necessarily beconstrued to represent a substantial difference over what is generally understood in the art.

[0025] As used in the specification, the singular forms “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a sample” includes a plurality of samples, including mixtures thereof.

[0026] A “pharmaceutical composition” refers to formulations of compounds of the disclosure and a medium generally accepted in the art for the delivery of compounds of the disclosure to mammals, e.g., humans. Such a medium includes all pharmaceutically acceptable carriers, diluents, or excipients therefore.

[0027] “Pharmaceutically acceptable carrier, diluent or excipient” includes, without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier.

[0028] Amino” refers to the -NH2 radical.

[0029] “Carboxy” or "carboxyl" refers to the -CO2H radical.

[0030] “Cyano” refers to the -CN radical.

[0031] “Hydroxy” or “hydroxyl” refers to the -OH radical.

[0032] “Nitro” refers to the -NO2 radical.

[0033] Oxo” refers to the =0 substituent.

[0034] Thiol” refers to the -SH substituent.

[0035] Thioxo” refers to the =S substituent.

[0036] “Alkyl” refers to a saturated, straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, having from one to twelve carbon atoms (C1-C12 alkyl), one to eight carbon atoms (Ci-Cs alkyl) or one to six carbon atoms (Ci-Ce alkyl), or any value within these ranges, such as C4-C6 alkyl and the like, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl,1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl and the like. The number of carbons referred to relates to the carbon backbone and carbon branching but does not include carbon atoms belonging to any substituents. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted.

[0037] “Alkenyl” refers to an unsaturated, straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, which contains one or more carbon-carbon double bonds, having from two to twelve carbon atoms (C2-C12 alkenyl), two to eight carbon atoms (C2-C8 alkenyl) or two to six carbon atoms (C2-C6 alkenyl), or any value within these ranges, and which is attached to the rest of the molecule by a single bond, e.g., ethenyl, prop-l-enyl, but-l-enyl, pent-l-enyl, penta- 1,4-dienyl, and the like. The number of carbons referred to relates to the carbon backbone and carbon branching but does not include carbon atoms belonging to any substituents. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted.

[0038] “Alkynyl” refers to unsaturated straight or branched hydrocarbon radical, having 2 to 12 carbon atoms (C2-C12 alkynyl), two to nine carbon atoms (C2-C9 alkynyl), or two to six carbon atoms (C2-C6 alkynyl), or any value within these ranges, and having at least one carbon- carbon triple bond. Examples of alkynyl groups may be selected from the group consisting of ethynyl, propargyl, but-l-ynyl, but-2-ynyl and the like. The number of carbons referred to relates to the carbon backbone and carbon branching but does not include carbon atoms belonging to any substituents. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted.

[0039] “Alkoxy” refers to a radical of the formula -ORa where Ra is an alkyl radical as defined above containing one to twelve carbon atoms (C1-C12 alkoxy), one to eight carbon atoms (Ci-Cs alkoxy) or one to six carbon atoms (Ci-Ce alkoxy), or any value within these ranges. Unless stated otherwise specifically in the specification, an alkoxy group is optionally substituted.

[0040] “Aminyl” refers to a radical of the formula -NRaRb, where Ra and Rb are each independently H or Ci-Ce alkyl as defined above. When both of Raand Rb are H, an "aminyl" group is the same as an "amino" group as defined above. The Ci-Ce alkyl portion of an aminyl group is optionally substituted unless stated otherwise.

[0041] “Aminylalkylcycloalkyl” refers to a radical of the formula -RaRbNRcRd where Ra is cycloalkyl as defined herein, Rb is Ci-Ce alkyl, Rc is H or Ci-Ce alkyl and Rd is Ci-Ce alkyl as defined above. The cycloalkyl and each Ci-Ce alkyl portion of an aminylalkylcycloalkyl group are optionally substituted unless stated otherwise.

[0042] Aromatic ring” refers to a cyclic planar molecule or portion of a molecule ( / .<., a radical) with a ring of resonance bonds that exhibits increased stability relative to other connective arrangements with the same sets of atoms. Generally, aromatic rings contain a set of covalently bound co-planar atoms and comprises a number of ^-electrons (for example,alternating double and single bonds) that is even but not a multiple of 4 (z.e., 4n + 2 n-electrons, where n = 0, 1, 2, 3, etc.). Aromatic rings include, but are not limited to, phenyl, naphthenyl, imidazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridonyl, pyridazinyl, pyrimidonyl. Unless stated otherwise specifically in the specification, an "aromatic ring" includes all radicals that are optionally substituted.

[0043] “Aryl” refers to a carbocyclic ring system radical comprising 6 to 18 carbon atoms, for example 6 to 10 carbon atoms (Ce-Cio aryl) and at least one carbocyclic aromatic ring. For purposes of embodiments of this invention, the aryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, an aryl group is optionally substituted.

[0044] “Cyanoalkyl” refers to an alkyl group comprising at least one cyano substituent. The -CN substituent may be on a primary, secondary, or tertiary carbon. Unless stated otherwise specifically in the specification, a cyanoalkyl group is optionally substituted.

[0045] "Carbocyclic" or "carbocycle" refers to a ring system, wherein each of the ring atoms are carbon.

[0046] “Cycloalkyl” refers to a non-aromatic monocyclic or polycyclic carbocyclic radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from three to fifteen ring carbon atoms (C3-C15 cycloalkyl), from three to ten ring carbon atoms (C3-C10 cycloalkyl), or from three to eight ring carbon atoms (C3-C8 cycloalkyl), or any value within these ranges such as three to four carbon atoms (C3-C4 cycloalkyl), and which is saturated or partially unsaturated and attached to the rest of the molecule by a single bond. Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group is optionally substituted.

[0047] “Alkylcycloalkyl” refers to a radical group of the formula -RaRb where Ra is a cycloalkyl group and Rb is an alkyl group as defined above. Unless otherwise stated specifically in the specification, an alkylcycloalkyl group is optionally substituted.

[0048] “Fused” refers to any ring structure described herein which is fused to anotherring structure.

[0049] Halo" refers to bromo, chloro, fluoro, or iodo.

[0050] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl,tri chloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl,1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group is optionally substituted.

[0051] “Halocycloalkyl” refers to a cycloalkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, tri chloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl,3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a halocycloalkyl group is optionally substituted.

[0052] “Haloalkylcycloalkyl” refers to a radical group of the formula -RaRb where Ra is a cycloalkyl group and Rb is a haloalkyl group as defined above. Unless otherwise stated specifically in the specification, a haloalkylcycloalkyl group is optionally substituted.

[0053] “Hydroxylalkyl” refers to an alkyl radical, as defined above that is substituted by one or more hydroxyl radical. The hydroxyalkyl radical is joined at the main chain through the alkyl carbon atom. Unless stated otherwise specifically in the specification, a hydroxylalkyl group is optionally substituted.

[0054] “Heterocyclyl” refers to a 3 - to 18-membered, for example 3- to 10-membered or 3- to 8-membered, non-aromatic ring radical having one to ten ring carbon atoms (e.g., two to ten) and from one to six ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is partially or fully saturated and is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused, spirocyclic and / or bridged ring systems. Nitrogen, carbon, and sulfur atoms in a heterocyclyl radical are optionally oxidized, and nitrogen atoms may be optionally quaternized. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, hexahydro- IH-pyrrolizine, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, piperidinyl, piperazinyl, 4-piperidonyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, aheterocyclyl group is optionally substituted.

[0055] “Haloheterocyclylalkyl” refers to a radical group of the formula -RaRb where Ra is an alkyl group and Rb is a haloheterocyclyl group as defined herein. Unless otherwise stated specifically in the specification, a haloheterocyclylalkyl group is optionally substituted.

[0056] “Heterocyclyl alkyl” refers to a radical group of the formula -RaRb where Ra is an alkyl group and Rb is a heterocyclyl group as defined herein. Unless otherwise stated specifically in the specification, a heterocyclylalkyl group is optionally substituted.

[0057] “Heteroaryl” refers to a 5- to 18-membered, for example 5- to 6-membered, ring system radical comprising one to thirteen ring carbon atoms, one to six ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring. Heteroaryl radicals may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodi oxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[Z>][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1 -phenyl- l / 7-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl ( / .<., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl group is optionally substituted.

[0058] Oxazolyl, isoxazolyl, 1, 2, 3 -oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5 -oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5 -thiadiazolyl and 1, 3, 4-thiadiazolyl refer to the following structures, respectively:

[0060] wherein the oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, and 1, 3, 4-thiadiazolyl are attached to the remainder of the molecule by a covalent bond to one of the carbon atoms in the ring of the oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, and 1, 3, 4-thiadiazolyl.

[0061] In some embodiments, a heteroaryl group has one of the following structures:

[0062] The term "substituted" as used herein means any of the above groups (e.g., alkyl, alkenyl, alkylene, alkylcarbonyl, alkoxy, alkoxyalkyl, aminylalkyl, aryl, cyanoalkyl, cycloalkyl, haloalkyl, heterocyclyl, heterocyclene, heterocyclylalkyl, heteroaryl, heteroarylalkyl and / or hydroxylalkyl) wherein at least one hydrogen atom e.g., 1, 2, 3 or all hydrogen atoms) is replaced by a bond to a non-hydrogen substituent. Examples of nonhydrogen substituents include, but are not limited to amino, carboxyl, cyano, hydroxyl, halo, nitro, oxo, thiol, thioxo, alkyl, alkenyl, alkylcarbonyl, alkoxy, aryl, cyanoalkyl, cycloalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaryl alkyl and / or hydroxylalkyl substituents, each of which may also be optionally substituted with one or more of the above substituents.

[0063] In some specific embodiments, the optional substitutions are independently selected from the group consisting of halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, Cs-Cs halocycloalkyl, Ce-Cio aryl, 5- or 6-membered heteroaryl, Ci-Ce alkoxy and 3-8 membered heterocyclyl.

[0064] The term "effective amount" or "therapeutically effective amount" refers to that amount of a compound described herein that is sufficient to affect the intended application including but not limited to treating hematological malignancies, as defined below.

[0065] Treatment” or “treating” refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder or medical condition, including but not limited to, hematological malignancies.

[0066] The term "co-administration," "administered in combination with," and theirgrammatical equivalents, as used herein, encompass administration of two or more agents to an animal, including humans, so that both agents and / or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.

[0067] “Pharmaceutically acceptable salt” includes both acid and base addition salts.

[0068] “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness of the free bases, which are biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S. M. Berge, et al., "Pharmaceutical Salts", J. Pharm. Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Preferred pharmaceutically acceptable acid addition salts are those that are pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response. Pharmaceutically acceptable acid addition salts which are formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane -1,2-di sulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-l,5-disulfonic acid, naphthalene-2-sulfonic acid, l-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like.

[0069] “Pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness of the free acids, which are biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S. M. Berge, etal., "Pharmaceutical Salts", J. Pharm. Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA,Zurich, 2002. Preferred pharmaceutically acceptable base addition salts are those that are pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response. Pharmaceutically acceptable base addition salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropyl amine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

[0070] The terms “antagonist” and “inhibitor” are used interchangeably, and they refer to a compound having the ability to inhibit a biological function of a target protein, whether by inhibiting the activity or expression of the protein, such as NLRP3 inflammasome or NEK7 or the association of NLRP3 inflammasome - NEK7. Accordingly, the terms "antagonist" and "inhibitors" may be defined in the context of the biological role of the target protein. While preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit a biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included within this definition.

[0071] The term “agonist” as used herein refers to a compound having the ability to initiate or enhance a biological function of a target protein. Accordingly, the term "agonist" is defined in the context of the biological role of the target polypeptide. While preferred agonists herein specifically interact with (e.g., bind to) the target, compounds that initiate or enhance a biological activity of the target polypeptide by interacting with other members of the signal transduction pathway of which the target polypeptide is a member are also specifically included within this definition.

[0072] "Signal transduction" is a process during which stimulatory or inhibitory signalsare transmitted into and within a cell to elicit an intracellular response.

[0073] The term "selective inhibition" or "selectively inhibit" refers to a biologically active agent refers to the agent’s ability to preferentially reduce the target signaling activity as compared to off target signaling activity, via direct or indirect interaction with the target.

[0074] “Subject” refers to an animal, such as a mammal, for example a human. The methods described herein can be useful in both human therapeutics and veterinary applications. In some embodiments, the subject is a mammal, and in some embodiments, the subject is human.

[0075] “Mammal” includes humans and both domestic animals such as laboratory animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like.

[0076] The term "in vivo" refers to an event that takes place in a subject’s body.

[0077] Certain embodiments are also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products may result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes. Accordingly, embodiments include compounds produced by a process comprising administering a compound of this disclosure to a mammal for a period of time sufficient to yield a metabolic product thereof. Such products are typically identified by administering a radiolabeled compound of the disclosure in a detectable dose to an animal, such as rat, mouse, guinea pig, monkey, or to human, allowing sufficient time for metabolism to occur, and isolating its conversion products from the urine, blood, or other biological samples.

[0078] Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0079] Often crystallizations produce a solvate of the compounds disclosed herein. As used herein, the term “solvate” refers to an aggregate that comprises one or more compounds of the disclosure with one or more molecules of solvent. In some embodiments, the solvent is water, in which case the solvate is a hydrate. Alternatively, in other embodiments, the solvent is an organic solvent. Thus, the compounds of the present disclosure may exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms. In some aspects, the compounds of the disclosure are a true solvate, while in other cases, the compounds of the disclosure merely retain adventitious water or is a mixture of water plus some adventitioussolvent.

[0080] A “stereoisomer’ ’ refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof and includes "enantiomers", which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0081] The compounds of the disclosure (compounds of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII) or their pharmaceutically acceptable salts may contain one or more centers of geometric asymmetry and may thus give rise to stereoisomers such as enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (5)- or, as (D)- or (L)- for amino acids. Embodiments thus include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (5)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

[0082] Embodiments of the present disclosure include all manner of rotamers and conformationally restricted states of a compound of the invention. Atropisomers, which are stereoisomers arising because of hindered rotation about a single bond, where energy differences due to steric strain or other contributors create a barrier to rotation that is high enough to allow for isolation of individual conformers, are also included. As an example, certain compounds of the disclosure may exist as mixtures of atropisomers or purified or enriched for the presence of one atropisomer.

[0083] In some embodiments, the compounds of Formula (0), Formula (I), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII) are a mixture of enantiomers or diastereomers. In other embodiments, the compounds of Formula (0), Formula (I), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII) are substantially one enantiomer or diastereomer.

[0084] A “tautomer” refers to a proton shift from one atom of a molecule to another atom of the same molecule. Embodiments thus include tautomers of the disclosed compounds.

[0085] The chemical naming protocol and structure diagrams used herein are a modified form of the I. U. P. A. C. nomenclature system, using the ACD / Name Version 9.07 software program and / or ChemDraw Professional Version 17.0.0.206 software naming program (CambridgeSoft). For complex chemical names employed herein, a substituent group is typically named before the group to which it attaches. For example, cyclopropylethyl comprises an ethyl backbone with a cyclopropyl substituent. Except as described below, all bonds are identified in the chemical structure diagrams herein, except for all bonds on some carbon atoms, which are assumed to be bonded to sufficient hydrogen atoms to complete the valency.

[0086] “Optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.

[0087] The disclosure provides that wherever embodiments are provided herein with the term “comprising,” the analogous embodiments described in terms of “consisting of’ and / or “consisting essentially of’ are also provided, if such analogous embodiments are not explicitly provided. The disclosure further provides that wherever embodiments are described herein with the phrase “consisting essentially of,” the analogous embodiments described in terms of “consisting of’ are also provided. The disclosure also provides that wherever embodiments are described herein with the phrase “consisting of,” the analogous embodiments described in terms of “consisting essentially of’ are also provided.

[0088] The term “and / or” as used in a phrase with a list of members is intended to include all members individually and all combination of full or partial list of members. For example, a phrase such as “A and / or B” herein is intended to include both A and B; A or B; A (alone); and B (alone). Likewise, the term “and / or” as used in a phrase such as “A, B, and / or C” is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0089] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.Non-Limiting Compounds Applied in the Method of Treating Hematological Malignancies

[0090] Described herein are methods of treating hematological diseases in a subject, comprising administering to the subject a composition comprising a compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII) or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. Also described herein are methods of preventing relapse in a subject who has or had a hematological disease, comprising administering to the subject a composition comprising a compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII) or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. Also described herein are methods of treating minimal residual disease (MRD) in a subject who has or had a hematological disease, comprising administering to the subject a composition comprising a compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII) or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. In some embodiments, the compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII) or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, inhibits NEK7 and / or modulates the activity of the NLRP3 inflammasome.

[0091] Embodiments described herein provide a compound having Formula (0):Formula (0) wherein:A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6;X is CH or N;X1is C or N;X2is C or N;X3is CH orN;X4is C or N;Y is NH;R1is H, Ci-6 alkyl, Ci-6 haloalkyl, or Ci-6 alkoxy;R2is hydrogen, Ci-Ce alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halogen, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl;R3is absent, H, halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkyl or C1-6 haloalkyl;R4is a Ce-Cio aryl, C3-C10 cycloalkyl, 3-12 membered heterocyclyl, 5- to 12- membered heteroaryl;R5is H;each R6is independently halogen, Ci-Ce alkyl, Ci-Ce alkoxy, cyano, Ci-Ce hydroxylalkyl, Ci-Ce haloalkyl,L is a direct bond, O, or CRL1RL2;RLis a Ce-Cio aryl substituted with 0-4 Rc, C-3-Cio cycloalkyl substituted with 0-4 Rc, 3-10 membered heterocyclyl substituted with 0-4 Rc, or 5-6 membered monocyclic heteroaryl substituted with 0-4 Rc, each of which is optionally substituted with one more substituents selected from halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkyl or C1-6 haloalkyl; andRL1and RL2are each independently selected from hydrogen, halogen, deuterium, tritium, C1-6 alkyl, C1-6 alkoxy, cyano, C1-6 hydroxyalkyl, C 1-6 haloalkyl, or R21and R22and the carbon to which they are attached together form a C 3-6 cycloalkyl.

[0092] Embodiments described herein provide a compound having Formula (I):or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein:A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6;Y is NH;R1is H or Ci-Ce alkyl;R2is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl;R3is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-Ce alkynyl and Ci-Ce alkoxy;R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3 -thiadi azolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-Ce alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclyl alkyl, 3-to 8-membered alkylheterocyclyl cycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-Cs halocycloalkyl, or combinations thereof;R5is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, Ce-Cio aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl and Ci-Ce alkoxy; andR6is, at each occurrence, independently halo, Ci-Ce alkyl, cyano, Ci-Ce hydroxylalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkyl.

[0093] In some embodiments of the compound of Formula (I):A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6;Y is NH;R1is H or Ci-Ce alkyl;R2is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl;R3is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-Ce alkynyl and Ci-Ce alkoxy;R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3 -thiadi azolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-Ce alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl and C3-C8 halocycloalkyl;R5is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, Ce-Cio aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl and Ci-Ce alkoxy; andR6is, at each occurrence, independently halo, Ci-Ce alkyl, or Ci-Ce haloalkyl.

[0094] In some embodiments of the compound of Formula (I):A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6;X is CH or N;Y is NH;R1is H or Ci-Ce alkyl;R2is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl;R3is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-Ce alkynyl and Ci-Ce alkoxy;R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3 -thiadi azolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-Ce alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl,C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclyl alkyl, 3-to 8-membered alkylheterocyclyl cycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-Cs halocycloalkyl;R5is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, Ce-Cio aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl and Ci-Ce alkoxy; andR6is, at each occurrence, independently halo, Ci-Ce alkyl, Ci-Ce alkoxy, cyano, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl.

[0095] In some embodiments, A is any suitable functional group as described herein. In some embodiments, A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6. In some embodiments, A is Ce-Cio aryl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6. In some embodiments, A is Ce-Cio aryl optionally substituted with one or more R6. In some embodiments, A is 5-6 membered monocyclic heteroaryl optionally substituted with one or more R6. In some embodiments, A is C3-C10 cycloalkyl. In some embodiments, A is 3-10 membered heterocyclyl optionally substituted with one or more R6.

[0096] In some embodiments, A is a divalent optionally substituted Ce-io aryl. In some embodiments, A is a divalent optionally substituted 3-8 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, A is a divalent optionally substituted 3-10 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, A is a divalent optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0097] In some embodiments, A is a divalent group selected from phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl,[2.2.2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, dithiazinyl, tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, IH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3-indolyl,isoindolinyl, isoindolenyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl;- 1,2,5-oxadiazolyl, 1.3.4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydro furanyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiadiazinyl, 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1.3.4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thi enothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, oxetanyl, azetidinyl, and xanthenyl; each of which is optionally substituted.

[0098] In some embodiments, A is a divalent group selected from phenyl, pyridinyl, cyclohexyl, and cyclohexenyl; each of which is optionally substituted. In other embodiments, A is phenyl. In some embodiments, A is saturated or unsaturated cyclohexyl. In more embodiments, A is pyridinyl.

[0099] In some embodiments, A is pyrimidinyl, which is optionally substituted.

[0100] In some embodiments, X is any suitable atom as described herein. In some embodiments, X is CH or N. In some embodiments, X is CH. In some embodiments, X is N.

[0101] In some embodiments, Y is any suitable linker as described herein. In some embodiments, Y is NH.

[0102] In some embodiments, R1is any suitable functional group described herein. In some embodiments, R1is H. In some embodiments, R1is Ci-Ce alkyl. In some embodiments, R1is methyl, ethyl, n-propyl, or isopropyl.

[0103] In some embodiments, R2is any suitable functional group described herein. In some embodiments, R2is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl. In some embodiments R2is Ci-Ce alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl. In some embodiments, R2is butyl, cyclopropyl, cyclobutyl,pyrrolidinyl, piperidinyl, pyridinyl, azetidinyl, or oxetanyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl. In some embodiments, R2is cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, or oxetanyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl. In some embodiments, R2is cyclopropyl or oxetanyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl. In some embodiments, R2is cyclopropyl. In some embodiments, R2is oxetanyl. In some embodiments, R2is unsubstituted cyclopropyl or oxetanyl. In some embodiments, R2is N-methyl substituted pyrrolidinyl. In some embodiments, R2is unsubstituted cyclobutyl.

[0104] In some embodiments, R2is:

[0105] In some embodiments, R2is:

[0106] In some embodiments, R3is any suitable functional group described herein. In some embodiments, R3is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-to 8-membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl and Ci-Ce alkoxy. In some embodiments, R3is H or Ci-Ce alkyl, wherein the Ci-Ce alkyl is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl and Ci-Ce alkoxy. In some embodiments, R3is H. In some embodiments, R3is Ci-Ce alkyl. In some embodiments, R3is methyl, ethyl, n-propyl, or isopropyl.

[0107] In some embodiments, R4is any suitable functional group described herein. In some embodiments, R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected fromhalo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkyl cycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkyl cycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, or combinations thereof. In some embodiments, R4is oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-triazolyl or 1, 3, 4-oxadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3-to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-Cs halocycloalkyl, and combinations thereof.

[0108] In some embodiments, R4is oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl or 1, 3, 4-oxadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkyl cycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof. In some embodiments, R4is isoxazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl and C3-C8 halocycloalkyl.

[0109] In some embodiments, R4is isoxazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof.

[0110] In some embodiments, R4is thiazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof.

[0111] In some embodiments, R4is isothiazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof.

[0112] In some embodiments, R4is 1,2,4-thiadiazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof.

[0113] In some embodiments, R4is 1,3,4-thiadiazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof.

[0114] In some embodiments, R4is 1,2,4-triazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof.

[0115] In some embodiments, R4is 1, 3, 4-oxadiazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, 3- to 8-membered heterocyclyl and C3-C8 halocycloalkyl, or combinations thereof.

[0116] In some embodiments, R4is substituted with Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl,3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof.

[0117] In some embodiments, R4is:

[0120] In some embodiments, R5is any suitable functional group described herein. In some embodiments, R5is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-to 8-membered heterocyclyl, Ce-Cio aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl and Ci-Ce alkoxy. In some embodiments, R5is H or Ci-Ce alkyl, wherein Ci-Ce alkyl is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl and Ci-Ce alkoxy. In some embodiments, R5is H. In some embodiments, R5is Ci-Ce alkyl. In some embodiments, R5is methyl, ethyl, n-propyl, or isopropyl.

[0121] In some embodiments, each R6is any suitable functional group described herein. In some embodiments, each R6is independently halo, Ci-Ce alkyl, cyano, Ci-Ce hydroxylalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkyl. In some embodiments, each R6is chloro or fluoro. In some embodiments, each R6is fluoro. In some embodiments, each R6is Ci-Cehydroxylalkyl. In some embodiments, each R6is Ci-Ce hydroxyl alkyl. In some embodiments, each R6is -CH2CH2OH. In other embodiments, each R6is cyano. In some embodiments, each R6is Ci-Ce alkoxy. In some embodiments, each R6is methoxy.

[0122] In some embodiments, A is:

[0123] In someis:

[0124] In some embodiments, the compound is a compound of Formula (la), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:wherein:R2ais C3-C4 cycloalkyl optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl; andR4ais isoxazolyl optionally substituted with one more substituents selected from Ci-Ce haloalkyl, C3-C8 cycloalkyl or C3-C8 haloalkylcycloalkyl.

[0125] In some embodiments, R2ais a branched Ci-Ce alkyl substituted with hydroxyl. In some embodiments, R2ais C3-C8 cycloalkyl. In some embodiments, R2ais:

[0126] In some embodiments, R4ais isoxazolyl substituted with C3-C8haloalkyl cycloalkyl. In some embodiments, R4ais C3-C8 fluoroalkylcycloalkyl. In some embodiments, R4ais fluoroalkylcyclopropyl or fluoroalkyl cyclobutyl. In some embodiments, R4ais:

[0127] In some embodiments, the compound is a compound of Formula (lb), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:wherein:A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6;X is CH or N;Y is NH;R1is H or Ci-Ce alkyl;R2is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl;R3is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-Ce alkynyl and Ci-Ce alkoxy;R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1,2,3 -oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, thiazolyl, isothiazolyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl and 1,3,4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkyl cycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl;R5is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, Ce-Cio aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl and Ci-Ce alkoxy; andR6is, at each occurrence, independently halo, Ci-Ce alkyl, Ci-Ce alkoxy, cyano, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl.

[0128] In some embodiments, the compound of Formula (I) is a modulator of the NLRP3 inflammasome. In some embodiments, the compound of Formula (I) is an inhibitor of NEK7 in a patient or in a biological sample. In some embodiments, the compound of Formula (I) inhibits NEK7 and / or modulates the activity of the NLRP3 inflammasome. In some embodiments, the compound of Formula (I) is administered to treat a hematological malignancy. The treatment may be treating MRD. The treatment may be preventing relapse of the hematological malignancy.

[0129] In various different embodiments, the compound has one of the structures set forth in Table 1 A below, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0130] Compounds in Table 1 A were prepared as described in the Examples or methods known in the art and analyzed by mass spectrometry and / or1H NMR.Table 1A: Representative Compounds of Formula (I)

[0131] Embodiments described herein provide a compound having Formula (II):or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein:X is N or CH;A is Ce-Cio arylene, C3-C10 cycloalkylene, 3-10 membered heterocyclylene, or 5-6 membered heteroarylene;R1is H, halo, Ci-Ce alkyl, C3-C10 cycloalkyl, or 3-10 membered heterocyclyl;R2is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C10 cycloalkyl, or 3-10 membered heterocyclyl;R3is aminylalkyl, 3-10 membered heterocyclyl, 3-10 membered heterocyclylalkyl, 3-10 membered heterocyclylcarbonyl, 3-10 membered heterocyclylalkenyl, 3-10 membered N-heterocyclyloxy, or 5-6 membered heteroaryl; orR3 joins with an occurrence of R4 attached to a carbon adjacent to a carbon to which R3 is attached to form a C3-C8 cycloalkyl;R4is, at each occurrence, independently halo, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, C3-C8 halocycloalkyl, or C3-C8 cycloalkyl; andn is 0, 1, 2, 3, or 4.

[0132] In some embodiments, A is Ce-Cio arylene. In certain embodiments, A is phenylene. In some specific embodiments, A is 5-6 membered heteroarylene. In certain specific embodiments, A is pyridinylene. In some more specific embodiments, A is C3-C10 cycloalkylene or 3-10 membered heterocyclylene.

[0133] In certain embodiments, A is substituted with one or more substituents selected from halo, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or C3-C8 cycloalkyl. In some embodiments, A is substituted with one or more halo substituents. In some specific embodiments, A is unsubstituted.

[0134] In some embodiments, R1is H. In certain embodiments, R1is Ci-Ce alkyl. In some specific embodiments, R1is methyl. In certain embodiments, R1is C3-C10 cycloalkyl, or 3-10 membered heterocyclyl. In some embodiments, R1is halo (e.g., fluoro, chloro, bromo, etc.).

[0135] In certain embodiments, R2is H. In some more specific embodiments, R2is halo. In more specific embodiments, R2is chloro or fluoro. In some other embodiments, R2is C3-C10 cycloalkyl (e.g., cyclopropyl). In some embodiments, R2is Ci-Ce alkyl, Ci-Ce haloalkyl, or 3-10 membered heterocyclyl. In some embodiments, R2is Ci-Ce alkyl (e.g., methyl).

[0136] In some embodiments, X is CH or CR3. In some specific embodiments, the compound has the following structure (Ila):or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0137] In some embodiments, the compound has the following structure (lib):or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0138] In certain embodiments, X is N. In certain more specific embodiments, the compound has the following structure (lie):or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0139] In some embodiments, the compound has the following structure (lid):or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, whereinR3ais, at each occurrence, independently halo, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, aminylalkyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, 3-10 membered heterocyclyl, 3-10 membered heterocyclylalkyl, 3-10 membered heterocyclylcarbonyl, 3-10 membered heterocyclylalkenyl, 3-10 membered N-heterocyclyloxy, or 5-6 membered heteroaryl; andm is 0, 1, 2, 3, or 4.

[0140] In some embodiments, R3ais, at each occurrence, independently halo or 3-10 membered heterocyclyl. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0. In certain embodiments, m is 1. In some embodiments, m is 1. In some embodiments, m is 2. In certain embodiments, m is 3.

[0141] In some embodiments, the compound has the following structure (lid 1 ):or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0142] In some embodiments, R3is substituted. In some embodiments, R3is unsubstituted. In some embodiments, R3is substituted with alkyl (e.g., Ci-Ce alkyl), heterocyclyl, halo, haloalkyl (e.g., Ci-Ce haloalkyl), alkylcarbonyl (e.g., -C(=O)CH3), hydroxyalkyl, alkoxyalkyl, cycloalkyl (e.g., C3-C8 cycloalkyl), alkylamino, or combinations thereof.

[0143] In some of the above embodiments, R3is aminylalkyl. In certain embodiments, R3has the following structure:

[0144] In some embodiments, R3is a 3-10 membered heterocyclyl. In some embodiments, R3is morpholino. In certain embodiments, R3is piperazinyl. In some specific embodiments, R3has one of the following structures:

[0145] In certain embodiments, R3is a 3-10 membered heterocyclylalkyl. In certain more specific embodiments, R3has one of the following structures:

[0146] In some embodiments, R3has one of the following structures:

[0147] In some embodiments, R3is 3-10 membered heterocyclylcarbonyl. In a more specific embodiment, R3has the following structure:

[0148] In some embodiments, R3is a 5-6 membered heteroaryl. For example, in some embodiments, R3has the following structure:

[0149] In some embodiments, R3is a 3-10 membered heterocyclylalkenyl. In more specific embodiments, R3has the following structure:

[0150] In some embodiments, R3is a 3-10 membered N-heterocyclyloxy. In more specific embodiments, R3has one of the following structures:

[0151] In some embodiments, R3has one of the following structures:

[0152] In some embodiments, n is 1 or 2. In some embodiments, n is 2. In some other embodiments, n is 1. In some specific embodiments, R4is, at each occurrence, independently chloro, fluoro, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Cs-Cs halocycloalkyl, or C3-C8 cycloalkyl. In certain embodiments, R4is, at each occurrence, independently methyl, chloro, fluoro, cyano, trifluoromethyl, methoxy, trifluoromethoxy, 2,2-difluorocyclopropyl, or cyclopropyl. In certain embodiments, R4is, at each occurrence, independently methyl, chloro, fluoro, cyano, trifluoromethyl, difluoromethyl, methoxy, trifluorom ethoxy, 2,2-difluorocyclopropyl, or cyclopropyl.

[0153] In some embodiments, X is N and n is 3. In some embodiments, X is N and n is 2. In more specific embodiments, X is N and n is 1. In some other embodiments, X is N and n is 0.

[0154] In some embodiments, X is CH and n is 4. In some other embodiments, X is CH and n is 3. In some embodiments, X is CH and n is 2. In more specific embodiments, X is CHand n is 1. In some other embodiments, X is CH and n is 0.

[0155] In some embodiments, the compound of Formula (II) is a modulator of the NLRP3 inflammasome. In some embodiments, the compound of Formula (II) is an inhibitor of NEK7 in a patient or in a biological sample. In some embodiments, the compound of Formula (II) inhibits NEK7 and / or modulates the activity of the NLRP3 inflammasome. In some embodiments, the compound of Formula (II) is administered to treat a hematological malignancy. The treatment may be treating MRD. The treatment may be preventing relapse of the hematological malignancy.

[0156] In various different embodiments, the compound has one of the structures set forth in Table IB below, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0157] Compounds in Table IB were prepared as described in the Examples or methods known in the art and analyzed by mass spectrometry and / or1H NMR.Table IB: Representative Compounds of Formula (II)

[0158] Embodiments described herein provide a compound having Formula (III):-n -or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein:A is Ce-Cio arylene, C3-C10 cycloalkylene, 3-10 membered heterocyclylene, or 5-6 membered heteroarylene;X is N or CR4;Y is N or CH;R1is Ci-Ce alkyl, Ci-Ce hydroxylalkyl, C3-C10 cycloalkyl, or 3-10 membered heterocyclyl;R2is a 3-10 membered heterocyclyl, 3-10 membered heterocyclylalkyl, 3-10 membered heterocyclylalkenyl, 3-10 membered heterocyclylcarbonyl, 3-10 membered heterocyclyloxy, or 5-6 membered heteroaryl; orR2joins with an occurrence of R3attached to a carbon adjacent to a carbon to which R2is attached to form a C3-C8 cycloalkyl;R3is, at each occurrence, independently halo, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or C3-C8 cycloalkyl;R4is H, Ci-Ce alkyl, Ci-Ce haloalkyl, or C3-C8 cycloalkyl; andn is 0, 1, 2, 3, or 4.

[0159] In some embodiments, A is Ce-Cio arylene. In some specific embodiments, A is phenylene. In certain embodiments, A is 5-6 membered heteroarylene. In certain specific embodiments, A is pyridinylene. In some embodiments, A is C3-C10 cycloalkylene or 3-10 membered heterocyclylene. In more specific embodiments, A is substituted with one or more substituents selected from halo, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or C3-C8 cycloalkyl. In certain more specific embodiments, A is substituted with one or more halo substituents. In other embodiments, A is unsubstituted.

[0160] In certain embodiments, X is CR4. In more specific embodiments, R4is H or Ci-Ce alkyl. In some embodiments, R4is H. In certain specific embodiments, X is N.

[0161] In some embodiments, R1is Ci-Ce alkyl. In some more specific embodiments, R1is methyl or iso-propyl. In certain embodiments, R1is Ci-Ce hydroxylalkyl. In certain morespecific embodiments, R1has one of the following structures:

[0162] In some embodiments, R1has one of the following structures:

[0163] In certain embodiments, R1is Ci-Ce carboxyalkyl. In more specific embodiments, R1has one of the following structures:

[0164] In some embodiments, R1is Ci-Ce alkoxyalkyl. In some embodiments, R1has the following structure:

[0165] In some embodiments, R1is C3-C10 cycloalkyl. In more specific embodiments, R1is cyclopropyl or cyclobutyl. In certain embodiments, R1is 3-10 membered heterocyclyl. In certain embodiments, R1is oxetanyl, pyrrolidinyl, or piperidinyl. In certain embodiments, R1is oxetanyl, pyrrolidinyl, azetidinyl, or piperidinyl.

[0166] In some embodiments, R1is Ci-Ce alkynyl. In certain embodiments, R1has one of the following structures:

[0167] In some embodiments, R1is substituted with one or more substituents selected from halo, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or C₃-C₈ cycloalkyl. In some embodiments, R¹ is substituted with one or more substituents selected from halo, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, -S(O)₂CH₃, -S(O)₂cyclopropyl, or C₃-C₈ cycloalkyl. In more specific embodiments, R1is substituted with one or more Ci-Ce alkyl substituents. In other embodiments, R1is unsubstituted.

[0168] In certain specific embodiments, R1has one of the following structures:

[0169] In some embodiments, R1has one of the following structures:

[0170] In some specific embodiments, the compound has the following Structure (Illa):or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0171] In some embodiments, Y is N. In other embodiments, Y is CH.

[0172] In certain specific embodiments, the compound has the following Structure (Illb):(nib)or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0173] In some embodiments, R2is a 3-10 membered heterocyclyl. In some specific embodiments, R2is morpholino. In other specific embodiments, R2is piperazinyl. In some more specific embodiments, R2has one of the following structures:

[0174] In some embodiments, R2is a 3-10 membered heterocyclylalkyl. In certain more specific embodiments, R2has one of the following structures:

[0175] In some more specific embodiments, R2has one of the following structures:

[0176] In some embodiments, R2is 3-10 membered heterocyclylcarbonyl. In certain more specific embodiments, R2has the following structure:

[0177] In some embodiments, R2is a 5-6 membered heteroaryl. In some more specific embodiments, R2has the following structure:

[0178] In some embodiments, R2is 3-10 membered heterocyclyloxy. In certain more specific embodiments, R2has the following structure:

[0179] In some embodiments, R2has one of the following structures:

[0180] In some more specific embodiments, R2has the following structure:

[0181] In some embodiments, n is 0. In some embodiments, n is 1 or 2. In certain embodiments, n is 1. In some embodiments, R3is halo, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or C3-C8 cycloalkyl. In certain specific embodiments, R3is methyl, chloro, fluoro, cyano, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, or cyclopropyl. In some specific embodiments, n is 1 or 2 and R3is halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or C3-C8 cycloalkyl. In some embodiments, n is 1 and R3is halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or C3-C8 cycloalkyl. In some embodiments, n is 1 and R3is methyl, chloro, fluoro, trifluoromethyl, methoxy, trifluoromethoxy, or cyclopropyl.

[0182] In some embodiments, the compound has the following Structure (IIIc):or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein:R3ais halo or 3-10 membered heterocyclyl; andnl is 1, 2, or 3.

[0183] In some embodiments, R3ais fluoro or piperazinyl. In more specific embodiments, the compound has the following Structure (IIIcl):or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0184] In some embodiments, the compound of Formula (III) is a modulator of the NLRP3 inflammasome. In some embodiments, the compound of Formula (III) is an inhibitor of NEK7 in a patient or in a biological sample. In some embodiments, the compound of Formula (III) inhibits NEK7 and / or modulates the activity of the NLRP3 inflammasome. In some embodiments, the compound of Formula (III) is administered to treat a hematological malignancy. The treatment may be treating MRD. The treatment may be preventing relapse of the hematological malignancy.

[0185] In various different embodiments, the compound has one of the structures set forth in Table 1C below, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0186] Compounds in Table 1C were prepared as described in the Examples or methods known in the art and analyzed by mass spectrometry and / or1H NMR.Table 1C: Representative compounds of Structure (III)- Ill -

[0187] Embodiments described herein provide a compound having Formula (IV):or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein:A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl, or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R5;Xis N or CR1C;Y is N or CRld;Z is C(R6)(R7) or NR6;Rla, Rlb, Rlc, and Rldare each independently H, halo, Ci-Ce alkyl, or C3-C8 cycloalkyl;R2aand R2bare each independently H, halo, cyano, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, C3-C8 cycloalkyl, or C3-C8 halocycloalkyl, provided that R2aand R2bare not both H;R3is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, heteroaryl, or aryl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and Ci-Ce alkoxy;R4is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, Ce-Cio aryl, or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and Ci-Ce alkoxy;R5is, at each occurrence, independently halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl;R6is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce hydroxylalkyl; and R7is H, OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce hydroxylalkyl.

[0188] In some embodiments, A is Ce-Cio aryl. In certain embodiments, A is C3-C10 cycloalkyl. In some specific embodiments, A is 3-10 membered heterocyclyl. In certain specific embodiments, A is 5-6 membered monocyclic heteroaryl. In some more specific embodiments, A is substituted with one or more occurrences of R5. In certain more specific embodiments, A is substituted with one or two occurrences of R5. In some embodiments, A is substituted with substituents selected from the group consisting of halo, Ci-Ce haloalkyl, and combinations thereof. In certain embodiments, A is substituted with substituents selected from the group consisting of fluoro, trifluoromethyl, and combinations thereof. In more specific embodiments, A is unsubstituted.

[0189] In some embodiments, X is N. In certain embodiments, X is CRlc. In some specific embodiments, Rlcis H. In certain more specific embodiments, Rlcis halo (e.g., Rlcis chloro). In some other embodiments, Rlcis Ci-Ce alkyl (e.g., Rlcis methyl). In certain embodiments, Rlcis C3-C8 cycloalkyl (e.g., Rlcis cyclopropyl).

[0190] In some embodiments, Y is N. In other embodiments, Y is CRld. In some embodiments, Rldis H. In certain specific embodiments, Rldis halo, Ci-Ce alkyl, or C3-C8 cycloalkyl.

[0191] In some embodiments, Z is C(R6)(R7). In more specific embodiments, R6is H. In some embodiments, R7is -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce hydroxylalkyl. In certain specific embodiments, R6and R7are both H.

[0192] In some other embodiments, Z is NR6. In certain embodiments, R6is H. In certain other embodiments, R6is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce hydroxylalkyl.

[0193] In certain embodiments, Rlais H. In some embodiments, Rlais Ci-Ce alkyl (e.g., Rlais methyl). In some embodiments, Rlais halo or C3-C8 cycloalkyl.

[0194] In some embodiments, Rlbis H. In certain embodiments, Rlbis halo, Ci-Ce alkyl, or C3-C8 cycloalkyl.

[0195] In certain embodiments, R2ais Ci-Ce alkyl (e.g., R2ais tert-butyl or methyl). In some embodiments, R2ais C3-C8 cycloalkyl. In more specific embodiments, R2ais cyclopropyl. In some embodiments, the cyclopropyl is unsubstituted. In some embodiments, the cyclopropyl is substituted with at least one haloalkyl (e.g., trifluoromethyl). In certain more specific embodiments, R2ahas the following structure:■V”

[0196] In some embodiments, R2bis H. In certain embodiments, R2bis halo, cyano, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, C3-C8 cycloalkyl, or C3-C8 halocycloalkyl.

[0197] In certain specific embodiments, R3is Ci-Ce alkyl (e.g., R3is methyl).

[0198] In some embodiments, R3is aryl. For example, in some embodiments, R3is phenyl. In certain embodiments, the phenyl is substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and Ci-Ce alkoxy. In certain other embodiments, the phenyl is unsubstituted.

[0199] In some other embodiments, R3is 3-10 membered heterocyclyl. In more specific embodiments, R3is piperidinyl. In certain specific embodiments, the piperidinyl is substitutedwith one or more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-Ce alkenyl, C2-C6 alkynyl, and Ci-Ce alkoxy. In certain embodiments, R3has the following structure:

[0200] In some embodiments, R4is H. In more specific embodiments, R4is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, Ce-Cio aryl, or 5- or 6-membered heteroaryl.

[0201] In some embodiments, the compound of Formula (IV) is a modulator of the NLRP3 inflammasome. In some embodiments, the compound of Formula (IV) is an inhibitor of NEK7 in a patient or in a biological sample. In some embodiments, the compound of Formula (IV) inhibits NEK7 and / or modulates the activity of the NLRP3 inflammasome. In some embodiments, the compound of Formula (IV) is administered to treat a hematological malignancy. The treatment may be treating MRD. The treatment may be preventing relapse of the hematological malignancy.

[0202] In various different embodiments, the compound has one of the structures set forth in Table ID below, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0203] Compounds in Table ID were prepared as described in the Examples or methods known in the art and analyzed by mass spectrometry and / or1H NMR.Table ID: Representative compounds of Structure (IV)

[0204] Embodiments described herein provide a compound having Formula (V):or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein:A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R5;X is N or CH;Yis CHOH orNH;R1is H or Ci-Ce alkyl;R2is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-Ce alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl;R3is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from amino, halo, cyano, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, C3-C8 alkylcycloalkyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl,Ci-Ce cyanoalkyl Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclylalkyl, 3-8 membered heterocyclylcycloalkyl, 3-8 membered haloheterocyclyl, 3-8 membered haloheterocyclylalkyl, Cs-Cs halocycloalkyl and Cs-Cs halocycloalkylalkyl, and combinations thereof;R4is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, Ce-Cio aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl and Ci-Ce alkoxy; andR5is, at each occurrence, independently halo, cyano, Ci-Ce alkyl, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl.

[0205] In some embodiments of structure (V), A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R5;X is N or CH;Yis CHOH orNH;R1is H or Ci-Ce alkyl;R2is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-Ce alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl;R3is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl and C3-C8 halocycloalkyl;R4is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, Ce-Cio aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl and Ci-Ce alkoxy; andR5is, at each occurrence, independently halo, Ci-Ce alkyl, Ci-Ce alkyl or Ci-Ce haloalkyl.

[0206] One embodiment provides a compound of structure (I) or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein:A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R5;X is N or CH;Yis CHOH orNH;R1is H or Ci-Ce alkyl;R2is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-Ce alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl;R3is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from amino, halo, cyano, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, Cs-Cs alkylcycloalkyl, Cs-Cs haloalkylcycloalkyl, Cs-Cs aminylalkylcycloalkyl, Ci-Ce cyanoalkyl, Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclylalkyl, 3-8 membered heterocyclylcycloalkyl, 3-8 membered haloheterocyclyl, 3-8 membered haloheterocyclylalkyl, Cs-Cs halocycloalkyl and Cs-Cs halocycloalkylalkyl, and combinations thereof;R4is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, Ce-Cio aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl and Ci-Ce alkoxy; andR5is, at each occurrence, independently halo, cyano, Ci-Ce alkyl, Ci-Ce hydroxylalkyl, Ci-Ce alkoxy, or Ci-Ce haloalkyl.

[0207] In certain embodiment, R1is H. In other embodiments, R1is Ci-Ce alkyl, such as methyl.

[0208] In one embodiment, compounds of Structure (I) are provided, where R2is branched C4-C6 alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to8-membered heterocyclyl.

[0209] In another embodiment, compounds of Structure (I) are provided, where R2is branched C4-C6 alkyl, C3-C4 cycloalkyl, or C3-C8 heterocyclyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl.

[0210] In specific embodiments, R2is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl.

[0211] In different embodiments, R2is methyl, isopropyl, 2-methylpropyl or allyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl.

[0212] In different embodiments, R2is methyl, ethyl, isopropyl, 2-methylpropyl or allyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl.

[0213] In other embodiments, R2is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl or dioxidotetrahydrothiophenyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-Ce alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl.

[0214] In other embodiments, R2is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, azetidinyl or dioxidotetrahydrothiophenyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, and 3- to 8-membered heterocyclyl.

[0215] In other embodiments, R2is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, azetidinyl pyrrolidinyl, or dioxidotetrahydrothiophenyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, and 3- to 8-membered heterocyclyl.

[0216] In still more embodiments, R2is pyridinyl optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl.

[0217] In any of the foregoing embodiments, R2is unsubstituted. In other of the foregoing embodiments, R2is substituted with one or more of hydroxyl and fluoro.

[0218] In any of the foregoing embodiments, R2is unsubstituted. In other of the foregoing embodiments, R2is substituted with one or more of hydroxyl, methyl, methoxy, and fluoro.

[0219] In more specific embodiments, R2has one of the following structures:

[0220] In further specific embodiments, R2has one of the following structures:

[0221] In further specific embodiments, R2has one of the following structures:

[0222] In some embodiments, optionally R2is substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, and 3-8 membered heterocyclyl.

[0223] In some embodiments, R2does not have the following structures:

[0224] In any of the foregoing embodiments, R3is oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl or 1, 3, 4-oxadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl and C3-C8 halocycloalkyl. For example, in certain embodiments, R3is isoxazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl and C3-C8 halocycloalkyl. In further specific embodiments, R3is substituted with Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl or C3-C8 halocycloalkyl.

[0225] In further embodiments, R3is oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 3, 4-oxadiazolyl, thiazolyl, isothiazolyl, 1, 2, 4-thiadiazolyl, 1, 3, 4-thiadiazolyl or 1, 2, 4-triazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl and C3-C8 halocycloalkyl, or combinations thereof.

[0226] In certain embodiments, R3is isoxazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl and C3-C8 halocycloalkyl, or combinations thereof.

[0227] In certain embodiments, R3is thiazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl and C3-C8 halocycloalkyl, or combinations thereof.

[0228] In certain embodiments, R3is isothiazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl and C3-C8 halocycloalkyl, or combinations thereof.

[0229] In certain embodiments, R3is 1,2, 4-thiadiazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl and C3-C8 halocycloalkyl, or combinations thereof.

[0230] In certain embodiments, R3is 1,3,4-thiadiazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl and C3-C8 halocycloalkyl, or combinations thereof.

[0231] In certain embodiments, R3is 1,3,4-oxadiazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl and C3-C8 halocycloalkyl, or combinations thereof.

[0232] In certain embodiments, R3is 1,2,4-triazolyl optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl and C3-C8 halocycloalkyl, or combinations thereof.

[0233] In further embodiments, R3is substituted with Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl or C3-C8 halocycloalkyl, or combinations thereof.

[0234] In various embodiments, R3has one of the following structures:

[0237] In other embodiments, R4is H. In other embodiments, R4Ci-Ce alkyl, such as methyl.

[0238] In certain embodiments, Y is CHOH. In other embodiments, Y is NH.

[0239] In other embodiments, X is N. In more embodiments, X is CH.

[0240] In various embodiments, A is Ce-Cio aryl, C3-C10 cycloalkyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6. It is understood that A is a divalent radical.

[0241] In certain embodiments, A is a divalent optionally substituted Ce-io aryl. In certain embodiments, A is a divalent optionally substituted 3-8 membered saturated or partially unsaturated carbocyclic ring. In certain embodiments, A is a divalent optionally substituted 3-10 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, A is a divalent optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0242] In certain embodiments, A is a divalent group selected from phenyl, pyridinyl, cyclohexyl, and cyclohexenyl; each of which is optionally substituted.

[0243] In other embodiments, A is phenyl. In different embodiments, A is saturated or unsaturated cyclohexyl. In more embodiments, A is pyridinyl.

[0244] In further embodiments, A is pyrimidinyl, which is optionally substituted.

[0245] In any of the foregoing embodiments, A is unsubstituted. In different of the foregoing embodiments, A is substituted with one or more R5. For example, in some embodiments R5is halo. In other embodiments, R5is fluoro. In other different embodiments, R5is chloro.

[0246] In some embodiments, R5is cyano. In some embodiments, R5is Ci-Ce alkyl. In certain embodiments, R5is methyl. In some embodiments, R5is Ci-Ce haloalkyl. In certainembodiments R5is difluoromethyl. In further embodiments, R5is Ci-Ce hydroxylalkyl. In certain embodiments R5is -CH2OH.

[0247] In certain embodiments, A is a divalent group selected from phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl,[2.2.2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, dithiazinyl, tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, IH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3-indolyl, isoindolinyl, isoindolenyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl;- 1,2,5-oxadiazolyl, 1.3.4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydro furanyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiadiazinyl, 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1.3.4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thi enothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, oxetanyl, azetidinyl, and xanthenyl; each of which is optionally substituted.

[0248] In specific embodiments, A has one of the following structures:

[0249] In other specific embodiments, A has one of the following structures:

[0250] In some embodiments, the compound of Formula (V) is a modulator of the NLRP3 inflammasome. In some embodiments, the compound of Formula (V) is an inhibitor of NEK7 in a patient or in a biological sample. In some embodiments, the compound of Formula (V) inhibits NEK7 and / or modulates the activity of the NLRP3 inflammasome. In some embodiments, the compound of Formula (V) is administered to treat a hematological malignancy. The treatment may be treating MRD. The treatment may be preventing relapse of the hematological malignancy.

[0251] In various different embodiments, the compound has one of the structures set forth in Table IE below, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0252] Compounds in Table IE were prepared as described in the Examples or methods known in the art and analyzed by mass spectrometry and / or1H NMR.Table IE. Representative Compounds of Structure (V)

[0253] Embodiments described herein provide a compound having Formula (VI):or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein:= represents a double or a single bond such that all valences are satisfied;A is an optionally substituted 5-6-membered heterocyclyl, an optionally substituted 6-membered aryl, or an optionally substituted 5-6-membered heteroaryl;X is N or CR3;Y is C or N;W is CH or N;Z is CH or N;R1is optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted Ci-Ce hydroxyalkyl, optionally substituted Ci-Ce alkoxyalkyl, optionally substituted Ci-Ce carboxyalkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted Ce-Cio aryl, optionally substituted 3-10 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl;R2is optionally substituted aryl or optionally substituted heteroaryl; andR3is hydrogen, halo, cyano, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ci-Ce alkoxy, optionally substituted Ci-Ce haloalkoxy, or optionally substituted C3-C8 cycloalkyl.

[0254] In some embodiments, = represents a double bond. In some other embodiments, = represents a single bond.

[0255] In some embodiments, A is a 5-membered heterocyclyl. In certain embodiments, A is a 6-membered heterocyclyl. In some embodiments, A is a 6-membered heteroaryl. In certain embodiments, A is a 5-membered heteroaryl. In some embodiments, A is a 6-membered aryl.

[0256] In some embodiments, Y is N. In some embodiments, A is unsubstituted. In certain embodiments, A is substituted. In some embodiments, A is substituted with one or more substituents selected from the group consisting of halo, cyano, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ci-Ce alkoxy, optionally substituted Ci-Ce haloalkoxy, or optionally substituted C3-C8 cycloalkyl.

[0257] In some embodiments, A is substituted with one or more substituents selected from the group consisting of halo, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ci-Ce alkoxy, and optionally substituted Ci-Cehaloalkoxy.

[0258] In some embodiments, A is substituted with one or more substituents selected from the group consisting of Ci-Ce alkyl, halo, and Ci-Ce haloalkyl. In some embodiments, A is substituted with one or more substituents selected from the group consisting of methyl, fluoro, and trifluoromethyl.

[0259] has the following structure:

[0260] In some embodiments, Z is CH. In certain embodiments, Z is N. In certain embodiments, X is N. In some embodiments, X is CR3. In some embodiments, R3is hydrogen or optionally substituted Ci-Ce alkyl. In certain embodiments, X is CH.

[0261] In some embodiments, R1is optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted Ci-Ce hydroxyalkyl, optionally substituted Ci-Ce alkoxyalkyl, optionally substituted Ci-Ce carboxyalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3-10 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In certain embodiments, R1is optionally substituted Ci-Ce alkyl. In some embodiments, R1is methyl, ethyl, or / .w-propyl. In certain embodiments, R1is optionally substituted Ci-Ce alkenyl or optionally substituted Ci-Ce alkynyl. In some more specific embodiments, R1has the following structure:

[0262] In some embodiments, R1is optionally substituted Ci-Ce hydroxyalkyl. In certain embodiments, R1has one of the following structures:

[0263] In some embodiments, R1is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some more specific embodiments, R1has one of the following structures:

[0264] In some embodiments, R1is optionally substituted 3-10 membered heterocyclyl. In certain embodiments, R1has the following structure:

[0265] In some embodiments, R1is optionally substituted 5-10 membered heteroaryl. In certain embodiments, R1is unsubstituted pyridinyl. In some embodiments, R1has one of the following structures:

[0266] In some embodiments, R1is optionally substituted Ci-Ce carboxyalkyl. In certainembodiments, R1has the following structure:

[0267] In some embodiments, R1is optionally substituted Ci-Ce alkoxyalkyl. In certain embodiments, R1has the following structure:

[0268] In certain embodiments, R2is optionally substituted phenyl or optionally substituted 5-membered heteroaryl. In some embodiments, R2is optionally substituted phenyl. In certain embodiments, R2is optionally substituted 5-membered heteroaryl. In certain embodiments, R2is optionally substituted isoxazolyl or optionally substituted pyrazolyl. In some embodiments, R2is optionally substituted with one or more substituents selected from the group consisting of halo, cyano, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ci-Ce alkoxy, optionally substituted Ci-Ce haloalkoxy, optionally substituted C3-C8 cycloalkyl, optionally substituted 5-10-membered heterocyclylalkyl, optionally substituted 5-10-membered heterocyclyloxy, and optionally substituted Ce-Cio aryl.

[0269] In some embodiments, R2is optionally substituted with one or more substituents selected from the following structures:

[0270] In some embodiments, R2has one of the following structures:

[0272] In various different embodiments, the compound has one of the structures set forthin Table IF below, or a stereoisomer, tautomer, or salt thereof. Compounds in Table IF were prepared as described in the Examples or methods known in the art and analyzed by mass spectrometry and / or1H NMR. In some embodiments, the compound of Formula (VI) is a modulator of the NLRP3 inflammasome. In some embodiments, the compound of Formula (VI) is an inhibitor of NEK7 in a patient or in a biological sample. In some embodiments, the compound of Formula (VI) inhibits NEK7 and / or modulates the activity of the NLRP3 inflammasome. In some embodiments, the compound of Formula (VI) is administered to treat a hematological malignancy. The treatment may be treating MRD. The treatment may be preventing relapse of the hematological malignancy.

[0273] In various different embodiments, the compound has one of the structures set forthin Table IF below, or a pharmaceutically accep table salt, stereoisomer, or prodrug thereof.

[0274] Compounds in Table IF were p repared as described in the Examples or methods known in the art and analyzed by mass spectrometry and / or1H NMR.Table IF: Representative compounds of Structure (VI)

[0275] Embodiments described herein provide a compound having Formula (VII):or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein:Ring A is a Ce-Cio aryl substituted with 0-4 RA, C3-10 cycloalkyl substituted with 0-4 RA, 3-10 membered heterocyclyl substituted with 0-4 RA, or 5-6 membered monocyclic heteroaryl substituted with 0-4 RA;R is one of the following structural formulas:wherein:L is a direct bond, O, or CR21R22;RLis a Ce-Cio aryl substituted with 0-4 Rc, C-3-Cio cycloalkyl substituted with 0-4 Rc, 3-10 membered heterocyclyl substituted with 0-4 Rc, or 5-6 membered monocyclic heteroaryl substituted with 0-4 Rc;XJis CR31orN;X2is C or N;X3is CR32orN;X4is C or N;Z1is CH orN;Z2is O or S;Z3is C orN;Z4is C orN;R1is Ce-Cio aryl substituted with 0-4 R°, C-3-Cio cycloalkyl substituted with 0-4 R°, 3-10 membered heterocyclyl substituted with 0-4 R°, or 5-6 membered monocyclic heteroaryl substituted with 0-4 R°, Ci-6 alkyl substituted with 0-4 R°, Ci-6 alkoxy substituted with 0-4 R°, C2-6 alkenyl substituted with 0-4 R°, C2-6 alkynyl substituted with 0-4 R°, orNRnR12;R2is hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy;RAare each independently selected from hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, cyano, hydroxy, C1-6 hydroxyalkyl, or C1-6 haloalkyl;RBare each independently selected from hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, Ce-io aryl substituted with 0-4 RB1, C3-10 cycloalkyl substituted with 0-4 RB1, 3-10 membered heterocyclyl substituted with 0-4 RB1, or 5-6 membered heteroaryl substituted with 0-4 RB1;RB1are each independently selected from halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkyl or C1-6 haloalkyl;Rcare each independently selected from hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkyl or C1-6 haloalkyl;R31is hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkyl or C1-6 haloalkyl;R32is hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkyl or C1-6 haloalkyl;R51and R52are each independently hydrogen, halogen, deuterium, tritium, or C1-6 alkyl, or R51and R52and the carbon to which they are attached together form a C3-6 cycloalkyl; R61and R62are each independently hydrogen, halogen, deuterium, tritium, or C1-6 alkyl, or R61and R62and the carbon to which they are attached together form a C3-6 cycloalkyl; R7is hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, Ce-io aryl substituted with 0-4 R70, C3-10 cycloalkyl substituted with 0-4 R70, 3-10 membered heterocyclyl substituted with 0-4 R70, or 5-6 membered heteroaryl substituted with 0-4 R70;R70is hydrogen, halogen, hydroxy, cyano, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, 3-8 membered heterocyclic group orNRnR12;R° are each independently selected from hydrogen, halogen, hydroxyl, cyano, Ci-ealkyl, C2-6 alkenyl, C2-6 alkynyl, 3-8 membered heterocyclyl orNRnR12;R11and R12are each independently selected from hydrogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, cyano, C1-6 hydroxyalkyl or C1-6 haloalkyl;R21and R22are each independently selected from hydrogen, halogen, deuterium, tritium, C1-6 alkyl, C1-6 alkoxy, cyano, C1-6 hydroxyalkyl, C 1-6 haloalkyl, or R21and R22and the carbon to which they are attached together form a C 3-6 cycloalkyl; andn is 1 or 2.

[0276] In some embodiments, Ring A is a Ce-Cio aryl substituted with 0-4 RA. In some embodiments, Ring A is a C3-10 cycloalkyl substituted with 0-4 RA. In some embodiments, Ring A is a 3-10 membered heterocyclyl substituted with 0-4 RA. In some embodiments, Ring A is a 5-6 membered monocyclic heteroaryl substituted with 0-4 RA. In some embodiments, Ring A is phenyl with 0 to 1 RA. In some embodiments, Ring A is pyridinyl with 0 to 1 RA. In some embodiments, Ring A is pyrimidinyl with 0 to 1 RA.

[0277] In some embodiments, RAis selected from halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 hydroxyalkyl, or C1-6 haloalkyl. In some embodiments, RAis selected from halogen.

[0278] In some embodiments, Ring A is one of the following structure:

[0279] In some embodiments, R2is hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, or Ci-6 alkoxy. In some embodiments, R2is hydrogen or Ci-6 alkyl. In some embodiments, R2is hydrogen. In some embodiments, R2is Ci-6 alkyl. In some embodiments, R2is Ci-6 haloalkyl. In some embodiments, R2is Ci-6 alkoxy.

[0280] In some embodiments, R1is Ce-Cio aryl substituted with 0-4 R°, C-3-Cio cycloalkyl substituted with 0-4 R°, 3-10 membered heterocyclyl substituted with 0-4 R°, or 5-6 membered monocyclic heteroaryl substituted with 0-4 R°, Ci-6 alkyl substituted with 0-4 R°, Ci-6 alkoxy substituted with 0-4 R°, C2-6 alkenyl substituted with 0-4 R°, C2-6 alkynyl substituted with 0-4 R°, or NRnR12. In some embodiments, R1is Ce-Cio aryl substituted with 0-4 R°, C-3-Cio cycloalkyl substituted with 0-4 R°, 3-10 membered heterocyclyl substituted with 0-4 R°, or 5-6 membered monocyclic heteroaryl substituted with 0-4 R°, C1-6 alkyl substituted with 0-4 R°, or C1-6 alkoxy substituted with 0-4 R°. In some embodiments, R1is a C3-10 cycloalkyl substituted with 0-4 R°, a 3-10 membered heterocyclic group substituted with 0-4 R°, or a C1-6 alkyl substituted with 0-4 R°; R° is each independently hydrogen, halogen, hydroxy, cyano, C1-6 alkyl or C1-6 haloalkyl. In some embodiments, Ri is a C3-10 cycloalkyl group such as a cyclopropyl group. In some embodiments, R1is a 3-10 membered heterocyclic group substituted with 0-1 R°, a C2-6 alkenyl group substituted with 0-1 R°, or a C1-6 alkyl group substituted with 0-1 R°; R° is independently selected from halogen, hydroxy, cyano or C1-3 alkoxy.

[0281] In some embodiments, R1is one of the following structures:

[0282] In some embodiments, R is one of the structural formulas:,

[0283] In some embodiments, R is isoxazolyl substituted with one R7, oxazolyl substituted with one R7, oxadiazolyl substituted with one R7, triazolyl substituted with one R7, thiazolyl substituted with one R7, isothiazolyl substituted with one R7or thiadiazolyl substituted with one R7wherein R7is hydrogen, halogen, Ci-6 alkyl, Ci-6 alkoxy, cyano, hydroxy, Ci-6 hydroxyalkyl, Ci-6 haloalkyl, Ce-io aryl substituted with 0-1 R70, C3-10 cycloalkyl substituted with 0-1 R70, 3-10 membered heterocyclyl substituted with 0-1 R70, or 5-6 membered heteroaryl substituted with 0-1 R70; R70is each independently selected from halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, Ci-ehydroxyalkyl or C1-6 haloalkyl. In someembodiments,hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C3-6 cycloalkyl substituted with 0-1 R70; R70is selected from hydrogen, halogen, hydroxy, cyano, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl or 3-8 membered heterocyclyl; Z2is O or S; Z3is C or N; Z4is C or N.

[0284] In some embodiments, Z2is O, Z3is CH, and Z4is N; or Z2is N, Z3is CH, and Z4is O; or Z2is S, Z3is CH, and Z4is N; or Z2is S, Z3is N, and Z4is N. In some embodiments, R is one of the following:wherein RBais a Ci-6 alkyl group, a Ci-6 haloalkyl group, or a C3-6 cyclic hydrocarbon group substituted with one RBla, wherein RBlais C1-6 alkyl or C1-6 haloalkyl.

[0285] In some embodiments, R iswherein RBis hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkylor C1-6 haloalkyl;aryl group substituted with 0-1 Rc, a C3-10 cycloalkyl group substituted with 0-1 Rc, a 3-10 membered heterocyclyl group substituted with 0-1 Rc, or a 5-6 membered heteroaryl group substituted with 0-1 Rc; and Rcis halogen or C1-6 alkyl.

[0286] In some embodiments, RLisRBbis Ci-6 alkyl.

[0287] In some embodiments, R is:L is O or CH2, RBbis C1-3 alkyl, and RBcis hydrogen or C1-3 haloalkyl, such as trifluoromethyl.

[0288] In some embodiments, R isRBbis C1-6 alkyl, R51and R52are each independently hydrogen, halogen, deuterium, tritium or C1-6 alkyl, or R51and R52and the carbon to which they are attached together form a C3-6 cycloalkyl; R61and R62are each independently hydrogen, halogen, deuterium, tritium or C1-6 alkyl, or R61and R62and the carbon to which they are attached together form a C3-6 cycloalkyl; and n is 1 or 2.

[0289] In some embodiments,R51and R52are each independently selected from hydrogen, halogen, deuterium or tritium, or R51and R52and the carbon to which they are attached together form a C3-6 cycloalkyl group; R61and R62are each independently selected from hydrogen, halogen, deuterium or tritium, or R61and R62and the carbon to which they are attached together form a C3-6 cycloalkyl group; and RBbis C1-6 alkyl; and n is 1 or 2.

[0290] In some embodiments, wherein X1and X2are both N, X3is CH, and X4is C. In some embodiments, wherein X1, X2, and X3are N, and X4is C. In some embodiments, X1and X3are CH, X2is C, and X4is N. In some embodiments, X1and X3are CH, X2is N, and X4is C. In some embodiments, X1and X4are N, X2is C, and X3is CH. In some embodiments, X1is CH, X2and X3are N, and X4is C. In some embodiments, X1is CH, X2is C, and X3and X4are N. In some embodiments, X1, X3, and X4are N, and X2is C.

[0291] In some embodiments, the compound has the structure of the following formula VII-A:or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein:R is one of the following structural formulas:wherein:L is a direct bond, O, or CR21R22;RLis a Ce-Cio aryl substituted with 0-4 Rc, C-3-Cio cycloalkyl substituted with 0-4 Rc, 3-10 membered heterocyclyl substituted with 0-4 Rc, or 5-6 membered monocyclic heteroaryl substituted with 0-4 Rc;XJis CR31orN;X2is C or N;X3is CR32orN;X4is C or N;X5is CR33orN;Z1is CH orN;Z2is O or S;Z3is C orN;R1is Ce-Cio aryl substituted with 0-4 R°, C-3-Cio cycloalkyl substituted with 0-4 R°, 3-10 membered heterocyclyl substituted with 0-4 R°, or 5-6 membered monocyclic heteroaryl substituted with 0-4 R°, Ci-6 alkyl substituted with 0-4 R°, Ci-6 alkoxy substituted with 0-4 R°, C2-6 alkenyl substituted with 0-4 R°, C2-6 alkynyl substituted with 0-4 R°, orNRnR12;RBare each independently selected from hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, Ce-io aryl substituted with 0-4 RB1, C3-10 cycloalkyl substituted with 0-4 RB1, 3-10 membered heterocyclyl substituted with 0-4 RB1, or 5-6 membered heteroaryl substituted with 0-4 RB1;RB1are each independently selected from halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkyl or C1-6 haloalkyl;Rcare each independently selected from hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkyl or C1-6 haloalkyl;R31is hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkyl or C1-6 haloalkyl;R32is hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkyl or C1-6 haloalkyl;R33is hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano, hydroxy, C1-6 hydroxyalkyl or C1-6 haloalkyl;R51and R52are each independently hydrogen, halogen, deuterium, tritium, or C1-6 alkyl, or R51and R52and the carbon to which they are attached together form a C3-6 cycloalkyl; R61and R62are each independently hydrogen, halogen, deuterium, tritium, or C1-6 alkyl, or R61and R62and the carbon to which they are attached together form a C3-6 cycloalkyl; R7is hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, Ce-io aryl substituted with 0-4 R70, C3-10 cycloalkyl substituted with 0-4 R70, 3-10 membered heterocyclyl substituted with 0-4 R70, or 5-6 membered heteroaryl substituted with 0-4 R70;R70is hydrogen, halogen, hydroxy, cyano, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, 3-8 membered heterocyclic group orNRnR12;R° are each independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3-8 membered heterocyclyl orNRnR12;R11and R12are each independently selected from hydrogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, cyano, C1-6 hydroxyalkyl or C1-6 haloalkyl;R21and R22are each independently selected from hydrogen, halogen, deuterium, tritium, C1-6 alkyl, C1-6 alkoxy, cyano, C1-6 hydroxyalkyl, C 1-6 haloalkyl, or R21and R22and the carbon to which they are attached together form a C 3-6 cycloalkyl; andn is 1 or 2.

[0292] In some embodiments, X5is CR33, wherein R33is fluorine, hydrogen, methoxy, or trifluorom ethoxy. In some embodiments, X5is N. In some embodiments, R1is a C3-10 cycloalkyl substituted with 0-1 R°, a 3-10 membered heterocyclic group substituted with 0-1 R°, or a C1-6 alkyl substituted with 0-1 R°; R° is each independently selected from hydrogen, halogen, hydroxy, cyano, C1-6 alkyl or C1-6 haloalkyl. In some embodiments, R1is a C3-10 cycloalkyl such as a cyclopropyl.. In some embodiments, R1is a 3-10 membered heterocyclic group substituted with 0-1 R°, a C2-6 alkenyl group substituted with 0-1 R°, or a C1-6 alkyl group substituted with 0-1 R°; R° is independently selected from halogen, hydroxy, cyano or C1-3 alkoxy.

[0293] In some embodiments, R1is one of the following structures:

[0294] In some embodiments X1and X2are both N, X3is CH, and X4is C; or X1, X2, and X3are N, and X4is C; or X1and X3are CH, X2is C, and X4is N; or X1and X3are CH, X2is N, and X4is C; or X1and X4are N, X2is C, and X3is CH; or, X1is CH, X2and X3are N,and X4is C; or X1is CH, X2is C, and X3and X4are N; or X1, X3, and X4are N, and X2is C.

[0295] In some embodiments,hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, or C3-6 cycloalkyl substituted with 0-1 R70; R70is selected from hydrogen, halogen, hydroxy, cyano, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl or 3-8 membered heterocyclyl; Z2is O or S; Z3is C or N; Z4is C or N.

[0296] In some embodiments, Z2is N, Z3is CH, Z4is O; or Z2is S, Z3is CH, Z4is N; or Z2is S, Z3is CH, Z4is N. In some embodiments, Z2is O, Z3is CH, Z4is N; or Z2is S, Z3is CH, Z4is N; or Z2is S, Z3is CH, Z4is N.

[0297] In some embodiments, R is one of the following:wherein RBais a C1-6 alkyl group, a C1-6 haloalkyl group, or a C3-6 cyclic hydrocarbon group substituted with one RBla, wherein RBlais C1-6 alkyl or C1-6 haloalkyl.

[0298] In some embodiments, R iswherein RBis hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkylor C1-6 haloalkyl;membered heterocyclyl group substituted with 1 Rc; and Rcis C1-3 alkyl.

[0299] In some embodiments, RLisRBbis C1-6 alkyl.

[0300] In some embodiments, R is:L is O or CH2, RBbis C1-3 alkyl, and RBcis hydrogen or C1-3 haloalkyl, such as trifluoromethyl. In some embodiments, RBbis methyl; and RBcis hydrogen or trifluoromethyl.

[0301] In some embodiments, R isRBbis C1-6 alkyl, R51and R52are each independently hydrogen, halogen, deuterium, tritium or C1-6 alkyl, or R51and R52and the carbon to which they are attached together form a C3-6 cycloalkyl; R61and R62are each independently hydrogen, halogen, deuterium, tritium or C1-6 alkyl, or R61and R62and the carbon to which they are attached together form a C3-6 cycloalkyl; and n is 1 or 2.

[0302] In some embodiments,R51and R52are each independently selected from hydrogen, halogen, deuterium or tritium, or R51and R52and the carbon to which they are attached together form a C3-6 cycloalkyl group; R61and R62are each independently selected from hydrogen, halogen, deuterium or tritium, or R61and R62and the carbon to which they are attached together form a C3-6 cycloalkyl group; and RBbis C1-6 alkyl; and n is 1 or 2. In some embodiments, RBbis methyl.

[0303] In some embodiments, the compound has the structure of the following formula VII-B:or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein:X1is CR31or N;X2is C or N;X3is CR32or N;X4is C or N;X5is CR33or N;R1is C6-C10aryl substituted with 0-4 R°, C-3-Cio cycloalkyl substituted with 0-4 R°, 3- 10 membered heterocyclyl substituted with 0-4 R°, or 5-6 membered monocyclic heteroaryl substituted with 0-4 R°, Ci-6 alkyl substituted with 0-4 R°, Ci-6 alkoxy substituted with 0-4 R°, C2-6 alkenyl substituted with 0-4 R°, C2-6 alkynyl substituted with 0-4 R°, orNRnR12;R31is hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkyl or C1-6 haloalkyl;R32is hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkyl or C1-6 haloalkyl;R33is hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano, hydroxy, C1-6 hydroxyalkyl or C1-6 haloalkyl;R° are each independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3-8 membered heterocyclyl orNRnR12;R11and R12are each independently selected from hydrogen, hydroxy, Ci-6 alkyl, Ci-6 alkoxy, cyano, Ci-6 hydroxyalkyl or Ci-6 haloalkyl;Ring B is a 5-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O or S, and the ring B is substituted with m number of R8;R8are each independently protium, deuterium, tritium, halogen, hydroxyl, cyano, Ci-6 alkyl optionally substituted with R80, Ci-6 alkoxy optionally substituted with R80, C3-6 cycloalkyl optionally substituted with R80, Ce-io aryl optionally substituted with R80, 3-10 membered heterocyclyl optionally substituted with R80, -CONR81R82or -COR83;R80are each independently deuterium, halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl or C1-6 haloalkoxy;R81and R82are each independently hydrogen or C1-6 alkyl;R83is C1-6 alkyl; andm is 1, 2, or 3.

[0304] In some embodiments, Ring B is one of the following:and wherein the B ring is substituted with two R8.

[0305] In some embodiments, ring B is:and ring B is substituted with 2 to 3 R8.

[0306] In some embodiments, two R8are C1-6 alkyl optionally substituted with protium, deuterium, tritium, halogen, or R80, and the other R8is aryl optionally substituted with R80. In some embodiments, X5is CR33, and R33is fluoro, hydrogen, methoxy, or trifluoromethyl.

[0307] In some embodiments X1and X2are both N, X3is CH, and X4is C; or X1, X2, and X3are N, and X4is C; or X1and X3are CH, X2is C, and X4is N; or X1and X3are CH, X2is N, and X4is C; or X1and X4are N, X2is C, and X3is CH; or, X1is CH, X2and X3are N, and X4is C; or X1is CH, X2is C, and X3and X4are N; or X1, X3, and X4are N, and X2is C. In some embodiments, X1and X2is N, X3is Ch, and X4is C.

[0308] In some embodiments, the compound has a structure of the following formulaVII-B1:or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein:R1is C-3-Cio cycloalkyl substituted with 0-4 R°, 3-10 membered heterocyclyl substituted with 0-4 R°, or Ci-6 alkyl substituted with 0-4 R°, Ci-6 alkoxy substituted with 0-4 R°, C2-6 alkenyl substituted with 0-4 R°, C2-6 alkynyl substituted with 0-4 R°, or NRnR12;R° are each independently selected from hydrogen, halogen, hydroxyl, cyano, Ci-ealkyl, or C1-6 haloalkyl;R33is halogen or C1-6 alkyl;R91is C1-6 alkyl optionally substituted with R90, C3-6 cycloalkyl optionally substituted with R90, C3-6 cycloalkyl optionally substituted with R90, 3-10 membered heterocyclyl optionally substituted with R90;R92is phenyl optionally substituted with R90or 3-10 membered heterocyclic group optionally substituted with R90;R93is protium, deuterium, tritium, halogen or C1-6 alkyl; andR90is each independently selected from protium, deuterium, tritium, halogen, cyano, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl;

[0309] In some embodiments, R1is C3-6 cycloalkyl, for example a cyclopropyl. In some embodiments, R91is a C1-6 alkyl group such as tert-butyl, R92is phenyl optionally substituted with R90, each R90are independently halogen such as fluorine, C1-6 alkyl such as methyl, ethyl or isopropyl, or C1-6 alkoxy such as methoxy; and R93is protium. In some embodiments, R91is a C3-6 cycloalkyl group optionally substituted with R90, each R90are independently aC1-6 haloalkyl, for example, R91is; R92is phenyl optionally substituted with R90; each R90being independently selected from halogen such as fluorine, C1-6 alkyl such as methyl, ethyl or isopropyl, or C1-6 alkoxy such as methoxy; and R93is protium. In someembodiments, R92is one of the follow structures:

[0310] In various different embodiments, the compound has one of the structures set forth in Table 1G below, or a stereoisomer, tautomer, or salt thereof. Compounds in Table 1G were prepared as described in by methods known in the art and analyzed by mass spectrometry and / or1H NMR. In some embodiments, the compound of Formula (VII) is a modulator of the NLRP3 inflammasome. In some embodiments, the compound of Formula (VII) is an inhibitor of NEK7 in a patient or in a biological sample. In some embodiments, the compound of Formula (VII) inhibits NEK7 and / or modulates the activity of the NLRP3 inflammasome. In some embodiments, the compound of Formula (VII) is administered to treat a hematological malignancy. The treatment may be treating MRD. The treatment may be preventing relapse of the hematological malignancy.

[0311] In various different embodiments, the compound has one of the structures set forth in Table 1G below, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0312] Compounds in Table 1G were prepared as described by methods known in the art and analyzed by mass spectrometry and / or1H NMR.Table 1G: Representative compounds of Structure (VII)Pharmaceutical Compositions

[0313] In one aspect, compounds provided herein are formulated into pharmaceutical compositions that are useful in a variety of applications including, but not limited to, therapeutic methods, such as the treatment of hematological malignancies. The treatment may be treating MRD. The treatment may be preventing relapse of the hematological malignancy. The methods of use may be in vitro, ex vivo, or in vivo methods. In various embodiments, the pharmaceutical compositions are formulated for delivery via oral administration.

[0314] The pharmaceutical compositions may contain any pharmaceutically acceptable carrier. “Pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable material, composition, or vehicle that is involved in carrying or transporting a compound of interest from one tissue, organ, or portion of the body to another tissue, organ, or portion of the body. For example, the carrier may be a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, or a combination thereof. Each component of the carrier must be “pharmaceutically acceptable” in that it must be compatible with the other ingredients of the formulation. It must also be suitable for use in contact with any tissues or organs with which it may come in contact, meaning that does not carry a risk of toxicity, irritation, allergic response, immunogenicity, or any other complication that excessively outweighs its therapeutic benefits.

[0315] In some embodiments, the pharmaceutical composition comprises about 0.5 mg to about 10 mg of the compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII). In some embodiments, the pharmaceutical composition comprises about 10 mg of the compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), orFormula (VII). In some embodiments, the pharmaceutical composition comprises about 9 mg of the compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII). In some embodiments, the pharmaceutical composition comprises about 8 mg of the compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII). In some embodiments, the pharmaceutical composition comprises about 7 mg of the compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII). In some embodiments, the pharmaceutical composition comprises about 6 mg of the compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII). In some embodiments, the pharmaceutical composition comprises about 5 mg of the compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII). In some embodiments, the pharmaceutical composition comprises about 4 mg of the compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII). In some embodiments, the pharmaceutical composition comprises about 3 mg of the compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII). In some embodiments, the pharmaceutical composition comprises about 2 mg of the compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII). In some embodiments, the pharmaceutical composition comprises about 1 mg of the compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII). In some embodiments, the pharmaceutical composition comprises about 0.5 mg of the compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII).

[0316] In some embodiments, pharmaceutical compositions of the compounds of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII) are modulators of the NLRP3 inflammasome. In some embodiments, pharmaceutical compositions of the compounds of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII) inhibit NEK7 when administered to a patient or a biological sample.

[0317] In some embodiments, the composition comprises a tablet comprising the active ingredient (a compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII)); and one or more excipients of Table 2 or 3 (e.g., sodium lauryl sulfate (Kolliphore SLS fine), partially pre-gelatinized maize starch(Starch 1500), microcrystalline cellulose (Avicel PH 101), sodium starch glycolate (type A), hydroxypropyl cellulose LF (Klucel LH Pharma), Anhydrous Colloidal silicon dioxide (Aerosil Pharma 200), magnesium stearate). The one or more excipients may be present in the tablet at the amount shown in Table 2 or 3. The one or more excipients may be present in the table at the weight percentage shown in Table 2 or 3.

[0318] In some embodiments, the pharmaceutical composition comprises about 0.5 mg to about 10 mg of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 10 mg of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 9 mg of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 8 mg of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 7 mg of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 6 mg of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 5 mg of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 4 mg of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 3 mg of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 2 mg of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 1 mg of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 0.5 mg of the compound of Formula (I).

[0319] In some embodiments, pharmaceutical compositions of the compounds of Formula (I) are modulators of the NLRP3 inflammasome. In some embodiments, pharmaceutical compositions of the compounds of Formula (I) inhibit NEK7 when administered to a patient or a biological sample.

[0320] In some embodiments, the composition of tablets containing the active ingredient, a compound of Formula (I), is as given in Table 2. In some embodiments, the composition of tablet containing the active ingredient, a compound of Formula (I), is as given in Table 3. As a non-limiting example, the compound of Formula (I) is Compound 10.Table 2. Composition of Compound 10 Tablets, 0.5 mg and 2 mgTable 3. Composition of Compound 10 Tablets, 4 mg and 5 mg* water is removed as part of the tablet manufacturing process**target weight gainJ50% extra quantity of Opadry reagent and water are dispensed to account for manufacturing losses (additional quantity not shown in the table)Methods of Treatment

[0321] Provided herein are methods of treating hematological malignancies in a subject in need thereof by administering to the subject a composition comprising a therapeutically effective amount of an inflammasome modulator. Provided herein are methods of treating hematological malignancies in a subject in need thereof by administering to the subject a composition comprising a therapeutically effective amount of a NEK7 inhibitor. Provided herein are methods of treating hematological malignancies in a subject in need thereof by administering to the subject a composition comprising a compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII). The treatment may be treating minimal residual disease (MRD) in a hematological malignancy. MRD may occur when leukemia cells are not detectable in the bone marrow using microscopy, but are detectable using flow cytometry or a nucleic acid detection method such as polymerase chain reaction. MRD may occur when leukemia cells are not detectable in the bone marrow using microscopy but are detectable using next-gen sequencing (NGS). MRD may occur when leukemia is not detectable in the bone marrow. MRD may occur when the blast cell percentage in the bone marrow is 5% or less. The treatment may be preventing relapse of the hematological malignancy. The treatment may treat active disease after relapse, e.g., at least 5% blast cells in bone marrow. The treatment of MRD may prevent relapse.

[0322] Provided herein is a method of treating a hematological malignancy, comprising administering to a subject in need thereof, wherein the subject has very low risk, low risk, intermediate risk, or high risk of myelodysplastic syndrome (MDS), a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

[0323] wherein: A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6; X is CH or N; Y is NH; R1is H; R2is Ci-Ce alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl; R3is H; R4is a heteroaryl selectedfrom oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl; R5is H; and each R6is independently halo, Ci-Ce alkyl, Ci-Ce alkoxy, cyano, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl. In some embodiments, the subject has very low risk, low risk, or intermediate risk of MDS, wherein the very low risk, low risk, or intermediate risk of MDS is classified according to the World Health Organization (WHO) 2022 classification or Revised International Prognostic Scoring System (IPSS-R) classification. In some embodiments, the subject has very low risk or low risk MDS. In some embodiments, the subject has high risk MDS.

[0324] Provided herein is a method of treating a hematological malignancy, comprising administering to a subject in need thereof, wherein the subject has very low risk or low risk of myelodysplastic syndrome (MDS), a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:wherein: A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6; X is CH or N; Y is NH; R1is H; R2is Ci-Ce alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl; R3is H; R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionallysubstituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, Cs-Cs haloalkylcycloalkyl, Cs-Cs aminylalkylcycloalkyl, Cs-Cs alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and Cs-Cs halocycloalkyl; R5is H; and each R6is independently halo, Ci-Ce alkyl, Ci-Ce alkoxy, cyano, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl.

[0325] A hematological malignancy includes Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Chronic Myeloid Leukemia (CML), Chronic Myelomonocytic Leukemia (CMML), Chronic Neutrophilic Leukemia (CNL), clonal hematopoiesis of indeterminate potential (CHIP), Essential Thrombocythemia (ET), Myelodysplastic Syndromes (MDS), Chronic Lymphocytic Leukemia (CLL), Multiple Myeloma (MM), Non-Hodgkin Lymphoma (NHL), Polycythemia Vera (PV), Primary Myelofibrosis (PMF), Systemic Mastocytosis and / or Hodgkin Lymphoma (HL).

[0326] Provided herein is a method of treating a hematological malignancy, wherein the hematological malignancy is Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Chronic Lymphocytic Leukemia (CLL), Chronic Myeloid Leukemia (CML), Chronic Neutrophilic Leukemia (CNL), clonal hematopoiesis of indeterminate potential (CHIP), Essential Thrombocythemia (ET), Multiple Myeloma (MM), Non-Hodgkin Lymphoma (NHL), Hodgkin Lymphoma (HL), Polycythemia Vera (PV), Primary Myelofibrosis (PMF), Systemic Mastocytosis or a combination thereof, comprising administering to a subject in need thereof, a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:wherein: A is Ce-Cio aryl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6; X is CH or N; Y is NH; R1is H; R2is Ci-Ce alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl;R3is H; R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkyl cycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkyl cycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl; R5is H; and each R6is independently halo, Ci-Ce alkyl, Ci-Ce alkoxy, cyano, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl.

[0327] Some example methods involve treating AML in a subject. The subject may have favorable-risk AML. The subject may have intermediate-risk AML. The subject may have high-risk AML. Genetic abnormalities that may characterize favorable risk disease include chromosomal translocations t(8;21)(q22;q22.1) or inv(16)(pl3.1q22); lack of FLT3-ITD (internal tandem duplication) mutations without mutated NPM1 or with CEBPA (bZIP inframe) mutations. Intermediate-risk AML may be characterized by the presence of a FLT3-ITD mutation or t(9; 1 l)(p21.3;q23.3, or MLL: KMT2A rearrangement). High-risk AML categorization can be the presence of monosomy 5 / del 5q or 7 / deletion 7q, other monosomal or complex karyotype (^3 unrelated abnormalities), and / or mutations in ASXL1, EZH2, SRSF2, or TP53.

[0328] Some example methods involve treating MDS in a subject. The subject may have very low risk MDS, low risk MDS, intermediate risk MDS, or high risk MDS, with or without symptomatic anemia. The subject may have high risk MDS with or without symptomatic anemia. The subject may have very low risk MDS, low risk MDS, or intermediate risk MDS, with or without symptomatic anemia. The subject may have a documented diagnosis of MDS or non-proliferative (WBC less than 13,000 per micro L) myelodysplastic or myeloproliferative neoplasm (MDS or MPN) according to World Health Organization (WHO) 2022 classification and Revised International Prognostic Scoring System (IPSS-R) classification of very low, low, intermediate, or high risk disease. The subject may have MDS with low blasts and isolated 5q deletion (MDS-5q), MDS with low blasts and SF3B1 mutation (MDS-SF3B1), MDS with low blasts (MDS-LB), MDS, hypoplastic (MDS-h), MDS with increased blasts (MDS-IB) MDS-IB1, or a combination of two or more thereof. The subject may have chronic myelomonocytic leukemiamyelodysplastic or myeloproliferative neoplasm with neutrophilia. The subject may have myelodysplastic or myeloproliferative neoplasm with SF3B1 mutation and thrombocytosis Myelodysplastic or myeloproliferative neoplasm, not otherwise specified. The subject may have less than 10 percent bone marrow myeloblasts. The subject may be refractory or intolerant of, or ineligible for treatment with an erythroid stimulating agent (ESA) as defined by any of the following: (a) Refractory to prior ESA treatment: Prior treatment with an ESA without response or no longer responding to an ESA alone or in combination with a myeloid growth factor (must have received recombinant erythropoietin (rHu EPO) with epoetin alfa greater than or equal to 40,000 IU per week for greater than 8 weeks or darbepoetin alpha 300-500 micro g Q 2-3 W for greater than 8 week; (b) Intolerant to prior ESA treatment Intolerant to prior ESA treatment with documentation of discontinuation due to intolerance or adverse event; or (c) ESA ineligible: Subject may have been ESA ineligible due to low probability of response to ESAs based upon endogenous serum erythropoietin level greater than 200 U per L for subjects not previously treated with ESAs. The subject may have an Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2. The subject may have symptomatic anemia with non-transfused hemoglobin.

[0329] The subject may have clonal hematopoiesis (CH), clonal hematopoiesis of indeterminate potential (CHIP), and / or clonal cytopenias of undetermined significance (CCUS). The subject may have clonal hematopoiesis (CH). The subject with CH may have CHIP, CCUS, or a combination thereof. The subject may have acquired mutations in genes associated with myeloid malignancies at a variant allele fraction (VAF) of 2% or greater, in the absence of cytopenia. The subject may have acquired mutations in genes associated with myeloid malignancies at a variant allele fraction (VAF) of 1% or greater, in the absence of cytopenia. The subject may have acquired mutations in genes associated with myeloid malignancies at a variant allele fraction (VAF) of 5% or greater, in the absence of cytopenia. Non-limiting example genes are DNMT3A, TET2, ASXL1, TP53. The subject may have an acquired mutation to the DNMT3A (DNA methyl transferase 3 alpha) gene The subject may have an acquired mutation to the TET2 gene. The subject may have an acquired mutation to the ASXL1 gene. The subject may have an acquired mutation to the TP53 gene. The subject may have novel acquired mutations. The treatment may include reduction of CHIP allele frequency in a subject.

[0330] Provided herein are methods of treating hemolytic anemia in a subject in need thereof by administering to the subject a composition comprising a therapeutically effective amount of an inflammasome modulator. Provided herein are methods of treating hemolyticanemia in a subject in need thereof by administering to the subject a composition comprising a therapeutically effective amount of a NEK7 inhibitor. Provided herein are methods of treating hemolytic anemia in a subject in need thereof by administering to the subject a composition comprising a compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII).

[0331] The treatment may be treating inherited hemolytic anemia or acquired hemolytic anemia. Inherited hemolytic anemia includes, but is not limited to sickle-cell disease, thalassemia, congenital dyserthropoietic anemia, hereditary spherocytosis, hereditary elliptocytosis, hereditary pyropoikilocytosis, hereditary stomatocytosis, hereditary exocytosis, glucose-6-phosphate dehydrogenase (G6PD) deficiency, and pyruvate kinase deficiency. Acquired hemolytic anemia includes, but is not limited to autoimmune hemolytic anemia, immune-mediated hemolytic anemia, drug-induced hemolytic anemia, paroxysmal nocturnal hemoglobinuria, malaria, and other infectious anemias.

[0332] The inflammasome modulator may be administered at a first dose of about 0.5 mg to about 10 mg. For example, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg or about 10 mg. The first dose may be administered for a first duration, at an interval of every day, 5 days on and 2 days off, three times a week (e.g., Monday, Wednesday, Friday), twice a week (e.g., Monday, Thursday), once a week, once every 2 weeks, or once a month. The inflammasome modulator may be administered at a second dose of about 0.5 mg to about 10 mg. For example, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg or about 10 mg. The second dose may be administered for a second duration, at an interval of every day, 5 days on and 2 days off, three times a week (e.g., Monday, Wednesday, Friday), twice a week (e.g., Monday, Thursday), once a week, once every 2 weeks, or once a month.

[0333] The NEK7 inhibitor may be administered at a first dose of about 0.5 mg to about 10 mg. For example, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg or about 10 mg. The first dose may be administered for a first duration, at an interval of every day, 5 days on and 2 days off, three times a week (e.g., Monday, Wednesday, Friday), twice a week (e.g., Monday, Thursday), once a week, once every 2 weeks, or once a month. The inflammasome modulator may be administered at a second dose of about 0.5 mg to about 10 mg. For example, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg about 6 mg, about 7 mg, about 8 mg, about 9 mg or about 10 mg. The second dose may be administered for a secondduration, at an interval of every day, 5 days on and 2 days off, three times a week (e.g., Monday, Wednesday, Friday), twice a week (e.g., Monday, Thursday), once a week, once every 2 weeks, or once a month.

[0334] The compound of Formula (0), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII) may be administered at a first dose of about 0.5 mg to about 10 mg. For example, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg or about 10 mg. The first dose may be administered for a first duration, at an interval of every day, 5 days on and 2 days off, three times a week (e.g., Monday, Wednesday, Friday), twice a week (e.g., Monday, Thursday), once a week, once every 2 weeks, or once a month. The inflammasome modulator may be administered at a second dose of about 0.5 mg to about 10 mg. For example, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg or about 10 mg. The second dose may be administered for a second duration, at an interval of every day, 5 days on and 2 days off, three times a week (e.g., Monday, Wednesday, Friday), twice a week (e.g., Monday, Thursday), once a week, once every 2 weeks, or once a month.

[0335] Treatment of hematological malignancies and hemolytic anemias may include treatment with a compound disclosed herein (e.g., inflammasome modulator, NEK7 inhibitor, a compound of Formulas (I)-(VII)), in combination with another therapy. The other therapy may include, without limitation, induction therapy, consolidation therapy, maintenance therapy, targeted therapy, CAR-T cell therapy, cytoreductive therapy (e.g., hydroxyurea), central nervous system prophylaxis including intrathecal chemotherapy or radiation therapy, hematopoietic stem cell transplantation (HSCT), autologous stem cell transplant (ASCT), phlebotomy, administration of cytarabine, an anthracycline fludarabine, cyclophosphamide, rituximab, tyrosine kinase inhibitors (TKIs) (e.g., imatinib), Bruton’s tyrosine kinase (BTK) inhibitors (e.g., ibrutinib, acalabrutinib), BCL-2 inhibitors (e.g., venetoclax), PI3K inhibitors (e.g., idelalisib), obinutuzumab, ofatumumab, doxorubicin hydrochloride (Adriamycin), bleomycin sulfate, vinblastine sulfate, dacarbazine, ABVD, brentuximab vedotin (anti-CD30), pembrolizumab, vincristine, prednisone, R-CHOP, proteasome inhibitors (e.g., bortezomib, carfilzomib), immunomodulatory drugs (e.g., lenalidomide, thalidomide), monoclonal antibodies (e.g., daratumumab), bispecific antibodies, hypomethylating agents (e.g., azacytidine, decitabine), JAK inhibitors (e.g., ruxolitinib), or any combination thereof.

[0336] The other therapy may include, without limitation, a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent comprises alkylating agents, nitrogenmustards, nitrosoureas, tetrazines, aziridines, cisplatins and derivatives, non-classical alkylating agents, mechlorethamine, cyclophosphamide, melphalan, chlorambucil, ifosfamide, busulfan, N-Nitroso-N-methylurea (MNU), carmustine (BCNU), lomustine (CCNU), semustine (MeCCNU), fotemustine, streptozotocin, dacarbazine, mitozolomide, temozolomide, thiotepa, mitomycin, diaziquone (AZQ), cisplatin, carboplatin, oxaliplatin, procarbazine, hexamethylmelamine, antimetabolites, anti-folates, methotrexate, pemetrexed, fluoropyrimidines, fluorouracil, capecitabine, deoxynucleoside analogues, cytarabine, gemcitabine, decitabine, azacitidine, fludarabine, nelarabine, cladribine, clofarabine, and pentostatin, thiopurines, thioguanine, mercaptopurine, anti -microtubule agents, vinca alkaloids, taxanes, vincristine, vinblastine, semi -synthetic vinca alkaloids, vinorelbine, vindesine, vinflunine, paclitaxel, docetaxel, podophyllotoxin, etoposide, teniposide, topoisomerase inhibitors, irinotecan, topotecan, camptothecin, etoposide, doxorubicin, mitoxantrone, teniposide, catalytic inhibitors, novobiocin, merbarone, aclarubicin, cytotoxic antibiotics, anthracyclines, bleomycins, mitomycin C, mitoxantrone, actinomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, anthracyclines, pirarubicin, aclarubicin, mitoxantrone, bleomycin, mitomycin, targeted therapies, monoclonal antibodies, naked monoclonal antibodies, conjugated monoclonal antibodies, chemolabeled antibodies, bispecific monoclonal antibodies, or any combination thereof.

[0337] The treatment or prevention may include the reduction of CHIP allele frequency in a subject. In some embodiments, the subject has clonal hematopoiesis (CH) or clonal hematopoiesis of indeterminate potential (CHIP). In some embodiments, the subject has the presence of acquired mutations in genes associated with myeloid malignancies at a variant allele fraction (VAF) of 2% or greater, in the absence of cytopenia. In some embodiments, the subject has the presence of acquired mutations in genes associated with myeloid malignancies at a variant allele fraction (VAF) of 1% or greater, in the absence of cytopenia. In some embodiments, the subject has the presence of acquired mutations in genes associated with myeloid malignancies at a variant allele fraction (VAF) of 3% or greater, in the absence of cytopenia. In some embodiments, the subject has the presence of acquired mutations in genes associated with myeloid malignancies at a variant allele fraction (VAF) of 4% or greater, in the absence of cytopenia. In some embodiments, the subject has the presence of acquired mutations in genes associated with myeloid malignancies at a variant allele fraction (VAF) of 5% or greater, in the absence of cytopenia. In some embodiments, the subject has somatic mutations in normal dividing cells. In some embodiments, the subject has clonal cytopenias of undetermined significance (CCUS).

[0338] Clonal hematopoiesis (CH), clonal hematopoiesis of indeterminate potential (CHIP), and / or clonal cytopenias of undetermined significance (CCUS) can be symptoms of biological aging. By treating CH, CHIP, and CCUS as described herein, the method may also treat biological aging.

[0339] Other symptoms include when the subject has the presence of acquired mutations in genes associated with myeloid malignancies at a variant allele fraction (VAF) of 2% or greater, in the absence of cytopenia. Other symptoms include when the subject has the presence of acquired mutations in genes associated with myeloid malignancies at a variant allele fraction (VAF) of 1% or greater, in the absence of cytopenia. Other symptoms include when the subject has the presence of acquired mutations in genes associated with myeloid malignancies at a variant allele fraction (VAF) of 5% or greater, in the absence of cytopenia. Non-limiting example genes are DNMT3A, TET2, ASXL1, TP53. In some aspects, the symptom includes the presence of an acquired mutation to the DNMT3 A (DNA methyl transferase 3 alpha) gene. In some aspects, the symptom includes the presence of an acquired mutation to the TET2 gene. In some aspects, the symptom includes the presence of an acquired mutation to the ASXL1 gene. In some aspects, the symptom includes the presence of an acquired mutation to the TP53 gene. In some aspects, the symptom includes the presence of novel acquired mutations.Embodiments

[0340] Some numbered embodiments are provided as follows:1. A method of treating a hematological malignancy, comprising administering to a subject in need thereof an inflammasome modulator.2. The method of embodiment 1, wherein the inflammasome modulator is a modulator of the NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome.3. The method of embodiment 2, wherein the inflammasome modulator inhibits the priming step of the NLRP3 inflammasome.4. The method of embodiment 3, wherein the inflammasome modulator inhibits signaling downstream of members of the TLR (toll -like receptor) family, IL-1R (interleukin 1 receptor) family, and / or TNFR1 / 2 (tumor necrosis factor receptor 1 / 2).5. The method of embodiment 3 or 4, wherein the inflammasome modulator prevents the activation of NF-kB (nuclear factor kappa-beta).6. The method of any one of embodiments 2-5, wherein the administering reduces the level of TNF-a, IL-6, or the components of the NLRP3 inflammasome (e.g., NLRP3, pro-IL-ip (pro-interleukin- Ibeta), pro-IL18 (pro-interleukin- 18)), or a combination thereof, in the subject.7. The method of embodiment 2, wherein the inflammasome modulator inhibits the assembly and activation step of the NLRP3 inflammasome.8. The method of embodiment 7, wherein the inflammasome modulator inhibits the formation of a NLRP3 (protein)-NEK7 (protein) interaction.9. The method of embodiment 8, wherein the inflammasome modulator inhibits the formation of the ASC speck and the NLRP3 inflammasome.10. The method of any one of embodiments 7-9, wherein the inflammasome modulator prevents caspase- 1 activation.11. The method of any one of embodiments 7-10, wherein the inflammasome modulator inhibits the production of IL-ip.12. The method of any one of embodiments 7-11, wherein the inflammasome modulator inhibits the production of IL-18.13. The method of any one of embodiments 7-12, wherein the inflammasome modulator inhibits the cleavage of gasdermin D.14. The method of any one of embodiments 7-13, wherein the inflammasome modulator prevents pyroptotic cell death.15. The method of any one of embodiments 1-14, wherein the administering comprises administering about 0.5 mg to about 10 mg of the inflammasome modulator to the subject.16. The method of any one of embodiments 1-15, wherein the administering comprises administering the inflammasome modulator to the subject every day, every other day, every two days, every three days, every four days, every five days, every six days, once a week, five days on and two days off, once every two weeks, or once a month.17. The method of any one of embodiments 1-16, wherein the administering comprises orally administering to the subject the inflammasome modulator.18. The method of any one of embodiments 1-17, wherein the inflammasome modulator is in the form of a tablet, capsule or pill.19. A method of treating a hematological malignancy, comprising administering to a subject in need thereof a compound of Formula (0), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:Formula (0)wherein:A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6;X is CH or N;X1is C or N;X2is C or N;X3is CH or N;X4is C or N;Y is NH;R1is H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy;R2is hydrogen, Ci-Ce alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halogen, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl;R3is absent, H, halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkyl or Ci-6 haloalkyl;R4is a Ce-Cio aryl, C3-C10 cycloalkyl, 3-12 membered heterocyclyl, 5- to 12- membered heteroaryl;R5is H;each R6is independently halogen, Ci-Ce alkyl, Ci-Ce alkoxy, cyano, Ci-Ce hydroxylalkyl, Ci-Ce haloalkyl,L is a direct bond, O, or CRL1RL2;RLis a Ce-Cio aryl substituted with 0-4 Rc, C-3-Cio cycloalkyl substituted with 0- 4 Rc, 3-10 membered heterocyclyl substituted with 0-4 Rc, or 5-6 membered monocyclic heteroaryl substituted with 0-4 Rc, each of which is optionally substitutedwith one more substituents selected from halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkyl or C1-6 haloalkyl; andRL1and RL2are each independently selected from hydrogen, halogen, deuterium, tritium, C1-6 alkyl, C1-6 alkoxy, cyano, C1-6 hydroxyalkyl, C1-6 haloalkyl, or R21and R22and the carbon to which they are attached together form a C3-6 cycloalkyl.20. A method of treating a hematological malignancy, comprising administering to a subject in need thereof a compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:Formula (I)wherein:A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6;X is CH or N;Y is NH;R1is H;R2is Ci-Ce alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl;R3is H;R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkyl cycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkyl cycloalkyl, 3- to 8-memberedheterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl;R5is H; andeach R6is independently halo, Ci-Ce alkyl, Ci-Ce alkoxy, cyano, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl;Formula (II) wherein:X is N or CH;A is Ce-Cio arylene, C3-C10 cycloalkylene, 3-10 membered heterocyclylene, or 5-6 membered heteroarylene;R1is H, halo, Ci-Ce alkyl, C3-C10 cycloalkyl, or 3-10 membered heterocyclyl;R2is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C10 cycloalkyl, or 3-10 membered heterocyclyl;R3is aminylalkyl, 3-10 membered heterocyclyl, 3-10 membered heterocyclylalkyl, 3-10 membered heterocyclylcarbonyl, 3-10 membered heterocyclylalkenyl, 3-10 membered N-heterocyclyloxy, or 5-6 membered heteroaryl; orR3joins with an occurrence of R4attached to a carbon adjacent to a carbon to which R3is attached to form a C3-C8 cycloalkyl;R4is, at each occurrence, independently halo, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci- Ce alkoxy, Ci-Ce haloalkoxy, C3-C8 halocycloalkyl, or C3-C8 cycloalkyl; andn is 0, 1, 2, 3, or 4;Formula (III)wherein:A is Ce-Cio arylene, C3-C10 cycloalkylene, 3-10 membered heterocyclylene, or 5-6 membered heteroarylene;X is N or CR4;Y is N or CH;R1is Ci-Ce alkyl, Ci-Ce hydroxylalkyl, C3-C10 cycloalkyl, or 3-10 membered heterocyclyl;R2is a 3-10 membered heterocyclyl, 3-10 membered heterocyclylalkyl, 3-10 membered heterocyclylalkenyl, 3-10 membered heterocyclylcarbonyl, 3-10 membered heterocyclyloxy, or 5-6 membered heteroaryl; orR2joins with an occurrence of R3attached to a carbon adjacent to a carbon to which R2is attached to form a C3-C8 cycloalkyl;R3is, at each occurrence, independently halo, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or C3-C8 cycloalkyl;R4is H, Ci-Ce alkyl, Ci-Ce haloalkyl, or C3-C8 cycloalkyl; andn is 0, 1, 2, 3, or 4;Formula (IV) wherein:A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl, or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R5;Xis N or CR1C;Y is N or CRld;Z is C(R6)(R7) or NR6;Rla, Rlb, Rlc, and Rldare each independently H, halo, Ci-Ce alkyl, or C3-C8 cycloalkyl;R2aand R2bare each independently H, halo, cyano, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, C3-C8 cycloalkyl, or C3-C8 halocycloalkyl, provided that R2aand R2bare not both H;R3is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, heteroaryl, or aryl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and Ci-Ce alkoxy;R4is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, Ce-Cio aryl, or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and Ci-Ce alkoxy;R5is, at each occurrence, independently halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl;R6is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce hydroxylalkyl; and R7is H, OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce hydroxylalkyl;Formula (V)wherein:A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R5;X is N or CH;Yis CHOH orNH;R1is H or Ci-Ce alkyl;R2is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-Ce alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl;R3is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from amino, halo, cyano, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Cs-Cscycloalkyl, Cs-Cs alkylcycloalkyl, Cs-Cs haloalkylcycloalkyl, Cs-Cs aminylalkylcycloalkyl, Ci-Ce cyanoalkyl Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclylalkyl, 3-8 membered heterocyclylcycloalkyl, 3-8 membered haloheterocyclyl, 3-8 membered haloheterocyclylalkyl, Cs-Cs halocycloalkyl and Cs-Cs halocycloalkylalkyl, and combinations thereof;R4is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, Ce-Cio aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl and Ci-Ce alkoxy; andR5is, at each occurrence, independently halo, cyano, Ci-Ce alkyl, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl;Formula (VI)wherein:represents a double or a single bond such that all valences are satisfied; A is an optionally substituted 5-6-membered heterocyclyl, an optionally substituted 6-membered aryl, or an optionally substituted 5-6-membered heteroaryl;X is N or CR3;Y is C or N;W is CH or N;Z is CH or N;R1is optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted Ci-Ce hydroxyalkyl, optionally substituted Ci-Ce alkoxyalkyl, optionally substituted Ci-Ce carboxyalkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted Ce-Cio aryl, optionally substituted 3-10 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl;R2is optionally substituted aryl or optionally substituted heteroaryl; and R3is hydrogen, halo, cyano, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ci-Ce alkoxy, optionally substituted Ci-Ce haloalkoxy, or optionally substituted C3-C8 cycloalkyl.21. A method of treating a hematological malignancy, comprising administering to a subject in need thereof a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:wherein:A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6;X is CH or N;Y is NH;R1is H;R2is Ci-Ce alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl;R3is H;R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkyl cycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkyl cycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl;R5is H; andeach R6is independently halo, Ci-Ce alkyl, Ci-Ce alkoxy, cyano, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl.22. The method of any one of embodiments 19-21, wherein the administering comprises administering about 0.5 mg to about 10 mg of the compound to the subject.23. The method of any one of embodiments 19-22, wherein the administering comprises administering the compound to the subject every day, every other day, every two days, every three days, every four days, every five days, every six days, once a week, five days on and two days off, once every two weeks, or once a month.24. The method of any one of embodiments 19-22, wherein the administering comprises orally administering to the subject the compound.25. The method of any one of embodiments 19-24, wherein the compound is in the form of a tablet, capsule or pill.26. A method of treating minimal residual disease in a hematological malignancy, comprising administering to a subject in need thereof an inflammasome modulator.27. The method of embodiment 26, wherein the inflammasome modulator is a modulator of the NLRP3 inflammasome.28. The method of embodiment27, wherein the inflammasome modulator inhibits the priming step of the NLRP3 inflammasome.29. The method of embodiment 28, wherein the inflammasome modulator inhibits signaling downstream of members of the TLR family, IL-1R family, and / or TNFR1 / 2.30. The method of embodiment 28 or 29, wherein the inflammasome modulator prevents the activation of NF-kB.31. The method of any one of embodiments 26-30, wherein the administering reduces the level of TNF-a, IL-6, or the components of the NLRP3 inflammasome (e.g., NLRP3, pro-IL-1b, pro-IL18), or a combination thereof, in the subject.32. The method of embodiment 27, wherein the inflammasome modulator inhibits the assembly and activation step of the NLRP3 inflammasome.33. The method of embodiment 32, wherein the inflammasome modulator inhibits the formation of a NLRP3 (protein)-NEK7 (protein) interaction.34. The method of embodiment 33, wherein the inflammasome modulator inhibits the formation of the ASC speck and the NLRP3 inflammasome.35. The method of any one of embodiments 32-34, wherein the inflammasome modulator prevents caspase- 1 activation.36. The method of any one of embodiments 32-35, wherein the inflammasome modulator inhibits the production of IL-ip.37. The method of any one of embodiments 32-36, wherein the inflammasome modulator inhibits the production of IL-18.38. The method of any one of embodiments32-37, wherein the inflammasome modulator inhibits the cleavage of gasdermin D.39. The method of any one of embodiments 32-38, wherein the inflammasome modulator prevents pyroptotic cell death.40. The method of any one of embodiments 26-39, wherein the administering comprises administering about 0.5 mg to about 10 mg of the inflammasome modulator to the subject.41. The method of any one of embodiments 26-40, wherein the administering comprises administering the inflammasome modulator to the subject every day, every other day, every two days, every three days, every four days, every five days, every six days, once a week, five days on and two days off, once every two weeks, or once a month.42. The method of any one of embodiments 26-41, wherein the administering comprises orally administering to the subject the inflammasome modulator.43. The method of any one of embodiments 26-42, wherein the inflammasome modulator is in the form of a tablet, capsule or pill.44. The method of embodiment 26, wherein the administering prevents relapse of the hematological malignancy.45. A method of treating minimal residual disease in a hematological malignancy, comprising administering to a subject in need thereof a compound of Formula (0), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:Formula (0) wherein:A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6;X is CH or N;X1is C or N;X2is C or N;X3is CH or N;X4is C or N;Y is NH;R1is H, Ci-6 alkyl, Ci-6 haloalkyl, or Ci-6 alkoxy;R2is hydrogen, Ci-Ce alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halogen, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl;R3is absent, H, halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkyl or Ci-6 haloalkyl;R4is a Ce-Cio aryl, C3-C10 cycloalkyl, 3-12 membered heterocyclyl, 5- to 12- membered heteroaryl;R5is H;each R6is independently halogen, Ci-Ce alkyl, Ci-Ce alkoxy, cyano, Ci-Ce hydroxylalkyl, Ci-Ce haloalkyl,L is a direct bond, O, or CRL1RL2;RLis a Ce-Cio aryl substituted with 0-4 Rc, C-3-Cio cycloalkyl substituted with 0- 4 Rc, 3-10 membered heterocyclyl substituted with 0-4 Rc, or 5-6 membered monocyclic heteroaryl substituted with 0-4 Rc, each of which is optionally substituted with one more substituents selected from halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkyl or C1-6 haloalkyl; andRL1and RL2are each independently selected from hydrogen, halogen, deuterium, tritium, C1-6 alkyl, C1-6 alkoxy, cyano, C1-6 hydroxyalkyl, C1-6 haloalkyl, or R21and R22and the carbon to which they are attached together form a C3-6 cycloalkyl.46. A method of treating minimal residual disease in a hematological malignancy, comprising administering to a subject in need thereof a compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:Formula (I)wherein:A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6;X is CH or N;Y is NH;R1is H;R2is Ci-Ce alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl;R3is H;R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkyl cycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkyl cycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl;R5is H; andeach R6is independently halo, Ci-Ce alkyl, Ci-Ce alkoxy, cyano, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl;Formula (II)wherein:X is N or CH;A is Ce-Cio arylene, C3-C10 cycloalkylene, 3-10 membered heterocyclylene, or 5-6 membered heteroarylene;R1is H, halo, Ci-Ce alkyl, C3-C10 cycloalkyl, or 3-10 membered heterocyclyl;R2is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C10 cycloalkyl, or 3-10 membered heterocyclyl;R3is aminylalkyl, 3-10 membered heterocyclyl, 3-10 membered heterocyclylalkyl, 3-10 membered heterocyclylcarbonyl, 3-10 membered heterocyclylalkenyl, 3-10 membered N-heterocyclyloxy, or 5-6 membered heteroaryl; orR3joins with an occurrence of R4attached to a carbon adjacent to a carbon to which R3is attached to form a C3-C8 cycloalkyl;R4is, at each occurrence, independently halo, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, C3-C8 halocycloalkyl, or C3-C8 cycloalkyl; andn is 0, 1, 2, 3, or 4;Formula (III)wherein:A is Ce-Cio arylene, C3-C10 cycloalkylene, 3-10 membered heterocyclylene, or 5-6 membered heteroarylene;X is N or CR4;Y is N or CH;R1is Ci-Ce alkyl, Ci-Ce hydroxylalkyl, C3-C10 cycloalkyl, or 3-10 membered heterocyclyl;R2is a 3-10 membered heterocyclyl, 3-10 membered heterocyclylalkyl, 3-10 membered heterocyclylalkenyl, 3-10 membered heterocyclylcarbonyl, 3-10 membered heterocyclyloxy, or 5-6 membered heteroaryl; orR2joins with an occurrence of R3attached to a carbon adjacent to a carbon to which R2is attached to form a C3-C8 cycloalkyl;R3is, at each occurrence, independently halo, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or C3-C8 cycloalkyl;R4is H, Ci-Ce alkyl, Ci-Ce haloalkyl, or C3-C8 cycloalkyl; andn is 0, 1, 2, 3, or 4;Formula (IV) wherein:A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl, or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R5;Xis N or CR1C;Y is N or CRld;Z is C(R6)(R7) or NR6;Rla, Rlb, Rlc, and Rldare each independently H, halo, Ci-Ce alkyl, or C3-C8 cycloalkyl;R2aand R2bare each independently H, halo, cyano, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, C3-C8 cycloalkyl, or C3-C8 halocycloalkyl, provided that R2aand R2bare not both H;R3is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, heteroaryl, or aryl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and Ci-Ce alkoxy;R4is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, Ce-Cio aryl, or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and Ci-Ce alkoxy;R5is, at each occurrence, independently halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl;R6is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce hydroxylalkyl; and R7is H, OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce hydroxylalkyl;Formula (V)wherein:A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R5;X is N or CH;Yis CHOH orNH;R1is H or Ci-Ce alkyl;R2is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-Ce alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl;R3is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from amino, halo, cyano, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, C3-C8 alkylcycloalkyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, Ci-Ce cyanoalkyl Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclylalkyl, 3-8 membered heterocyclylcycloalkyl, 3-8 membered haloheterocyclyl, 3-8 membered haloheterocyclylalkyl, C3-C8 halocycloalkyl and C3-C8 halocycloalkylalkyl, and combinations thereof;R4is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, Ce-Cio aryl or 5- or 6-membered heteroaryl, each of which is optionallysubstituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl and Ci-Ce alkoxy; andR5is, at each occurrence, independently halo, cyano, Ci-Ce alkyl, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl;Formula (VI)wherein:represents a double or a single bond such that all valences are satisfied; A is an optionally substituted 5-6-membered heterocyclyl, an optionally substituted 6-membered aryl, or an optionally substituted 5-6-membered heteroaryl;X is N or CR3;Y is C or N;W is CH or N;Z is CH or N;R1is optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted Ci-Ce hydroxyalkyl, optionally substituted Ci-Ce alkoxyalkyl, optionally substituted Ci-Ce carboxyalkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted Ce-Cio aryl, optionally substituted 3-10 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl;R2is optionally substituted aryl or optionally substituted heteroaryl; andR3is hydrogen, halo, cyano, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ci-Ce alkoxy, optionally substituted Ci-Ce haloalkoxy, or optionally substituted C3-C8 cycloalkyl.47. A method of treating minimal residual disease in a hematological malignancy, comprising administering to a subject in need thereof a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:wherein:A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6;X is CH or N;Y is NH;R1is H;R2is Ci-Ce alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl;R3is H;R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkyl cycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkyl cycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl;R5is H; andeach R6is independently halo, Ci-Ce alkyl, Ci-Ce alkoxy, cyano, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl.48. The method of embodiment 46 or 47, wherein the administering comprises administering about 0.5 mg to about 10 mg of the compound to the subject.49. The method of any one of embodiments 46-48, wherein the administering comprises administering the compound to the subject every day, every other day, every two days, every three days, every four days, every five days, every six days, once a week, five days on and two days off, once every two weeks, or once a month.50. The method of any one of embodiments 46-49, wherein the administering comprises orally administering to the subject the compound.51. The method of any one of embodiments 46-50, wherein the compound is in the form of a tablet, capsule or pill.52. The method of any one of embodiments 21 or 47, wherein R2is butyl, cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, pyridinyl, azetidinyl, or oxetanyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl.53. The method of any one of embodiments 21, 47, or 52, wherein R2is:54. The method of any one of embodiments 21, 47, 52, or 53, wherein R4is oxazolyl, isoxazolyl, 1, 2, 3 -oxadiazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-triazolyl or 1, 3, 4-oxadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof.55. The method of any one of embodiments 20, 45, or 50-52, wherein R4is substituted with Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, or C3-C8 halocycloalkyl, or combinations thereof.56. The method of any one of embodiments 21, 47, or 52 to 55, wherein R4has one of the following structures:57. The method of any one of embodiments 21, 47, or 52 to 56, wherein A is Ce-Cio aryl, C3-C10 cycloalkyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6.58. The method of any one of embodiments 21, 47, or 52 to 57, wherein A is cyclohexyl, cyclohexenyl, phenyl, pyridinyl, or pyrimidinyl.59. The method of any one of embodiments 21, 47, or 52 to 58, wherein A is phenyl. 60. The method of any one of embodiments 21, 47, or 52 to 59, wherein A is unsubstituted.61. The method of any one of embodiments 21, 47, or 52 to 59, wherein A is substituted with one or more R6.62. The method of any one of embodiments 21, 47, or 52 to 59, wherein R6is chloro, fluoro, -CHF2, -CH2CH2OH, cyano, or methoxy.63. The method of any one of embodiments 21, 47, or 52 to 58, wherein A is:64. The method of any one of embodiments 21, 47, or 52 to 59 or 61 to 63, wherein the compound is a compound of Formula (la), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:wherein:R2ais C3-C4 cycloalkyl optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl; andR4ais isoxazolyl optionally substituted with one more substituents selected from Ci- Ce haloalkyl, C3-C8 cycloalkyl or C3-C8 haloalkyl cycloalkyl.65. The method of embodiment 64, wherein R2ais cyclopropyl.66. The method of embodiment 64 or 65, wherein R4ais:67. The method of embodiment 21 or 47, wherein the compound of Formula (I) is listed in Table 1, or a pharmaceutically acceptable salt or solvate thereof.68. The method of any one of embodiments 21 to 67, wherein the compound of Formulapharmaceutically acceptable salt or solvate thereof.69. The method of any one of embodiments 1 to 68, wherein the hematological malignancy is Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Chronic Lymphocytic Leukemia (CLL), Chronic Myeloid Leukemia (CML), Chronic Myelomonocytic Leukemia (CMML), Chronic Neutrophilic Leukemia (CNL), clonal hematopoiesis of indeterminate potential (CHIP), Essential Thrombocythemia (ET), Multiple Myeloma (MM), Myelodysplastic Syndromes (MDS), Non-Hodgkin Lymphoma (NHL), Hodgkin Lymphoma (HL), Polycythemia Vera (PV), Primary Myelofibrosis (PMF), Systemic Mastocytosis or a combination thereof.70. The method of any one of embodiments 1-67, wherein the hematological malignancy is Acute Lymphoblastic Leukemia (ALL).71. The method of any one of embodiments 1-69, wherein the hematological malignancy is Acute Myeloid Leukemia (AML).72. The method of embodiments 71, wherein the hematological malignancy is favorable-risk Acute Myeloid Leukemia (AML).73. The method of embodiments 71, wherein the hematological malignancy is intermediate-risk Acute Myeloid Leukemia (AML).74. The method of embodiment 71, wherein the hematological malignancy is high-risk Acute Myeloid Leukemia (AML).75. The method of any one of embodiments 1 to 69, wherein the hematological malignancy is Chronic Myelomonocytic Leukemia (CMML).76. The method of any one of embodiments 1 to 69, wherein the hematological malignancy is Multiple Myeloma (MM).77. The method of any one of embodiments 1 to 69, wherein the hematological malignancy is Non-Hodgkin Lymphoma (NHL).78. The method of any one of embodiments 1 to 69, wherein the hematological malignancy is Hodgkin Lymphoma (HL).79. The method of any one of embodiments 1 to 69, wherein the hematological malignancy is Acute Lymphoblastic Leukemia (ALL).80. The method of any one of embodiments 1 to 69, wherein the hematological malignancy is a Myelodysplastic Syndrome (MDS).81. The method of any one of embodiments 1 to 69, wherein the hematological malignancy is Chronic Myeloid Leukemia (CML).82. The method of any one of embodiments 1 to 69, wherein the hematological malignancy is Polycythemia Vera (PV).83. The method of any one of embodiments 1 to 69, wherein the hematological malignancy is Essential Thrombocythemia (ET).84. The method of any one of embodiments 1 to 69, wherein the hematological malignancy is Primary Myelofibrosis (PMF).85. The method of any one of embodiments 1 to 69, wherein the hematological malignancy is Systemic Mastocytosis.86. The method of any one of embodiments 1 to 69, wherein the hematological malignancy is Chronic Neutrophilic Leukemia (CNL).87. The method of any one of embodiments 1 to 86, wherein the subject has reached minimal residual disease of the hematological malignancy.88. The method of any one of embodiments 1 to 87, wherein the subject is at risk of relapse of the hematological malignancy.89. The method of any one of embodiments 1 to 88, wherein the subject presents below the traditional remission definition of 5% blasts by morphological assessment.90. The method of any one of embodiments 1 to 89, wherein the subject has a positive test for minimal residual disease of the hematological malignancy as measured by flow cytometry.91. The method of any one of embodiments 1 to 90, wherein the subject has a positive test for minimal residual disease of the hematological malignancy as measured by polymerase chain reaction (PCR).92. The method of any one of embodiments 1 to 91, wherein the subject has a positive test for minimal residual disease of the hematological malignancy as measured by next-generation sequencing (NGS).93. The method of any one of embodiments 1 to 92, further comprising administering to a subject in need thereof chemotherapy, chimeric antigen receptor (CAR) T-cell therapy, immunotherapy, radiation therapy, or a combination thereof.94. The method of any one of embodiments 1 to 93, further comprising administering to a subject in need thereof chemotherapy.95. The method of any one of embodiments 1 to 94, further comprising administering to a subject in need thereof chimeric antigen receptor (CAR) T-cell therapy.96. The method of any one of embodiments 1 to 95, further comprising administering to a subject in need thereof immunotherapy.97. The method of any one of embodiments 1 to 96, further comprising administering to a subject in need thereof radiation therapy.98. The method of any one of embodiments 1 to 97, wherein the hematological malignancy is clonal hematopoiesis of indeterminate potential (CHIP).99. A method of treating hemolytic anemia, comprising administering to a subject in need thereof a compound of Formula (0), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:Formula (0) wherein:A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6;X is CH or N;X1is C or N;X2is C or N;X3is CH or N;X4is C or N;Y is NH;R1is H, Ci-6 alkyl, Ci-6 haloalkyl, or Ci-6 alkoxy;R2is hydrogen, Ci-Ce alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halogen, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl;R3is absent, H, halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkyl or Ci-6 haloalkyl;R4is a Ce-Cio aryl, C3-C10 cycloalkyl, 3-12 membered heterocyclyl, 5- to 12- membered heteroaryl;R5is H;each R6is independently halogen, Ci-Ce alkyl, Ci-Ce alkoxy, cyano, Ci-Ce hydroxylalkyl, Ci-Ce haloalkyl,L is a direct bond, O, or CRL1RL2;RLis a Ce-Cio aryl substituted with 0-4 Rc, C-3-Cio cycloalkyl substituted with 0- 4 Rc, 3-10 membered heterocyclyl substituted with 0-4 Rc, or 5-6 membered monocyclic heteroaryl substituted with 0-4 Rc, each of which is optionally substituted with one more substituents selected from halogen, C1-6 alkyl, C1-6 alkoxy, cyano, hydroxy, C1-6 hydroxyalkyl or C1-6 haloalkyl; andRL1and RL2are each independently selected from hydrogen, halogen, deuterium, tritium, C1-6 alkyl, C1-6 alkoxy, cyano, C1-6 hydroxyalkyl, C1-6 haloalkyl, or R21and R22and the carbon to which they are attached together form a C3-6 cycloalkyl.100. A method of treating hematolytic anemia, comprising administering to a subject in need thereof a compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:Formula (I)wherein:A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6;X is CH or N;Y is NH;R1is H;R2is Ci-Ce alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl;R3is H;R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkyl cycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkyl cycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl;R5is H; andeach R6is independently halo, Ci-Ce alkyl, Ci-Ce alkoxy, cyano, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl;Formula (II)wherein:X is N or CH;A is Ce-Cio arylene, C3-C10 cycloalkylene, 3-10 membered heterocyclylene, or 5-6 membered heteroarylene;R1is H, halo, Ci-Ce alkyl, C3-C10 cycloalkyl, or 3-10 membered heterocyclyl;R2is H, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C10 cycloalkyl, or 3-10 membered heterocyclyl;R3is aminylalkyl, 3-10 membered heterocyclyl, 3-10 membered heterocyclylalkyl, 3-10 membered heterocyclylcarbonyl, 3-10 membered heterocyclylalkenyl, 3-10 membered N-heterocyclyloxy, or 5-6 membered heteroaryl; orR3joins with an occurrence of R4attached to a carbon adjacent to a carbon to which R3is attached to form a C3-C8 cycloalkyl;R4is, at each occurrence, independently halo, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, C3-C8 halocycloalkyl, or C3-C8 cycloalkyl; andn is 0, 1, 2, 3, or 4;Formula (III)wherein:A is Ce-Cio arylene, C3-C10 cycloalkylene, 3-10 membered heterocyclylene, or 5-6 membered heteroarylene;X is N or CR4;Y is N or CH;R1is Ci-Ce alkyl, Ci-Ce hydroxylalkyl, C3-C10 cycloalkyl, or 3-10 membered heterocyclyl;R2is a 3-10 membered heterocyclyl, 3-10 membered heterocyclylalkyl, 3-10 membered heterocyclylalkenyl, 3-10 membered heterocyclylcarbonyl, 3-10 membered heterocyclyloxy, or 5-6 membered heteroaryl; orR2joins with an occurrence of R3attached to a carbon adjacent to a carbon to which R2is attached to form a C3-C8 cycloalkyl;R3is, at each occurrence, independently halo, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, or C3-C8 cycloalkyl;R4is H, Ci-Ce alkyl, Ci-Ce haloalkyl, or C3-C8 cycloalkyl; andn is 0, 1, 2, 3, or 4;Formula (IV) wherein:A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl, or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R5;Xis N or CR1C;Y is N or CRld;Z is C(R6)(R7) or NR6;Rla, Rlb, Rlc, and Rldare each independently H, halo, Ci-Ce alkyl, or C3-C8 cycloalkyl;R2aand R2bare each independently H, halo, cyano, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, C3-C8 cycloalkyl, or C3-C8 halocycloalkyl, provided that R2aand R2bare not both H;R3is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, heteroaryl, or aryl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and Ci-Ce alkoxy;R4is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, Ce-Cio aryl, or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and Ci-Ce alkoxy;R5is, at each occurrence, independently halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl;R6is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce hydroxylalkyl; and R7is H, OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce hydroxylalkyl;Formula (V)wherein:A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R5;X is N or CH;Yis CHOH orNH;R1is H or Ci-Ce alkyl;R2is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-Ce alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl;R3is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from amino, halo, cyano, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, C3-C8 alkylcycloalkyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, Ci-Ce cyanoalkyl Ci-Ce aminyl, Ci-Ce hydroxylalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclylalkyl, 3-8 membered heterocyclylcycloalkyl, 3-8 membered haloheterocyclyl, 3-8 membered haloheterocyclylalkyl, C3-C8 halocycloalkyl and C3-C8 halocycloalkylalkyl, and combinations thereof;R4is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, Ce-Cio aryl or 5- or 6-membered heteroaryl, each of which is optionallysubstituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl and Ci-Ce alkoxy; andR5is, at each occurrence, independently halo, cyano, Ci-Ce alkyl, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl;Formula (VI)wherein:represents a double or a single bond such that all valences are satisfied; A is an optionally substituted 5-6-membered heterocyclyl, an optionally substituted 6-membered aryl, or an optionally substituted 5-6-membered heteroaryl;X is N or CR3;Y is C or N;W is CH or N;Z is CH or N;R1is optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted Ci-Ce hydroxyalkyl, optionally substituted Ci-Ce alkoxyalkyl, optionally substituted Ci-Ce carboxyalkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted Ce-Cio aryl, optionally substituted 3-10 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl;R2is optionally substituted aryl or optionally substituted heteroaryl; andR3is hydrogen, halo, cyano, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ci-Ce alkoxy, optionally substituted Ci-Ce haloalkoxy, or optionally substituted C3-C8 cycloalkyl.101. A method of treating hemolytic anemia, comprising administering to a subject in need thereof a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:wherein:A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6;X is CH or N;Y is NH;R1is H;R2is Ci-Ce alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl;R3is H;R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkyl cycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkyl cycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl;R5is H; andeach R6is independently halo, Ci-Ce alkyl, Ci-Ce alkoxy, cyano, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl.102. The method of any one of embodiments 99 to 101, wherein the administering comprises administering about 0.5 mg to about 10 mg of the compound to the subject.103. The method of any one of embodiments 99 to 102, wherein the administering comprises administering the compound to the subject every day, every other day, every two days, every three days, every four days, every five days, every six days, once a week, five days on and two days off, once every two weeks, or once a month.104. The method of any one of embodiments 99 to 103, wherein the administering comprises orally administering to the subject the compound.105. The method of any one of embodiments 99 to 104, wherein the compound is in the form of a tablet, capsule or pill.106. The method of any one of embodiments 99 to 105, wherein R2is butyl, cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, pyridinyl, azetidinyl, or oxetanyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl.107. The method of embodiment 106, wherein R2is:108. The method of any one of embodiments 99 to 107, wherein R4is oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-triazolyl or 1, 3, 4-oxadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof.109. The method of any one of embodiments 99 to 108, wherein R4is substituted with Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, or C3-C8 halocycloalkyl, or combinations thereof.110. The method of any one of embodiments 99 to 109, wherein R4has one of the following structures:111. The method of any one of embodiments 99 to 110, wherein A is Ce-Cio aryl, C3-C10 cycloalkyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6.112. The method of any one of embodiments 99 to 111, wherein A is cyclohexyl, cyclohexenyl, phenyl, pyridinyl, or pyrimidinyl.113. The method of any one of embodiments 99 to 112, wherein A is phenyl.114. The method of any one of embodiments 99 to 113, wherein A is unsubstituted.115. The method of any one of embodiments 99 to 113, wherein A is substituted with one or more R6.116. The method of any one of embodiments 99 to 113 or 115, wherein R6is chloro, fluoro, -CHF2, -CH2CH2OH, cyano, or methoxy.117. The method of any one of embodiments 99 to 116, wherein A is:118. The method of any one of embodiments 99 to 117, wherein the compound is a compound of Formula (la), or a pharmaceutically acceptable salt, stereoisomer, or solvatewherein:R2ais C3-C4 cycloalkyl optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl; andR4ais isoxazolyl optionally substituted with one more substituents selected from Ci- Ce haloalkyl, C3-C8 cycloalkyl or C3-C8 haloalkyl cycloalkyl.119. The method of embodiment 118, wherein R2ais cyclopropyl.120. The method of embodiment 128 or 129, wherein R4ais:121. The method of any one of embodiments 100 to 120, wherein the compound of Formula (I) is listed in Table 1, or a pharmaceutically acceptable salt or solvate thereof.122. The method of any one of embodiments 100 to 121, wherein the compound ofFormula (pharmaceutically acceptable salt or solvate thereof.123. The method of any one of embodiments 99 to 122, wherein the hemolytic anemia is inherited hemolytic anemia.124. The method of any one of embodiments 99 to 123, wherein the hemolytic anemia is sickle-cell disease, thalassemia, congenital dyserythropoietic anemia, or a combination thereof.125. The method of embodiment 124, wherein the hemolytic anemia is sickle-cell disease.126. The method of any one of embodiment 99 to 122, wherein the hemolytic anemia is acquired hemolytic anemia.127. The method of any one of embodiments 1 to 126, wherein the subject has clonal hematopoiesis (CH) or clonal hematopoiesis of indeterminate potential (CHIP).128. The method of any one of embodiments 1 to 126, wherein the subject has clonal cytopenias of undetermined significance (CCUS).129. A method of treating a hematological malignancy, comprising administering to a subject having a very low risk, low risk, intermediate risk, or high risk of myelodysplastic syndrome (MDS), a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:wherein:A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6;X is CH or N;Y is NH;R1is H;R2is Ci-Ce alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl;R3is H;R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkyl cycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkyl cycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl;R5is H; andeach R6is independently halo, Ci-Ce alkyl, Ci-Ce alkoxy, cyano, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl.130. The method of embodiment 129, the subject has very low risk, low risk, or intermediate risk of MDS, wherein the very low risk, low risk, or intermediate risk of MDS is classified according to the World Health Organization (WHO) 2022 classification or Revised International Prognostic Scoring System (IPSS-R) classification.131. The method of embodiment 129 or 130, wherein the subject has very low risk or low risk MDS.132. A method of treating a hematological malignancy, comprising administering to a subject, wherein the subject has low blast cells according to the WHO 2022 classification or IPSS-R classification, of myelodysplastic syndrome (MDS), a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:wherein:A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6;X is CH or N;Y is NH;R1is H;R2is Ci-Ce alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl;R3is H;R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkyl cycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkyl cycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl;R5is H; andeach R6is independently halo, Ci-Ce alkyl, Ci-Ce alkoxy, cyano, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl.133. The method of any one of embodiments 129 to 132, wherein R2is butyl, cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, pyridinyl, azetidinyl, or oxetanyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl.134. The method of any one of embodiments 129 to 133, wherein R2is:135. The method of any one of embodiments 129 to 134, wherein R4is oxazolyl, isoxazolyl, 1, 2, 3 -oxadiazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-triazolyl or 1, 3, 4-oxadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof.136. The method of any one of embodiments 129 to 135, wherein R4is substituted with Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, or C3-C8 halocycloalkyl, or combinations thereof.137. The method of any one of embodiments 129 to 135, wherein R4has one of the following structures:138. The method of any one of embodiments 129 to 137, wherein A is phenyl.139. The method of any one of embodiments 129 to 138, wherein A is unsubstituted.140. The method of any one of embodiments 129 to 139, wherein A is substituted with one or more R6.141. The method of any one of embodiments 129 to 138 or 140, wherein R6is chloro, fluoro, -CHF2, -CH2CH2OH, cyano, or methoxy.142. The method of any one of embodiments 129 to 141, wherein A is:143. The method of any one of embodiments 129 to 138 or 140 to 142, wherein the compound is a compound of Formula (la), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:wherein:R2ais C3-C4 cycloalkyl optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl; andR4ais isoxazolyl optionally substituted with one more substituents selected from Ci- Ce haloalkyl, C3-C8 cycloalkyl or C3-C8 haloalkyl cycloalkyl.144. The method of embodiment 143, wherein R2ais cyclopropyl.145. The method of embodiment 144, wherein R4ais:146. The method of any one of embodiments 129 to 145, wherein the compound of Formula (I) is listed in Table 1, or a pharmaceutically acceptable salt or solvate thereof. 147. The method of any one of embodiments 129 to 146, wherein the compound ofFormulapharmaceutically acceptable salt or solvate thereof.148. The method of any one of embodiments 129 to 147, wherein the hematological malignancy is Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Chronic Lymphocytic Leukemia (CLL), Chronic Myeloid Leukemia (CML), Chronic Myelomonocytic Leukemia (CMML), Chronic Neutrophilic Leukemia (CNL), clonal hematopoiesis of indeterminate potential (CHIP), Essential Thrombocythemia (ET), Multiple Myeloma (MM), Myelodysplastic Syndromes (MDS), Non-Hodgkin Lymphoma (NHL), Hodgkin Lymphoma (HL), Polycythemia Vera (PV), Primary Myelofibrosis (PMF), Systemic Mastocytosis or a combination thereof.149. The method of any one of embodiments 129 to 148, wherein the subject has a positive test for minimal residual disease of the hematological malignancy as measured by flow cytometry.150. The method of any one of embodiments 129 to 148, wherein the subject has a positive test for minimal residual disease of the hematological malignancy as measured by polymerase chain reaction (PCR).151. The method of any one of embodiments 129 to 148, wherein the subject has a positive test for minimal residual disease of the hematological malignancy as measured by next-generation sequencing (NGS).152. A method of treating a hematological malignancy, wherein the hematological malignancy is Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Chronic Lymphocytic Leukemia (CLL), Chronic Myeloid Leukemia (CML), Chronic Neutrophilic Leukemia (CNL), clonal hematopoiesis of indeterminate potential (CHIP), Essential Thrombocythemia (ET), Multiple Myeloma (MM), Non-Hodgkin Lymphoma (NHL), Hodgkin Lymphoma (HL), Polycythemia Vera (PV), Primary Myelofibrosis (PMF), Systemic Mastocytosis, or minimal residual disease (MRD), or a combination thereof, comprising administering to a subject in need thereof, a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:wherein:A is Ce-Cio aryl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6;X is CH or N;Y is NH;R1is H;R2is Ci-Ce alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl;R3is H;R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkyl cycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl;R5is H; andeach R6is independently halo, Ci-Ce alkyl, Ci-Ce alkoxy, cyano, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl.153. The method of embodiment 152, wherein R2is butyl, cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, pyridinyl, azetidinyl, or oxetanyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl.154. The method of embodiment 152 or 153, wherein R2is:155. The method of any one of embodiments 152 to 154, wherein R4is oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-triazolyl or 1, 3, 4-oxadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof.156. The method of any one of embodiments 152 to 155, wherein R4is substituted with Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, or C3-C8 halocycloalkyl, or combinations thereof.157. The method of any one of embodiments 152 to 156, wherein R4has one of the following structures:158. The method of any one of embodiments 152 to 157, wherein A is phenyl.159. The method of any one of embodiments 152 to 158, wherein A is unsubstituted. 160. The method of any one of embodiments 152 to 159, wherein A is substituted with one or more R6.161. The method of any one of embodiments 152 to 158 or 160, wherein R6is chloro, fluoro, -CHF2, -CH2CH2OH, cyano, or methoxy.162. The method of any one of embodiments 152 to 161, wherein A is:163. The method of any one of embodiments 152 to 158 or 160 to 162, wherein the compound is a compound of Formula (la), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:wherein:R2ais C3-C4 cycloalkyl optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl; andR4ais isoxazolyl optionally substituted with one more substituents selected from Ci- Ce haloalkyl, C3-C8 cycloalkyl or C3-C8 haloalkyl cycloalkyl.164. The method of embodiment 163, wherein R2ais cyclopropyl.165. The method of embodiment 163 or 164, wherein R4ais:166. The method of any one of embodiments 152 to 165, wherein the compound of Formula (I) is listed in Table 1, or a pharmaceutically acceptable salt or solvate thereof.167. The method of any one of embodiments 152 to 166, wherein the compound ofFormula (pharmaceutically acceptable salt or solvate thereof.168. The method of any one of embodiments 152 to 167, wherein the subject has MRD, wherein the MRD is MRD in Acute Myeloid Leukemia (AML).169. The method of any one of embodiments 152 to 167, wherein the subject has MRD, wherein the MRD is MRD in Myelodysplastic Syndromes (MDS).170. The method of any one of embodiments 152 to 169, wherein the MRD is defined by leukemia cells not detectable in the bone marrow of the subject.171. The method of embodiment 170, wherein the MRD is defined by leukemia cells not detectable in the bone marrow of the subject using microscopy but are detectable using flow cytometry or a nucleic acid detection method.172. The method of embodiment 170, wherein the MRD is defined by leukemia cells not detectable in the bone marrow of the subject using microscopy but are detectable using next-generation sequencing (NGS).173. The method of any one of embodiments 129 to 172, wherein the subject has low blast cells according to the WHO 2022 classification or IPSS-R classification.174. The method of embodiment 173, wherein the blast cell percentage in bone marrow of the subject is 10% or less.175. The method of embodiment 173 or 174, wherein the blast cell percentage in bone marrow of the subject is 5% or less.176. The method of any one of embodiments 173 to 175, wherein the blast cell is myeloblasts.177. The method of any one of embodiments 129 to 176, wherein the subject has an isolated 5q deletion or SF3B1 mutation, or a combination thereof.178. The method of any one of embodiments 129 to 177, wherein the administering comprises administering about 0.5 mg to about 10 mg of the compound to the subject.179. The method of any one of embodiments 129 to 178, wherein the administering comprises administering the compound to the subject every day, every other day, every two days, every three days, every four days, every five days, every six days, once a week, five days on and two days off, once every two weeks, or once a month.180. The method of any one of embodiments 129 to 179, wherein the administering comprises orally administering to the subject the compound.181. The method of any one of embodiments 129 to 180, wherein the compound is in the form of a tablet, capsule or pill.182. The method of any one of embodiments 129 to 181, wherein the subject has symptomatic anemia, optionally wherein the subject with symptomatic anemia has a hemoglobin level of less than 13.0 g / dL.183. The method of embodiment 182, wherein the subject has a hemoglobin level of less than 9.0 g / dL.184. The method of embodiment 182 or 183, wherein the subject has serum ferritin levels of greater than 50 ng / ml.185. The method of any one of embodiments 182 to 184, wherein the subject does not have B12 or folate deficiencies, autoimmune or hereditary hemolysis, or gastrointestinal bleeding.186. The method of any one of embodiments 129 to 185, wherein the administering prevents relapse of the hematological malignancy.EXAMPLES

[0341] The following examples are illustrative of the embodiments described herein and are not to be interpreted as limiting the scope of this disclosure. To the extent that specific materials are mentioned, it is merely for purposes of illustration and is not intended to be limiting. One skilled in the art may develop equivalent means or reactants without the exercise of inventive capacity and without departing from the scope of this disclosure.

[0342] Examples and procedures for compounds 1 to 66 are herein incorporated by reference from US Patent No. 11,713,321.

[0343] Examples and procedures for compounds II-1 to II-67 are herein incorporated by reference from PCT publication WO2022226182A1.

[0344] Examples and procedures for compounds III- 1 to III- 118 are herein incorporated by reference from PCT publication WO2022216680A1.

[0345] Examples and procedures for compounds IV- 1 to IV-22 are herein incorporated by reference from PCT publication WO2022159835A1.

[0346] Examples and procedures for compounds V-1 to V-80 are herein incorporated by reference from US Patent Application Publication US 2023 / 0203045 Al and PCT publication WO2021226547A2.

[0347] Examples and procedures for compounds VI- 1 to VI- 137 are herein incorporated by reference from PCT publication W02024059200A1.Example 1: Synthesis Scheme

[0348] The following General Reaction Schemes illustrate examples of compounds of Structure (I):or pharmaceutically acceptable salts, stereoisomers or prodrug thereof, wherein each of A, X, Y, R1, R2, R3, R4and R5are as defined herein.General Reaction Scheme 1The following General Reaction Scheme, wherein X1and X2are independently halogens, and X, R1, R2, R3and A have the meanings described herein, illustrates examples of methods of making the amine Intermediate D:1. Cu(II)acetate orReagent 1. NH4OH2. Electrophilic R2or 2. MicrowaveR2boronateIntermediate B1. Carbocyclic or heterocyclic boronic acid or dioxoborolane derivative / Pd; or2a. Carbocyclic or heterocyclicboronic acid derivative / PdIntermediate C 2b. Fe / NH4C1 Intermediate DAs shown in General Reaction Scheme 1, alkylation of the pyrimidine / pyridine pyrrole (i.e., Intermediate A) with a cycloalkyl boronate or an appropriate electrophile in presence of base affords the Intermediate B. This precursor is treated with ammonium hydroxide to form the pyrrolopyrimidine / pyridine-4-amine derivative Intermediate C. The resulting Intermediate C can then be subject to palladium catalyzed arylation to form Intermediate D.General Reaction Scheme 2The following General Reaction Scheme illustrates examples of methods of making the carbamate Intermediate E:Intermediate EAs shown in General Reaction Scheme 2, Intermediate E can be prepared the in presence of base by reaction of phenyl chloroformates and the indicated heteroaryl amine (an amine-substituted analogue of R4). General Reaction Scheme 2 depicts preparation of compounds wherein R5is H; however, compounds wherein R5is other than H can be prepare by similar methods by instilling R5after preparation of Intermediate E, or by using an appropriately substituted heteroaryl amine.General Reaction Scheme 3The following General Reaction Scheme illustrates examples of methods of making the compounds of Structure (I):Intermediate D Intermediate EIntermediate D and Intermediate E are treated with a base (e.g., trimethylamine, DIPEA, DMAP, and the like) in THF to afford the compounds of Structure (I).General Reaction Scheme 4The following General Reaction Scheme illustrates examples of methods of making the compounds of Structure (I):Intermediate D Intermediate EbaseTHFCompounds of Structure (I) Intermediate D is reacted with the phenyl carb onochlori date shown under appropriate conditions to yield Intermediate E. Intermediate E is then coupled with the amine using a suitable base (e.g., trimethylamine, DIPEA, DMAP, and the like) in THF to afford the compounds of Structure (I).

[0349] Any of the above reaction scheme can be modified at any step to add and / or modify a substituent may be added or modified as appropriate during any stage of the overall synthesis of desired compounds.

[0350] An intermediate Al (4-chloro-5-iodo-7h-pyrrolo[2,3-d]pyrimidinewas prepared as follows: N-iodosuccinimide (1.465 g, 6.51 mmol) was added to a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.000 g, 6.51 mmol) in DMF (10 mL) at 0 °C and the resulting mixture was stirred at 25 °C for 12 h. Following completion of the reaction (as indicated by TLC), the reaction mixture was poured into ice cold water (100 mL) and stirred at 25 °C for 15 min. The resulting solid was filtered, washed with water (2 x 25 mL), and dried to afford the title compound as an off-white solid (1.7 g, 93% yield). 1H NMR (400 MHz, DMSO-d6) 6 = 12.96 (bs, 1H), 8.60 (s, 1H), 7.95 (d, J = 2.40 Hz, 1H); LCMS: 279.9 [M+H],

[0351] An intermediate B 1 (4-chloro-7-cyclopropyl-5-iodo-7h-pyrrolo[2,3-d]pyrimidinewas prepared as follows: Copper (II) acetate (0.650 g, 3.58 mmol), 2,2'-bipyridine (0.559 g, 3.58 mmol), and sodium bicarbonate (0.601 g, 7.16 mmol) were added to a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Al, 1.000 g, 3.58 mmol) and cyclopropylboronic acid (0.615 g, 7.16 mmol) in dichloroethane (10 mL) and the resulting mixture was stirred at 70 °C under oxygen atmosphere for 12 h. Following completion of the reaction (as indicated by TLC), the reaction mixture was filtered through a pad of celite which was then rinsed with DCM (2 x 20 mL). The combined filtrates were washed with water (20 mL) and brine (25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude material which was purified by flash chromatography (silica gel 230-400 mesh, eluting with 15% EtOAc in petroleum ether), affording the title compound as an off-white solid (0.7 g, 61% yield). 1H NMR (400 MHz, DMSO-d6) 8 = 8.67 (s, 1H), 7.96 (s, 1H), 3.63-3.69 (m, 1H), 1.06-1.10 (m, 4H). LCMS: 319.9 [M+H],

[0352] An intermediate Cl (7-cyclopropyl-5-iodo-7h-pyrrolo[2,3-d]pyrimidin-4-aminewas prepared as follows: A mixture of 4-chloro-7-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Bl, 1.00 g, 2.191 mmol) and ammonium hydroxide (25% in water, 5 mL) was subjected to microwave irradiation at 150 °C for 1 h. Following completion of the reaction (as indicated by TLC), the reaction mixture was concentrated under reduced pressure to afford the title compound as an off-white solid (0.75 g, 80% yield). 1H NMR (400 MHz, DMSO-d6) 6 = 8.12 (s, 1H), 7.39 (s, 1H), 6.57 (bs, 2H), 3.48-3.54 (m, 1H), 0.97-1.01 (m, 4H). LCMS: 301.0 [M+H],

[0353] An intermediate DI (5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7h-pyrrolo[2,3-d]pyrimidin-4-aminewas prepared as follows: A mixture of 7-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Cl, 0.160 g, 0.533 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (0.190 g, 0.800 mmol), and K2CO3 (0.221 g, 1.599 mmol) in 1,4-dioxane (1 mL) and water (0.3 mL) was purged with N2 for 10 min. Pd(PPh3)4 (0.062 g, 0.053 mmol) was then added and the reaction mixture was stirred at 100 °C for 12 h. Following completion of the reaction (as indicated by TLC), the mixture was filtered through a pad celite which was then rinsed with EtOAc (2 x 10 mL). The combined filtrates were concentrated under reduced pressure to yield crude material which was purified by flash chromatography (silica gel 230-400 mesh, eluting with 3% MeOH in DCM), affording the title compound as a yellow solid (0.110 g, 73% yield). 1HNMR (400 MHz, DMSO-d6) 6 = 8.14 (s, 1H), 7.13 (s, 1H), 7.05-7.09 (m, 1H), 6.95-6.98 (m, 1H), 6.82-6.86 (m, 1H), 6.10 (bs, 2H), 5.22 (bs, 2H), 3.52-3.58 (m, 1H), 1.00-1.04 (m, 4H). LCMS: 284.1 [M+H],

[0354] Compoundwas prepared following the general procedure for urea formation starting from 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (DI, 0.10 g, 0.35 mmol) and phenyl (5-(l-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)carbamate (0.11 g, 0.35 mmol

[0355] Specifically, triethylamine (2.0 eq.) was added to a mixture of DI (1.0 eq.) and El (1.0 eq.) in THF (10 Vol.) and the resulting mixture was stirred at 60 °C for 12 h in a sealed tube. Following completion of the reaction (as indicated by LCMS), the reaction mixture was concentrated under reduced pressure to give crude material which was purified by reverse phase preparative HPLC to afford the desired product. Compound 10 was obtained as an off-white solid (0.010 g, 6% yield). 1HNMR (400 MHz, DMSO-d6) 8 = 9.99 (bs, 1H), 8.86 (bs, 1H), 8.14-8.18 (m, 2H), 7.24-7.36 (m, 3H), 6.90 (s, 1H), 6.15 (bs, 2H), 3.56-3.61 (m, 1H), 1.48-1.57 (m, 4H), 1.02-1.07 (m, 4H). LCMS: 502.2 [M+H],Example 2: Safety

[0356] Compound 10 was administered to 36 patients in a Phase I study. No Serious Adverse Event (SAE) occurred. No Treatment Emergent Adverse Event (TEAE) occurred with a grade 3 or higher.

[0357] Compound 10 was administered to 41 patients in a Phase II study. No SAEs occurred. No TEAEs occurred with a grade 3 or higher.

[0358] To date, compound 10 has been dosed over 6 different dose cohorts [Img single dose (SD) 2mg SD, 3mg SD, 4mg SD, 1 mg 5 days on 2 days off, 2 mg 5 days on 2 days off, 3 mg 5 days on 2 days off, 4 mg 5 days on 2 days off]. No serious adverse events (SAEs) have been reported to date and no treatment-emergent AEs ^CTCAE grade 3 occurred to date.Phase 1 Clinical trial of Compound 10

[0359] A phase 1 clinical trial was performed to evaluate the safety and tolerability of Compound 10 when administered as single oral doses escalating dose levels in healthy volunteer subjects.Table 4. Synopsis of Phase 1 StudySingle Ascending Dose Phase:Example 3: Phase 2a Clinical trial of Compound 10 for treatment of MDS

[0360] A phase 2a clinical trial was performed, and is ongoing, to evaluate the efficacy and safety of Compound 10 in subjects with very low, low, or intermediate Risk Myelodysplastic Syndrome (MDS) and Symptomatic Anemia.

[0361] Table 5. Synopsis of Phase 2a, Centralized, Open Label Study of Compound 10 in subjects with very low, low, or intermediate risk MDS who are refractory, intolerant of orineligible for treatment with an ESA.Example 4: Phase 2 Clinical trial of Compound 10 for treatment of AML

[0362] A phase 2 clinical trial is performed to evaluate the efficacy and safety of Compound 10 in subjects with Acute Myeloid Leukemia (AML).

[0363] Table 6. Synopsis of Phase 2, Centralized, Open Label Study of Compound 10 in subjects with Acute Myeloid Leukemia (AML).Example 5: Phase 2 Clinical trial of Compound 10 for treatment of MRD in AML

[0364] A phase 2 clinical trial is performed to evaluate the efficacy and safety of Compound 10 in subjects with Minimal Residual Disease (MRD) in Acute Myeloid Leukemia (AML).

[0365] Table 7. Synopsis of Phase 2, Centralized, Open Label Study of Compound 10 in subjects with Minimal Residual Disease (MRD) in Acute Myeloid Leukemia (AML).Example 6: Dosing Regimen of Compound 10 for Phase 2 Clinical Trial for MDS

[0366] A phase 2 clinical trial is performed to evaluate the efficacy and safety for a variety of dosing regimens for Compound 10 in subjects with MDS as in Example 3. The dosing regimen is modified to include the following arms: doses in the range of 0.5 mg to 10 mg Compound 10 at frequencies of once a day, 5 days on then 2 days off, three times per week, twice per week, once per week, once every 2 weeks, or once per month.Example 7: Use of Compound 10 for treatment of MDS; Assessment of Improvement of Quality of LifeQuality of life may be assessed with the following health-related quality of life survey.Sample health-related quality of life surveyHeath-Related Quality of LifeThis study includes patients and explores their perception of experiences they have had with their heath.Personal Data ProtectionAll information that may permit an identification of the participants in this study will be kept strictly confidential, will be used only for the purpose of the study, and will not be disclosed for any reason without previous written consent, unless requested by Law.Instructions:1. Answer the question by selecting one answer.Example: (Meric the appropriate answer)2. If you are not sure about the right choice for your answer, mark the closest match and write a comment in the left margin.3. If necessary, you can ask the dedicated Staff for assistance.Thank you for your participation in this studyIntroduction:1. In general, you would say that your health is:2. Compared to a month ago, your health is:Physical Well-Being:3. In the last week, some daily activities may have been limited by your health, such as:Functional Well-Being:4. In the last week, what problems have you had in daily activities because of your health?5. During the last week was it difficult for you to stay awake during the daytime?Social or Family Well-Being:6. According to you, are the following statements true or false?7. Your health is an impediment for you to keep a paid job (whether you are of retirement age or not).8. In the last week, was sexual arousal a problem for you?Disturbances, Related to Disease:9. In the last week, how much did fatigue get in the way with your daily chores?10. In the last week, how much fatigue did you have?11. In the last week, how much did the following problems disturb you?12. During the last week, did you get enough sleep?13. During the last week, did shortness of breath while climbing stairs disturb you?14. What effects of the disease disturb your daily life?Example 8: Compound 10 Demonstrates Robust and Sustained Hematologic Response in Subjects with IPSS-R Very Low, Low, or Intermediate Risk Myelodysplastic Syndrome (MDS) and Symptomatic Anemia

[0367] With few exceptions, current MDS therapeutics are not effective across all subsets of the disease and none address the core pathogenetic root cause of MDS. The NLRP3 inflammasome is a key driver of ineffective hematopoiesis and inflammation in MDS that directs caspase- 1 and IL-ip maturation, leading to GATA-1 degradation, myeloid skewing and pyroptotic cell death of hematopoietic stem and progenitor cells (HSPC). Compound 10 is an oral allosteric inhibitor of NEK7 (NIMA-related kinase 7), a scaffold protein that is indispensable for NLRP3 inflammasome activation. Compound 10 blocks inflammasome complex assembly, promotes ASC speck dissolution and inhibits myddosome activation of NF-kB. Compound 10 is being developed to extinguish the pro-inflammatory microenvironment that sustains MDS clones and restore effective hematopoiesis.

[0368] A Phase 2 multi-center, Simon’s two stage trial evaluating erythroid hematologic improvement (HI-E) in subjects with IPSS-R (Revised International Prognostic Scoring System) very low, low, or intermediate-risk MDS and symptomatic anemia was conducted. Subjects self-administered a 2mg capsule of Compound 10 daily for five consecutive days, followed by a two-day drug holiday, for four 28-day cycles (16 weeks). Per International Working Group (IWG) 2018 criteria, hematologic improvement was assessed as >16-week transfusion independence in subjects with transfusion dependence (TD) at baseline and >16-week maintenance of hemoglobin improvement in subjects who were not transfusion dependent (NTB) at baseline. Subjects with EH-E continued treatment for an additional 16 weeks, for a maximum of 32 weeks of treatment. The primary endpoint was rate of hematological improvement after >16 weeks of treatment with Compound 10. Stage 1 required 18 subjects evaluable for the primary endpoint; >3 hematologic responses (17% response rate) would prompt initiation of Stage 2.

[0369] Across 6 sites in India, 23 subjects (57% male, 43% female, mean age 63.7 [range31-83]) were enrolled in Stage 1 and were evaluable for safety. 5 subjects were foundto be ineligible or did not complete the treatment period; 18 subjects (mean age 64.1, [range 31-83]) were evaluable for assessment of HI-E, including 12 (67%) transfusion-dependent (TD) and 6 (33%) not transfusion-dependent (NTD) at baseline. 11 subjects (61%) were refractory to prior erythropoiesis-stimulating agents (ESA). HI-E was assessed per IWG 2018 for TD and for NTD subjects. 13 subjects had HI-E response of >16 weeks duration, including 8 subjects with TD and 5 with NTD, for an overall HI-E response rate of 72%; an additional NTD subject experienced a >1.5 g / dL hemoglobin rise for 12 weeks before reaching maximum study duration and met criteria for response but not HI-E. In 9 of the 13 HI-E responders, HI-E was maintained for 32 weeks (the maximum treatment duration). Among the 11 subjects refractory to ESA, 10 subjects (91%) achieved HI-E, including 8 subjects (73%) with HI-E response for 32 weeks. Morphologic WHO subtypes included MDS-LB (n-13), MDS-SF3B1 (n=2), MDS-IB (n=l) and MDS / MPN (n=2); corresponding HI-E responses by subtype were 9 (69%), 2 (100%), 0, and 2 (100%). 67% of subjects with > 1 somatic mutation had HI-E. Among all responders, the median rise in hemoglobin was 3.5 g / dL over 16 weeks and 3.1 g / dL over 32 weeks. Among 23 subjects evaluable for safety, 6 (26%) experienced 18 treatment-related adverse events (TRAE), none of which was an SAE. TRAEs occurring in at least 2 patients (10%) were constipation (n=2), leukocytosis (n=2) and hyperkalemia (n=2). No myelosuppression of any grade was observed. All TRAEs resolved and no TRAE resulted in dose reduction or study discontinuation. With 13 responses (72% response rate) in Stage 1, enrollment into Stage 2 is underway.

[0370] In subjects with low risk MDS and anemia, Compound 10 administered orally induced clinically meaningful and sustained 16- and 32-week erythroid responses across WHO subtypes, including transfusion-dependent and -independent subjects, and irrespective of somatic mutation type. Importantly, Compound 10 supported sustained 32-week HI-E in difficult-to-treat ESA-refractory and ESA-intolerant populations. With a robust HI-E rate, favorable safety profile, absence of myelosuppression, a relevant and targeted mechanism of action, Compound 10 offers a novel oral alternative that eases the burden of current treatments in a diverse MDS population.Example 9: Compound 10 Suppresses Heme-Induced Inflammation, Representing a Novel Therapeutic Strategy for Hemolytic Anemias

[0371] Hemolytic anemia occurs due to red blood cells being destroyed faster than they are replaced and can affect multiple organs in the body. This can lead to further complications, including hypoxia. Hemolytic anemia can either be inherited or acquired. Common treatment for hemolytic anemia includes blood transfusions and plasmapheresis.However, these treatment methods are time consuming and inefficient for the subject. New methods to treat hemolytic anemia are needed.

[0372] Hemolytic anemias, such as sickle cell disease, are characterized by accelerated red blood cell destruction, which results in the release of cell-free heme. This free heme acts as a damage-associated molecular pattern, triggering activation of the NLRP3 inflammasome in immune and endothelial cells. Activation of the inflammasome leads to caspase-1-mediated cleavage of pro-inflammatory cytokines, vascular inflammation, and pyroptotic cell death. Inhibition of the NLRP3 inflammasome has been shown to mitigate inflammation and cell death in preclinical models of hemolytic anemia.

[0373] Compound 10 is a novel, orally bioavailable small molecule that selectively inhibits NLRP3 inflammasome activation by allosteric modulation of NEK7, a critical scaffolding protein for inflammasome assembly. The efficacy of Compound 10 in a human monocytic cell model of heme-induced NLRP3 activation is investigated.

[0374] THP-1 monocytes were differentiated into macrophage-like cells using PMA (100,000 cells / well; 48h treatment). After PMA differentiation, cells were rested in RPMI with 10% FBS with no PMA. After resting, cells were switched to serum-free media to eliminate interference with heme activation. Cells were pre-treated with Compound 10 for 1 hour before LPS priming (250 ng / mL, 3h), followed by heme stimulation (50 pM, Ih). IL-ip secretion was quantified by ELISA. Intracellular cleaved IL-ip and ASC speck formation were evaluated by confocal microscopy.

[0375] Heme stimulation led to robust NLRP3 activation, evidenced by elevated IL-ip secretion, intracellular cleaved IL-ip, and ASC speck formation. Compound 10 pre-treatment resulted in a dose-dependent reduction of IL-ip secretion (ICso = 123 nM), achieving a maximal inhibition of 89.9% at 1 pM. Confocal imaging mirrored these findings, showing marked reductions in cleaved IL-ip and ASC speck formation, indicating effective blockade of inflammasome activity.

[0376] Compound 10 potently inhibits heme-induced activation of the NLRP3 inflammasome in vitro, reducing both inflammatory cytokine release and pyroptotic markers. These findings support continued investigation of Compound 10 as a promising therapeutic approach in sickle cell disease and other hemolytic anemias characterized by NLRP3-mediated inflammation.Example 10: Use of Compound 10 for treatment or prevention of the symptom of clonal hematopoiesis (CH), clonal hematopoiesis of indeterminate potential (CHIP), or clonal cytopenias of undetermined significance (CCUS)

[0377] An experiment is performed to evaluate the efficacy and safety of Compound 10 in subjects with CH, CHIP, or CCUS.Table 4a. Synopsis of experiment of Compound 10 in subjects with CH, CHIP, or CCUS.

[0378] While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the disclosure. It should be understood that various alternatives to the embodiments of the disclosure described herein may be employed in practicing the disclosure. It is intended that the following claims define the scope of the disclosure and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A method of treating a hematological malignancy, comprising administering to a subject having a very low risk, low risk, intermediate risk, or high risk of myelodysplastic syndrome (MDS), a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:wherein:A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6;X is CH or N;Y is NH;R1is H;R2is Ci-Ce alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl;R3is H;R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkyl cycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkyl cycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl;R5is H; andeach R6is independently halo, Ci-Ce alkyl, Ci-Ce alkoxy, cyano, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl.

2. The method of claim 1, wherein the subject has very low risk, low risk, or intermediate risk of MDS, wherein the very low risk, low risk, or intermediate risk of MDS is classified according to the World Health Organization (WHO) 2022 classification or Revised International Prognostic Scoring System (IPSS-R) classification.

3. The method of claim 1 or 2, wherein the subject has very low risk or low risk MDS.

4. A method of treating a hematological malignancy, comprising administering to a subject, wherein the subject has low blast cells according to the WHO 2022 classification or IPSS-R classification of myelodysplastic syndrome (MDS), a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:wherein:A is Ce-Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6;X is CH or N;Y is NH;R1is H;R2is Ci-Ce alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl;R3is H;R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkyl cycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl;R5is H; andeach R6is independently halo, Ci-Ce alkyl, Ci-Ce alkoxy, cyano, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl.

5. The method of any one of claims 1 to 4, wherein R2is butyl, cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, pyridinyl, azetidinyl, or oxetanyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl.

6. The method of any one of claims 1 to 5, wherein R2is:

7. The method of any one of claims 1 to 6, wherein R4is oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-triazolyl or 1, 3, 4-oxadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkyl cycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkyl cycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof.

8. The method of any one of claims 1 to 7, wherein R4is substituted with Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3-to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, or C3-C8 halocycloalkyl, or combinations thereof.

9. The method of any one of claims 1 to 8, wherein R4has one of the following structures:

10. The method of any one of claims 1 to 9, wherein A is phenyl.

11. The method of any one of claims 1 to 10, wherein A is unsubstituted.

12. The method of any one of claims 1 to 10, wherein A is substituted with one or more R6.

13. The method of any one of claims 1 to 10 or 12, wherein R6is chloro, fluoro, -CHF2, - CH2CH2OH, cyano, or methoxy.

14. The method of any one of claims 1 to 13, wherein A is:

15. The method of any one of claims 1 to 10 or 12 to 14, wherein the compound is a compound of Formula (la), or a pharmaceutically acceptable salt, stereoisomer, or solvatewherein:R2ais C3-C4 cycloalkyl optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl; andR4ais isoxazolyl optionally substituted with one more substituents selected from Ci- Ce haloalkyl, C3-C8 cycloalkyl or Cs-Cs haloalkyl cycloalkyl.

16. The method of claim 15, wherein R2ais cyclopropyl.

17. The method of claim 15 or 16, wherein R4ais:

18. The method of any one of claims 1 to 17, wherein the compound of Formula (I) is listed in Table 1, or a pharmaceutically acceptable salt or solvate thereof.

19. The method of any one of claims 1 to 18, wherein the compound of Formula (I) isor a pharmaceutically acceptable salt or solvate thereof.

20. The method of any one of claims 1 to 19, wherein the hematological malignancy is Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Chronic Lymphocytic Leukemia (CLL), Chronic Myeloid Leukemia (CML), Chronic Myelomonocytic Leukemia (CMML), Chronic Neutrophilic Leukemia (CNL), clonal hematopoiesis of indeterminate potential (CHIP), Essential Thrombocythemia (ET), Multiple Myeloma (MM), Myelodysplastic Syndromes (MDS), Non-Hodgkin Lymphoma (NHL), Hodgkin Lymphoma (HL), Polycythemia Vera (PV), Primary Myelofibrosis (PMF), Systemic Mastocytosis or a combination thereof.

21. The method of any one of claims 1 to 20, wherein the subject has a positive test for minimal residual disease of the hematological malignancy as measured by flow cytometry.

22. The method of any one of claims 1 to 20, wherein the subject has a positive test for minimal residual disease of the hematological malignancy as measured by polymerase chain reaction (PCR).

23. The method of any one of claims 1 to 20, wherein the subject has a positive test for minimal residual disease of the hematological malignancy as measured by next -generation sequencing (NGS).

24. A method of treating a hematological malignancy, wherein the hematological malignancy is Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Chronic Lymphocytic Leukemia (CLL), Chronic Myeloid Leukemia (CML), Chronic Neutrophilic Leukemia (CNL), clonal hematopoiesis of indeterminate potential (CHIP), Essential Thrombocythemia (ET), Multiple Myeloma (MM), Non-Hodgkin Lymphoma (NHL), Hodgkin Lymphoma (HL), Polycythemia Vera (PV), Primary Myelofibrosis (PMF), Systemic Mastocytosis, or minimal residual disease (MRD), or a combination thereof, comprising administering to a subject in need thereof, a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:wherein:A is Ce-Cio aryl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6;X is CH or N;Y is NH;R1is H;R2is Ci-Ce alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl;R3is H;R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkyl cycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkyl cycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl;R5is H; andeach R6is independently halo, Ci-Ce alkyl, Ci-Ce alkoxy, cyano, Ci-Ce hydroxylalkyl or Ci-Ce haloalkyl.

25. The method of claim 24, wherein R2is butyl, cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, pyridinyl, azetidinyl, or oxetanyl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3- to 8-membered heterocyclyl.

26. The method of claim 24 or 25, wherein R2is:

27. The method of any one of claims 24 to 26, wherein R4is oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-triazolyl or 1, 3, 4-oxadiazolyl, each of which is optionally substituted with one more substituents selected from halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkyl cycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkyl cycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof.

28. The method of any one of claims 24 to 27, wherein R4is substituted with Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, Ci-Ce hydroxylalkyl, Ci-Ce cyanoalkyl, 3-to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, or C3-C8 halocycloalkyl, or combinations thereof.

29. The method of any one of claims 24 to 28, wherein R4has one of the following structures:

30. The method of any one of claims 24 to 29, wherein A is phenyl.

31. The method of any one of claims 24 to 30, wherein A is unsubstituted.

32. The method of any one of claims 24 to 30, wherein A is substituted with one or more R6.

33. The method of any one of claims 24 to 30 or 32, wherein R6is chloro, fluoro, -CHF2, -CH2CH2OH, cyano, or methoxy.

34. The method of any one of claims 24 to 33, wherein A is:

35. The method of any one of claims 24 to 30 or 32 to 34, wherein the compound is a compound of Formula (la), or a pharmaceutically acceptable salt, stereoisomer, or solvatewherein:R2ais C3-C4 cycloalkyl optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy and 3-8 membered heterocyclyl; andR4ais isoxazolyl optionally substituted with one more substituents selected from Ci- Ce haloalkyl, C3-C8 cycloalkyl or C3-C8 haloalkyl cycloalkyl.

36. The method of claim 35, wherein R2ais cyclopropyl.

37. The method of claim 35 or 36, wherein R4ais:

38. The method of any one of claims 24 to 37, wherein the compound of Formula (I) is listed in Table 1, or a pharmaceutically acceptable salt or solvate thereof.

39. The method of any one of claims 24 to 38, wherein the compound of Formula (I) is, or a pharmaceutically acceptable salt or solvate thereof.

40. The method of any one of claims 24 to 39, wherein the subject has MRD, wherein the MRD is MRD in Acute Myeloid Leukemia (AML).

41. The method of any one of claims 24 to 39, wherein the subject has MRD, wherein the MRD is MRD in Myelodysplastic Syndromes (MDS).

42. The method of any one of claims 24 to 41, wherein the MRD is defined by leukemia cells not detectable in the bone marrow of the subject.

43. The method of claim 42, wherein the MRD is defined by leukemia cells not detectable in the bone marrow of the subject using microscopy but are detectable using flow cytometry or a nucleic acid detection method.

44. The method of claim 42, wherein the MRD is defined by leukemia cells not detectable in the bone marrow of the subject using microscopy but are detectable using next-generation sequencing (NGS).

45. The method of any one of claims 1 to 44, wherein the subject has low blast cells according to the WHO 2022 classification or IPSS-R classification.

46. The method of claim 45, wherein the blast cell percentage in bone marrow of the subject is 10% or less.

47. The method of claim 45 or 46, wherein the blast cell percentage in bone marrow of the subject is 5% or less.

48. The method of any one of claims 45 to 47, wherein the blast cell is myeloblasts.

49. The method of any one of claims 1 to 48, wherein the subject has an isolated 5q deletion or SF3B1 mutation, or a combination thereof.

50. The method of any one of claims 1 to 49, wherein the administering comprises administering about 0.5 mg to about 10 mg of the compound to the subject.

51. The method of any one of claims 1 to 50, wherein the administering comprises administering the compound to the subject every day, every other day, every two days, every three days, every four days, every five days, every six days, once a week, five days on and two days off, once every two weeks, or once a month.

52. The method of any one of claims 1 to 51, wherein the administering comprises orally administering to the subject the compound.

53. The method of any one of claims 1 to 52, wherein the compound is in the form of a tablet, capsule or pill.

54. The method of any one of claims 1 to 53, wherein the subject has symptomatic anemia, optionally wherein the subject with symptomatic anemia has a hemoglobin level of less than 13.0 g / dL.

55. The method of claim 54, wherein the subject has a hemoglobin level of less than 9.0 g / dL.

56. The method of claim 54 or 55, wherein the subject has serum ferritin levels of greater than 50 ng / ml.

57. The method of any one of claims 54 to 56, wherein the subject does not have B12 or folate deficiencies, autoimmune or hereditary hemolysis, or gastrointestinal bleeding.

58. The method of any one of claims 1 to 57, wherein the administering prevents relapse of the hematological malignancy.

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