SOS1 inhibitors for treatment of philadelphia chromosome positive leukemia

Abstract

The present disclosure provides methods for treating Philadelphia chromosome positive (Ph +) leukemia, such as CML (chronic myeloid leukemia, chronic myeloid leukemia, chronic myeloid SOS-1 inhibitors (such as bicyclic or macrocyclic compounds) of Ph + ALL (acute lymphoblastic leukemia), Ph + AML (acute lymphoblastic lymphoma), alone or in combination with TKI (such as dasatinib or imatinib) against BCR-ABL tyrosine kinases are disclosed.

Description

Cross-referencing

[0001] This application claims the benefits of U.S. Provisional Application No. 63 / 581, 969, filed September 11, 2023, and U.S. Provisional Application No. 63 / 572,066, filed March 29, 2024, each of which is incorporated herein by reference in its entirety. sequence list

[0002] This application includes a sequence list submitted electronically in XML format and incorporated herein by reference in its entirety. The XML copy was created on August 29, 2024, named 56690_772_601_SL.xml, and has a size of 4,103 bytes. Background Technology

[0003] Philadelphia positive chromosome (Ph+) abnormalities resulting from the reciprocal translocation of t(9;22)(q34;qll) are associated with various types of blood cancers. This translocation of the long arms of chromosomes 9 and 22 will affect c- ABL1 The gene moved from chromosome 9 to chromosome 22. BCR The 5' half of the gene, thus producing a type called BCR-ABL A novel hybrid gene encoding p210 BCR-ABL or p190 BCR -ABL This depends on the location of the breakpoint on chromosome 22. This cytogenetic trait is present in over 90% of patients with chronic myeloid leukemia (CML), 20% to 35% of adults with acute lymphoblastic leukemia (ALL), and 5% or fewer of children with ALL or acute myeloid leukemia. In 2023, an estimated 9,000 new patients will be diagnosed with CML in the United States, and approximately 1,310 will die from CML. In addition, approximately 6,540 new cases of ALL will be diagnosed (20-35% of which are Ph+), and approximately 1,390 will die from ALL.

[0004] The advent of tyrosine kinase inhibitors, starting with the first-generation imatinib, has significantly improved patient life expectancy. Most of these tyrosine kinase inhibitors target the ATP site of the BCR-ABL oncoprotein, with the exception of asciminib, which binds to an allosteric site. However, long-term use of tyrosine kinase inhibitors has led to resistance, with a staggering prevalence of 20-30% in treated CML patients. Am. J. Hematol. 2016; 91:252-265; Blood.2012;119:1123-1129. More than 90 different BCR-ABL mutations have been detected. Among them, point mutations T315, Y253, E255, M351, G250, F359 and H396 are the most common and associated with drug resistance. JCO Glob. Oncol. 2021;7:GO.21.00058.

[0005] Son of Sevenless 1 (SOS1) is a homolog of SOS2 in mammalian cells and acts as a guanine nucleotide exchange factor (GEF) to promote the release of inactive GDP from RAS family proteins, thereby enabling GTP binding (Chardin et al., Science, 1993, 260(5112): 1338-43). SOS1 is associated with cancer due to its ability to activate RAS family protein signaling. SOS1 interacts with the adaptor protein Grb2, and the resulting SOS1 / Grb2 complex binds to activated / phosphorylated receptor tyrosine kinases (e.g., EGFR, ErbB2, ErbB3, ErbB4, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1 / 2 / 3). SOS1 is also recruited to other phosphorylated cell surface receptors, such as the T-cell receptor (TCR), B-cell receptor (BCR), and monocyte colony-stimulating factor receptor (Salojin et al., J. Biol. Chem. 2000, 275(8):5966-75). SOS1 localizes to the plasma membrane, close to RAS family proteins, enabling SOS1 to promote RAS family protein activation. SOS1 activation of RAS family proteins can also be mediated through the interaction of SOS1 / Grb2 with BCR-ABL oncoprotein, which is common in chronic myeloid leukemia (Kardinal et al., 2001, Blood, 98:1773-81). Summary of the Invention

[0006] There is an urgent need to identify relevant monotherapy and combination therapies to meet the long-term need for sustained therapeutic benefits in patients with Philadelphia positive (Ph+) disorders, including various types of blood cancer. This invention addresses these needs and provides relevant advantages.

[0007] In one aspect, this disclosure provides a method of treating a subject with Philadelphia chromosome-positive (Ph+) blood cancer, comprising administering to the subject a pharmaceutical composition comprising an effective amount of a small molecule SOS1 inhibitor, wherein the subject has been treated with a tyrosine kinase inhibitor (TKI) targeting BCR-ABL tyrosine kinase prior to the administration of the SOS1 inhibitor. Exemplary Ph+ diseases are various blood cancers, including but not limited to chronic myeloid leukemia (CML), Ph+ acute lymphoblastic leukemia (Ph+ ALL), or Ph+ lymphoblastic lymphoma (Ph+ LBL). Resistance to the TKI may be characterized by progression of Philadelphia chromosome-positive (Ph+) blood cancer, BCR-ABL Gene mutation, BCR-ABL Gene overexpression, changes in drug transporter activity, activation of compensatory signaling pathways, changes in cell metabolism, epigenetic alterations, changes in the microenvironment and immune status, changes in microRNA expression, DNA damage repair, and alterations in genomic instability. Alternatively, resistance to TKIs may be characterized by... BCR-ABL One or more mutations in the gene that reduce the binding affinity of TKI to BCR-ABL tyrosine kinase. In some embodiments, resistance to TKI is characterized by mutations (1) that result in increased BCR-ABL kinase activity, increased half-life of BCR-ABL in cells, or increased expression of BCR-ABL in cells, or (2) mutations in the P ring (ATP binding site), the C ring (catalytic domain), the activating (A) ring, the myristic acid pocket, and / or mutations that directly affect TKI binding (drug contact site). Related to resistance BCR-ABL Non-limiting examples of gene mutations include T315I, F359V, Y253H, E255K, M351T, G250E, F359I, and H396. In some embodiments, subjects exhibiting CML relapse are characterized by the recurrence of abnormal hematological, molecular, and / or cytogenetic responses.

[0008] In another aspect, this disclosure provides a method for treating Philadelphia chromosome-positive (Ph+) diseases, including blood cancers, in subjects of need, comprising administering a pharmaceutical composition containing an effective amount of a small molecule SOS1 inhibitor, wherein the subject is identified as having a genetic aberration in BCR-ABL. In some embodiments, the genetic aberration is a mutation in BCR-ABL associated with resistance to a tyrosine kinase inhibitor (TKI) targeting BCR-ABL tyrosine kinase. In some embodiments, the genetic aberration is characterized by mutations in the P loop (ATP binding site), mutations in the C loop (catalytic domain), mutations on the activating (A) loop, mutations in the myristic acid pocket, and / or mutations that directly affect TKI binding (drug contact site). In some embodiments, the genetic aberration is characterized by... BCR-ABL Mutations in the gene, wherein the mutations are selected from T315I, F359V, Y253H, E255K, M351T, G250E, F359I and H396.

[0009] In another aspect, this disclosure provides a method of combination therapy comprising administering (a) a small molecule SOS1 inhibitor and (b) a tyrosine kinase inhibitor (TKI) targeting BCR-ABL tyrosine kinase to a subject in need, wherein the administration of (a) occurs before, simultaneously with, or after the administration of (b), and wherein the combination therapy synergistically slows the progression of Philadelphia chromosome-positive (Ph+) blood cancer and / or reduces undesirable side effects associated with the TKI. In some embodiments, one or both of (a) and (b) are administered at a subtherapeutic dose, but when (a) or (b) is administered at its respective therapeutically effective dose, the achieved therapeutic effect is at least equivalent to that achieved by administering (a) or (b) alone. In some embodiments, the combination therapy exhibits a synergistic effect in slowing the progression of chronic myeloid leukemia (CML), Ph+ acute lymphoblastic leukemia (Ph+ ALL), or Ph+ lymphoblastic lymphoma (Ph+ LBL). In some embodiments, slowing the progression of Philadelphia chromosome-positive (Ph+) leukemia is demonstrated by improvements selected from the following responses: hematologic response, molecular response, and cytogenetic response of the subject. In some embodiments, improvements in the hematologic response are characterized by a return of the subject's blood cells to normal levels. In some embodiments, improvements in the molecular response are characterized by a reduction in the amount of the BCR-ALB1 gene present in the subject's blood, as determined by nucleic acid assays. In some embodiments, improvements in the cytogenetic response are characterized by a reduction in the number of bone marrow cells containing the Philadelphia chromosome. In some embodiments, combination therapy exhibits a synergistic effect in reducing TKI-related side effects, including but not limited to cardiotoxicity, nausea, vomiting, diarrhea, muscle cramps, bone pain, fatigue, rash, and edema.

[0010] If needed, the TKI used in combination therapy is dasatinib, administered at the following subtherapeutic doses: less than 100 mg daily for chronic phase CML, or less than 140 mg daily for accelerated and blast crisis CML and Ph+ ALL. In some embodiments, the TKI used in combination therapy is imatinib, administered at the following subtherapeutic doses: less than 400 mg daily for chronic phase CML, or less than 600 mg daily for accelerated and blast crisis CML and Ph+ ALL. In some embodiments, the TKI used in combination therapy is nilotinib, administered at the following subtherapeutic doses: less than 300 mg twice daily for chronic phase CML, or less than 400 mg twice daily for resistant (second-line) and accelerated or blast crisis CML. In some embodiments, the TKI used in the combination therapy is aciminib, administered at subtherapeutic doses of less than 80 mg daily, less than 40 mg twice daily, or less than 200 mg twice daily for Ph+ hematologic malignancies with a T315I mutation. In some embodiments, the TKI used in the combination therapy is ponatinib, administered at a subtherapeutic dose of less than 45 mg daily. In some embodiments, the TKI used in the combination therapy is ratotinib, flumatinib, or olverembatinib, administered at the subtherapeutic dose approved for its intended indication.

[0011] In another aspect, this disclosure provides a method for treating Philadelphia chromosome-positive (Ph+) leukemia in a subject of need. The method may include administering to the subject a pharmaceutical composition comprising an effective amount of a small molecule SOS1 inhibitor, wherein the SOS1 inhibitor inhibits the growth of CML cell lines with an IC50 of less than about 50 nM, as determined in a growth inhibition assay using CML cell lines.

[0012] In another aspect, the present invention provides a method for reducing the proliferation of cells containing the Philadelphia chromosome. The method comprises administering to cells (a) a small molecule SOS1 inhibitor disclosed herein and (b) at least one tyrosine kinase inhibitor (TKI) targeting BCR-ABL tyrosine kinase, wherein the administration of (a) and (b) synergistically inhibits the growth of CML cells, as demonstrated by: (1) administering less than 90% of the SOS1 inhibitor compared to the amount required to administer the SOS1 inhibitor alone; or (2) administering less than 90% of the TKI compared to the amount required to administer the TKI alone, achieving a comparable or greater degree of growth inhibition. In some embodiments, the TKI administered is less than about 80%, 70%, 60%, 50%, 40%, 30%, 25%, 20%, 15%, or 10% of the amount required to achieve a comparable or greater degree of growth inhibition. In some embodiments, the practice of this method for reducing the proliferation of Ph+ chronic myeloid leukemia (CML) cells, Ph+ ALL cells, or Ph+ LBL cells is performed in vitro, ex vivo, or in vivo.

[0013] In another aspect, this disclosure provides a method for reducing the proliferation of cells containing the Philadelphia chromosome, the method comprising administering to the cells (a) a small molecule SOS1 inhibitor and (b) at least one tyrosine kinase inhibitor (TKI) targeting BCR-ABL, wherein the administration of (a) and (b) synergistically inhibits the growth of CML cells, the synergistic value determined by the Bliss Independent Criterion being at least about 0.1, 0.2, 0.3, 0.4, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 9, 10, 11, 12, 13, 14, 15 or greater. In some embodiments, the combination therapy is characterized by a synergistic value determined by the Bliss Independent Criterion being about 0.1 to about 1, about 1.0-5, about 5 to about 10, or about 10-15. The synergistic value is determined by the Bliss Independent Criterion according to the following formula: Y AB,O -Y AB,P in: Y AB,O The percentage of cancer cell growth inhibition observed by applying (a) and (b) containing (a) at dose A and (b) at dose B; and Y AB,P Y is the percentage of cancer cell growth inhibition predicted by applying (a) and (b) containing (a) at dose A and (b) at dose B, where Y AB,P = Y A + Y B – Y A Y B , Further, including: Y A The percentage of cancer cell growth inhibition observed by using dose A alone (a); Y B The percentage of cancer cell growth inhibition observed by using dose B alone (b); and Y A Y B It is Y A and Y B The product of.

[0014] Any method disclosed herein can be applied to the treatment of Ph+ blood cancers, including chronic myeloid leukemia (CML), Ph+ acute lymphoblastic leukemia (Ph+ ALL), and Ph+ lymphoblastic lymphoma (Ph+ LBL). A subject SOS1 inhibitor can be administered as monotherapy or in combination with other agents or therapies. A variety of suitable other agents include, but are not limited to, TKIs, immunomodulators, antinausea (or antiemetics), analgesics, and chemotherapeutic agents. In some embodiments, the additional agent is the same TKI as previously administered to the subject. In some embodiments, the additional agent is a different TKI than previously administered to the subject. In some embodiments, the additional agent is the same TKI as previously administered to the subject, but administered at a different dose. In some embodiments, the additional agent is a different TKI than administered to the subject at a subtherapeutic dose. If desired, the additional agent may be an immunomodulator, cytokine, or checkpoint immune blockade agent. In some implementations, the additional agent is selected from anti-PD-L1 antibody, anti-CTLA-4 antibody, anti-PD-1 antibody, anti-LAG3 antibody, anti-TIM3 antibody, and combinations thereof.

[0015] In some implementations, SOS1 inhibitors are administered in combination with other therapies selected from surgery, cell therapy, chemotherapy, bone marrow transplantation, or radiation.

[0016] The TKIs suitable for any method of this disclosure are selected from imatinib, dasatinib, nilotinib, bosutinib, raditinib, flumatinib, ponatinib, olabatitinib, and aciminib.

[0017] SOS1 inhibitors used in any of the methods of this disclosure typically exhibit high potency against SOS1 in cells and / or cause downregulation of SOS1 in the subject upon administration. In some embodiments, the methods disclosed herein utilize small molecule SOS1 inhibitors of formula (I-1) or formula (A-1). Incorporation

[0018] All publications, patents and patent applications mentioned in this specification are incorporated herein by reference to the extent that each individual publication, patent or patent application is specifically and individually indicated to be incorporated herein by reference. Attached Figure Description

[0019] The novel features of the invention are set forth in detail in the appended claims. The features and advantages of the invention will be better understood by referring to the following detailed description and accompanying drawings (also referred to herein as “Figures” and “FIG.”), which illustrate illustrative embodiments utilizing the principles of the invention, in which: Figure 1 A KCL22 xenograft study is presented, in which mice were treated with or without the disclosed SOS1 inhibitor (compound A) alone or in combination with dasatinib or imatinib. Results showed that the disclosed SOS1 inhibitor, in combination with existing TKIs, synergistically reduced tumor volume and prolonged the duration of tumor growth control, and also induced sensitivity to imatinib resistance.

[0020] Figure 2 The study of Ba / F3-p210-BCR-ABL1-T315I allogeneic transplantation is shown, in which mice were treated with or without the disclosed SOS1 inhibitor (compound A) alone or in combination with aciminib or ponatinib.

[0021] Figure 3A The percentage of growth inhibition in Ba / F3-p210-BCR-ABL1-T315I cells after 5 days of treatment with the SOS1 inhibitor of this disclosure (compound A), ponatinib, or a 1:1 molar ratio of compound A and ponatinib is depicted.

[0022] Figure 3B The percentage of growth inhibition in Ba / F3-p210-BCR-ABL1-T315I cells after treatment for 5 days with the SOS1 inhibitor (compound A) of this disclosure, acimenil, or a 1:1 molar ratio of compound A and acimenil was depicted.

[0023] Figure 4 The Ph+ pre-B-ALL cell line SUP-B15 was shown to be sensitive to treatment with the SOS1 inhibitor (compound A) disclosed herein in a 3-day growth inhibition assay. The activity of compound A was compared with other SOS1 inhibitors and the TKIs imatinib and dasatinib.

[0024] Figure 5A The extent of growth inhibition of KCL-22 cells after treatment with (i) a single SOS1 inhibitor of this disclosure (compound A), (ii) imatinib alone, or (iii) a combination of different concentrations of (i) and (ii) is shown.

[0025] Figure 5B The calculation using the BLISS independent model is shown. Figure 5A The degree of synergy between the combinations.

[0026] Figure 6A The extent of growth inhibition of KCL-22 cells after treatment with (i) a single SOS1 inhibitor of this disclosure (compound A), (ii) dasatinib alone, or (iii) a combination of different concentrations of (i) and (ii) is shown.

[0027] Figure 6B The calculation using the BLISS independent model is shown. Figure 6A The degree of synergy between the combinations.

[0028] Figure 7 This study illustrates a KCL22-r xenograft experiment in mice, where mice were treated with or without the disclosed SOS1 inhibitor (compound A) alone or in combination with dasatinib. Results showed that in models refractory to dasatinib monotherapy, the disclosed SOS1 inhibitor in combination with dasatinib synergistically reduced tumor volume.

[0029] Figure 8 This study illustrates a KCL22 xenograft experiment in which mice with a high disease burden were treated with dasatinib alone or in combination with the disclosed SOS1 inhibitor (compound A). Results showed that, in a model simulating a remission-inducible design, the disclosed SOS1 inhibitor in combination with dasatinib synergistically reduced tumor volume. Detailed Implementation

[0030] Unless otherwise stated, the practice of some of the embodiments disclosed herein employs conventional techniques of immunology, biochemistry, chemistry, molecular biology, microbiology, cell biology, genomics, and recombinant DNA, which are within the scope of the art. See, for example, Sambrook and Green, *Molecular Cloning: A Laboratory Manual*, 4th edition (2012); the *Recent Experimental Methods in Molecular Biology* series (edited by F.M.A. Susubel et al.); the *Enzymatic Methods* series (Academic Press, Inc.); *PCR 2: Practical Methods* (edited by M.J. MacPherson, B.D. Hames, and G.G. Taylor (1995)); *Antibodies, A Laboratory Manual* (edited by Harlow and Lane (1988)); and *Animal Cell Culture: A Handbook of Basic Techniques and Specialized Applications*, 6th edition (edited by R.R. Freshney (2010)).

[0031] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. If multiple definitions exist for terms herein, those defined in this section shall prevail. All patents, patent applications, publications, and published nucleotide and amino acid sequences (e.g., sequences available in GenBank or other databases) mentioned herein are incorporated herein by reference. Chemical structures herein are based on, as stated in ChemDraw... ® Naming conventions are used in the software (Perkin Elmer, Inc., Cambridge, MA). Section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter. As used in the specification and claims, the singular forms “a,” “an,” and “the” include the plural referent unless the context clearly specifies otherwise.

[0032] When referring to measurable values ​​such as quantity or duration, the word “about” as used herein is intended to include a variation of ±10% of the said number or value.

[0033] Term "C" x-y "or "C x -C y When used in conjunction with chemical moieties such as alkyl, alkenyl, or alkynyl, it means to include groups containing x to y carbons in the chain. For example, the term "C x-y "Alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group, including straight-chain alkyl and branched alkyl groups containing x to y carbons in the chain.

[0034] "Alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group, including straight-chain and branched alkyl groups. Alkyl groups can contain 1 to 12 carbon atoms (e.g., C12). 1-12 Alkyl groups, such as those with 1 to 8 carbon atoms (C 1-8 Alkyl groups or 1 to 6 carbon atoms (C 1-6 Alkyl groups. Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, and decyl. The alkyl group is attached to the remainder of the molecule by a single bond. Unless otherwise specified in the specification, the alkyl group may optionally be substituted with one or more substituents (such as those described herein).

[0035] "Halogenated alkyl" refers to an alkyl group that is substituted with one or more halogens. Exemplary halogenated alkyl groups include trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl.

[0036] "Alkenyl" refers to a substituted or unsubstituted hydrocarbon group containing at least one double bond, including straight-chain and branched alkenyl groups. Alkenyl groups can contain 2 to 12 carbon atoms (e.g., C12). 2-12 Alkenyl groups, such as those with 2 to 8 carbon atoms (C 2-8 alkenyl) or 2 to 6 carbon atoms (C 2-6 Alkenyl groups. Exemplary alkenyl groups include ethenyl (i.e., vinyl), propenyl, butenyl, pentenyl, pent-1,4-dienyl, etc. Unless otherwise specifically stated in the specification, alkenyl groups may optionally be substituted with one or more substituents (such as those described herein).

[0037] "Alynyl" refers to a substituted or unsubstituted hydrocarbon group containing at least one triple bond, including straight-chain and branched alkynyl groups. Alynyl groups can contain 2 to 12 carbon atoms (e.g., C12, C23, C12, C23, C24 ...23, C24, C23, C24, C25, C26, C27, C28, C29, C29 2-12 Alkyne group), such as 2 to 8 carbon atoms (C 2-8 (alkynyl group) or 2 to 6 carbon atoms (C 2-6 Alynyl group. Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentylyl, hexynyl, etc. Unless otherwise specifically stated in the specification, the alkynyl group may optionally be substituted by one or more substituents (such as those described herein).

[0038] "alkylene" or "alkylene chain" refers to a substituted or unsubstituted divalent saturated hydrocarbon group, including straight-chain alkylene and branched-chain alkylene, which contains 1 to 12 carbon atoms (e.g., C12). 1-12 Alkylenes, such as those with 1 to 8 carbon atoms (C 1-8 Alkylene or 1 to 6 carbon atoms (C 1-6 Alkylenes. Exemplary alkylenes include methylene, ethylene, propylene, and n-butylene. Similarly, "alkenylene" and "ynyneene" refer to alkylenes as defined above, each containing one or more carbon-carbon double or triple bonds. The connection point between the alkylene, alkenyl, or ynyneene chain and the rest of the molecule can be through one or any two carbons in the chain. Unless otherwise specifically stated in the specification, alkylene, alkenyl, or ynyneenes may optionally be substituted with one or more substituents (such as those described herein).

[0039] “Heteroalkyl,” “heteroalkenyl,” and “heteroyneyl” refer to substituted or unsubstituted alkyl, alkenyl, and ynyl groups, respectively, in which one or more (e.g., 1, 2, or 3) carbon atoms are substituted with heteroatoms (e.g., O, N, P, Si, S, or combinations thereof). Any nitrogen, phosphorus, and sulfur heteroatoms present in the chain may optionally be oxidized, and any nitrogen heteroatomium may optionally be quaternized. If given, numerical ranges refer to the total chain length. For example, 3- to 8-membered heteroalkyl groups have chain lengths of 3 to 8 atoms. Connection to the remainder of the molecule can be made via heteroatoms or carbons in the heteroalkyl, heteroalkenyl, or heteroyne group. Unless otherwise specifically stated in the specification, the heteroalkyl, heteroalkenyl, or heteroyne group may optionally be substituted with one or more substituents (as described herein).

[0040] “Hypoalkylene,” “heteroenylene,” and “heteroynylene” refer to substituted or unsubstituted alkylene, alkenylene, and ynylene groups, respectively, in which one or more (e.g., 1, 2, or 3) carbon atoms are substituted with heteroatoms (e.g., O, N, P, Si, S, or combinations thereof). Any nitrogen, phosphorus, and sulfur heteroatoms present in the chain may optionally be oxidized, and any nitrogen heteroatom may optionally be quaternized. If given, numerical ranges refer to the total chain length. For example, 3- to 8-membered heteroalkylene groups have chain lengths of 3 to 8 atoms. The connection point between the heteroalkylene, alkenylene, or ynylene group and the rest of the molecule may be through one heteroatom or one carbon atom in the heteroalkylene, alkenylene, or ynylene group, or any two heteroatoms, any two carbons, or any one heteroatom and any one carbon. Unless otherwise specifically stated in the specification, the heteroalkylene, alkenylene, or ynylene group may optionally be substituted with one or more substituents (as described herein).

[0041] A "carbon ring" refers to a saturated ring, unsaturated ring, or aromatic ring, where each atom of the ring is a carbon atom. Carbon rings can include C atoms. 3-10 Single ring, C 6-12 Double ring, C 6-12 Spiral rings and C 6-12 Bridged ring. Each ring of the bicyclic carbon ring can be selected from saturated rings, unsaturated rings, and aromatic rings. In some embodiments, the carbon ring is C 6-12 Aryl, such as C 6-10 Aryl. In some embodiments, the carbide ring is C. 6-12 Cycloalkyl. In some embodiments, the carbide ring is C10. 6-12Cycloalkenyl. In one exemplary embodiment, an aromatic ring (e.g., phenyl) may be fused with a saturated or unsaturated ring (e.g., cyclohexane, cyclopentane, or cyclohexene). Any combination of saturated bicyclic, unsaturated bicyclic, and aromatic bicyclic rings is included in the definition of a carbocyclic ring, provided the valence allows. Exemplary carbocyclic rings include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Unless otherwise specifically stated in the specification, the carbocyclic ring may optionally be substituted with one or more substituents (such as those described herein).

[0042] A "heterocycle" refers to a saturated, unsaturated, or aromatic ring containing one or more heteroatoms, such as one, two, or three heteroatoms selected from O, S, and N. Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, 6- to 12-membered spirocyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic heterocycle can be selected from saturated, unsaturated, and aromatic rings. If valence permits, the heterocycle can be attached to the rest of the molecule by any atom of the heterocycle, such as a carbon or nitrogen atom. In some embodiments, the heterocycle is a 5- to 10-membered heteroaryl, such as a 5- or 6-membered heteroaryl. In some embodiments, the heterocycle is a 3- to 12-membered heterocyclic alkyl. In an exemplary embodiment, the heterocycle (e.g., a pyridyl group) may be fused with a saturated or unsaturated ring (e.g., cyclohexane, cyclopentane, or cyclohexene). Exemplary heterocycles include pyrrolidinyl, pyrrolithyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, pyrimidinyl, pyridazinyl, thiophenyl, oxazolyl, thiazolyl, morpholinyl, indazole, indolyl, and quinolinyl. Unless otherwise specifically stated in the specification, the heterocycle may optionally be substituted with one or more substituents (such as those described herein).

[0043] "Heteroaryl" refers to a 5- to 12-membered aromatic ring containing at least one heteroatom, such as one, two, or three heteroatoms selected from O, S, and N. As used herein, the heteroaryl ring can be selected from monocyclic or bicyclic systems—including fused ring systems, spirocyclic systems, and bridged ring systems—where at least one ring in the ring system is aromatic. The heteroatom in the heteroaryl group may optionally be oxidized. One or more nitrogen atoms (if present) may optionally be quaternized. If the valence allows, the heteroaryl group can be attached to the rest of the molecule via any atom of the heteroaryl group, such as a carbon or nitrogen atom of the heteroaryl group. Examples of heteroaryl groups include, but are not limited to, azaheptenyl, benzimidazolyl, benzisisothiazolyl, benzisisooxazolyl, benzofuranyl, benzothiazolyl, benzothiophenyl, benzooxazolyl, furanyl, imidazolyl, indazole, indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, purinyl, pyrazinyl, pyrazolylalkyl, pyrazolyl, pyridinyl, pyridinyl, pyridinyl, pyrimidinyl, pyrroleyl, quinazolinyl, quinolinyl, quinoxalolinyl, tetrahydroquinolinyl, thiadiazolyl, thiazolyl, and thiophenyl. Unless otherwise specifically stated in the specification, heteroaryl groups may optionally be substituted with one or more substituents (such as those described herein).

[0044] Unless otherwise stated, hydrogen atoms are implicitly included in the structure described herein as necessary to satisfy the valence requirements.

[0045] A wavy line drawn across a key. "or dashed key" "These terms can be used interchangeably in this document to indicate where a key break or connection occurs. For example, in a structure..." In the middle, if R 7 Is it like this? In 1-cyclopropyl-1-carboxynitrile, then R 7 It can be described as " "or" ".

[0046] The term "substituted" refers to a portion of a structure having a substituent that replaces hydrogen atom on one or more carbon or heteroatoms. It should be understood that "substituted" or "replaced by" includes the implicit limiting condition that such substitution meets the permissible valence of the substituted atom and the substituent, and that the substitution results in a stable compound, for example, which does not spontaneously undergo transformations such as rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is contemplated to include all permissible substituents in organic compounds. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents in organic compounds. For a suitable organic compound, permissible substituents may be one or more, and may be the same or different. For the purposes of this disclosure, heteroatoms such as nitrogen may have any permissible substituent in organic compounds that meet the valence of heteroatoms as described herein.

[0047] The compounds disclosed herein, such as those of formula (I), are optionally substituted by one or more, such as 1, 2 or 3, substituents selected from the following: Halogen, oxo, =NH, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon ring, -CH2-(C 3-10 Carbon rings), 3- to 10-membered heterocycles, -CH2- (3- to 10-membered heterocycles), -OR 21 -SR 21 -N(R) 22 (R) 23 -C(O)OR 22 -C(O)N(R) 22 (R) 23 -C(O)C(O)N(R) 22 (R) 23 ), -OC(O)N(R 22 (R) 23 ), -N(R 24 )C(O)N(R 22 (R) 23 ), -N(R 24 )C(O)OR 25 -N(R) 24 )C(O)R 25 -N(R) 24 )S(O)2R 25 -C(O)R 25 -S(O)2R 25 -S(O)2N(R) 22 (R) 23 -OCH2C(O)OR 22and -OC(O)R 25 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon ring, -CH2-(C 3-10 The carbocyclic ring (3 to 10-membered heterocycle) and -CH2- (3 to 10-membered heterocycle) are optionally substituted by one, two, or three independent groups selected from the following: halogen, oxo, =NH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -OR 21 -SR 21 -N(R) 22 (R) 23 -C(O)OR 22 -C(O)N(R) 22 (R) 23 -C(O)C(O)N(R) 22 (R) 23 ), -OC(O)N(R 22 (R) 23 ), -N(R 24 )C(O)N(R 22 (R) 23 ), -N(R 24 )C(O)OR 25 -N(R) 24 )C(O)R 25 -N(R) 24 )S(O)2R 25 -C(O)R 25 -S(O)2R 25 -S(O)2N(R) 22 (R) 23 ) and -OC(O)R 25 ; R 21 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 3-10 The carbide ring and the 3 to 10-membered heterocycle are optionally substituted by one, two, or three independent groups selected from the following: halogen and C. 1-6 alkyl; R 22 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 3-10 The carbide ring and the 3 to 10-membered heterocycle are optionally substituted by one, two, or three independent groups selected from the following: halogen and C. 1-6 alkyl; R 23 Each time it appears, it is independently selected from H and C. 1-6 alkyl; R 24 Each time it appears, it is independently selected from H and C. 1-6 Alkyl; and R 25 Each time it appears, it is independently selected from C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 1-6 Alkyl, C 3-10 The carbide ring and the 3 to 10-membered heterocycle are optionally substituted by one, two, or three independent groups selected from the following: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-10 Carbon rings and 3 to 10-membered heterocycles.

[0048] In some embodiments, the compounds disclosed herein, such as those of formula (I), are optionally substituted by one or more, such as 1, 2, or 3, substituents selected from: Halogen, oxo, =NH, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon ring, -CH2-(C 3-10 Carbon rings), 3- to 10-membered heterocycles, -CH2- (3- to 10-membered heterocycles), -OR 21 -SR 21 -N(R) 22 (R) 23 -C(O)OR 22 -C(O)N(R) 22 (R) 23 -C(O)C(O)N(R) 22 (R) 23 ), -OC(O)N(R 22 (R) 23 ), -N(R 24 )C(O)N(R 22(R) 23 ), -N(R 24 )C(O)OR 25 -N(R) 24 )C(O)R 25 -N(R) 24 )S(O)2R 25 -C(O)R 25 -S(O)2R 25 -S(O)2N(R) 22 (R) 23 -OCH2C(O)OR 22 and -OC(O)R 25 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon ring, -CH2-(C 3-10 The carbocyclic ring (3 to 10-membered heterocycle) and -CH2- (3 to 10-membered heterocycle) are optionally substituted by one, two, or three independent groups selected from the following: halogen, oxo, =NH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -OR 21 -SR 21 and -N(R) 22 (R) 23 ); R 21 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 3-10 The carbide ring and the 3 to 10-membered heterocycle are optionally substituted by one, two, or three independent groups selected from the following: halogen and C. 1-6 alkyl; R 22 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 3-10 The carbide ring and the 3 to 10-membered heterocycle are optionally substituted by one, two, or three independent groups selected from the following: halogen and C. 1-6 alkyl; R 23Each time it appears, it is independently selected from H and C. 1-6 alkyl; R 24 Each time it appears, it is independently selected from H and C. 1-6 Alkyl; and R 25 Each time it appears, it is independently selected from C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 1-6 Alkyl, C 3-10 The carbide ring and the 3 to 10-membered heterocycle are optionally substituted by one, two, or three independent groups selected from the following: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-10 Carbon rings and 3 to 10-membered heterocycles.

[0049] In some embodiments, the compounds disclosed herein, such as those of formula (I), are optionally substituted by one or more, such as 1, 2, or 3, substituents selected from: halogen, oxo, =NH, -CN, -NO2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon ring, -CH2-(C 3-10 Carbon rings), 3- to 10-membered heterocycles, -CH2- (3- to 10-membered heterocycles), -OH, -OCH3, -OCH2CH3, -NH2, -NHCH3 and -NHCH2CH3, where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon ring, -CH2-(C 3-10 The carbon ring, 3 to 10-membered heterocycles and -CH2- (3 to 10-membered heterocycles) are optionally substituted by one, two or three independent groups selected from the following: halogen, oxo, =NH, -CN, -NO2, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -OH, -OCH3, -OCH2CH3, -NH2, -NHCH3 and -NHCH2CH3.

[0050] Those skilled in the art will understand that the substituted element itself can be substituted if appropriate. Unless specifically stated as “unsubstituted,” references to the chemical part herein should be understood to include substituted variants. For example, references to a “heteroaryl” group or partly implicitly include both substituted and unsubstituted variants.

[0051] When divalent substituents are specified herein by their conventional chemical formula written from left to right, they are intended to cover isomers arising from writing the structure from right to left; for example, -CH2O- is also intended to cover -OCH2-.

[0052] "Optional" or "optionally" means that the subsequent described event or circumstance may or may not occur, and the description includes both the case where the event or circumstance occurs and the case where the event or circumstance does not occur. For example, an "optionally substituted" group may be unsubstituted or substituted.

[0053] The compounds of the present disclosure also include crystalline and amorphous forms of these compounds, pharmaceutically acceptable salts, and active metabolites having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including dehydrates), conformational polymorphs, amorphous forms of the compounds, and mixtures thereof.

[0054] The compounds described herein may exhibit their natural isotope abundances, or one or more of the atoms may be artificially enriched with a specific isotope having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variants of the compounds of the present disclosure, whether radioactive or not, are covered within the scope of the present disclosure. For example, hydrogen has three naturally occurring isotopes, designated as 1 H (protium), 2 H (deuterium), and 3 H (tritium). Protium is the most abundant hydrogen isotope in nature. Enrichment of deuterium can provide certain therapeutic advantages, such as increased in vivo half-life and / or exposure, or can provide compounds for studying in vivo drug elimination and metabolic pathways. Examples of isotopes that can be incorporated into the compounds of the present disclosure include, but are not limited to, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 36 Cl, and 18 F. Particular interest lies in compounds of formula (I) enriched with tritium or carbon-14, which can be used, for example, in tissue distribution studies; compounds of the present disclosure enriched with deuterium (especially at metabolic sites), which result in, for example, higher metabolic stability of the compounds; and compounds enriched with positron-emitting isotopes such as 11 C, 18 F, 15 O, and 13Compounds of formula (I) with N can be used, for example, in positron emission tomography (PET) studies. The isotope-rich compounds can be prepared using conventional techniques well known to those skilled in the art.

[0055] As used herein, the phrases “of a form,” “having a form,” or “having a structure” are not intended to be restrictive and are used in the same manner as the commonly used term “comprising.” For example, if a structure is described, it should be understood to encompass all stereoisomers and tautomers unless otherwise stated.

[0056] Some of the compounds described herein contain one or more asymmetric centers and are therefore capable of producing enantiomers, diastereomers, and other stereoisomers, the asymmetric centers of which may be defined as (R)- or (S)- according to absolute stereochemistry. In some embodiments, to optimize the therapeutic activity of the compounds of this disclosure, for example, to treat fibrosis, it may be necessary for the carbon atoms to have a specific configuration (e.g., (R,R), (S,S), (S,R), or (R,S)) or be rich in stereoisomers having such configurations. The compounds of this disclosure may be provided as racemic mixtures. Therefore, unless otherwise stated, this disclosure relates to racemic mixtures, pure stereoisomers (e.g., enantiomers and diastereomers), mixtures rich in stereoisomers, etc. When a chemical structure without any stereochemistry is described herein, it should be understood that all possible stereoisomers are covered by such structures. Similarly, when specific stereoisomers are shown or named herein, those skilled in the art will understand that, unless otherwise stated, small amounts of other stereoisomers may be present in the compositions disclosed herein, provided that the presence of such other isomers does not negate the utility of the composition as a whole. Individual stereoisomers can be obtained by many methods known in the art, including preparation using chiral synthons or chiral reagents, resolution using chiral chromatography utilizing a suitable chiral stationary phase or support, or by chemically converting them to diastereomers, separating diastereomers by conventional means such as chromatography or recrystallization, and then regenerating the original stereoisomers.

[0057] In addition, where applicable, unless otherwise stated, all cis-trans or E / Z isomers (geometric isomers), tautomers and topological isomers of the compounds described herein are included within the scope of this disclosure.

[0058] The term "pharmaceutically acceptable" means a material that is not biologically or otherwise unacceptable when used in the subject composition and methods. For example, the term "pharmaceutically acceptable carrier" refers to materials such as adjuvants, excipients, glidants, sweeteners, diluents, preservatives, dyes, colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that can be incorporated into a composition and administered to a patient without causing unacceptable biological effects or interacting with other components of the composition in an unacceptable manner. Such pharmaceutically acceptable materials generally meet the requirements of toxicological and manufacturing testing standards and include those materials that have been determined by the U.S. Food and Drug Administration to be suitable inactive ingredients.

[0059] The terms "salt" and "pharmaceutically acceptable salt" refer to salts prepared from bases or acids. Pharmaceutically acceptable salts are suitable for administration to patients, such as mammals (e.g., salts with acceptable mammalian safety for a given dosage regimen). Salts can be formed from inorganic bases, organic bases, inorganic acids, and organic acids. Furthermore, when a compound comprises both a basic moiety (such as an amine, pyridine, or imidazole) and an acidic moiety (such as a carboxylic acid or tetraazole), zwitterions can be formed and included in the term "salt" as used herein. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0060] "Pharmaceutically acceptable acid addition salts" refer to salts that retain the biological effectiveness and properties of the free base, are not biologically or otherwise undesirable, and are formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc. This also includes salts formed with organic acids such as aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanes, hydroxyalkanes, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc., including, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. Therefore, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, caprylates, sebacic acid salts, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, etc. Salts of amino acids such as arginine salts, gluconates, and galacturons are also considered (see, for example, Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science). , 66:1-19 (1997)). In some embodiments, the acid addition salt of a basic compound is prepared by contacting a sufficient amount of the desired acid with a free base form to produce a salt, according to methods and techniques familiar to a skilled craftsman.

[0061] "Pharmaceutically acceptable base addition salts" refer to salts that retain the bioavailability and properties of the free acid and are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to a free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed using metals or amines such as alkali metals and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from organic bases include, but are not limited to, salts of the following substances: primary, secondary, and tertiary amines; substituted amines, including naturally occurring substituted amines; cyclic amines; and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, and procaine. N,N -Dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenediphenylamine N methyl-reduced glucosamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N -Ethylpiperidine, polyamine resins, etc. See Berge et al. (ibid.).

[0062] As used herein, “treating” or “treatment” means a method used to obtain a beneficial or desired outcome for a subject’s disease, symptom, or medical condition (such as cancer), including but not limited to: (a) preventing the occurrence of the disease or medical condition, such as preventing the recurrence of the disease or medical condition, or providing preventative treatment to a subject susceptible to the disease or medical condition; (b) improving the disease or medical condition, such as eliminating or resolving the subject’s disease or medical condition; (c) suppressing the disease or medical condition, such as slowing or halting the progression of the subject’s disease or medical condition; or (d) alleviating the symptoms of the subject’s disease or medical condition. For example, “treating cancer” would include preventing the occurrence of cancer, improving cancer, suppressing cancer, and alleviating the symptoms of cancer. Furthermore, a therapeutic benefit may be achieved by eradicating or improving one or more of the physiological symptoms associated with an underlying condition, resulting in an improvement observed in the subject, although the subject may still have the underlying condition.

[0063] As used herein, the term "therapeutic effect" encompasses the therapeutic benefits and / or preventive benefits described above. Preventive effects include delaying or eliminating the onset of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, stopping, or reversing the progression of a disease or condition, or any combination thereof.

[0064] The terms “administer,” “administering,” “administration,” and their derivatives refer to methods that can be used to deliver a composition to a desired biological site of action. These methods include, but are not limited to, parenteral administration (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, intrathecal, intranasal, intravitreal, infusion, and local injection), transmucosal injection, oral administration, suppository administration, and local administration. Administration can be performed via any route, including parenteral administration. Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intravenous, and intracranial administration. Other delivery methods include, but are not limited to, the use of liposomal formulations, intravenous infusion, transplantation, etc. Those skilled in the art will recognize other methods for administering a therapeutically effective amount of the composition of this disclosure to prevent or alleviate one or more symptoms associated with a disease.

[0065] The terms "effective amount," "therapeutic effective amount," or "therapeutic dose" refer to the amount of a pharmaceutical agent sufficient to achieve a beneficial or desired outcome. A therapeutically effective amount can vary based on one or more of the following factors: the subject and disease condition being treated, the subject's weight and age, the severity of the disease condition, the method of administration, etc., which can be readily determined by one of ordinary skill in the art. An effective amount of an active pharmaceutical agent can be administered in a single dose or multiple doses. Components may be described herein as having at least an effective amount, or at least an effective quantity, as relevant to a specific target or purpose (as described herein). The term "effective amount" also applies to the dose that will provide an image for detection by a suitable imaging method. A specific dose can vary based on one or more of the following factors: the specific pharmaceutical agent selected, the dosing regimen to be followed, whether it is administered in combination with other compounds, the time of administration, the tissue to be imaged, and the physical delivery system carrying it.

[0066] The terms “subtherapeutic dose,” “subeffective dose,” and “subtherapeutic amount” are used interchangeably and refer to the amount of a drug below the effective amount of a drug, but can produce the desired results when combined with the effective amount or subtherapeutic dose of a different drug, for example by the synergistic effect of (i) the subtherapeutic dose of the drug and (ii) the combination of different drugs (e.g., one or more different drugs) in terms of the resulting effective effect and / or reduced side effects. For example, a drug may be approved for clinical use in a specific indication at a defined dose or range (e.g., 150 mg / day) in one or more administrations, and the subtherapeutic dose of such a drug may be at least about 0.1, 0.2, 0.5, 1, 2, 5, 10, 20, 50, 100, 200, 500, 1,000, 2,000, 5,000, 10,000, 20,000, 50,000, 100,000, or more times lower than its approved dose or range. Subtherapeutic doses of such medications can be up to approximately 100,000, 50,000, 20,000, 10,000, 5,000, 2,000, 1,000, 500, 200, 100, 50, 20, 10, 5, 2, 1, 0.5, 0.2, 0.1, or less below their approved dose or range. Subtherapeutic doses can be achieved by reducing the amount of medication per dose and / or reducing the number of administrations (or cycles) to the subject.

[0067] The term "synergistic" or "synergizing" effect refers to a desired effect (e.g., one or more distinct effects) of a combination (or combination therapy) comprising two or more different therapeutic components (e.g., two or more different therapies, two or more therapeutic agents, etc.) that is greater than (i) the effect of each therapeutic component alone and / or (ii) the sum of the effects of each therapeutic component when applied individually (e.g., the sum of individual effects). A synergistic effect can be at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 150%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1,000%, 5,000%, or more of the sum of the effects of each therapeutic component alone and / or the sum of the individual effects. This effect can be any measurable effect, including but not limited to enhancing the therapeutic effect of a single component in the combination or reducing the side effects of a single component in the combination. In some embodiments, this effect is a pharmacodynamic effect, such as phosphorylated ERK (p-ERK) and / or DUSP6 inhibition, optionally assessed in whole blood. To produce a synergistic effect, the two or more different therapeutic components of the combination therapy disclosed herein can be administered simultaneously or sequentially as individual components or as unit doses. For example, the synergistic effect of a combination comprising a first agent and a second agent can produce a desired therapeutic outcome (e.g., in the treatment of cancer) that is comparable (e.g., substantially the same) or better than (i) the therapeutic outcome of each therapeutic component alone at a therapeutically effective amount and / or (ii) the sum of the individual effects, wherein either or both of the first agent and the second agent are administered at their respective subtherapeutic doses. In another embodiment, the synergistic effect of a combination comprising a first agent and a second agent can produce a desired therapeutic outcome (e.g., reducing the side effects of either agent) that is comparable (e.g., substantially the same) or better than the therapeutic outcome of each therapeutic component alone.

[0068] The term "IC50" refers to the half-maximal inhibitory concentration (e.g., concentration) at which an inhibitor inhibits a biological or biochemical effect. IC50 can be a quantitative measure indicating how much of a specific inhibitor is needed to inhibit a given biological or biochemical effect (e.g., the expression and / or activity level of a gene / protein of interest, cell growth or growth rate, etc.) by approximately half (e.g., about 50%). For example, IC50 can be determined by establishing and constructing dose-response curves and examining the effects of different concentrations of inhibitor on reducing cell growth (e.g., inhibiting cancer cell proliferation), and determining the inhibitor concentration at which 50% inhibition of cell growth is observed.

[0069] When the term "combination" is applied to pharmaceutical agents that include inhibitors disclosed herein, it refers to the use of two or more agents (e.g., an SOS1 inhibitor and at least one other inhibitor targeting a different signaling molecule) in vitro, in vivo, or ex vivo. The two or more agents in a combination may be formulated in a single formulation or in separate formulations. Combination therapy or treatment of two or more agents may be administered in any temporal sequence, simultaneously, or individually.

[0070] The term "combination" refers to the timing of the use of two or more agents (e.g., an SOS1 inhibitor and at least one other inhibitor targeting a different signaling molecule) in vitro, in vivo, or ex vivo. For example, one agent from a group of agents of interest may be administered before, after, or simultaneously with the administration of a second agent from that group. Simultaneous administration can be achieved by administering multiple agents simultaneously as individual agents or as a unit dose comprising multiple agents.

[0071] The terms “antagonist” and “inhibitor” are used interchangeably, and they refer to compounds that have the ability to inhibit the biological function (e.g., activity, expression, binding, protein-protein interactions) of a target protein (e.g., SOS1). Therefore, the terms “antagonist” and “inhibitor” are defined in the context of the biological function of the target protein. While the preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit the biological activity of a target protein by interacting with other members of a signal transduction pathway, wherein the target protein is a member of that signal transduction pathway, are also specifically included within this definition.

[0072] The term "selective inhibition" or "selective inhibition" refers to the ability of a bioactive drug to preferentially reduce the target signal transduction activity compared to off-target signal transduction activity through direct or indirect interaction with the target.

[0073] The terms “object,” “individual,” and “patient” are used interchangeably herein and refer to an animal, such as a mammal, like a human. The methods described herein can be used for both human treatment and veterinary applications. In some embodiments, the object is a mammal, such as a human. “Mammalian” includes humans and livestock, such as laboratory animals and domesticated pets (e.g., cats, dogs, pigs, cattle, sheep, goats, horses, rabbits), as well as non-livestock animals, such as wild animals. It also includes tissues, cells, and their progeny from biological entities obtained in vivo or cultured in vitro.

[0074] The terms "therapeutic agent," "therapeutic capable agent," or "treatment agent" are used interchangeably and refer to a molecule or compound that, when applied to a subject, imparts a beneficial effect. Beneficial effects include enabling a diagnosis; improving a disease, symptom, condition, or pathological state; reducing or preventing the onset of a disease, symptom, condition, or pathological state; and generally combating a disease, symptom, condition, or pathological state.

[0075] The terms “polypeptide,” “peptide,” and “protein” are used interchangeably herein and refer to a polymer of amino acids of any length. This polymer may be linear or branched, may contain modified amino acids, and may be interrupted by non-amino acid components. The term also encompasses amino acid polymers that have been modified (e.g., by disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation, such as conjugation with a labeled component). As used herein, the term “amino acid” refers to natural and / or non-natural or synthetic amino acids, including glycine and its D or L optical isomers, as well as amino acid analogs and peptide mimics.

[0076] The terms “polynucleotide,” “nucleotide,” “nucleotide sequence,” “nucleic acid,” and “oligonucleotide” are used interchangeably. They refer to polymeric forms of nucleotides or their analogues of deoxyribonucleotides or ribonucleotides of any length. Polynucleotides can have any three-dimensional structure and can perform any known or unknown function. The following are non-limiting examples of polynucleotides: coding or non-coding regions of genes or gene segments, loci (loci / locus) defined by linkage analysis, exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, short interfering RNA (siRNA), short hairpin RNA (shRNA), microRNA (miRNA), ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA with any sequence, isolated RNA with any sequence, nucleic acid probes, and primers. Polynucleotides can contain one or more modified nucleotides, such as methylated nucleotides and nucleotide analogs, such as peptide nucleic acids (PNAs), morpholino oligonucleotides and locked nucleic acids (LNAs), glycerol nucleic acids (GNAs), threonine nucleic acids (TNAs), 2'-fluoronucleotides, 2'-OMe nucleic acids, and phosphorylated DNA. If present, modifications to the nucleotide structure can be conferred before or after polymer assembly. The sequence of the nucleotides can be interrupted by non-nucleotide components. Polynucleotides can be further modified after polymerization, such as by conjugation with labeled components or other conjugation targets.

[0077] The term "small molecule" refers to one or more members of the group comprising ions, lipids, chemical compounds (e.g., natural or synthetic), amino acids (e.g., natural or synthetic), and polypeptides (e.g., peptides or proteins).

[0078] The term "nucleic acid agent" refers to an inhibitor capable of downregulating (e.g., reducing or inhibiting) the expression and / or activity of a target moiety (e.g., a protein or a gene encoding it). In some embodiments, the nucleic acid agent may consist of nucleic acid molecules. In some embodiments, the nucleic acid agent may contain nucleic acid molecules. In some embodiments, the nucleic acid agent may contain both nucleic acid molecules and non-nucleic acid molecules. Nucleic acid molecules and non-nucleic acid molecules may be operably coupled to each other to produce an inhibitory effect on the target moiety. Nucleic acid molecules and non-nucleic acid molecules may be coupled to each other (e.g., covalently and / or non-covalently). In some cases, nucleic acid molecules and non-nucleic acid molecules may be linked to each other via a connector. In some cases, nucleic acid molecules may be configured to bind to non-nucleic acid molecules. In some cases, non-nucleic acid molecules may be configured to bind to nucleic acid molecules. Non-limiting examples of non-nucleic acid molecules include small molecules, peptides (e.g., enzymes), etc. In some cases, the non-nucleic acid molecule is a nuclease, such as an endonuclease.

[0079] As used herein, “expression” refers to the process by which polynucleotides are transcribed from a DNA template (e.g., into mRNA or other RNA transcripts) and / or the transcribed mRNA is subsequently translated into peptides, polypeptides, or proteins. Transcripts and encoded polypeptides can be collectively referred to as “gene products.” If the polynucleotides are derived from genomic DNA, expression can include the splicing of mRNA in eukaryotic cells.

[0080] An "antigen" is a portion or molecule containing an epitope and therefore specifically binding to an antibody. An "antigen-binding unit" can be the whole or a fragment (or multiple fragments) of a full-length antibody, a structural variant of that antibody, a functional variant of that antibody, or a combination thereof. Full-length antibodies can be, for example, monoclonal antibodies, recombinant antibodies, chimeric antibodies, deimmunized antibodies, humanized antibodies, and human antibodies. Examples of fragments of full-length antibodies may include, but are not limited to, variable heavy chains (VH), variable light chains (VL), and heavy chains (VHH or VL) found in camelidae animals such as camels, llamas, and alpacas. HH), heavy chains (V-NAR domains) found in sharks, single-domain antibodies (sdAbs, i.e., "nanobodies") containing a single antigen-binding domain, Fv, Fd, Fab, Fab', F(ab')2 and "r IgG" (or haptens). Examples of modified fragments of antibodies may include, but are not limited to, scFv, di-scFv or bi(s)-scFv, scFv-Fc, scFv-zipper, scFab, Fab2, Fab3, diabody, single-chain bifunctional antibody, tandem bifunctional antibody, tandem di-scFv, tandem tri-scFv, minibody (e.g., (VH-VL-CH3)2, (scFv-CH3)2, ((scFv)2-CH3+CH3), ((scFv)2-CH3) or (scFv-CH3-scFv)2, and multibody (e.g., triabody or tetrabody).

[0081] The terms “antibody” and “antibodies” encompass any antigen-binding unit, including but not limited to: monoclonal antibodies, human antibodies, humanized antibodies, camel-derived antibodies, chimeric antibodies, and any other epitope-binding fragments.

[0082] The term "disease cell" refers to a cell, tissue, or organism that deviates from a normal or healthy state. Disease cells may be caused by pathogens, toxic substances, radiation, or internal cellular disorders (e.g., gene mutations). In one instance, a disease cell is a cell infected by a pathogenic virus. In another instance, a disease cell is a malignant cell or tumor cell that can constitute or cause cancer in an object (e.g., a mammal, such as a human object).

[0083] “Prodrug” means a compound that can be converted into the bioactive compound described herein (e.g., a compound of formula (I)) under physiological conditions or by solvent degradation. Therefore, the term “prodrug” refers to a precursor of a pharmaceutically acceptable bioactive compound. In some respects, a prodrug may be inactive when administered to a subject, but can be converted into an active compound in vivo, for example, by hydrolysis. Prodrug compounds often offer advantages in mammalian organisms such as solubility, tissue compatibility, or delayed release (see, for example, Bundgard, H., Design of Prodrugs (1985), pp. 7–9, 21–24 (Elsevier, Amsterdam); Higuchi, T. et al., “Pro-drugs as Novel Delivery Systems,” (1987) ACS Symposium Series, Vol. 14; and Bioreversible Carriers in Drug Design, edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press). (Each of these is incorporated herein by reference in its entirety). The term "prodrug" also means any covalently bonded carrier that, when administered to a mammalian subject, releases the active compound in vivo. As described herein, prodrugs of active compounds are typically prepared by modifying functional groups present in the active compound in such a manner that the modification is cleaved into the parent active compound under conventional procedures or in vivo. Prodrugs include compounds in which a hydroxyl, amino, or thiol group is bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free thiol group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives with hydroxyl functional groups, or acetamide, formamide, and benzamide derivatives with amine functional groups in the active compound.

[0084] The term "in vivo" refers to an event that occurs within the body of an object. The term "ex vivo" refers to an event that first occurs outside the body of an object, intended for subsequent application inside the body. For example, ex vivo preparation may involve preparing cells outside the body of an object for the purpose of introducing the prepared cells into the body of the same or different objects. The term "in vitro" refers to an event that occurs outside the body of an object. For example, in vitro assays cover any assay performed outside the body of an object. In vitro assays cover cell-based assays in which live or dead cells are used. In vitro assays also cover cell-free assays in which intact cells are not used.

[0085] This disclosure also refers to the in vivo metabolites of the disclosed compounds. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, esterification, etc., of the applied compound, primarily due to enzymatic processes. Therefore, this disclosure includes compounds produced by a process comprising administering the disclosed compound to a mammal for a duration sufficient to produce its metabolites. Such products are typically identified by administering the radiolabeled compound of this disclosure at a detectable dose to an animal (e.g., rat, mouse, guinea pig, monkey, or human), allowing sufficient time for metabolism, and by isolating its metabolites from urine, blood, or other biological samples.

[0086] The term "Ras" or "RAS" refers to proteins in the Rat Sarcoma (Ras) superfamily of small GTPases, such as proteins in the Ras subfamily. The Ras superfamily includes, but is not limited to, the Ras subfamily, Rho subfamily, Rab subfamily, Rap subfamily, Arf subfamily, Ran subfamily, Rheb subfamily, RGK subfamily, Rit subfamily, Miro subfamily, and unclassified subfamilies. In some embodiments, the Ras protein is selected from KRAS (K-Ras or K-ras or Kras), HRAS (or H-Ras), NRAS (or N-Ras), MRAS (or M-Ras), ERAS (or E-Ras), RRAS2 (or R-Ras2), RALA (or RalA), RALB (or RalB), RIT1, and any combination thereof, such as those selected from KRAS, HRAS, NRAS, RALA, RALB, and any combination thereof.

[0087] compound The SOS1 inhibitor used in this disclosure can be any SOS1 inhibitor known in the art and can include any entity that causes downregulation of SOS1 in the subject upon administration. For example, suitable SOS1 inhibitors can be selected from a variety of types of molecules. Specifically, SOS1 inhibitors can be biological or chemical compounds, such as simple or complex organic or inorganic molecules, peptides, peptide mimics, proteins (e.g., antibodies), liposomes, or polynucleotides (e.g., small interfering RNA, short hairpin RNA, microRNA, antisense, aptamers, ribozymes, triple helices). In some embodiments, the methods disclosed herein utilize small molecule SOS1 inhibitors. As used herein, the term "small molecule" refers to a low molecular weight organic compound, such as a compound with a molecular weight less than 1500 g / mol, less than 1250 g / mol, less than 1000 g / mol, or less than 750 g / mol. Many compounds are known to inhibit SOS1 (e.g., compounds of WO2005 / 097119, the entire contents of which are incorporated herein by reference).

[0088] In some embodiments, the small molecule SOS1 inhibitor may be conjugated to a degradation tag. The degradation tag may be configured to bind a degradation moiety having the ability to degrade at least a portion of the target moiety to which the degradation tag is bound. In some embodiments, the target moiety is SOS1 or a substrate of SOS1.

[0089] In some embodiments, the subject SOS1 inhibitor disrupts the interaction between SOS1 and KRAS with an IC50 of less than about 20 nM, 10 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, 0.1 nM, or even less, as determined by the Ras-SOS interaction assay described in Example 3. In some embodiments, the potency of the SOS1 inhibitor is at least 5 times stronger than BI-3406, MRTX0902, BAY293, RMC-5845, or BI-1701963, such as at least 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 times stronger, as determined by the Ras-SOS interaction assay described in Example 3. In some implementations, the subject SOS1 inhibitor inhibits RAS signaling in mutant receptor tyrosine kinase cell lines (such as H1975, H358, or A375 cell lines) with IC50 values ​​of less than about 10 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, 0.1 nM, or even smaller, as determined by a pERK inhibition assay. In some embodiments, the SOS1 inhibitor inhibits RAS signaling in mutant receptor tyrosine kinase cell lines (such as H1975, H358, or A375 cell lines) with a potency at least 5-fold stronger than BI-3406, MRTX0902, BAY293, RMC-5845, or BI-1701963, such as at least 10-fold, 50-fold, 100-fold, 200-fold, 300-fold, 500-fold, 1000-fold, 1500-fold, or 2000-fold stronger, as determined by a pERK inhibition assay. In some implementations, the subject SOS1 inhibitor inhibits the growth of Ph+ cells (such as the CML cell line) with IC50 values ​​of less than about 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, 0.1 nM, or even smaller, as determined in a growth inhibition assay, optionally utilizing the CML cell line. In some implementations, the SOS1 inhibitor inhibits CML cell lines selected from K562, BV173, KCL22-s, KCL22-imatinib resistant cell lines, Ba / F3 (BRC-ABL), Ba / F3 (BCR-ABL with T315I mutation), and Ba / F3 (BCR-ABL with F359V mutation) with IC50 values ​​of less than about 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 5 nM, 4 nM, 3 nM, 2 nM, 2 nM, 1 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, 0.1 nM, or even smaller.In some implementations, the SOS1 inhibitor inhibits the growth of CML cell lines with the following IC50: , , The IC50 of RMC-5845 or BI-1701963 is at least 1 / 10, 1 / 50, 1 / 100, 1 / 200, 1 / 300, 1 / 500 or 1 / 1000 lower. In some embodiments, the SOS1 inhibitor inhibits the growth of CML cell lines with an IC50 that is at least 1 / 10, 1 / 50, 1 / 100, 1 / 200, 1 / 300, 1 / 500, or 1 / 1000 of the IC50 of the SOS inhibitors described in WO2021092115, WO2018172250, WO2019201848, WO2019122129, WO2018115380, WO2021127429, WO2020180768, or WO2020180770, each of which is incorporated herein by reference in its entirety for all purposes. In some embodiments, the SOS1 inhibitor is combined with a tyrosine kinase inhibitor (TKI) targeting BCR-ABL tyrosine kinase to synergistically inhibit the growth of Ph+ cells such as CML cell lines. Exemplary TKIs used in such combinations may be one or more of imatinib, dasatinib, nilotinib, bosutinib, raldotinib, flumatinib, ponatinib, olabatinib, and aciminib. In some embodiments, the SOS1 inhibitor is characterized in that, in an in vitro growth inhibition assay using CML cells, when an SOS1 inhibitor of less than about 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, or 0.1 nM is combined with a TKI applied at its IC50 molar concentration, it synergistically inhibits the growth of CML cells to produce at least about 80% growth inhibition. In some embodiments, the SOS1 inhibitor is characterized in that, when an SOS1 inhibitor of less than about 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 5 nM, 4 nM, 3 nM, 2 nM, or 1 nM is combined with a TKI applied at its IC10 molar concentration, it synergistically increases the percentage of cell growth inhibition from about 10% to at least about 50%, as determined in an in vitro growth inhibition assay using CML cells. In some embodiments, the SOS1 inhibitor is characterized in that, in an in vitro growth inhibition assay using CML cells, when an SOS1 inhibitor of less than about 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 5 nM, 4 nM, 3 nM, 2 nM, or 1 nM is combined with a TKI applied at its IC50 molar concentration, it synergistically increases the percentage of cell growth inhibition from about 50% to at least about 80%.

[0090] The compounds of formulas (I) and (A) disclosed herein—including compounds of formulas (IA), (IB), (I-1), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), (I-E1), (II-B), (II-C), (III), (A-1), and (Aa-1)—or pharmaceutically acceptable salts or solvates thereof, are SOS modulators and have broad applications in therapeutics, diagnostics, and other biomedical research.

[0091] In some respects, this disclosure provides a compound of formula (I): (I), Or a pharmaceutically acceptable salt or solvate thereof, wherein: Selected from C 5-7 Carbon rings and 5- to 7-membered heterocycles, each of which is optionally bounded by one or more R 11 replace; Does not exist or selected from C 3-8 Carbon rings and 3 to 8-membered heterocycles, each of which is optionally bounded by one or more R 11a replace; L 1 Selected from key, C 1-6 Alkylene and C 1-6 Halogenated alkylene; L 2 Selected from C 5-25 Alkylene, C 5-25 imidene group, C 5-25 5- to 25-membered heteroalkyl and 5- to 25-membered heteroenyl, each of which is optionally divided by one or more R 11b Replace, where L 2 Covalently bound to W 3 W 4 W 5 W 6 or W 7 One of them; or L 2 Yes -L 3 -DL 4 -, where L 4 Covalently bound to W 3 W 4 W 5 W 6 or W 7 one of; L 3 Selected from C 1-10 Alkylene, C2-10 imidene group, C 2-10 Alynyl, 2 to 10 heteroalkyl, and 3 to 10 heteroenyl, each of which is optionally divided by one or more R 11b replace; D does not exist or is selected from C. 3-12 Carbon rings and 3 to 12-membered heterocycles, each of which is optionally bounded by one or more R... 11d replace; L 4 Selected from C 1-10 Alkylene, C 2-10 imidene group, C 2-10 Alynyl, 2 to 10 heteroalkyl, and 3 to 10 heteroenyl, each of which is optionally divided by one or more R 11b replace; W 2 Selected from N(R) 2b ), N, C(R) 2 ), C(R 2 (R) 2a ) and C(O); W 3 Selected from N(R) 3b ), N, C(R) 3 ), C(R 3 (R) 3a ) and C(O); W 4 Selected from N(R) 4b ), N, C(R) 4 ), C(R 4 (R) 4a ) and C(O); W 5 Selected from N(R) 5b ), N, C(R) 5 ), C(R 5 (R) 5a ) and C(O); W 6 Selected from N(R) 6b ), N, C(R) 6 ), C(R 6 (R) 6a ) and C(O); W 7 Selected from N(R) 7b ), N, C(R) 7 ), C(R 7 (R) 7a ) and C(O); W 8 Selected from N(R) 8b ), N, C(R) 8), C(R 8 (R) 8a ) and C(O); W 9 Selected from N, C(R) 9 ) and C; W 10 Selected from N, C(R) 10 ) and C; R 1 It is optionally controlled by one or more R 11c Replacement C 1-3 alkyl; R 2 R 2a R 3a R 4a R 5a R 6a R 7a R 8 and R 8a Each is independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 -S(=O)(=NH)N(R) 12 (R) 13-CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 and -CH2S(O)2N(R 12 (R) 13 ), where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are independently and optionally separated by one, two, or three R... 20 replace; R 3 R 4 R 5 R 6 and R 7 Each independently selected from L 2 bonds, hydrogen, halogens, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 -S(=O)(=NH)N(R) 12 (R)13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 and -CH2S(O)2N(R 12 (R) 13 ), where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are independently and optionally separated by one, two, or three R... 20 replace; R 2b and R 8b Each is independently selected from hydrogen, -CN, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -SR 12 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 -S(=O)(=NH)N(R) 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 and -CH2S(O)2N(R 12 (R) 13 ), where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are independently and optionally separated by one, two, or three R...20 replace; R 3b R 4b R 5b R 6b and R 7b Each independently selected from L 2 bonds, hydrogen, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -SR 12 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 -S(=O)(=NH)N(R) 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 and -CH2S(O)2N(R 12 (R) 13 ), where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are independently and optionally separated by one, two, or three R... 20 replace; R 9 and R 10 Each is independently selected from hydrogen and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon ring, -CH2-(C 3-10 Carbon rings), 3- to 10-membered heterocycles and -CH2- (3- to 10-membered heterocycles), wherein each C 1-6 Alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon ring, -CH2-(C 3-10 The carbon ring, 3- to 10-membered heterocycles, and -CH2- (3- to 10-membered heterocycles) are independently and optionally surrounded by one, two, or three R... 20 replace; R 11 R 11a and R 11d Each time it appears, it is independently selected from halogen, -CN, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 -S(=O)(=NH)N(R) 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 -CH2S(O)2N(R) 12 (R) 13 ), -CH2N(R 12)S(O)2(R 13 ) and -P(O)(R 17 (R) 17a ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 replace; R 11b Each time it appears, it is independently selected from halogen, oxo, -CN, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 -S(=O)(=NH)N(R) 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 -CH2S(O)2N(R) 12 (R) 13 ), -CH2N(R12 )S(O)2(R 13 ) and -P(O)(R 17 (R) 17a ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 replace; R 11c Each time it appears, it is independently selected from halogen, -OR 12 and -N(R) 12 (R) 13 ); R 12 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 replace; R 13 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl; or R 12 and R 13 Together with the nitrogen atoms they are attached to, they form a structure optionally bounded by one, two, or three R atoms. 20 Replaced 3- to 10-membered heterocycles; R 14 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R 15 Each time it appears, it is independently selected from C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 replace; R 17 and R17a Each time it appears, it is independently selected from C. 1-6 Alkyl and C 3-6 cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl groups are optionally surrounded by one, two, or three R groups. 20 Replace; or R 17 and R 17a Together with the phosphorus atoms they are attached to, they form 3 to 10-membered heterocycles; R 20 Each time it appears, it is independently selected from halogen, oxo, =NH, -CN, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon ring, -CH2-(C 3-10 Carbon rings), 3- to 10-membered heterocycles, -CH2- (3- to 10-membered heterocycles), -OR 21 -SR 21 -N(R) 22 (R) 23 -C(O)OR 22 -C(O)N(R) 22 (R) 23 -C(O)C(O)N(R) 22 (R) 23 ), -OC(O)N(R 22 (R) 23 ), -N(R 24 )C(O)N(R 22 (R) 23 ), -N(R 24 )C(O)OR 25 -N(R) 24 )C(O)R 25 -N(R) 24 )S(O)2R 25 -C(O)R 25 -S(O)2R 25 -S(O)2N(R) 22 (R) 23 -OCH2C(O)OR 22 and -OC(O)R 25 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon ring, -CH2-(C 3-10The carbocyclic ring (3 to 10-membered heterocycle) and -CH2- (3 to 10-membered heterocycle) are optionally substituted by one, two, or three independent groups selected from the following: halogen, oxo, =NH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -OR 21 -SR 21 -N(R) 22 (R) 23 -C(O)OR 22 -C(O)N(R) 22 (R) 23 -C(O)C(O)N(R) 22 (R) 23 ), -OC(O)N(R 22 (R) 23 ), -N(R 24 )C(O)N(R 22 (R) 23 ), -N(R 24 )C(O)OR 25 -N(R) 24 )C(O)R 25 -N(R) 24 )S(O)2R 25 -C(O)R 25 -S(O)2R 25 -S(O)2N(R) 22 (R) 23 ) and -OC(O)R 25 ; R 21 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 3-10 The carbide ring and the 3 to 10-membered heterocycle are optionally substituted by one, two, or three independent groups selected from the following: halogen and C. 1-6 alkyl; R 22 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 3-10The carbide ring and the 3 to 10-membered heterocycle are optionally substituted by one, two, or three independent groups selected from the following: halogen and C. 1-6 alkyl; R 23 Each time it appears, it is independently selected from H and C. 1-6 alkyl; R 24 Each time it appears, it is independently selected from H and C. 1-6 alkyl; R 25 Each time it appears, it is independently selected from C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 1-6 Alkyl, C 3-10 The carbide ring and the 3 to 10-membered heterocycle are optionally substituted by one, two, or three independent groups selected from the following: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-10 Carbon rings and 3 to 10-membered heterocycles; and This indicates a single or double bond, such that all valences are satisfied.

[0092] In some respects, this disclosure provides a compound of formula (I): (I), Or a pharmaceutically acceptable salt or solvate thereof, wherein: Selected from C 5-7 Carbon rings and 5- to 7-membered heterocycles, each of which is optionally bounded by one or more R 11 replace; Does not exist or selected from C 3-8 Carbon rings and 3 to 8-membered heterocycles, each of which is optionally bounded by one or more R 11a replace; L 1 Selected from key, C 1-6 Alkylene and C 1-6 Halogenated alkylene; L 2 Selected from C 5-25 Alkylene, C 5-25 imidene group, C 5-25 5- to 25-membered heteroalkyl and 5- to 25-membered heteroenyl, each of which is optionally divided by one or more R 11b Replace, where L 2 Covalently bound to W3 W 4 W 5 W 6 or W 7 one of; W 2 Selected from N(R) 2b ), N, C(R) 2 ), C(R 2 (R) 2a ) and C(O); W 3 Selected from N(R) 3b ), N, C(R) 3 ), C(R 3 (R) 3a ) and C(O); W 4 Selected from N(R) 4b ), N, C(R) 4 ), C(R 4 (R) 4a ) and C(O); W 5 Selected from N(R) 5b ), N, C(R) 5 ), C(R 5 (R) 5a ) and C(O); W 6 Selected from N(R) 6b ), N, C(R) 6 ), C(R 6 (R) 6a ) and C(O); W 7 Selected from N(R) 7b ), N, C(R) 7 ), C(R 7 (R) 7a ) and C(O); W 8 Selected from N(R) 8b ), N, C(R) 8 ), C(R 8 (R) 8a ) and C(O); W 9 Selected from N, C(R) 9 ) and C; W 10 Selected from N, C(R) 10 ) and C; R 1 It is optionally controlled by one or more R 11c Replacement C 1-3 alkyl; R 2 R 2a R 3a R 4a R 5a R 6a R 7a R 8 and R 8a Each is independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 -S(=O)(=NH)N(R) 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 and -CH2S(O)2N(R 12 (R) 13 ), where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10The carbon ring and 3 to 10-membered heterocycles are independently and optionally separated by one, two, or three R... 20 replace; R 3 R 4 R 5 R 6 and R 7 Each independently selected from L 2 bonds, hydrogen, halogens, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 -S(=O)(=NH)N(R) 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 and -CH2S(O)2N(R 12 (R) 13 ), where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3-10 The carbon ring and 3 to 10-membered heterocycles are independently and optionally separated by one, two, or three R... 20 replace; R 2b and R 8b Each is independently selected from hydrogen, -CN, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -SR 12 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 -S(=O)(=NH)N(R) 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 and -CH2S(O)2N(R 12 (R) 13 ), where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are independently and optionally separated by one, two, or three R... 20 replace; R 3b R 4b R 5b R 6b and R 7b Each independently selected from L 2 bonds, hydrogen, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12-SR 12 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 -S(=O)(=NH)N(R) 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 and -CH2S(O)2N(R 12 (R) 13 ), where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are independently and optionally separated by one, two, or three R... 20 replace; R 9 and R 10 Each is independently selected from hydrogen and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon ring, -CH2-(C 3-10 Carbon rings), 3- to 10-membered heterocycles and -CH2- (3- to 10-membered heterocycles), wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon ring, -CH2-(C 3-10 The carbon ring, 3- to 10-membered heterocycles, and -CH2- (3- to 10-membered heterocycles) are independently and optionally surrounded by one, two, or three R... 20 replace; R 11 and R 11a Each time it appears, it is independently selected from halogen, -CN, C. 1-6 Alkyl, C 2-6 alkenyl, C2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 -S(=O)(=NH)N(R) 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 -CH2S(O)2N(R) 12 (R) 13 ), -CH2N(R 12 )S(O)2(R 13 ) and -P(O)(R 17 (R) 17a ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 replace; R 11b Each time it appears, it is independently selected from halogen, oxo, -CN, C. 1-6 Alkyl, C 2-6alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 -S(=O)(=NH)N(R) 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 -CH2S(O)2N(R) 12 (R) 13 ), -CH2N(R 12 )S(O)2(R 13 ) and -P(O)(R 17 (R) 17a ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 replace; R 11c Each time it appears, it is independently selected from halogen, -OR 12 and -N(R)12 (R) 13 ); R 12 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 replace; R 13 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl; or R 12 and R 13 Together with the nitrogen atoms they are attached to, they form a structure optionally bounded by one, two, or three R atoms. 20 Replaced 3- to 10-membered heterocycles; R 14 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R 15 Each time it appears, it is independently selected from C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 replace; R 17 and R 17a Each time it appears, it is independently selected from C. 1-6 Alkyl and C 3-6 cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl groups are optionally surrounded by one, two, or three R groups. 20 Replace; or R 17 and R 17a Together with the phosphorus atoms they are attached to, they form 3 to 10-membered heterocycles; R 20 Each time it appears, it is independently selected from halogen, oxo, =NH, -CN, C. 1-6Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon ring, -CH2-(C 3-10 Carbon rings), 3- to 10-membered heterocycles, -CH2- (3- to 10-membered heterocycles), -OR 21 -SR 21 -N(R) 22 (R) 23 -C(O)OR 22 -C(O)N(R) 22 (R) 23 -C(O)C(O)N(R) 22 (R) 23 ), -OC(O)N(R 22 (R) 23 ), -N(R 24 )C(O)N(R 22 (R) 23 ), -N(R 24 )C(O)OR 25 -N(R) 24 )C(O)R 25 -N(R) 24 )S(O)2R 25 -C(O)R 25 -S(O)2R 25 -S(O)2N(R) 22 (R) 23 -OCH2C(O)OR 22 and -OC(O)R 25 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon ring, -CH2-(C 3-10 The carbocyclic ring (3 to 10-membered heterocycle) and -CH2- (3 to 10-membered heterocycle) are optionally substituted by one, two, or three independent groups selected from the following: halogen, oxo, =NH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -OR 21 -SR 21 -N(R) 22 (R) 23 -C(O)OR 22 -C(O)N(R) 22 (R) 23 -C(O)C(O)N(R) 22 (R)23 ), -OC(O)N(R 22 (R) 23 ), -N(R 24 )C(O)N(R 22 (R) 23 ), -N(R 24 )C(O)OR 25 -N(R) 24 )C(O)R 25 -N(R) 24 )S(O)2R 25 -C(O)R 25 -S(O)2R 25 -S(O)2N(R) 22 (R) 23 ) and -OC(O)R 25 ; R 21 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 3-10 The carbide ring and the 3 to 10-membered heterocycle are optionally substituted by one, two, or three independent groups selected from the following: halogen and C. 1-6 alkyl; R 22 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 3-10 The carbide ring and the 3 to 10-membered heterocycle are optionally substituted by one, two, or three independent groups selected from the following: halogen and C. 1-6 alkyl; R 23 Each time it appears, it is independently selected from H and C. 1-6 alkyl; R 24 Each time it appears, it is independently selected from H and C. 1-6 alkyl; R 25 Each time it appears, it is independently selected from C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 1-6 Alkyl, C 3-10The carbide ring and the 3 to 10-membered heterocycle are optionally substituted by one, two, or three independent groups selected from the following: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-10 Carbon rings and 3 to 10-membered heterocycles; and This indicates a single or double bond, such that all valences are satisfied.

[0093] In some embodiments, the compound of formula (I) is the same as the compound of formula (IA): (IA), Or its pharmaceutically acceptable salts or solvates.

[0094] In some embodiments, the compound of formula (IA) is selected from the following compounds: , , , , , , , and .

[0095] In some embodiments, the compound of formula (I) is a compound of formula (IB), such as compounds of formula (I-B1) or (I-B2): (IB) (I-B1) or (I-B2), Or its pharmaceutically acceptable salts or solvates.

[0096] In some embodiments, the compound of formula (IB) is selected from the following compounds: , , and .

[0097] In some embodiments, the compound of formula (I) is a compound of formula (IC), such as a compound of formula (I-C1), (I-C2), or (I-C3): (IC) (I-C1) (I-C2) or (I-C3), Or its pharmaceutically acceptable salts or solvates.

[0098] In some embodiments, the compound of formula (IC) is selected from the following compounds: , , , , , , , , , , and .

[0099] In some embodiments, the compound of formula (I) is a compound of formula (ID), such as compounds of formula (I-D1) or (I-D2): (ID) (I-D1) or (I-D2), Or its pharmaceutically acceptable salts or solvates.

[0100] In some embodiments, the compound of formula (ID) is selected from the following compounds: , , , , , and .

[0101] In some embodiments, the compound of formula (I) is a compound of formula (IE), such as a compound of formula (I-E1): (IE) or (I-E1), Or its pharmaceutically acceptable salts or solvates.

[0102] In some embodiments, the compound of formula (IE) is selected from the following compounds: , , , , , , , , , , , , , and .

[0103] In some implementations, for compounds of formula (I), (IA), (IB), (IC), (ID), or (IE), W 2 It is N. In some implementations, W 3 Selected from N(R) 3b ), N, C(R) 3 W and C(O), such as NCH3, N, CH, CCH3 and C(O). In some implementations, W 3 Selected from C(R) 3 W and C(O), such as CH, CCH3, and C(O). In some implementations, W 3 It is CH. In some implementations, W 3 It is CCH3. In some implementations, W 4 Selected from N(R) 4b ), N, C(R) 4 ) and C(O), such as N(R) 4b ), N, C(R) 4 ) and C(O), where R 4b and R 4 Each is independent of L 2 The key. In some implementations, W 4 Selected from N(R) 4b ) and N, such as N(R) 4b ), where R 4b Is with L 2 The key. In some implementations, W 4 It is N. In some implementations, W 5 Selected from N(R) 5b ), N, C(R) 5 ) and C(O), such as N(R) 5b ), NCH3, N, CH, C(R) 5 ) and C(O), where R 5b and R 5 Each is independent of L 2 The key. In some implementations, W 5 Selected from N(R) 5b ), N and C(R) 5 ), such as N(R) 5b ), NCH3, N, CH and C(R) 5 ), where R 5b and R 5 Each is independent of L 2 The key. In some implementations, W 5 Selected from N(R) 5b ) and C(R 5 ), such as N(R) 5b), NCH3 and CH, where R 5b Is with L 2 The key. In some implementations, W 5 It is N(R) 5b In some implementations, W 6 Selected from C(R) 6 ) and C(O), such as COCH3, CH, C(R) 6 ) and C(O), where R 6 Is with L 2 The key. In some implementations, W 6 It is C(O). In some implementations, W 7 It is C(R) 7 ), such as W 7 It is C(R) 7 )where R 7 Is with L 2 The key. In some implementations, W 7 It is C(R) 7 ), where R 7 Not hydrogen, such as R 7 Selected from C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl and -OR 12 C 3-10 Cycloalkyl and 3 to 10-membered heterocyclic alkyl groups are optionally surrounded by one, two or three R 20 Replacement. In some implementations, W 8 It is C(R) 8 ), such as W 8 It is CH. In some implementations, W 9 It is C. In some implementations, W 10 It's C.

[0104] In some implementations, for compounds of formula (I), (IA), (IC), (ID), or (IE), W 2 It is N; W 3 It is N(R) 3b );W 4 It is C(O); and W 9 and W 10 Each is C, like W 2 It is N; W 3 It is NCH3; W 4 It is C(O); and W 9 and W 10 Each is C. In some embodiments, for compounds of formula (I), (IB), (IC), (ID), or (IE), W 2 It is N; W 3 It is C(O); W 4It is N(R) 4b ); and W 9 and W 10 Each is C, like W 2 It is N; W 3 It is C(O); W 4 It is N(R) 4b ), where R 4b Is with L 2 The key; and W 9 and W 10 Each is C. In some embodiments, for compounds of formula (I), (IA), (IC), (ID), or (IE), W 2 It is N; W 3 It is C(R) 3 );W 4 It is N; and W 9 and W 10 Each is C, like W 2 It is N; W 3 It is CH or CCH3; W 4 It is N; and W 9 and W 10 Each is C. In some embodiments, for compounds of formula (I), (IA), (IB), (IC), (ID), or (IE), W 5 It is C(R) 5 );W 6 It is C(R) 6 );W 7 It is C(R) 7 );W 8 It is C(R) 8 ); and W 9 and W 10 Each is C, like W 5 Is it CH or C(R)? 5 ), where R 5 Is with L 2 The key; W 6 Is it CH or C(R)? 6 ), where R 6 Is with L 2 The key; W 7 It is C(R) 7 );W 8 It is CH; and W 9 and W 10 Each is C. In some embodiments, for compounds of formula (I), (IA), (IB), (IC), or (IE), W 5 It is N(R) 5b );W 6 It is C(O); W 7 It is C(R)7 );W 8 It is C(R) 8 ); and W 9 and W 10 Each is C, like W 5 It is NCH3 or N(R) 5b ), where R 5b Is with L 2 The key; W 6 It is C(O); W 7 It is C(R) 7 );W 8 It is CH; and W 9 and W 10 Each is C. In some embodiments, for compounds of formula (I), (IA), (IB), (ID), or (IE), W 5 It is N; W 6 It is C(R) 6 );W 7 It is C(R) 7 );W 8 It is C(R) 8 ); and W 9 and W 10 Each is C, like W 5 It is N; W 6 It is COCH3, CH or C(R) 6 ), where R 6 Is with L 2 The key; W 7 It is C(R) 7 );W 8 It is CH; and W 9 and W 10 Each is C. In some embodiments, for compounds of formula (I), (IA), (IB), (IC), (ID), or (IE), W 2 It is N; W 3 Selected from N(R) 3b ), N, C(R) 3 ) and C(O); W 4 Selected from N(R) 4b ), N, C(R) 4 ) and C(O); W 5 Selected from N(R) 5b ), N and C(R) 5 );W 6 Selected from C(R) 6 ) and C(O); W 7 It is C(R) 7 );W 8 It is C(R) 8 ); and W 9and W 10 Each is C, like W 2 It is N; W 3 Selected from NCH3, N, CH, CCH3 and C(O); W 4 Selected from N(R) 4b ), N, C(R) 4 ) and C(O), where R 4b and R 4 Each is independent of L 2 The key; W 5 Selected from N(R) 5b ), NCH3, N, CH and C(R) 5 ), where R 5b and R 5 Each is independent of L 2 The key; W 6 Selected from COCH3, CH, C(R) 6 ) and C(O), where R 6 Is with L 2 The key; W 7 It is C(R) 7 );W 8 It is CH; and W 9 and W 10 Each is C. In some embodiments, for compounds of formula (I), (IA), (IB), (IC), (ID), or (IE), W 2 It is N; W 3 Selected from C(R) 3 ) and C(O); W 4 Selected from N(R) 4b ) and N; W 5 Selected from N(R) 5b ) and C(R 5 );W 6 Selected from C(R) 6 ) and C(O); W 7 It is C(R) 7 );W 8 It is CH; and W 9 and W 10 Each is C, like W 2 It is N; W 3 Selected from CH, CCH3, and C(O); W 4 Selected from N(R) 4b ) and N, where R 4b Is with L 2 The key; W 5 Selected from N(R) 5b ), NCH3, CH and C(R) 5 ), where R 5b and R5 Each is independent of L 2 The key; W 6 Selected from COCH3, CH, C(R) 6 ) and C(O), where R 6 Is with L 2 The key; W 7 It is C(R) 7 );W 8 It is CH; and W 9 and W 10 Each is C.

[0105] In some implementations, for compounds of formula (I), Selected from , , , and In some implementation schemes, Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and In some implementation schemes, Selected from , , , , , , and In some implementation schemes, Selected from , , and In some implementation schemes, yes ,like In some implementation schemes, yes ,like or In some implementation schemes, yes In some implementation schemes, yes ,like In some implementation schemes, Selected from , and In some implementation schemes, yes In some implementation schemes, yes In some implementation schemes, yes .

[0106] In some implementations, for compounds of formula (I), (IA), (IB), (IC), (ID), or (IE), R 2 R 2a R 3a R 4a R 5a R 6a R 7a R 8 and R 8a Each is independently selected from hydrogen, halogen, -CN, C 1-3 Alkyl, C 1-3Halogenated alkyl groups, -OH, -NH2, -NHCH3, and -N(CH3)2. In some embodiments, R 2 R 2a R 3a R 4a R 5a R 6a R 7a R 8 and R 8a Each is independently selected from hydrogen and -CH3, such as hydrogen.

[0107] In some implementations, for compounds of formula (I), (IA), (IB), (IC), (ID), or (IE), R 3 R 4 R 5 and R 6 Each independently selected from L 2 bonds, hydrogen, halogens, -CN, C 1-6 Alkyl, C 3-6 Carbon rings, 3- to 6-membered heterocycles, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 and -S(O)2N(R 12 (R) 13 ), where each C 1-6 Alkyl, C 3-6 The carbon ring and 3- to 6-membered heterocycles are independently and optionally separated by one, two, or three R... 20 Replace; and R 7 Selected from L 2 The key, C 1-6 Alkyl, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -N(R) 12 (R) 13 -C(O)R 15 -C(O)N(R) 12 (R) 13 -S(O)2R 15 and -SO2N(R 12 (R)13 ), where C 1-6 Alkyl, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 Replacement. In some implementations, R 3 R 4 R 5 and R 6 Each independently selected from L 2 bonds, hydrogen, halogens, -CN, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2; and R 7 Selected from L 2 The key, C 1-6 Alkyl, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -N(R) 12 (R) 13 -C(O)R 15 -C(O)N(R) 12 (R) 13 -S(O)2R 15 and -SO2N(R 12 (R) 13 ), where C 1-6 Alkyl, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 Replacement. In some implementations, R 3 R 4 R 5 and R 6 Each independently selected from L 2 The bonds, hydrogens, -CH3 and -OCH3; and R 7 Selected from L 2 The key, C 1-6 Alkyl, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -N(R) 12 (R) 13 -C(O)R 15 -C(O)N(R) 12 (R) 13 -S(O)2R 15 and -SO2N(R 12 (R) 13 ), where C 1-6 Alkyl, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 replace.

[0108] In some implementations, for compounds of formula (I), (IA), (IB), (IC), (ID), or (IE), R 2b and R 8b Each is independently selected from hydrogen and C. 1-3 Alkyl groups, such as hydrogen and -CH3. In some embodiments, R 3b R 4b R 5b R 6b and R 7b Each independently selected from L 2 bonds, hydrogen and C 1-3 Alkyl groups, such as those with L 2 The bonds, hydrogen, and -CH3. In some implementations, R 3b R 4b R 5b R 6b and R 7b Each independently selected from L 2 The bond and -CH3. In some implementations, R 3b R 4b R 5b R 6b and R 7b Each independently selected from L 2 The key. In some implementations, R 9 and R 10 Each is hydrogen.

[0109] For compounds of formula (I) (where L) 2 Yes -L 3 -DL 4 -), it should be understood that for R 3 R 4 R 5 R 6 R 7 R 3b R 4b R 5b R 6b Or R 7b Choose one of them, "with L". 2 The "key" inherently includes -L 3 -DL 4 - key, especially with L 4 The key. To avoid ambiguity, including "with L" 2 The key of R 3 R 4 R 5 R 6 R 7 R3b R 4b R 5b R 6b and / or R 7b Any enumeration may also be considered to include "with L" 4 The key.

[0110] In some embodiments, for compounds of formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), or (I-E1), R 1 Selected from C 1-3 Alkyl and C 1-3 Halogenated alkyl groups, such as -CH3, -CH2CH3, -CH(CH3)2, -CH2F, -CHF2, -CF3, CH2CH2F, -CH2CHF2, and -CH2CF3. In some embodiments, R... 1 Selected from C 1-3 Alkyl groups, such as -CH3 and -CH2CH3. In some embodiments, R 1 It is -CH3. In some implementations, R 1 yes( R )-CH3. In some implementations, R 1 yes( S )-CH3.

[0111] In some embodiments, for compounds of formula (I), (IB), (IC), (I-C1), (I-C3), (ID), (I-D1), (I-D2), (IE), or (I-E1), R 3 Selected from hydrogen, halogens, -CN, C 1-6 Alkyl, C 3-6 Carbon rings, 3- to 6-membered heterocycles, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 and -S(O)2N(R 12 (R) 13 ), where each C1-6 Alkyl, C 3-6 The carbon ring and 3- to 6-membered heterocycles are independently and optionally separated by one, two, or three R... 20 Replacement. In some implementations, R 3 Selected from hydrogen, halogens, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2. In some embodiments, R 3 Selected from hydrogen, halogen, -CN, -OR 12 and optionally by one, two or three R 20 Replacement C 1-6 Alkyl group. In some embodiments, R 3 It can be arbitrarily determined by one, two, or three Rs. 20 Replacement C 1-6 Alkyl group. In some embodiments, R 3 It is hydrogen or -CH3. In some implementations, R 3 It is hydrogen. In some implementations, R 3 It is -CH3.

[0112] In some implementations, for compounds of formula (I), (IB), (IC), (I-C2), (ID), or (IE), R 3b Selected from hydrogen and C 1-3 Alkyl groups, such as hydrogen and -CH3. In some embodiments, R 3b It is -CH3. In some implementations, R 3b It is hydrogen.

[0113] In some embodiments, for compounds of formula (I), (IA), (IB), (I-B2), (ID), (I-D2), (IE), or (I-E1), R 5 Selected from hydrogen, halogens, -CN, C 1-6 Alkyl, C 3-6 Carbon rings, 3- to 6-membered heterocycles, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15and -S(O)2N(R 12 (R) 13 ), where each C 1-6 Alkyl, C 3-6 The carbon ring and 3- to 6-membered heterocycles are independently and optionally separated by one, two, or three R... 20 Replacement. In some implementations, R 5 Selected from hydrogen, halogens, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2. In some embodiments, R 5 Selected from hydrogen, -OR 12 and optionally by one, two or three R 20 Replacement C 1-6 Alkyl group. In some embodiments, R 5 It is hydrogen or -CH3. In some implementations, R 5 It is hydrogen. In some implementations, R 5 It is -CH3.

[0114] In some implementations, for compounds of formula (I), (IA), (IB), (I-B1), (ID), or (IE), R 5b Selected from hydrogen and C 1-3 Alkyl groups, such as hydrogen and -CH3. In some embodiments, R 5b Selected from hydrogen and optionally by one, two or three R 20 Replacement C 1-6 Alkyl group. In some embodiments, R 5b It is -CH3. In some implementations, R 5b It is hydrogen. In some implementations, R 5b Is with L 2 The key.

[0115] In some embodiments, for compounds of formula (I), (IA), (IB), (I-B2), (IC), (I-C3), (IE), or (I-E1), R 6 Selected from hydrogen, halogens, -CN, C 1-6 Alkyl, C 3-6 Carbon rings, 3- to 6-membered heterocycles, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R)12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 and -S(O)2N(R 12 (R) 13 ), where each C 1-6 Alkyl, C 3-6 The carbon ring and 3- to 6-membered heterocycles are independently and optionally separated by one, two, or three R... 20 Replacement. In some implementations, R 6 Selected from hydrogen, halogens, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, -OH, -OCH3, -NH2, -NHCH3, and -N(CH3)2. In some embodiments, R 6 Selected from hydrogen, -OR 12 and optionally by one, two or three R 20 Replacement C 1-6 Alkyl, and wherein R 12 Selected from C 1-6 Alkyl group. In some embodiments, R 6 Selected from hydrogen and -OCH3. In some embodiments, R 6 It is hydrogen. In some implementations, R 6 It is -OCH3.

[0116] In some embodiments, for compounds of formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), or (I-D2), R 7 Selected from C 1-6 Alkyl, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)R 15 -C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R15 -CH2S(O)2R 15 and -CH2S(O)2N(R 12 (R) 13 ), where each C 1-6 Alkyl, C 3-10 The carbon ring and 3 to 10-membered heterocycles are independently and optionally separated by one, two, or three R... 20 Replacement. In some implementations, R 7 Selected from C 1-6 Alkyl, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -N(R) 12 (R) 13 -C(O)R 15 -C(O)N(R) 12 (R) 13 -S(O)2R 15 and -SO2N(R 12 (R) 13 ), where C 1-6 Alkyl, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 Replacement. In some implementations, R 7 Selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl and -N(R) 12 (R) 13 ), where C 1-6 Alkyl, C 3-10 Cycloalkyl and 3 to 10-membered heterocyclic alkyl groups are optionally surrounded by one, two or three R 20 Replacement. In some implementations, R 7 It can be arbitrarily determined by one, two, or three Rs. 20 Substituted 3- to 10-membered heterocyclic alkyl groups, such as R 7 It can be arbitrarily determined by one, two, or three Rs. 20 Substituted 4- to 6-membered heterocyclic alkyl groups. In some embodiments, R 7 It can be arbitrarily determined by one, two, or three Rs. 20 The substituted 3- to 10-membered heterocyclic alkyl group, wherein the heterocyclic alkyl group contains at least one O, N, or S atom, such as one O atom, one or two N atoms, or one S atom. In some embodiments, R 7 It can be arbitrarily determined by one, two, or three Rs. 20 Substituted 3- to 6-membered heterocyclic alkyl groups, wherein the heterocyclic alkyl group comprises S(O)₂. In some embodiments, R 7 It can be arbitrarily determined by one, two, or three Rs. 20 Replacement C3-10 cycloalkyl groups, such as R 7 It can be arbitrarily determined by one, two, or three Rs. 20 Replacement C 3-6 Cycloalkyl. In some embodiments, R 7 It is arbitrarily assigned to an R 20 Replacement C 3-4 cycloalkyl, optionally wherein R 20 Yes -CN. In some implementations, R 7 It can be arbitrarily determined by one, two, or three Rs. 20 Replacement C 1-6 Alkyl groups, such as R 7 Is it by one or two Rs 20 Replacement C 1-6 Alkyl group. In some embodiments, R 7 It is -N(R) 12 (R) 13 In some implementations, R 7 Yes - OR 12 Such as -O (3 to 6-membered heterocyclic alkyl). In some embodiments, R 7 Replaced by at least one -CN. In some implementations, R 7 It is not replaced. In some implementations, R 7 Selected from C 3-10 Carbon rings and 3 to 10-membered heterocycles, each of which is optionally bounded by one, two, or three R... 20 Replacement. In some implementations, R 7 Selected from C 3-10 Carbocyclic rings and 3 to 10-membered heterocycles, each of which is optionally surrounded by one, two, or three elements selected from oxo, -CN, and C. 1-6 Alkyl substituents. In some embodiments, R 7 It is selected by one, two, or three elements chosen from oxo, -CN, and C. 1-3 The alkyl group is a 4- to 6-membered heterocyclic alkyl group that has been substituted with an alkyl substituent. In some embodiments, R 7 It is selected by one, two, or three elements chosen from oxo, -CN, and C. 1-3 Alkyl substituents substituted C 3-4 Cycloalkyl.

[0117] In some embodiments, for compounds of formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), or (I-D2), R 7 Selected from C 1-6 Alkyl, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR12 -SR 12 -N(R) 12 (R) 13 -C(O)R 15 -C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)(NR) 12 )R 15 -S(O)2N(R) 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 -CH2S(O)(NR) 12 )R 15 and -CH2S(O)2N(R 12 (R) 13 ), where each C 1-6 Alkyl, C 3-10 The carbon ring and 3 to 10-membered heterocycles are independently and optionally separated by one, two, or three R... 20 Replacement. In some implementations, R 7 Selected from C 1-6 Alkyl, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -N(R) 12 (R) 13 -C(O)R 15 -C(O)N(R) 12 (R) 13 -S(O)2R 15 -S(O)(NR) 12 )R 15 and -SO2N(R 12 (R) 13 ), where C 1-6 Alkyl, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 Replacement. In some implementations, R 7 It can be arbitrarily determined by one, two, or three Rs. 20 Substituted 3- to 6-membered heterocyclic alkyl groups, wherein the heterocyclic alkyl group comprises S(O)(NR) 12 ).

[0118] In some embodiments, for compounds of formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), or (I-D2), R 7 yes ,in: n1 is an integer from 1 to 3; n2 is an integer from 0 to 2; n3 is an integer between 0 and 2; n4 is 0 or 1; and X is selected from -O-, -S(O2)-, -P(O)-, -CH2-, -CH(OH)-, -CH(OR)-. 12 )-、-CH(R 20 )-、-C(R 20 )2-、-NR 12 -、-CH(N(R 12 (R) 13 ))-、-CH(C(O)N(R 12 (R) 13 ))- and -CH(S(O)2N(R 12 (R) 13 ))-, Where R 12 R 13 and R 20 As defined elsewhere in this article, and Choose any two of R 20 Group or R 20 and R 12 They bond together with the atoms they are connected to to form rings.

[0119] For example, R 7 Can be selected , , , , , , , , and In some implementations, X is selected from -O-, -S(O)2-, -S(O)(NR)2-, and -S(O)(NR). 12 )-, -P(O)-, -CH2-, -CH(OH)-, -CH(OR 12 )-、-CH(R 20 )-、-C(R 20 )2-、-NR 12 -、-CH(N(R 12 (R)13 ))-、-CH(C(O)N(R 12 (R) 13 ))- and -CH(S(O)2N(R 12 (R) 13 ))-.

[0120] In some embodiments, for compounds of formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), or (I-D2), R 7 Selected from , , , , , , , , , , , , , , , , , , , , , , , and In some implementations, R 7 Selected from , , , , , , , , , , , , , , , , , , , , , , , and In some implementations, R 7 Selected from , , , , , , , , , , and In some implementations, R 7 Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , and In some implementations, R 7 Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , and In some implementations, R 7 Selected from , , , , , , , , , , , , , , and In some implementations, R 7 Selected from , , , , , , , , , , , , , , , , , , , , , , , , , and In some implementations, R 7 Selected from , , , , , , , , , , , , and In some implementations, R 7 Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and In some implementations, R 7 Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and In some implementations, R 7 Selected from , , , , , , , , , , , , , , , , , , and In some implementations, R 7 Selected from , , , , , , , , , , , , , , , , , , , , , , , and In some implementations, R 7 Selected from , , , , , , , , , , , , , , , , , , , and In some implementations, R 7 Selected from , , , , , , , , , , , , , , , , and In some implementations, R 7 Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and In some implementations, R 7 yes In some implementations, R 7 Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and In some implementations, R 7 Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and In some implementations, R 7 Selected from , , , , , , , , , , , , , , , , , , , , , , , , and In some implementations, R 7 Selected from , and In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementation schemes, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes .

[0121] In some embodiments, for compounds of formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), or (I-E1), R 8 Selected from hydrogen, halogens, and optionally by one, two, or three R... 20 Replacement C 1-6 Alkyl group. In some embodiments, R 8 It is hydrogen.

[0122] In some embodiments, for compounds of formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), or (I-E1), Selected from C 3-10 Carbon rings and 3- to 10-membered heterocycles, such as C 5-7 Carbon rings and 5- to 7-membered heterocycles, each of which is optionally bounded by one or more R 11 Replacement. In some implementations, Selected from C 5-7 Cycloalkyl, 5- to 7-membered heterocycloalkyl, 5- to 7-membered heteroaryl, and phenyl, each of which is optionally bound by one or more R 11 Replacement. In some implementations, Selected from phenyl, pyridyl, and thiophene, each of which is optionally separated by one or more R 11 Replacement. In some implementations, Selected from , , , and ,like , , and In some implementations, R 11 When present, it is independently selected from fluorine and -CH3 on each occurrence. In some embodiments, Selected from and ,like and In some implementation schemes, yes In some implementation schemes, yes In some implementation schemes, yes .

[0123] In some embodiments, for compounds of formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), or (I-E1), L 1 Selected from C 1-6 Alkylene and C 1-6 Alkyl halides, such as C 1-3 Alkylene and C 1-3 Alkyl halide. In some embodiments, L 1Selected from key and C 1-3 Alkyl halide. In some embodiments, L 1 It is C 1-3 Alkyl halides, such as -CF2-, -CF2CH2-, or -CF2CH2CH2-. In some embodiments, L 1 It is C 1-2 Alkyl halides, such as -CF2- or -CF2CH2-. In some embodiments, L 1 It is -CF2-. In some implementations, L 1 It is -CF2CH2-. In some implementations, L 1 It is -CF2CH2CH2-. In some implementations, L 1 It is a key. In some implementations, L 1 Selected from key, -O-, -NR 12 -、-S-、C 1-6 Alkylene, C 1-6 Halogenated alkylene and 2 to 6-membered heteroalkylene, wherein C 1-6 Alkylene, C 1-6 The haloalkylene and 2 to 6-membered heteroalkylene are optionally separated by one or more R 11b Replacement. In some implementations, L 1 Selected from -O-, -NR 12 -, -S- and 2 to 6-membered heteroalkylene groups, wherein the 2 to 6-membered heteroalkylene groups are optionally surrounded by one or more R 11b Replacement. In some implementations, L 1 It is optionally controlled by one or more R 11b (such as one, two or three R) 11b ) replaced by C 1-6 Alkylene. In some embodiments, L 1 Selected from key, -O-, -NR 12 -、-S-、C 1-3 Alkylene, C 1-3 Halogenated alkylene and 2- to 3-membered heteroalkylene, wherein C 1-3 Alkylene, C 1-3 The haloalkylene and 2- to 3-membered heteroalkylene are optionally separated by one or more R 11b Replacement. In some implementations, L 1 Selected from -O-, -NR 12 -, -S- and 2 to 3 heteroalkylene groups, wherein the 2 to 3 heteroalkylene groups are optionally surrounded by one or more R 11b Replacement. In some implementations, L 1 It is by one or more R 11b (such as one, two or three R) 11b ) replaced by C 1-3Alkylene.

[0124] In some embodiments, for compounds of formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), or (I-E1), Does not exist or selected from C 4-8 Carbon rings and 4 to 8-membered heterocycles, each of which is optionally bounded by one or more R 11a Replacement. In some implementations, It is absent or selected from phenyl and 4 to 8-membered heterocycles, each of which is optionally separated by one or more R 11a Replacement. In some implementations, Selected from phenyl and 4 to 8-membered heterocycles, each of which is optionally bound by one or more R 11a Replacement. In some implementations, It is absent or selected from phenyl, azacyclic butane, pyrrolidine and piperidine, each of which is optionally separated by one or more R 11a Replacement. In some implementations, Selected from phenyl, azacyclobutane, pyrrolidine, and piperidine, each of which is optionally converted by one or more R 11a Replacement. In some implementations, The hydrocarbon is selected from aziridine, pyrrolidine, and piperidine, each of which is optionally substituted with one or more -CH3 groups. In some embodiments, It is a phenyl group, which is optionally bonded by one or more R groups. 11a Replacement. In some implementations, yes It is optionally controlled by one or more R 11a Replacement. In some implementations, yes In some implementation schemes, It is a aziridine, which is optionally separated by one or more R 11a Replacement. In some implementations, yes It is optionally controlled by one or more R 11a Replacement. In some implementations, yes In some implementation schemes, It is a pyrrolidine, which is optionally mixed with one or more R 11a Replacement. In some implementations, It is piperidine, which is optionally reacted with one or more R 11a Replacement. In some implementations, yes It is optionally controlled by one or more R 11a Replacement. In some implementations, yes In some implementation schemes, It is not replaced. In some implementations, by one or more R 11a (such as one, two or three R) 11a ) replace. In some implementations, R 11a Each time it appears, it is independently selected from halogen, -CN, C. 1-6 Alkyl, C 3-6 Carbon rings, 3- to 6-membered heterocycles, -OR 12 -N(R) 12 (R) 13 ), -N(R 14 )S(O)2R 15 -C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 and -S(O)2N(R 12 (R) 13 ), where C 1-6 Alkyl, C 3-6 The carbon ring and 3- to 6-membered heterocycles are optionally separated by one, two, or three R... 20 Replacement. In some implementations, R 11a Each time it appears, it is independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R 11a Each time it appears, it is independently selected from C. 1-6 Alkyl group. In some embodiments, R 11a It is -CH3.

[0125] In some embodiments, for compounds of formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), or (I-E1), L 2 Selected from C 5-25 Alkylene, C 5-25 imidene group, C 5-25 5- to 25-membered heteroalkyl and 5- to 25-membered heteroenyl, each of which is optionally divided by one or more R 11b Replacement. In some implementations, L 2 Selected from C5-25 Alkylene, C 5-25 alkenyl, 5- to 25-membered heteroalkyl, and 5- to 25-membered heteroalkyl, each of which is optionally bound by one or more R 11b Replacement. In some implementations, L 2 Together with the atoms it is attached to, it forms 16 to 36-membered macrocycles, such as 16 to 24-membered macrocycles. In some implementations, L 2 Selected from C 6-15 Alkylene, C 6-15 imidene group, C 6-15 Alynyl, 6- to 15-membered heteroalkyl, and 6- to 15-membered heteroenyl, each of which is optionally bound by one or more R 11b Replacement. In some implementations, L 2 Selected from C 5-10 Alkylene, C 5-10 alkenyl, 5- to 10-membered heteroalkyl, and 5- to 10-membered heteroalkyl, each of which is optionally bound by one or more R 11b Replacement. In some implementations, L 2 The alkenyl or heteroalkenyl group contains a carbon-carbon double bond. In some embodiments, L 2 The heteroalkyl or heteroene group contains at least one oxygen or nitrogen atom. In some embodiments, L 2 The heteroalkyl or heteroene group contains at least one basic nitrogen. In some embodiments, L 2 Selected from C 5-9 Alkylene, C 5-9 alkenyl and 5 to 9-membered heteroalkylene groups, each of which is optionally divided by one or more R 11b Replacement. In some implementations, L 2 Selected from C 6-9 Alkylene, C 6-9 alkenyl and 6 to 9-membered heteroalkylene groups, each of which is optionally divided by one or more R 11b Replacement. In some implementations, L 2 Selected from C 5-8 Alkylene, C 5-8 alkenyl and 5 to 8-membered heteroalkylene groups, each of which is optionally divided by one or more R 11b Replacement. In some implementations, L 2 Selected from C 6-8 Alkylene, C 6-8 alkenyl and 6- to 8-membered heteroalkylene groups, each of which is optionally divided by one or more R 11b Replacement. In some implementations, L 2 Selected from C 6-8 Alkylene and C 6-8alkenyl groups, each of which is optionally divided by one or more R groups. 11b Replacement. In some implementations, L 2 Selected from C6 alkylene and C6 alkenylene, each of which is optionally divided by one or more R 11b Replacement. In some implementations, L 2 Selected from C7 alkylene and C7 alkenylene, each of which is optionally divided by one or more R 11b Replacement. In some implementations, L 2 Selected from C8 alkylene and C8 alkenylene, each of which is optionally divided by one or more R 11b Replacement. In some implementations, L 2 It is -CH2CHCH(CH2)4-. In some implementations, L 2 It is a 6- to 8-membered heteroalkylene group, optionally bounded by one or more R 11b Replacement. In some implementations, L 2 It is a 6-membered heteroalkylene group, which is optionally divided by one or more R 11b Replacement. In some implementations, L 2 It is a 7-membered heteroalkylene group, which is optionally divided by one or more R 11b Replacement. In some implementations, L 2 It is an 8-membered heteroalkylene group, which is optionally divided by one or more R 11b Replacement. In some implementations, L 2 It is an 8-membered heteroalkylene group, wherein the heteroalkylene group contains one oxygen atom. In some embodiments, L 2 It is -(CH2) 2-5 O(CH2) 0-5 -, such as L 2 It is -(CH2) 2-5 O(CH2) 2-5 - In some implementations, L 2 It is -(CH2)4O(CH2)3-. In some implementations, R 11b Each time it appears, it is independently selected from halogen, oxidative, and C. 1-6 Alkyl, C 1-6 Haloalkyl, (C 1-6 Alkyl)-OH and -OH. In some embodiments, R 11b Each occurrence is independently selected from -F, =O, -CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2OH, and -OH. In some embodiments, R 11b Each time it appears, it is independently selected from -CH3, -CH2OH, -CH2F, -CHF2, and -CF3, or two R. 11bCombine to form =O or C 3-6 Cycloalkyl groups, such as cyclopropyl groups. In some embodiments, R... 11b Each time it appears, it is independently selected from -CH3, -CH2OH, -CH2F, -CHF2, and -CF3, or two R. 11b Combine to form C 3-6 Cycloalkyl groups, such as cyclopropyl groups. In some embodiments, R... 11b Each occurrence is independently selected from -CH3, -F, -CN, and -OH. In some embodiments, L 2 Includes -C(O)N(R) 14 - or -N(R) 14 )C(O)-. In some implementations, L 2 Includes -O-. In some implementations, L 2 It may be substituted with at least one -CH3, -CH2OH, -CH2F, -CHF2, or -CF3, or two substituents may be combined to form a cyclopropyl group. In some embodiments, L 2 It is replaced by at least one -CH3, -F, -CN, or -OH. In some embodiments, L 2 It is not replaced.

[0126] In some embodiments, for compounds of formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), or (I-E1), L 2 Yes - (C 1-5 alkylene)-C(O)N(R 14 )-(C 1-5 alkylene)-, such as -(C 1-5 alkylene)-C(O)N(CH3)-(C 1-5 alkylene)- or -(C 1-5 alkylene)-C(O)NH-(C 1-5 alkylene)-, where C 1-5 Alkylene is optionally surrounded by one or more R 11b Replacement. In some implementations, L 2 Yes - (C 1-2 alkylene)-C(O)N(R 14 )-(C 3-4 alkylene)-, such as -(C 1-2 alkylene)-C(O)N(CH3)-(C 3-4 alkylene)- or -(C 1-2 alkylene)-C(O)NH-(C 3-4 alkylene)-, where C1-2 Alkylene and C 3-4 Each alkylene group is independently and optionally surrounded by one or more R 11b Replacement. In some implementations, R 11b Each time it appears, it is independently selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, (C 1-6 Alkyl)-OH and -OH. In some embodiments, R 11b Each occurrence is independently selected from -F, -CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2OH, and -OH. In some embodiments, R 11b Each time it appears, it is independently selected from -CH3, -CH2OH, -CH2F, -CHF2, and -CF3, or two R. 11b Combine to form C 3-6 Cycloalkyl groups, such as cyclopropyl groups. In some embodiments, R... 11b Each occurrence is independently selected from -CH3, -F, -CN, and -OH. In some embodiments, L 2 It is replaced by at least one -CH3, -F, -CN or -OH.

[0127] In some implementations, L 2 Selected from -C(R) 11b (R) 11b )-(C 3-10 alkylene)-C(R 11b (R) 11b )-、-CH(R 11b )-(C 3-10 alkylene)-C(R 11b (R) 11b )-、-CH2-(C 3-10 alkylene)-C(R 11b (R) 11b )-、-CH(R 11b )-(C 3-10 alkylene)-CH(R 11b )-、-CH2-(C 3-10 alkylene)-CH(R 11b )-、-C(R 11b (R) 11b )-(C 3-10 (Ideinyl)-C(R) 11b (R) 11b )-、-CH(R 11b )-(C 3-10 (Ideinyl)-C(R) 11b (R) 11b)-、-CH2-(C 3-10 (Ideinyl)-C(R) 11b (R) 11b )-、-CH(R 11b )-(C 3-10 (imide-alkenyl)-CH(R) 11b )-、-CH2-(C 3-10 (imide-alkenyl)-CH(R) 11b )-、-C(R 11b (R) 11b )-(3 to 10-membered heteroalkylene)-C(R 11b (R) 11b )-、-CH(R 11b )-(3 to 10-membered heteroalkylene)-C(R 11b (R) 11b )-、-CH2-(3 to 10-membered heteroalkylene)-C(R 11b (R) 11b )-、-CH(R 11b )-(3 to 10-membered heteroalkylene)-CH(R 11b )-、-CH2-(3 to 10-membered heteroalkylene)-CH(R 11b )-、-C(R 11b (R) 11b )-(3 to 10-membered hemienyl)-C(R 11b (R) 11b )-、-CH(R 11b )-(3 to 10-membered hemienyl)-C(R 11b (R) 11b )-、-CH2-(3 to 10-membered hemienyl)-C(R 11b (R) 11b )-、-CH(R 11b )-(3 to 10-membered hemienyl)-CH(R) 11b )- and -CH2-(3 to 10-membered hemienyl)-CH(R 11b In some implementations, L 2 Selected from -C(R) 11b (R) 11b )-(C 3-10 alkylene)-C(R 11b (R) 11b )-、-CH(R 11b )-(C 3-10 alkylene)-C(R 11b (R) 11b )-、-CH2-(C 3-10 alkylene)-C(R 11b (R) 11b)-、-CH(R 11b )-(C 3-10 alkylene)-CH(R 11b )- and -CH2-(C 3-10 alkylene)-CH(R 11b In some implementations, L 2 Selected from -C(R) 11b (R) 11b )-(C 3-10 (Ideinyl)-C(R) 11b (R) 11b )-、-CH(R 11b )-(C 3-10 (Ideinyl)-C(R) 11b (R) 11b )-、-CH2-(C 3-10 (Ideinyl)-C(R) 11b (R) 11b )-、-CH(R 11b )-(C 3-10 (imide-alkenyl)-CH(R) 11b )- and -CH2-(C 3-10 (imide-alkenyl)-CH(R) 11b In some implementations, L 2 Selected from -C(R) 11b (R) 11b )-(3 to 10-membered heteroalkylene)-C(R 11b (R) 11b )-、-CH(R 11b )-(3 to 10-membered heteroalkylene)-C(R 11b (R) 11b )-、-CH2-(3 to 10-membered heteroalkylene)-C(R 11b (R) 11b )-、-CH(R 11b )-(3 to 10-membered heteroalkylene)-CH(R 11b )- and -CH2-(3 to 10-membered heteroalkylene)-CH(R 11b In some implementations, L 2 Selected from -C(R) 11b (R) 11b )-(3 to 10-membered hemienyl)-C(R 11b (R) 11b )-、-CH(R 11b )-(3 to 10-membered hemienyl)-C(R 11b (R) 11b )-、-CH2-(3 to 10-membered hemienyl)-C(R 11b (R) 11b)-、-CH(R 11b )-(3 to 10-membered hemienyl)-CH(R) 11b )- and -CH2-(3 to 10-membered hemienyl)-CH(R 11b )-。 Any C in this paragraph 3-10 Alkylene, C 3-10 The alkenyl group, 3 to 10 heteroalkyl group, or 3 to 10 heteroalkyl group may optionally be surrounded by one or more R groups. 11b Replacement. In some implementations, R 11b Each time it appears, it is independently selected from halogen, oxidative, and C. 1-6 Alkyl, C 1-6 Haloalkyl, (C 1-6 Alkyl)-OH and -OH. In some embodiments, R 11b Each occurrence is independently selected from -F, -CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2OH, and -OH. In some embodiments, R 11b Each time it appears, it is independently selected from -CH3, -CH2OH, -CH2F, -CHF2, and -CF3, or two R. 11b Combine to form =O or C 3-6 Cycloalkyl groups, such as cyclopropyl groups.

[0128] In some embodiments, for compounds of formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), or (I-E1), L 2 Yes -L 3 -DL 4 -, where L 3 Selected from C 1-10 Alkylene, C 2-10 imidene group, C 2-10 Alynyl, 2 to 10 heteroalkyl, and 3 to 10 heteroenyl, each of which is optionally divided by one or more R 11b Replace; D does not exist or is selected from C. 3-12 Carbon rings and 3 to 12-membered heterocycles, each of which is optionally bounded by one or more R... 11d Replace; and L 4 Selected from C 1-10 Alkylene, C 2-10 imidene group, C 2-10 Alynyl, 2 to 10 heteroalkyl, and 3 to 10 heteroenyl, each of which is optionally divided by one or more R 11bSubstitution. As mentioned above, the alkenyl and alkyneyl groups each contain one or more carbon-carbon double or triple bonds (i.e., containing two or more carbon atoms, for example, as in C). 2-10 imidene group, C 2-10 Ethyne group, C 2-8 imidene group, C 2-8 Ethyne group, C 5-25 imidene group, C 5-25 Ethyne group, C 6-15 imidene group, C 6-15 Ethyne group, C 5-10 imide and C 5-10 In the alkynyl group). Similarly, the alkynyl group contains one or more carbon-carbon double bonds (i.e., contains two or more carbon atoms and one or more heteroatoms, for example, in 3- to 10-membered alkynyl groups, 3- to 8-membered alkynyl groups, 5- to 25-membered alkynyl groups, 6- to 15-membered alkynyl groups, and 5- to 10-membered alkynyl groups). In some embodiments, L 2 Yes -L 3 -DL 4 -, where L 3 Selected from C 1-10 Alkylene, C 2-10 imidene group, C 2-10 Alynyl, 2 to 10 heteroalkyl, and 3 to 10 heteroenyl, each of which is optionally divided by one or more R 11b Replace; D is selected from C 3-12 Carbon rings and 3 to 12-membered heterocycles, each of which is optionally bounded by one or more R... 11d Replace; and L 4 It does not exist. In some implementations, L 2 Yes -L 3 -DL 4 -, where L 3 Selected from C 1-8 Alkylene, C 2-8 alkenyl, 2- to 8-membered heteroalkyl, and 3- to 8-membered heteroalkyl, each of which is optionally divided by one or more R 11b Replace; D does not exist or is selected from C. 3-10 Carbon rings and 3 to 10-membered heterocycles, each of which is optionally bounded by one or more R... 11d Replace; and L 4 Selected from C 1-8 Alkylene, C 2-8 alkenyl, 2- to 8-membered heteroalkyl, and 3- to 8-membered heteroalkyl, each of which is optionally divided by one or more R 11b Replacement. In some implementations, L 2 Yes -L 3 -DL 4 -, where L3 Selected from C 1-8 Alkylene, C 2-8 alkenyl, 2- to 8-membered heteroalkyl, and 3- to 8-membered heteroalkyl, each of which is optionally divided by one or more R 11b Replace; D is selected from C 3-10 Carbon rings and 3 to 10-membered heterocycles, each of which is optionally bounded by one or more R... 11d Replace; and L 4 Selected from C 1-8 Alkylene, C 2-8 alkenyl, 2- to 8-membered heteroalkyl, and 3- to 8-membered heteroalkyl, each of which is optionally divided by one or more R 11b Replacement. In some implementations, R 11b Each time it appears, it is independently selected from halogen, oxidative, and C. 1-6 Alkyl, C 1-6 Haloalkyl, (C 1-6 Alkyl)-OH and -OH. In some embodiments, R 11b Each occurrence is independently selected from -F, -CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2OH, and -OH. In some embodiments, R 11b Each time it appears, it is independently selected from -CH3, -CH2OH, -CH2F, -CHF2, and -CF3, or two R. 11b Combine to form =O or C 3-6 Cycloalkyl, such as cyclopropyl. In some embodiments, D is selected from phenyl and 5 to 8-membered heteroaryl groups, such as triazoles and imidazoles. In some embodiments, D is unsubstituted. In some embodiments, D is substituted with one or more R groups. 11d (such as one, two or three R) 11d )replace.

[0129] In some implementations, for compounds of formula (I), L 2 Covalently bound to W 3 W 4 W 5 W 6 or W 7 One of them; or L 2 Yes -L 3 -DL 4 -, where L 4 Covalently bound to W 3 W 4 W 5 W 6 or W 7 One of them. For example, L 2 It can covalently bind to W3 —where R 3b Or R 3 Is with L 2 The key—as described in formula (IA). In some implementations, L 2 Covalently bound to W 4 —where R 4b Or R 4 Is with L 2 The key—as described in formula (IB). In some implementations, L 2 Covalently bound to W 5 —where R 5b Or R 5 Is with L 2 The key—as described in formula (IC). In some implementations, L 2 Covalently bound to W 6 —where R 6b Or R 6 Is with L 2 The key—as described in formula (ID). In some implementations, L 2 Covalently bound to W 7 —where R 7b Or R 7 Is with L 2 The key is as described in the formula (IE).

[0130] In some embodiments, for compounds of formula (I), (IA), (IB), (I-1), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), or (I-E1): R 20 Each time it appears, it is independently selected from halogen, oxo, =NH, -CN, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon ring, -CH2-(C 3-10 Carbon rings), 3- to 10-membered heterocycles, -CH2- (3- to 10-membered heterocycles), -OR 21 -SR 21 -N(R) 22 (R) 23 -C(O)OR 22 -C(O)N(R) 22 (R) 23 -C(O)C(O)N(R) 22 (R) 23 ), -OC(O)N(R 22 (R)23 ), -N(R 24 )C(O)N(R 22 (R) 23 ), -N(R 24 )C(O)OR 25 -N(R) 24 )C(O)R 25 -N(R) 24 )S(O)2R 25 -C(O)R 25 -S(O)2R 25 -S(O)2N(R) 22 (R) 23 -OCH2C(O)OR 22 and -OC(O)R 25 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon ring, -CH2-(C 3-10 The carbocyclic ring (3 to 10-membered heterocycle) and -CH2- (3 to 10-membered heterocycle) are optionally substituted by one, two, or three independent groups selected from the following: halogen, oxo, =NH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -OR 21 -SR 21 and -N(R) 22 (R) 23 ); R 21 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 3-10 The carbide ring and the 3 to 10-membered heterocycle are optionally substituted by one, two, or three independent groups selected from the following: halogen and C. 1-6 alkyl; R 22 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 3-10The carbide ring and the 3 to 10-membered heterocycle are optionally substituted by one, two, or three independent groups selected from the following: halogen and C. 1-6 alkyl; R 23 Each time it appears, it is independently selected from H and C. 1-6 alkyl; R 24 Each time it appears, it is independently selected from H and C. 1-6 Alkyl; and R 25 Each time it appears, it is independently selected from C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 1-6 Alkyl, C 3-10 The carbide ring and the 3 to 10-membered heterocycle are optionally substituted by one, two, or three independent groups selected from the following: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-10 Carbon rings and 3 to 10-membered heterocycles.

[0131] In some embodiments, for compounds of formula (I), (IA), (IB), (I-1), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), or (I-E1), R 20 Each time it appears, it is independently selected from halogen, oxidative, and =NR. 22 -CN,C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon ring, -CH2-(C 3-10 Carbon rings), 3- to 10-membered heterocycles, -CH2- (3- to 10-membered heterocycles), -OR 21 -SR 21 -N(R) 22 (R) 23 -C(O)OR 22 -C(O)N(R) 22 (R) 23 -C(O)C(O)N(R) 22 (R) 23 ), -OC(O)N(R 22 (R) 23 ), -N(R 24 )C(O)N(R 22 (R)23 ), -N(R 24 )C(O)OR 25 -N(R) 24 )C(O)R 25 -N(R) 24 )S(O)2R 25 -C(O)R 25 -S(O)2R 25 -S(O)(NR) 22 )R 25 -S(O)2N(R) 22 (R) 23 -OCH2C(O)OR 22 and -OC(O)R 25 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon ring, -CH2-(C 3-10 The carbocyclic ring (3 to 10-membered heterocycle) and -CH2- (3 to 10-membered heterocycle) are optionally substituted by one, two, or three independent groups selected from the following: halogen, oxo, =NR 22 -CN,C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -OR 21 -SR 21 and -N(R) 22 (R) 23 ).

[0132] In some embodiments, for compounds of formula (I), (IA), (IB), (I-1), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), or (I-E1), R 20 Each time it appears, it is independently selected from halogen, oxo, =NH, -CN, -NO2, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon ring, -CH2-(C 3-10 Carbon rings), 3- to 10-membered heterocycles, -CH2- (3- to 10-membered heterocycles), -OH, -OCH3, -OCH2CH3, -NH2, -NHCH3 and -NHCH2CH3, where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3-10 Carbon ring, -CH2-(C 3-10 The carbon ring, 3 to 10-membered heterocycles and -CH2- (3 to 10-membered heterocycles) are optionally substituted by one, two or three independent groups selected from the following: halogen, oxo, =NH, -CN, -NO2, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -OH, -OCH3, -OCH2CH3, -NH2, -NHCH3 and -NHCH2CH3.

[0133] In some implementations, for compounds of formula (I-B1), R 5b It is -CH3; R 7 Selected from C 1-6 Alkyl, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -N(R) 12 (R) 13 -C(O)R 15 -C(O)N(R) 12 (R) 13 -S(O)2R 15 and -SO2N(R 12 (R) 13 ), where C 1-6 Alkyl, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 Replace; and R 8 It is hydrogen. In some embodiments, for compounds of formula (I-B2), R 5 It is hydrogen; R 6 Selected from hydrogen and -OCH3; R 7 Selected from C 1-6 Alkyl, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -N(R) 12 (R) 13 -C(O)R 15 -C(O)N(R) 12 (R) 13 -S(O)2R 15 and -SO2N(R 12 (R) 13 ), where C 1-6 Alkyl, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 Replace; and R 8 It is hydrogen.

[0134] In some implementations, for compounds of formula (I-C1), R 3 It is hydrogen or -CH3; R 7Selected from C 1-6 Alkyl, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -N(R) 12 (R) 13 -C(O)R 15 -C(O)N(R) 12 (R) 13 -S(O)2R 15 and -SO2N(R 12 (R) 13 ), where C 1-6 Alkyl, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 Replace; and R 8 It is hydrogen. In some embodiments, for compounds of formula (I-C2), R 3b It is -CH3; R 7 Selected from C 1-6 Alkyl, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -N(R) 12 (R) 13 -C(O)R 15 -C(O)N(R) 12 (R) 13 -S(O)2R 15 and -SO2N(R 12 (R) 13 ), where C 1-6 Alkyl, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 Replace; and R 8 It is hydrogen. In some embodiments, for compounds of formula (I-C3), R 3 It is hydrogen or -CH3; R 6 Selected from hydrogen and -OCH3; R 7 Selected from C 1-6 Alkyl, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -N(R) 12 (R) 13 -C(O)R 15 -C(O)N(R) 12 (R) 13 -S(O)2R 15 and -SO2N(R 12 (R) 13 ), where C 1-6 Alkyl, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 Replace; and R 8It is hydrogen.

[0135] In some embodiments, for compounds of formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), or (I-E1): R 1 It is -CH3; Selected from phenyl and 5 to 7-membered heteroaryl groups, each of which is optionally separated by one or more R 11 Replace; L 1 Selected from key and C 1-3 Halogenated alkylene; Selected from non-existent, phenyl, and 4 to 8-membered heterocycles, wherein the phenyl and 4 to 8-membered heterocycles are optionally separated by one or more R 11a Replace; and L 2 Selected from C 5-10 Alkylene, C 5-10 alkenyl, 5- to 10-membered heteroalkyl, and 5- to 10-membered heteroalkyl, each of which is optionally bound by one or more R 11b Replacement. In some implementations, R 11 It is fluorine when present; R 11a When present, it is -CH3; and R 11b When present, it is selected from halogen, oxo, C. 1-6 Alkyl, C 1-6 Haloalkyl, (C 1-6 Alkyl)-OH and -OH.

[0136] In some embodiments, for compounds of formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), or (I-E1): R 1 It is -CH3; Selected from and L 1 It is C 1-2 Halogenated alkylene; yes It is optionally controlled by one or more R 11a Replace; and L 2 Selected from C 6-8 Alkylene, C 6-8 alkenyl and 6- to 8-membered heteroalkylene groups, each of which is optionally divided by one or more R 11b Replacement. In some implementations, R 1 It is -CH3; yes L 1 It is C 1-2 Halogenated alkylene; yes ;and L 2 It is a 6- to 8-membered heteroalkylene group, optionally bounded by one or more R 11b Replacement. In some implementations, R 1 It is -CH3; Selected from and L 1 It is C 1-2 Halogenated alkylene; yes It is optionally controlled by one or more R 11a Replace; and L 2 Selected from C 6-8 Alkylene and C 6-8 alkenyl groups, each of which is optionally divided by one or more R groups. 11b Replacement. In some implementations, R 1 It is -CH3; yes L 1 It is C 1-2 Halogenated alkylene; yes ;and L 2 It is C 6-8 alkenyl groups, which are optionally surrounded by one or more R groups 11b Replacement. In some implementations, R 1 It is -CH3; Selected from and L 1 It is C 1-2 Halogenated alkylene; yes It is optionally controlled by one or more R 11a Replace; and L 2 Yes - (C 1-2 alkylene)-C(O)N(CH3)-(C 3-4 alkylene)- or -(C 1-2 alkylene)-C(O)NH-(C 3-4 alkylene)-, where C 1-2 Alkylene and C 3-4 Each alkylene group is independently and optionally surrounded by one or more R 11b Replacement. In some implementations, R 11a When present, it is -CH3; and R 11b When present, it is selected from halogens, -CN, oxo, and C. 1-3 Alkyl, C1-3 Haloalkyl, (C 1-3 Alkyl)-OH and -OH.

[0137] In some embodiments, for compounds of formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), or (I-E1): R 1 It is -CH3; Selected from and L 1 It is C 1-2 Halogenated alkylene; yes ;and L 2 Selected from C 6-8 Alkylene, C 6-8 alkenyl and 6- to 8-membered heteroalkylene groups, each of which is optionally divided by one or more R 11b Replacement. In some implementations, R 1 It is -CH3; Selected from and L 1 It is C 1-2 Halogenated alkylene; yes ;and L 2 Selected from C 6-8 Alkylene and C 6-8 alkenyl groups, each of which is optionally divided by one or more R groups. 11b Replacement. In some implementations, R 1 It is -CH3; Selected from and L 1 It is C 1-2 Halogenated alkylene; yes ;and L 2 Yes - (C 1-2 alkylene)-C(O)N(CH3)-(C 3-4 alkylene)- or -(C 1-2 alkylene)-C(O)NH-(C 3-4 alkylene)-, where C 1-2 Alkylene and C 3-4 Each alkylene group is independently and optionally surrounded by one or more R 11b Replacement. In some implementations, R 11b When present, it is selected from halogens, -CN, oxo, and C. 1-3 Alkyl, C1-3 Haloalkyl, (C 1-3 Alkyl)-OH and -OH.

[0138] In some embodiments, the compound of formula (I) is a compound of the following formula: ,like or , where R 50 Is it hydrogen or R? 11 and R 51 It is hydrogen or halogen.

[0139] In some embodiments, the compound of formula (I) is a compound of the following formula: ,like , or , where R 50 It is hydrogen or fluorine. In some embodiments, the compound of formula (IA) is a compound of the following formula: ,like , or , where R 50 It is hydrogen or fluorine. In some embodiments, the compound of formula (IB) is a compound of the following formula: ,like , or , where R 50 It is hydrogen or fluorine. In some embodiments, the compound of formula (IC) is a compound of the following formula: ,like , or , where R 50 It is hydrogen or fluorine. In some embodiments, the compound of formula (IC) is a compound of the following formula: like , or , where R 50 It is hydrogen or fluorine. In some embodiments, the compound of formula (ID) is a compound of the following formula: ,like , or , where R 50 It is hydrogen or fluorine. In some embodiments, the compound of formula (IE) is a compound of the following formula: ,like , or , where R 50 It is hydrogen or fluorine. In some implementations, L 1 It is C 1-3 Alkyl halides, such as C 1-2 Halogenated alkylene or C 1-2 Fluoroalkylene oxides. In some embodiments, L... 2 Selected from C 6-8 Alkylene, C 6-8 alkenyl and 6- to 8-membered heteroalkylene groups, each of which is optionally divided by one or more R 11b Replacement. In some implementations, L 2 Selected from C 6-8 Alkylene and C 6-8 alkenyl groups, each of which is optionally divided by one or more R groups. 11b Replacement. In some implementations, L 2 Yes - (C 1-2 alkylene)-C(O)N(CH3)-(C 3-4 alkylene)- or -(C 1-2 alkylene)-C(O)NH-(C 3-4 alkylene)-, where C 1-2 Alkylene and C 3-4 Each alkylene group is independently and optionally surrounded by one or more R 11b Replacement. In some implementations, R 11b When present, it is selected from halogens, -CN, C. 1-3 Alkyl, C 1-3 Haloalkyl, (C 1-3 Alkyl)-OH and -OH. In some embodiments, R 50 It is hydrogen. In some implementations, R 50 It's fluorine.

[0140] In some respects, this disclosure provides a compound of formula (I-C1): (I-C1), Or a pharmaceutically acceptable salt or solvate thereof, wherein: Selected from , , , and ; Selected from aziridine, pyrrolidine and piperidine, each of which is optionally substituted with one or more -CH3; L 1 It is C 1-3 Halogenated alkylene; L 2 Selected from C 5-10 Alkylene, C 5-10 alkenyl, 5- to 10-membered heteroalkyl, and 5- to 10-membered heteroalkyl, each of which is optionally bound by one or more R 11b replace; R 1 It is -CH3; R 3 It is hydrogen or -CH3; R 7 Selected from , , , , , , , , , , , , , , , , , , , , , , , , and ; R 8 It is hydrogen; R 11 Selected from fluorine and -CH3; and R 11b Selected from halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, (C 1-6 Alkyl)-OH and -OH.

[0141] In some respects, this disclosure provides a compound of formula (I-C1): (I-C1), Or a pharmaceutically acceptable salt or solvate thereof, wherein: Selected from and ; Selected from azacyclic butane, pyrrolidine, and piperidine; L 1 Selected from -CF2-, -CF2CH2- and -CF2CH2CH2-; L 2 Selected from C 5-10 Alkylene, C 5-10 alkenyl, 5- to 10-membered heteroalkyl and 5- to 10-membered heteroalkyl; R 1 It is -CH3; R 3 It is hydrogen or -CH3; R 7 Selected from , , , , , , , , , , , , , , , , , , , , , , , , and ;and R 8 It is hydrogen.

[0142] In some respects, this disclosure provides a compound of formula (I-C1): (I-C1), Or a pharmaceutically acceptable salt or solvate thereof, wherein: Selected from , , , and ; Selected from aziridine, pyrrolidine and piperidine, each of which is optionally substituted with one or more -CH3; L 1 It is C 1-3 Halogenated alkylene; L 2 It is optionally controlled by one or more R 11b Replacement C 5-10 alkenyl; R 1It is -CH3; R 3 It is -CH3; R 7 Selected from , and ; R 8 It is hydrogen; R 11 Selected from fluorine and -CH3; and R 11b Selected from halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, (C 1-6 Alkyl)-OH and -OH.

[0143] In some respects, this disclosure provides a compound of formula (I-C1): (I-C1), Or a pharmaceutically acceptable salt or solvate thereof, wherein: Selected from , , , and ; Selected from aziridine, pyrrolidine and piperidine, each of which is optionally substituted with one or more -CH3; L 1 It is C 1-3 Halogenated alkylene; L 2 Selected from one or more R 11b Substituted 5- to 10-membered heteroalkylene groups; R 1 It is -CH3; R 3 It is hydrogen or -CH3; R 7 Selected from , and ; R 8 It is hydrogen; R 11 Selected from fluorine and -CH3; and R 11b Selected from halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, (C 1-6 Alkyl)-OH and -OH.

[0144] In some respects, this disclosure provides a compound of formula (I): (I), Or a pharmaceutically acceptable salt or solvate thereof, wherein: Selected from phenyl and 5 to 7-membered heteroaryl groups, each of which is optionally separated by one or more R 11 replace; It is absent or selected from phenyl and 4 to 8-membered heterocycles, each of which is optionally separated by one or more R 11a replace; L 1 Selected from key and C 1-3 Halogenated alkylene; L 2 Selected from C 5-10 Alkylene, C 5-10 alkenyl, 5- to 10-membered heteroalkyl, and 5- to 10-membered heteroalkyl, each of which is optionally bound by one or more R 11b Replace, where L 2 Covalently bound to W 3 W 4 W 5 W 6 or W 7 One of them; or L 2 Yes -L 3 -DL 4 -, where L 4 Covalently bound to W 3 W 4 W 5 W 6 or W 7 one of; L 3 Selected from C 1-8 Alkylene, C 2-8 alkenyl, 2- to 8-membered heteroalkyl, and 3- to 8-membered heteroalkyl, each of which is optionally divided by one or more R 11b replace; D is selected from C 3-10 Carbon rings and 3 to 10-membered heterocycles, each of which is optionally bounded by one or more R... 11d replace; L 4 Selected from C 1-8 Alkylene, C 2-8 alkenyl, 2- to 8-membered heteroalkyl, and 3- to 8-membered heteroalkyl, each of which is optionally divided by one or more R 11b replace W 2 It is N; W 3 Selected from N(R) 3b ), N, C(R) 3 ) and C(O); W 4 Selected from N(R) 4b ), N, C(R) 4 ) and C(O); W 5 Selected from N(R) 5b ), N and C(R) 5 ); W 6 Selected from C(R) 6 ) and C(O); W 7 It is C(R) 7 ); W 8 It is C(R) 8 ); W 9 and W 10 Each is C; R 1 It is -CH3; R 2 R 2a R 3a R 4a R 5a R 6a R 7a R 8 and R 8a Each is independently selected from hydrogen and -CH3; R 3 R 4 R 5 and R 6 Each independently selected from L 2 bonds, hydrogen, halogens, -CN, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2; R 7 Selected from L 2 The key, C 1-6 Alkyl, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -N(R) 12 (R) 13 -C(O)R 15 -C(O)N(R) 12 (R) 13 -S(O)2R 15 and -SO2N(R 12 (R)13 ), where C 1-6 Alkyl, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 replace; R 3b R 4b and R 5b Each independently selected from L 2 bonds, hydrogen and C 1-3 alkyl; R 11 R 11a and R 11d Each time it appears, it is independently selected from halogen, -CN, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 -S(=O)(=NH)N(R) 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15-CH2S(O)2N(R) 12 (R) 13 ), -CH2N(R 12 )S(O)2(R 13 ) and -P(O)(R 17 (R) 17a ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 replace; R 11b Each time it appears, it is independently selected from halogen, oxo, -CN, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 -S(=O)(=NH)N(R) 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R15 -CH2S(O)2N(R) 12 (R) 13 ), -CH2N(R 12 )S(O)2(R 13 ) and -P(O)(R 17 (R) 17a ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 replace; R 12 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 replace; R 13 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl; or R 12 and R 13 Together with the nitrogen atoms they are attached to, they form a structure optionally bounded by one, two, or three R atoms. 20 Replaced 3- to 10-membered heterocycles; R 14 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R 15 Each time it appears, it is independently selected from C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 replace; R 17 and R 17a Each time it appears, it is independently selected from C.1-6 Alkyl and C 3-6 cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl groups are optionally surrounded by one, two, or three R groups. 20 Replace; or R 17 and R 17a Together with the phosphorus atoms they are attached to, they form 3 to 10-membered heterocycles; R 20 Each time it appears, it is independently selected from halogen, oxo, =NH, -CN, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon ring, -CH2-(C 3-10 Carbon rings), 3- to 10-membered heterocycles, -CH2- (3- to 10-membered heterocycles), -OR 21 -SR 21 -N(R) 22 (R) 23 -C(O)OR 22 -C(O)N(R) 22 (R) 23 -C(O)C(O)N(R) 22 (R) 23 ), -OC(O)N(R 22 (R) 23 ), -N(R 24 )C(O)N(R 22 (R) 23 ), -N(R 24 )C(O)OR 25 -N(R) 24 )C(O)R 25 -N(R) 24 )S(O)2R 25 -C(O)R 25 -S(O)2R 25 -S(O)2N(R) 22 (R) 23 -OCH2C(O)OR 22 and -OC(O)R 25 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon ring, -CH2-(C 3-10 The carbocyclic ring (3 to 10-membered heterocycle) and -CH2- (3 to 10-membered heterocycle) are optionally substituted by one, two, or three independent groups selected from the following: halogen, oxo, =NH, -CN, C. 1-6 Alkyl, C1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -OR 21 -SR 21 -N(R) 22 (R) 23 -C(O)OR 22 -C(O)N(R) 22 (R) 23 -C(O)C(O)N(R) 22 (R) 23 ), -OC(O)N(R 22 (R) 23 ), -N(R 24 )C(O)N(R 22 (R) 23 ), -N(R 24 )C(O)OR 25 -N(R) 24 )C(O)R 25 -N(R) 24 )S(O)2R 25 -C(O)R 25 -S(O)2R 25 -S(O)2N(R) 22 (R) 23 ) and -OC(O)R 25 ; R 21 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 3-10 The carbide ring and the 3 to 10-membered heterocycle are optionally substituted by one, two, or three independent groups selected from the following: halogen and C. 1-6 alkyl; R 22 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 3-10 The carbide ring and the 3 to 10-membered heterocycle are optionally substituted by one, two, or three independent groups selected from the following: halogen and C. 1-6 alkyl; R 23 Each time it appears, it is independently selected from H and C. 1-6alkyl; R 24 Each time it appears, it is independently selected from H and C. 1-6 alkyl; R 25 Each time it appears, it is independently selected from C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 1-6 Alkyl, C 3-10 The carbide ring and the 3 to 10-membered heterocycle are optionally substituted by one, two, or three independent groups selected from the following: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-10 Carbon rings and 3 to 10-membered heterocycles; and This indicates a single or double bond, such that all valences are satisfied.

[0145] In some respects, this disclosure provides a compound of formula (III): (III), Or a pharmaceutically acceptable salt or solvate thereof, wherein: Selected from one or more R 11a Replaced 3- to 8-membered heterocycles; L 1 Selected from key, C 1-6 Alkylene and C 1-6 Halogenated alkylene; L 2 Selected from C 5-25 Alkylene, C 5-25 imidene group, C 5-25 5- to 25-membered heteroalkyl and 5- to 25-membered heteroenyl, each of which is optionally divided by one or more R 11b Replace, where L 2 Covalently bound to W 3 W 4 W 5 W 6 or W 7 One of them; or L 2 Yes -L 3 -DL 4 -, where L 4 Covalently bound to W 3 W 4 W 5 W 6 or W 7one of; L 3 Selected from C 1-10 Alkylene, C 2-10 imidene group, C 2-10 Alynyl, 2 to 10 heteroalkyl, and 3 to 10 heteroenyl, each of which is optionally divided by one or more R 11b replace; D does not exist or is selected from C. 3-12 Carbon rings and 3 to 12-membered heterocycles, each of which is optionally bounded by one or more R... 11d replace; L 4 Selected from C 1-10 Alkylene, C 2-10 imidene group, C 2-10 Alynyl, 2 to 10 heteroalkyl, and 3 to 10 heteroenyl, each of which is optionally divided by one or more R 11b replace; W 3 Selected from N(R) 3b ) and N, and W 4 Selected from C(R) 4 ) and C(O); or W 3 Selected from C(R) 3 ) and C(O), and W 4 Selected from N(R) 4b ) and N; W 5 Selected from N(R) 5b ), N and C(R) 5 ); W 6 Selected from N, C(R) 6 ) and C(O); W 7 Selected from N, C(R) 7 ) and C(O); R 50 It is hydrogen or halogen; R 3 R 4 R 5 R 6 and R 7 Each independently selected from L 2 bonds, hydrogen, halogens, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -SR 12 -N(R) 12 (R) 13-C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 -S(=O)(=NH)N(R) 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 and -CH2S(O)2N(R 12 (R) 13 ), where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are independently and optionally separated by one, two, or three R... 20 replace; R 3b R 4b and R 5b Each independently selected from L 2 bonds, hydrogen, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -SR 12 -C(O)OR 12 -OC(O)N(R) 12 (R) 13-C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 -S(=O)(=NH)N(R) 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 and -CH2S(O)2N(R 12 (R) 13 ), where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are independently and optionally separated by one, two, or three R... 20 replace; R 11a and R 11d Each time it appears, it is independently selected from halogen, -CN, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R)13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 -S(=O)(=NH)N(R) 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 -CH2S(O)2N(R) 12 (R) 13 ), -CH2N(R 12 )S(O)2(R 13 ) and -P(O)(R 17 (R) 17a ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 replace; R 11b Each time it appears, it is independently selected from halogen, oxo, -CN, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12(R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 -S(=O)(=NH)N(R) 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 -CH2S(O)2N(R) 12 (R) 13 ), -CH2N(R 12 )S(O)2(R 13 ) and -P(O)(R 17 (R) 17a ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 replace; R 12 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 replace; R 13 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl; or R 12 and R 13 Together with the nitrogen atoms they are attached to, they form a structure optionally bounded by one, two, or three R atoms. 20 Replaced 3- to 10-membered heterocycles; R 14 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl and C1-6 Halogenated alkyl groups; R 15 Each time it appears, it is independently selected from C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 replace; R 17 and R 17a Each time it appears, it is independently selected from C. 1-6 Alkyl and C 3-6 cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl groups are optionally surrounded by one, two, or three R groups. 20 Replace; or R 17 and R 17a Together with the phosphorus atoms they are attached to, they form 3 to 10-membered heterocycles; R 20 Each time it appears, it is independently selected from halogen, oxo, =NH, -CN, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon ring, -CH2-(C 3-10 Carbon rings), 3- to 10-membered heterocycles, -CH2- (3- to 10-membered heterocycles), -OR 21 -SR 21 -N(R) 22 (R) 23 -C(O)OR 22 -C(O)N(R) 22 (R) 23 -C(O)C(O)N(R) 22 (R) 23 ), -OC(O)N(R 22 (R) 23 ), -N(R 24 )C(O)N(R 22 (R) 23 ), -N(R 24 )C(O)OR 25 -N(R) 24 )C(O)R 25 -N(R) 24 )S(O)2R 25 -C(O)R25 -S(O)2R 25 -S(O)2N(R) 22 (R) 23 -OCH2C(O)OR 22 and -OC(O)R 25 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon ring, -CH2-(C 3-10 The carbocyclic ring (3 to 10-membered heterocycle) and -CH2- (3 to 10-membered heterocycle) are optionally substituted by one, two, or three independent groups selected from the following: halogen, oxo, =NH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -OR 21 -SR 21 -N(R) 22 (R) 23 -C(O)OR 22 -C(O)N(R) 22 (R) 23 -C(O)C(O)N(R) 22 (R) 23 ), -OC(O)N(R 22 (R) 23 ), -N(R 24 )C(O)N(R 22 (R) 23 ), -N(R 24 )C(O)OR 25 -N(R) 24 )C(O)R 25 -N(R) 24 )S(O)2R 25 -C(O)R 25 -S(O)2R 25 -S(O)2N(R) 22 (R) 23 ) and -OC(O)R 25 ; R 21 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 3-10The carbide ring and the 3 to 10-membered heterocycle are optionally substituted by one, two, or three independent groups selected from the following: halogen and C. 1-6 alkyl; R 22 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 3-10 The carbide ring and the 3 to 10-membered heterocycle are optionally substituted by one, two, or three independent groups selected from the following: halogen and C. 1-6 alkyl; R 23 Each time it appears, it is independently selected from H and C. 1-6 alkyl; R 24 Each time it appears, it is independently selected from H and C. 1-6 alkyl; R 25 Each time it appears, it is independently selected from C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 1-6 Alkyl, C 3-10 The carbide ring and the 3 to 10-membered heterocycle are optionally substituted by one, two, or three independent groups selected from the following: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-10 Carbon rings and 3 to 10-membered heterocycles; and This indicates a single or double bond, such that all valences are satisfied.

[0146] In some respects, this disclosure provides a compound of formula (III): (III), Or a pharmaceutically acceptable salt or solvate thereof, wherein: Selected from one or more R 11a Replaced 3- to 8-membered heterocycles; L 1 Selected from key, C 1-6 Alkylene and C 1-6 Halogenated alkylene; L 2 Selected from C 5-25 Alkylene, C 5-25 imidene group, C5-25 5- to 25-membered heteroalkyl and 5- to 25-membered heteroenyl, each of which is optionally divided by one or more R 11b Replace, where L 2 Covalently bound to W 3 W 4 W 5 W 6 or W 7 one of; W 3 Selected from N(R) 3b ) and N, and W 4 Selected from C(R) 4 ) and C(O); or W 3 Selected from C(R) 3 ) and C(O), and W 4 Selected from N(R) 4b ) and N; W 5 Selected from N(R) 5b ), N and C(R) 5 ); W 6 Selected from N, C(R) 6 ) and C(O); W 7 Selected from N, C(R) 7 ) and C(O); R 50 It is hydrogen or halogen; R 3 R 4 R 5 R 6 and R 7 Each independently selected from L 2 bonds, hydrogen, halogens, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 -S(=O)(=NH)N(R) 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 and -CH2S(O)2N(R 12 (R) 13 ), where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are independently and optionally separated by one, two, or three R... 20 replace; R 3b R 4b and R 5b Each independently selected from L 2 bonds, hydrogen, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -SR 12 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 -S(O)2R 15 -S(O)2N(R) 12(R) 13 -S(=O)(=NH)N(R) 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 and -CH2S(O)2N(R 12 (R) 13 ), where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are independently and optionally separated by one, two, or three R... 20 replace; R 11a Each time it appears, it is independently selected from halogen, -CN, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 -S(=O)(=NH)N(R) 12 (R) 13-CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 -CH2S(O)2N(R) 12 (R) 13 ), -CH2N(R 12 )S(O)2(R 13 ) and -P(O)(R 17 (R) 17a ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 replace; R 11b Each time it appears, it is independently selected from halogen, oxo, -CN, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 -S(=O)(=NH)N(R) 12 (R)13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 -CH2S(O)2N(R) 12 (R) 13 ), -CH2N(R 12 )S(O)2(R 13 ) and -P(O)(R 17 (R) 17a ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 replace; R 12 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 replace; R 13 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl; or R 12 and R 13 Together with the nitrogen atoms they are attached to, they form a structure optionally bounded by one, two, or three R atoms. 20 Replaced 3- to 10-membered heterocycles; R 14 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R 15 Each time it appears, it is independently selected from C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 replace; R 17 and R 17a Each time it appears, it is independently selected from C. 1-6 Alkyl and C 3-6 cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl groups are optionally surrounded by one, two, or three R groups. 20 Replace; or R 17 and R 17a Together with the phosphorus atoms they are attached to, they form 3 to 10-membered heterocycles; R 20 Each time it appears, it is independently selected from halogen, oxo, =NH, -CN, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon ring, -CH2-(C 3-10 Carbon rings), 3- to 10-membered heterocycles, -CH2- (3- to 10-membered heterocycles), -OR 21 -SR 21 -N(R) 22 (R) 23 -C(O)OR 22 -C(O)N(R) 22 (R) 23 -C(O)C(O)N(R) 22 (R) 23 ), -OC(O)N(R 22 (R) 23 ), -N(R 24 )C(O)N(R 22 (R) 23 ), -N(R 24 )C(O)OR 25 -N(R) 24 )C(O)R 25 -N(R) 24 )S(O)2R 25 -C(O)R 25 -S(O)2R 25 -S(O)2N(R) 22 (R) 23 -OCH2C(O)OR 22 and -OC(O)R 25 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10Carbon ring, -CH2-(C 3-10 The carbocyclic ring (3 to 10-membered heterocycle) and -CH2- (3 to 10-membered heterocycle) are optionally substituted by one, two, or three independent groups selected from the following: halogen, oxo, =NH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -OR 21 -SR 21 -N(R) 22 (R) 23 -C(O)OR 22 -C(O)N(R) 22 (R) 23 -C(O)C(O)N(R) 22 (R) 23 ), -OC(O)N(R 22 (R) 23 ), -N(R 24 )C(O)N(R 22 (R) 23 ), -N(R 24 )C(O)OR 25 -N(R) 24 )C(O)R 25 -N(R) 24 )S(O)2R 25 -C(O)R 25 -S(O)2R 25 -S(O)2N(R) 22 (R) 23 ) and -OC(O)R 25 ; R 21 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 3-10 The carbide ring and the 3 to 10-membered heterocycle are optionally substituted by one, two, or three independent groups selected from the following: halogen and C. 1-6 alkyl; R 22 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 3-10The carbide ring and the 3 to 10-membered heterocycle are optionally substituted by one, two, or three independent groups selected from the following: halogen and C. 1-6 alkyl; R 23 Each time it appears, it is independently selected from H and C. 1-6 alkyl; R 24 Each time it appears, it is independently selected from H and C. 1-6 alkyl; R 25 Each time it appears, it is independently selected from C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 1-6 Alkyl, C 3-10 The carbide ring and the 3 to 10-membered heterocycle are optionally substituted by one, two, or three independent groups selected from the following: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-10 Carbon rings and 3 to 10-membered heterocycles; and This indicates a single or double bond, such that all valences are satisfied.

[0147] In some embodiments, the compound of formula (III) is a compound of the following formula: , or .

[0148] In some embodiments, the compound of formula (III) is a compound of the following formula: , or .

[0149] In some implementations, for compounds of formula (III), Selected from azacyclic butanes, pyrrolidines, and piperidines, each of which is optionally converted by one or more R... 11a Replacement. In some implementations, yes Each of them is optionally controlled by one or more R 11a Replacement. In some implementations, yes It is optionally controlled by one or more R 11a Replacement. In some implementations, L 1 It is C 1-3 Alkyl halide. In some embodiments, L2 Selected from C 5-10 Alkylene, C 5-10 alkenyl, 5- to 10-membered heteroalkyl, and 5- to 10-membered heteroalkyl, each of which is optionally bound by one or more R 11b Replace, where L 2 Covalently bound to W 3 W 4 W 5 W 6 or W 7 One of them; or L 2 Yes -L 3 -DL 4 -, where L 4 Covalently bound to W 3 W 4 W 5 W 6 or W 7 One of them; L 3 Selected from C 1-8 Alkylene, C 2-8 alkenyl, 2- to 8-membered heteroalkyl, and 3- to 8-membered heteroalkyl, each of which is optionally divided by one or more R 11b Replace; D is selected from C 3-10 Carbon rings and 3 to 10-membered heterocycles, each of which is optionally bounded by one or more R... 11d Replace; and L 4 Selected from C 1-8 Alkylene, C 2-8 alkenyl, 2- to 8-membered heteroalkyl, and 3- to 8-membered heteroalkyl, each of which is optionally divided by one or more R 11b replace.

[0150] In some respects, this disclosure provides compounds of the following formula: , Or a pharmaceutically acceptable salt or solvate thereof, wherein: L 2 Selected from C 5-10 Alkylene, C 5-10 alkenyl, 5- to 10-membered heteroalkyl, and 5- to 10-membered heteroalkyl, each of which is optionally bound by one or more R 11b Replace, where L 2 Covalently bound to W 3 W 4 W 5 W 6 or W 7 One of them; or L 2 Yes -L 3 -DL 4 -, where L4 Covalently bound to W 3 W 4 W 5 W 6 or W 7 one of; L 3 Selected from C 1-8 Alkylene, C 2-8 alkenyl, 2- to 8-membered heteroalkyl, and 3- to 8-membered heteroalkyl, each of which is optionally divided by one or more R 11b replace; D is selected from C 3-10 Carbon rings and 3 to 10-membered heterocycles, each of which is optionally bounded by one or more R... 11d replace; L 4 Selected from C 1-8 Alkylene, C 2-8 alkenyl, 2- to 8-membered heteroalkyl, and 3- to 8-membered heteroalkyl, each of which is optionally divided by one or more R 11b replace; W 2 Selected from N(R) 2b ), N, C(R) 2 ), C(R 2 (R) 2a ) and C(O); W 3 Selected from N(R) 3b ), N, C(R) 3 ), C(R 3 (R) 3a ) and C(O); W 4 Selected from N(R) 4b ), N, C(R) 4 ), C(R 4 (R) 4a ) and C(O); W 5 Selected from N(R) 5b ), N, C(R) 5 ), C(R 5 (R) 5a ) and C(O); W 6 Selected from N(R) 6b ), N, C(R) 6 ), C(R 6 (R) 6a ) and C(O); W 7 Selected from N(R) 7b ), N, C(R) 7), C(R 7 (R) 7a ) and C(O); W 8 Selected from N(R) 8b ), N, C(R) 8 ), C(R 8 (R) 8a ) and C(O); W 9 Selected from N, C(R) 9 ) and C; W 10 Selected from N, C(R) 10 ) and C; R 2 R 2a R 3a R 4a R 5a R 6a R 7a R 8 and R 8a Each is independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13-S(=O)(=NH)N(R) 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 and -CH2S(O)2N(R 12 (R) 13 ), where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are independently and optionally separated by one, two, or three R... 20 replace; R 3 R 4 R 5 R 6 and R 7 Each independently selected from L 2 bonds, hydrogen, halogens, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R)13 -S(=O)(=NH)N(R) 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 and -CH2S(O)2N(R 12 (R) 13 ), where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are independently and optionally separated by one, two, or three R... 20 replace; R 2b and R 8b Each is independently selected from hydrogen, -CN, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -SR 12 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 -S(=O)(=NH)N(R) 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 and -CH2S(O)2N(R 12 (R) 13 ), where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3-10 The carbon ring and 3 to 10-membered heterocycles are independently and optionally separated by one, two, or three R... 20 replace; R 3b R 4b R 5b R 6b and R 7b Each independently selected from L 2 bonds, hydrogen, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -SR 12 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 -S(=O)(=NH)N(R) 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 and -CH2S(O)2N(R 12 (R) 13 ), where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are independently and optionally separated by one, two, or three R... 20 replace; R 9 and R 10 Each is independently selected from hydrogen and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon ring, -CH2-(C 3-10Carbon rings), 3- to 10-membered heterocycles and -CH2- (3- to 10-membered heterocycles), wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon ring, -CH2-(C 3-10 The carbon ring, 3- to 10-membered heterocycles, and -CH2- (3- to 10-membered heterocycles) are independently and optionally surrounded by one, two, or three R... 20 replace; R 11d Each time it appears, it is independently selected from halogen, -CN, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 -S(=O)(=NH)N(R) 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 -CH2S(O)2N(R) 12 (R) 13), -CH2N(R 12 )S(O)2(R 13 ) and -P(O)(R 17 (R) 17a ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 replace; R 11b Each time it appears, it is independently selected from halogen, oxo, -CN, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 -S(=O)(=NH)N(R) 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 -CH2S(O)2N(R) 12 (R)13 ), -CH2N(R 12 )S(O)2(R 13 ) and -P(O)(R 17 (R) 17a ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 replace; R 12 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 replace; R 13 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl; or R 12 and R 13 Together with the nitrogen atoms they are attached to, they form a structure optionally bounded by one, two, or three R atoms. 20 Replaced 3- to 10-membered heterocycles; R 14 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R 15 Each time it appears, it is independently selected from C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 replace; R 17 and R 17a Each time it appears, it is independently selected from C. 1-6 Alkyl and C 3-6 cycloalkyl, wherein C 1-6Alkyl and C 3-6 Cycloalkyl groups are optionally surrounded by one, two, or three R groups. 20 Replace; or R 17 and R 17a Together with the phosphorus atoms they are attached to, they form 3 to 10-membered heterocycles; R 20 Each time it appears, it is independently selected from halogen, oxo, =NH, -CN, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon ring, -CH2-(C 3-10 Carbon rings), 3- to 10-membered heterocycles, -CH2- (3- to 10-membered heterocycles), -OR 21 -SR 21 -N(R) 22 (R) 23 -C(O)OR 22 -C(O)N(R) 22 (R) 23 -C(O)C(O)N(R) 22 (R) 23 ), -OC(O)N(R 22 (R) 23 ), -N(R 24 )C(O)N(R 22 (R) 23 ), -N(R 24 )C(O)OR 25 -N(R) 24 )C(O)R 25 -N(R) 24 )S(O)2R 25 -C(O)R 25 -S(O)2R 25 -S(O)2N(R) 22 (R) 23 -OCH2C(O)OR 22 and -OC(O)R 25 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon ring, -CH2-(C 3-10 The carbocyclic ring (3 to 10-membered heterocycle) and -CH2- (3 to 10-membered heterocycle) are optionally substituted by one, two, or three independent groups selected from the following: halogen, oxo, =NH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6Halogenated alkoxy groups, -OR 21 -SR 21 -N(R) 22 (R) 23 -C(O)OR 22 -C(O)N(R) 22 (R) 23 -C(O)C(O)N(R) 22 (R) 23 ), -OC(O)N(R 22 (R) 23 ), -N(R 24 )C(O)N(R 22 (R) 23 ), -N(R 24 )C(O)OR 25 -N(R) 24 )C(O)R 25 -N(R) 24 )S(O)2R 25 -C(O)R 25 -S(O)2R 25 -S(O)2N(R) 22 (R) 23 ) and -OC(O)R 25 ; R 21 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 3-10 The carbide ring and the 3 to 10-membered heterocycle are optionally substituted by one, two, or three independent groups selected from the following: halogen and C. 1-6 alkyl; R 22 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 3-10 The carbide ring and the 3 to 10-membered heterocycle are optionally substituted by one, two, or three independent groups selected from the following: halogen and C. 1-6 alkyl; R 23 Each time it appears, it is independently selected from H and C. 1-6 alkyl; R 24 Each time it appears, it is independently selected from H and C.1-6 alkyl; R 25 Each time it appears, it is independently selected from C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 1-6 Alkyl, C 3-10 The carbide ring and the 3 to 10-membered heterocycle are optionally substituted by one, two, or three independent groups selected from the following: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-10 Carbon rings and 3 to 10-membered heterocycles; and This indicates a single or double bond, such that all valences are satisfied.

[0151] In some respects, this disclosure provides a compound of formula (II-B) or (II-C): (II-B) or (II-C), Or a pharmaceutically acceptable salt or solvate thereof, wherein: It does not exist or is optionally controlled by one or more R 11a Replaced 4- to 8-membered heterocycles; L 1 It is C 1-3 Halogenated alkylene; L 2 Selected from C 5-10 Alkylene, C 5-10 alkenyl, 5- to 10-membered heteroalkyl, and 5- to 10-membered heteroalkyl, each of which is optionally bound by one or more R 11b Replace; or L 2 Yes -L 3 -DL 4 -; L 3 Selected from C 1-8 Alkylene, C 2-8 alkenyl, 2- to 8-membered heteroalkyl, and 3- to 8-membered heteroalkyl, each of which is optionally divided by one or more R 11b replace; D is selected from C 3-10 Carbon rings and 3 to 10-membered heterocycles, each of which is optionally bounded by one or more R... 11d replace; L 4 Selected from C 1-8 Alkylene, C 2-8alkenyl, 2- to 8-membered heteroalkyl, and 3- to 8-membered heteroalkyl, each of which is optionally divided by one or more R 11b replace; R 3 and R 8 Each is independently selected from hydrogen and -CH3; R 7 Selected from C 3-8 Carbon rings and 3 to 8-membered heterocycles, each of which is optionally bounded by one, two, or three R... 20 replace; R 5b Selected from hydrogen and C 1-3 alkyl; R 50 Selected from hydrogen and halogens; R 11a and R 11d Each time it appears, it is independently selected from halogen, -CN, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 -S(=O)(=NH)N(R) 12 (R) 13 -CH2C(O)N(R) 12 (R)13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 -CH2S(O)2N(R) 12 (R) 13 ), -CH2N(R 12 )S(O)2(R 13 ) and -P(O)(R 17 (R) 17a ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 replace; R 11b Each time it appears, it is independently selected from halogen, oxo, -CN, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 -S(=O)(=NH)N(R) 12 (R) 13 -CH2C(O)N(R) 12(R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 -CH2S(O)2N(R) 12 (R) 13 ), -CH2N(R 12 )S(O)2(R 13 ) and -P(O)(R 17 (R) 17a ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 replace; R 12 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 replace; R 13 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl; or R 12 and R 13 Together with the nitrogen atoms they are attached to, they form a structure optionally bounded by one, two, or three R atoms. 20 Replaced 3- to 10-membered heterocycles; R 14 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R 15 Each time it appears, it is independently selected from C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs.20 replace; R 17 and R 17a Each time it appears, it is independently selected from C. 1-6 Alkyl and C 3-6 cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl groups are optionally surrounded by one, two, or three R groups. 20 Replace; or R 17 and R 17a Together with the phosphorus atoms they are attached to, they form 3 to 10-membered heterocycles; R 20 Each time it appears, it is independently selected from halogen, oxo, =NH, -CN, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon ring, -CH2-(C 3-10 Carbon rings), 3- to 10-membered heterocycles, -CH2- (3- to 10-membered heterocycles), -OR 21 -SR 21 -N(R) 22 (R) 23 -C(O)OR 22 -C(O)N(R) 22 (R) 23 -C(O)C(O)N(R) 22 (R) 23 ), -OC(O)N(R 22 (R) 23 ), -N(R 24 )C(O)N(R 22 (R) 23 ), -N(R 24 )C(O)OR 25 -N(R) 24 )C(O)R 25 -N(R) 24 )S(O)2R 25 -C(O)R 25 -S(O)2R 25 -S(O)2N(R) 22 (R) 23 -OCH2C(O)OR 22 and -OC(O)R 25 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon ring, -CH2-(C 3-10The carbocyclic ring (3 to 10-membered heterocycle) and -CH2- (3 to 10-membered heterocycle) are optionally substituted by one, two, or three independent groups selected from the following: halogen, oxo, =NH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -OR 21 -SR 21 -N(R) 22 (R) 23 -C(O)OR 22 -C(O)N(R) 22 (R) 23 -C(O)C(O)N(R) 22 (R) 23 ), -OC(O)N(R 22 (R) 23 ), -N(R 24 )C(O)N(R 22 (R) 23 ), -N(R 24 )C(O)OR 25 -N(R) 24 )C(O)R 25 -N(R) 24 )S(O)2R 25 -C(O)R 25 -S(O)2R 25 -S(O)2N(R) 22 (R) 23 ) and -OC(O)R 25 ; R 21 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 3-10 The carbide ring and the 3 to 10-membered heterocycle are optionally substituted by one, two, or three independent groups selected from the following: halogen and C. 1-6 alkyl; R 22 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 3-10The carbide ring and the 3 to 10-membered heterocycle are optionally substituted by one, two, or three independent groups selected from the following: halogen and C. 1-6 alkyl; R 23 Each time it appears, it is independently selected from hydrogen and C. 1-6 alkyl; R 24 Each time it appears, it is independently selected from hydrogen and C. 1-6 Alkyl; and R 25 Each time it appears, it is independently selected from C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 1-6 Alkyl, C 3-10 The carbide ring and the 3 to 10-membered heterocycle are optionally substituted by one, two, or three independent groups selected from the following: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-10 Carbon rings and 3 to 10-membered heterocycles.

[0152] In some embodiments, this disclosure provides a compound of formula (II-B) or (II-C): (II-B) or (II-C), Or a pharmaceutically acceptable salt or solvate thereof, wherein: It does not exist or is optionally controlled by one or more R 11a Replaced 4- to 8-membered heterocycles; L 1 It is C 1-3 Halogenated alkylene; L 2 Selected from C 5-10 Alkylene, C 5-10 alkenyl, 5- to 10-membered heteroalkyl, and 5- to 10-membered heteroalkyl, each of which is optionally bound by one or more R 11b replace; R 3 R 5b and R 8 Each is independently selected from hydrogen and -CH3; R 7 Selected from C 3-8 Carbon rings and 3 to 8-membered heterocycles, each of which is optionally bounded by one, two, or three R... 20 replace; R 50Selected from hydrogen and halogens; R 11a Each time it appears, it is independently selected from halogens, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; R 11b Each time it appears, it is independently selected from halogen, oxo, -CN, C. 1-3 Alkyl groups and -OH; and R 20 Each time it appears, it is independently selected from halogen, oxo, -CN, and C. 1-6 alkyl.

[0153] In some embodiments, this disclosure provides a compound of formula (II-C): (II-C), Or a pharmaceutically acceptable salt or solvate thereof, wherein: It does not exist or is optionally controlled by one or more R 11a Replaced 4- to 8-membered heterocycles; L 1 It is C 1-3 Halogenated alkylene; L 2 Selected from C 5-10 Alkylene, C 5-10 alkenyl, 5- to 10-membered heteroalkyl, and 5- to 10-membered heteroalkyl, each of which is optionally bound by one or more R 11b replace; R 3 It is hydrogen; R 8 Selected from hydrogen and -CH3; R 7 Selected from and ; R 50 Selected from hydrogen and halogens; R 11a Each time it appears, it is independently selected from halogens, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; R 11b Each time it appears, it is independently selected from halogen, oxo, -CN, C. 1-3 Alkyl groups and -OH; and R 20 Each time it appears, it is independently selected from halogen, oxo, -CN, and C. 1-6 alkyl.

[0154] In some embodiments, this disclosure provides a compound of formula (II-C): (II-C), Or a pharmaceutically acceptable salt or solvate thereof, wherein: It is optionally controlled by one or more R 11a Replaced 4- to 8-membered heterocycles; L 1 It is C 1-3 Halogenated alkylene; L 2 Selected from C 5-10 Alkylene, C 5-10 alkenyl, 5- to 10-membered heteroalkyl, and 5- to 10-membered heteroalkyl, each of which is optionally bound by one or more R 11b replace; R 3 Selected from hydrogen and -CH3; R 8 Selected from hydrogen and -CH3; R 7 Selected from , , , , and ; R 50 Selected from hydrogen and halogens; R 11a Each time it appears, it is independently selected from halogens, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; and R 11b Each time it appears, it is independently selected from halogen, oxo, -CN, C. 1-3 Alkyl groups and -OH.

[0155] In some embodiments, this disclosure provides a compound of formula (II-C): (II-C), Or a pharmaceutically acceptable salt or solvate thereof, wherein: It is a 4- to 6-membered heterocyclic ring; L 1 It is C 1-3 Halogenated alkylene; L 2 Selected from C 5-10 Alkylene, C 5-10 alkenyl and 5 to 10 heteroalkyl groups; R 3 Selected from hydrogen and -CH3; R 8 It is hydrogen; R 7 Selected from , , , , and ;and R 50 Selected from hydrogen and halogens.

[0156] In some embodiments, this disclosure provides a compound of formula (II-C): (II-C), Or a pharmaceutically acceptable salt or solvate thereof, wherein: yes ; L 1 It is -CF2CH2-; L 2 It is a 5- to 10-membered heteroalkylene group, wherein the heteroalkylene group contains one oxygen atom; R 3 Selected from hydrogen and -CH3; R 8 It is hydrogen; R 7 Selected from , , , , and ;and R 50 Selected from hydrogen and halogens.

[0157] In some embodiments, this disclosure provides a compound of formula (II-C): (II-C), Or a pharmaceutically acceptable salt or solvate thereof, wherein: yes ; L 1 It is -CF2-; L 2 Selected from C 5-10 alkenyl; R 3 Selected from hydrogen and -CH3; R 8 It is hydrogen; R 7 Selected from , , , , and ;and R 50 Selected from hydrogen and halogens.

[0158] In some embodiments, the compound of formula (II-B) is a compound of the following formula: , or In some implementations, R 5b It is -CH3; R 8 It is hydrogen; and R 50 Selected from hydrogen and fluorine. In some embodiments, R 5b It is -CH3; R 8 It is hydrogen; and R 50 It is hydrogen. In some implementations, R 5b It is -CH3; R 8 It is hydrogen; and R 50 It is fluorine. In some implementations, R 7 Selected from , and In some implementations, R 5b It is -CH3; R 8 It is hydrogen; R 50 It is hydrogen; and R 7 Selected from , and In some implementations, R 5b It is -CH3; R 8 It is hydrogen; R 50 It is fluorine; and R 7 Selected from , and In some implementations, R 5b It is -CH3; R 8 It is hydrogen; R 50 Selected from hydrogen and fluorine; and R 7 yes In some implementations, R 5b It is -CH3; R 8 It is hydrogen; R 50 Selected from hydrogen and fluorine; and R 7 yes In some implementations, R 5b It is -CH3; R 8 It is hydrogen; R 50 Selected from hydrogen and fluorine; and R 7 yes .

[0159] In some embodiments, the compound of formula (II-C) is a compound of the following formula: , or In some embodiments, the compound of formula (II-C) is a compound of the following formula: , or In some implementations, R 3 Selected from hydrogen and -CH3; R 8 It is hydrogen; and R 50 Selected from hydrogen and fluorine. In some embodiments, R 3 Selected from hydrogen and -CH3; R 8 It is hydrogen; and R 50 It is hydrogen. In some implementations, R 3 Selected from hydrogen and -CH3; R 8 It is hydrogen; and R 50 It is fluorine. In some implementations, R 3 It is hydrogen; R 8 It is hydrogen; and R 50 It is hydrogen. In some implementations, R 3 It is hydrogen; R 8 It is hydrogen; and R 50 It is fluorine. In some implementations, R 3 It is -CH3; R 8 It is hydrogen; and R 50 It is hydrogen. In some implementations, R 3 It is -CH3; R 8 It is hydrogen; and R 50 It is fluorine. In some implementations, R 7 Selected from , and In some implementations, R 3 Selected from hydrogen and -CH3; R 8 It is hydrogen; R 50 It is hydrogen; and R 7 Selected from , and In some implementations, R 3 Selected from hydrogen and -CH3; R 8 It is hydrogen; R 50 It is fluorine; and R 7 Selected from , and In some implementations, R 3 It is hydrogen; R 8 It is hydrogen; R50 Selected from hydrogen and fluorine; and R 7 Selected from and In some implementations, R 3 It is hydrogen; R 8 It is hydrogen; R 50 It is hydrogen; and R 7 Selected from , and In some implementations, R 3 It is hydrogen; R 8 It is hydrogen; R 50 It is fluorine; and R 7 Selected from , and In some implementations, R 3 It is -CH3; R 8 It is hydrogen; R 50 It is hydrogen; and R 7 Selected from , and In some implementations, R 3 It is -CH3; R 8 It is hydrogen; R 50 It is fluorine; and R 7 Selected from , and In some implementations, R 3 Selected from hydrogen and -CH3; R 8 It is hydrogen; R 50 Selected from hydrogen and fluorine; and R 7 yes In some implementations, R 3 Selected from hydrogen and -CH3; R 8 It is hydrogen; R 50 Selected from hydrogen and fluorine; and R 7 yes In some implementations, R 3 Selected from hydrogen and -CH3; R 8 It is hydrogen; R 50 Selected from hydrogen and fluorine; and R 7 yes .

[0160] The embodiments disclosed herein relating to compounds of formulas (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), and / or (I-E1) are also intended to be applicable to compounds of formulas (I-1), (II-B), (II-C), and (III), unless the context of the embodiment explicitly specifies otherwise (e.g., the embodiment refers only to variables not present in compounds of formulas (I-1), (II-B), (II-C), or (III), such as R). 1 ).

[0161] In some embodiments, the compound of formula (I) is a compound of the following formula: , , , , , , , , , , , , or Or its salts or solvates.

[0162] In some respects, this disclosure provides a compound of formula (I-1): (I-1), Or a pharmaceutically acceptable salt or solvate thereof, wherein: Selected from C 5-7 Carbon rings and 5- to 7-membered heterocycles, each of which is optionally bounded by one or more R 11 replace; Does not exist or selected from C 3-8 Carbon rings and 3 to 8-membered heterocycles, each of which is optionally bounded by one or more R 11a replace; L 1 Selected from key, C 1-6 Alkylene and C 1-6 Halogenated alkylene; L 2 Selected from C 5-25 Alkylene, C 5-25 imidene group, C 5-25 5- to 25-membered heteroalkyl and 5- to 25-membered heteroenyl, each of which is optionally divided by one or more R 11b Replace, where L2 Covalently bound to W 3 W 4 W 5 W 6 or W 7 one of; W 3 Selected from N(R) 3b ), N, C(R) 3 ) and C(O); W 4 Selected from N(R) 4b ), N, C(R) 4 ) and C(O); W 5 Selected from N(R) 5b ), N and C(R) 5 ); W 6 Selected from C(R) 6 ) and C(O); W 7 It is C(R) 7 ); R 1 It is optionally controlled by one or more R 11c Replacement C 1-3 alkyl; R 8 Selected from hydrogen, halogens, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 -S(=O)(=NH)N(R) 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 and -CH2S(O)2N(R 12 (R) 13 ), where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are independently and optionally separated by one, two, or three R... 20 replace; R 3 R 4 R 5 R 6 and R 7 Each independently selected from L 2 bonds, hydrogen, halogens, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 -S(=O)(=NH)N(R) 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 and -CH2S(O)2N(R 12 (R) 13 ), where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are independently and optionally separated by one, two, or three R... 20 replace; R 3b R 4b and R 5b Each independently selected from L 2 bonds, hydrogen, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -SR 12 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 -S(=O)(=NH)N(R) 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15-CH2S(O)2R 15 and -CH2S(O)2N(R 12 (R) 13 ), where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are independently and optionally separated by one, two, or three R... 20 replace; R 11 and R 11a Each time it appears, it is independently selected from halogen, -CN, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 -S(=O)(=NH)N(R) 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 -CH2S(O)2N(R) 12 (R)13 ), -CH2N(R 12 )S(O)2(R 13 ) and -P(O)(R 17 (R) 17a ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 replace; R 11b Each time it appears, it is independently selected from halogen, oxo, -CN, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 -S(=O)(=NH)N(R) 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 -CH2S(O)2N(R) 12(R) 13 ), -CH2N(R 12 )S(O)2(R 13 ) and -P(O)(R 17 (R) 17a ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 replace; R 11c Each time it appears, it is independently selected from halogen, -OR 12 and -N(R) 12 (R) 13 ); R 12 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 replace; R 13 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl; or R 12 and R 13 Together with the nitrogen atoms they are attached to, they form a structure optionally bounded by one, two, or three R atoms. 20 Replaced 3- to 10-membered heterocycles; R 14 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R 15 Each time it appears, it is independently selected from C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 replace; R 17 and R 17a Each time it appears, it is independently selected from C. 1-6 Alkyl and C 3-6 cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl groups are optionally surrounded by one, two, or three R groups. 20 Replace; or R 17 and R 17a Together with the phosphorus atoms they are attached to, they form 3 to 10-membered heterocycles; R 20 Each time it appears, it is independently selected from halogen, oxo, =NH, -CN, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon ring, -CH2-(C 3-10 Carbon rings), 3- to 10-membered heterocycles, -CH2- (3- to 10-membered heterocycles), -OR 21 -SR 21 -N(R) 22 (R) 23 -C(O)OR 22 -C(O)N(R) 22 (R) 23 -C(O)C(O)N(R) 22 (R) 23 ), -OC(O)N(R 22 (R) 23 ), -N(R 24 )C(O)N(R 22 (R) 23 ), -N(R 24 )C(O)OR 25 -N(R) 24 )C(O)R 25 -N(R) 24 )S(O)2R 25 -C(O)R 25 -S(O)2R 25 -S(O)2N(R) 22 (R) 23 -OCH2C(O)OR 22 and -OC(O)R 25 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon ring, -CH2-(C 3-10The carbocyclic ring (3 to 10-membered heterocycle) and -CH2- (3 to 10-membered heterocycle) are optionally substituted by one, two, or three independent groups selected from the following: halogen, oxo, =NH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -OR 21 -SR 21 -N(R) 22 (R) 23 -C(O)OR 22 -C(O)N(R) 22 (R) 23 -C(O)C(O)N(R) 22 (R) 23 ), -OC(O)N(R 22 (R) 23 ), -N(R 24 )C(O)N(R 22 (R) 23 ), -N(R 24 )C(O)OR 25 -N(R) 24 )C(O)R 25 -N(R) 24 )S(O)2R 25 -C(O)R 25 -S(O)2R 25 -S(O)2N(R) 22 (R) 23 ) and -OC(O)R 25 ; R 21 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 3-10 The carbide ring and the 3 to 10-membered heterocycle are optionally substituted by one, two, or three independent groups selected from the following: halogen and C. 1-6 alkyl; R 22 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 3-10The carbide ring and the 3 to 10-membered heterocycle are optionally substituted by one, two, or three independent groups selected from the following: halogen and C. 1-6 alkyl; R 23 Each time it appears, it is independently selected from H and C. 1-6 alkyl; R 24 Each time it appears, it is independently selected from H and C. 1-6 alkyl; R 25 Each time it appears, it is independently selected from C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 1-6 Alkyl, C 3-10 The carbide ring and the 3 to 10-membered heterocycle are optionally substituted by one, two, or three independent groups selected from the following: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-10 Carbon rings and 3 to 10-membered heterocycles; and This indicates a single or double bond, such that all valences are satisfied.

[0163] In some embodiments, the compound of formula (I-1) is a compound of formula (I-B1) or (I-B2): (I-B1) or (I-B2), Or its pharmaceutically acceptable salts or solvates.

[0164] In some embodiments, the compound of formula (I-1) is a compound of formula (I-C1), (I-C2), or (I-C3): (I-C1) (I-C2) or (I-C3), Or its pharmaceutically acceptable salts or solvates.

[0165] In some embodiments, for compounds of formula (I-1), (I-B1), (I-B2), (I-C1), (I-C2), or (I-C3), R 1 -CH3. In some embodiments, for compounds of formula (I-1), (I-C1), or (I-C3), R 3 Selected from hydrogen, -CN, -OR 12and -CH3. In some embodiments, for compounds of formula (I-1), (I-B2), or (I-C3), R 6 Selected from hydrogen, -OR 12 and optionally by one, two or three R 20 Replacement C 1-6 Alkyl, and wherein R 12 Selected from C 1-6 Alkyl group. In some embodiments, for compounds of formula (I-1), (I-B1), (I-B2), (I-C1), (I-C2), or (I-C3), R 8 It is hydrogen.

[0166] In some embodiments, for compounds of formula (I-1), (I-B1), (I-B2), (I-C1), (I-C2), or (I-C3), R 7 Selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl and -N(R) 12 (R) 13 ), where C 1-6 Alkyl, C 3-10 Cycloalkyl and 3 to 10-membered heterocyclic alkyl groups are optionally surrounded by one, two or three R 20 Replacement. In some implementations, R 7 Selected from , , , , , , , , , , , , , , , , , , , , , , , , and In some implementations, R 7 Selected from , and .

[0167] In some embodiments, for compounds of formula (I-1), (I-B1), (I-B2), (I-C1), (I-C2), or (I-C3), Selected from phenyl and 5 to 7-membered heteroaryl groups, each of which is optionally separated by one or more R 11 Replacement. In some implementations, Selected from , , , and In some implementations, R 11 It is independently selected from fluorine and -CH3.

[0168] In some embodiments, for compounds of formula (I-1), (I-B1), (I-B2), (I-C1), (I-C2), or (I-C3), L 1 C 1-3 Alkyl halide. In some embodiments, L 1 Selected from -CF2-, -CF2CH2- and -CF2CH2CH2-.

[0169] In some embodiments, for compounds of formula (I-1), (I-B1), (I-B2), (I-C1), (I-C2), or (I-C3), Selected from non-existent, phenyl, and 4 to 8-membered heterocycles, wherein the phenyl and 4 to 8-membered heterocycles are optionally separated by one or more R 11a Replacement. In some implementations, Selected from aziridine, pyrrolidine, and piperidine, each of which is optionally substituted with one or more -CH3 groups.

[0170] In some embodiments, for compounds of formula (I-1), (I-B1), (I-B2), (I-C1), (I-C2), or (I-C3), L 2 Selected from C 6-15 Alkylene, C 6-15 imidene group, C 6-15 Alynyl, 6- to 15-membered heteroalkyl, and 6- to 15-membered heteroenyl, each of which is optionally bound by one or more R 11b Replacement. In some implementations, L 2 Selected from C 5-10 Alkylene, C 5-10 alkenyl, 5- to 10-membered heteroalkyl, and 5- to 10-membered heteroalkyl, each of which is optionally bound by one or more R 11bSubstitution. In some embodiments, the alkenyl and heteroalkenyl groups contain a carbon-carbon double bond. In some embodiments, the heteroalkyl and heteroalkenyl groups contain at least one oxygen or nitrogen atom.

[0171] In some embodiments, for compounds of formula (I-1), (I-B1), or (I-B2), R 5 It is hydrogen; R 5b -CH3; R 6 Selected from hydrogen and -OCH3; R 7 Selected from C 1-6 Alkyl, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -N(R) 12 (R) 13 -C(O)R 15 -C(O)N(R) 12 (R) 13 -S(O)2R 15 and -SO2N(R 12 (R) 13 ), where C 1-6 Alkyl, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 Replace; and R 8 It is hydrogen.

[0172] In some embodiments, for compounds of formula (I-1), (I-C1), (I-C2), or (I-C3), R 3 It is hydrogen or -CH3; R 3b -CH3; R 6 Selected from hydrogen and -OCH3; R 7 Selected from C 1-6 Alkyl, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -N(R) 12 (R) 13 -C(O)R 15 -C(O)N(R) 12 (R) 13 -S(O)2R 15 and -SO2N(R 12 (R) 13 ), where C 1-6 Alkyl, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 Replace; and R 8 It is hydrogen.

[0173] In some respects, this disclosure provides a compound of formula (A): (A), Or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 It is a 3-12-membered cycloalkyl ring, a 3-12-membered heterocycloalkyl ring, a 6-10-membered aromatic ring, or a 5-10-membered heteroaromatic ring, wherein the 3-12-membered cycloalkyl ring, the 3-12-membered heterocycloalkyl ring, the 6-10-membered aromatic ring, and the 5-10-membered heteroaromatic ring are optionally separated by one or more R 10 replace; L 1 Is it a key or C? 1-6 alkyl; R 2 Yes - OR 2a -NR 2b R 2c -SR 2g -S(O)R 2h -S(O)2R 2h -S(O)2NR 2b R 2c -C(R) 2d (R) 2e (R) 2f ), C(O)NR 2b R 2c -CN or halogen; R 2a Selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 heteroaryl, -C(O)OR 12 -C(O)R 15 -C(O)N(R) 12 (R) 13 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two or three R 20a replace; R 2b Selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 heteroaryl, -C(O)OR 12 -C(O)R 15 -C(O)N(R) 12 (R) 13 -S(O)2R 15 and -S(O)2N(R 12 (R) 13 ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two or three R 20a replace; R 2c Selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three R groups. 20a Replace; or R 2b and R 2c Together with the nitrogen atoms they are attached to, they form a mixture optionally bounded by one, two, or three R atoms. 20a Replacement C 2-9 Heterocyclic alkyl rings; R 2d Selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 -S(=O)(=NH)N(R) 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 -CH2S(O)2N(R) 12 (R) 13 ), -CH2N(R 12 )S(O)2(R 13 ) and -P(O)(R 17 (R) 17a ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two or three R 20a replace; R 2e Selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two or three R 20a replace; R 2f Selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two or three R 20a replace; R 2g Selected from hydrogen, C 2-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 heteroaryl, -C(O)OR 12 -C(O)R 15 -C(O)N(R) 12 (R) 13 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 ), where C 2-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two or three R 20a replace; R 2h Selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two or three R 20a replace; R 3 Selected from halogens, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 heteroaryl, -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15 、N(R 14 )S(O)R 15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13a -C(O)C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 ), -S(O)N(R 12 (R) 13 -S(=O)(=NH)N(R) 12 (R) 13 -CH2C(O)N(R)12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 -CH2S(O)2N(R) 12 (R) 13 ), -CH2N(R 12 )S(O)2(R 13 CH2S(O)R 15 -CH2S(O)N(R) 12 (R) 13 ), -CH2N(R 12 )S(O)(R 13 ) and -P(O)(R 17 (R) 17a ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two or three R 20b replace; R 4 Selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R 5 Selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R 6 Selected from hydrogen, halogens, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15-C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 -S(=O)(=NH)N(R) 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 -CH2S(O)2N(R) 12 (R) 13 ), -CH2N(R 12 )S(O)2(R 13 ) and -P(O)(R 17 (R) 17a ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl and C 2-9 Heterocyclic alkyl groups are optionally surrounded by one, two, or three R groups. 20c replace; R 7 Selected from hydrogen, halogens, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 1-9 Mixed aromatics, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15-N(R) 14 )S(O)2R 15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 -S(=O)(=NH)N(R) 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 -CH2S(O)2N(R) 12 (R) 13 ), -CH2N(R 12 )S(O)2(R 13 ) and -P(O)(R 17 (R) 17a ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl and C 1-9 The heteroaryl group is optionally surrounded by one, two or three R 20c replace; Each R 10 Independently selected from halogens, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14)C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 -S(=O)(=NH)N(R) 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 -CH2S(O)2N(R) 12 (R) 13 ), -CH2N(R 12 )S(O)2(R 13 ) and -P(O)(R 17 (R) 17a ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two or three R 20d replace; Each R 12 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C2-6 alkynyl group, C 3-7 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two or three R 20e replace; Each R 13 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl; or R 12 and R 13 Together with the nitrogen atoms they are attached to, they form a mixture optionally bounded by one, two, or three R atoms. 20f Replacement C 2-9 Heterocyclic alkyl rings; R 13a Selected from C 1-6 Alkyl and C 1-6 Halogenated alkyl; or R 12 and R 13a Together with the nitrogen atoms they are attached to, they form a mixture optionally bounded by one, two, or three R atoms. 20f Replacement C 2-9 Heterocyclic alkyl rings; Each R 14 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 15 Selected independently from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two or three R 20g replace; Each R 17 and each R 17a Each was independently selected from C 1-6 Alkyl and C 3-6 cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl groups are optionally surrounded by one, two, or three R groups. 20h Replace; or R 17 and R 17aCombining to form C 2-9 Heterocyclic alkyl rings; Each R 20a R 20b R 20c R 20d R 20e R 20f R 20g and R 20h Each is independently selected from halogen, oxo, =NH, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, -CH2-C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, -CH2-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 21 -SR 21 -N(R) 22 (R) 23 -C(O)OR 22 -C(O)N(R) 22 (R) 23 -C(O)C(O)N(R) 22 (R) 23 ), -OC(O)N(R 22 (R) 23 ), -N(R 24 )C(O)N(R 22 (R) 23 ), -N(R 24 )C(O)OR 25 -N(R) 24 )C(O)R 25 -N(R) 24 )S(O)2R 25 -C(O)R 25 -S(O)2R 25 -S(O)2N(R) 22 (R) 23 -OCH2C(O)OR 22 and -OC(O)R 25 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, -CH2-C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, -CH2-C2-9 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl and C 1-9 The heteroaryl group may optionally be substituted by one, two, or three independently selected groups from the following: halogen, oxo, =NH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -OR 21 -SR 21 -N(R) 22 (R) 23 -C(O)OR 22 -C(O)N(R) 22 (R) 23 -C(O)C(O)N(R) 22 (R) 23 ), -OC(O)N(R 22 (R) 23 ), -N(R 24 )C(O)N(R 22 (R) 23 ), -N(R 24 )C(O)OR 25 -N(R) 24 )C(O)R 25 -N(R) 24 )S(O)2R 25 -C(O)R 25 -S(O)2R 25 -S(O)2N(R) 22 (R) 23 ) and -OC(O)R 25 ; Each R 21 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 3-7 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally substituted by one, two, or three independently selected groups from the following: halogen and C. 1-6 alkyl; Each R 22 Independently selected from H and C1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 3-7 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally substituted by one, two, or three independently selected groups from the following: halogen and C. 1-6 alkyl; Each R 23 Independently selected from H and C 1-6 alkyl; Each R 24 Independently selected from H and C 1-6 Alkyl; and Each R 25 Selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 3-7 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally substituted by one, two, or three independently selected groups from the following: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-7 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Mixed aromatic compounds.

[0174] In some respects, this disclosure provides a compound of formula (A-1): (A-1), Or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 It is optionally controlled by one or more R 10 Replaced 6-10 aryl rings; L 1 It is a key; R 2 Yes - OR2a Or halogen; R 2a Selected from C 1-6 Alkyl, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 heteroaryl, of which C 1-6 Alkyl, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two or three R 20a replace; R 3 Selected from halogens, C 1-6 Alkyl, C 3-14 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 3-14 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two or three R 20b replace; R 4 Selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R 5 Selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R 6 Selected from hydrogen, halogens, -CN and C 1-6 Alkyl, wherein C 1-6 Alkyl groups are optionally surrounded by one, two, or three R groups. 20c replace; Each R 10 Independently selected from halogens, -CN, C 1-6 Alkyl, C 3-7 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 heteroaryl, of which C 1-6 Alkyl, C 3-7 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two or three R 20d replace; Each R20a R 20b R 20c and R 20d Each is independently selected from halogens, oxometalates, =NH, -CN, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, -CH2-C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, -CH2-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 21 -SR 21 -N(R) 22 (R) 23 -C(O)OR 22 -C(O)N(R) 22 (R) 23 -C(O)C(O)N(R) 22 (R) 23 ), -OC(O)N(R 22 (R) 23 ), -N(R 24 )C(O)N(R 22 (R) 23 ), -N(R 24 )C(O)OR 25 -N(R) 24 )C(O)R 25 -N(R) 24 )S(O)2R 25 -C(O)R 25 -S(O)2R 25 -S(O)2N(R) 22 (R) 23 -OCH2C(O)OR 22 and -OC(O)R 25 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, -CH2-C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, -CH2-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl and C 1-9The heteroaryl group may optionally be substituted by one, two, or three independently selected groups from the following: halogen, oxo, =NH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, OR 21 -SR 21 -N(R) 22 (R) 23 -C(O)OR 22 -C(O)N(R) 22 (R) 23 -C(O)C(O)N(R) 22 (R) 23 ), -OC(O)N(R 22 (R) 23 ), -N(R 24 )C(O)N(R 22 (R) 23 ), -N(R 24 )C(O)OR 25 -N(R) 24 )C(O)R 25 -N(R) 24 )S(O)2R 25 -C(O)R 25 -S(O)2R 25 -S(O)2N(R) 22 (R) 23 ) and -OC(O)R 25 ; Each R 21 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 3-7 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally substituted by one, two, or three independently selected groups from the following: halogen and C. 1-6 alkyl; Each R 22 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3-7 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 3-7 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally substituted by one, two, or three independently selected groups from the following: halogen and C. 1-6 alkyl; Each R 23 Independently selected from H and C 1-6 alkyl; Each R 24 Independently selected from H and C 1-6 Alkyl; and Each R 25 Selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 3-7 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally substituted by one, two, or three independently selected groups from the following: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-7 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Mixed aromatic compounds.

[0175] In some embodiments, the compound of formula (A-1) is a compound of formula (Aa-1): (Aa-1), or a pharmaceutically acceptable salt or solvate thereof.

[0176] In some embodiments, for compounds of formula (A), (A-1), or (Aa-1), R 2a To be optionally controlled by one, two or three R 20a Replacement C 1-6 Alkyl group. In some embodiments, R 2a For unreplaced C 1-6 Alkyl group. In some embodiments, R 2a It is -CH3.

[0177] In some embodiments, for compounds of formula (A), (A-1), or (Aa-1), R 3 To be optionally controlled by one, two or three R 20b Replacement C 2-9 Heterocyclic alkyl groups. In some embodiments, R 3 To be optionally controlled by one, two or three R 20b Replacement C 3-10 Cycloalkyl. In some embodiments, R 3 To be arbitrarily used by an R 20b Replacement C 3-4 Cycloalkyl. In some embodiments, R 20b It is -CN or halogen. In some implementations, R 3 for or .

[0178] In some embodiments, for compounds of formula (A), (A-1), or (Aa-1), R 6 Selected from hydrogen, halogens and unsubstituted C 1-6 Alkyl group. In some embodiments, R 6 It is hydrogen. In some implementations, R 5 C 1-6 Alkyl group. In some embodiments, R 5 For -CH3. In some implementations, R 4 It is hydrogen.

[0179] In some embodiments, for compounds of formula (A), (A-1), or (Aa-1), R 1 For one or more R 10 Substituted phenyl groups. In some embodiments, R 10 Independently selected from halogens and C 1-6 Alkyl, wherein C 1-6 Alkyl groups are optionally surrounded by one, two, or three R groups. 20d Replacement. In some implementations, each R 10 Independently selected from halogens and C 1-6 Alkyl, wherein C 1-6 Alkyl groups are formed by one, two, or three R groups. 20d Replace, and each R 20d It is a halogen or -OH. In some embodiments, R 1 Selected independently and In some implementations, R 20d C is optionally substituted with one, two, or three groups independently selected from F and -OH. 1-6Alkyl group. In some embodiments, R 20d C replaced by a -OH group 1-3 Alkyl group. In some embodiments, R 1 Selected from , , , , and .

[0180] Small molecule SOS1 inhibitors applicable to the subject method (including those synergistically inhibiting the growth of Ph+ cells (such as CML cell lines) in combination with tyrosine kinase inhibitors (TKIs) targeting BCR-ABL tyrosine kinases) include compounds of formula (I); formula (IA); formula (IB); formula (I-1), including compounds A and B; formula (I-B1); formula (I-B2); formula (IC); formula (I-C1); formula (I-C2); formula (I-C3); formula (ID); formula (I-D1); formula (I-D2); formula (IE); formula (I-E1); formula (II-B); formula (II-C); formula (III); formula (A); formula (A-1); and formula (Aa-1). Exemplary small molecule SOS1 inhibitors include, but are not limited to, compounds selected from Table 1 (including compounds A and B), Table 2, or their salts or solvates.

[0181] In some embodiments, the compounds disclosed herein, such as those of formulas (I), (IA), (IB), (I-1), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), (I-E1), (II-B), (II-C), (III), (A), (A-1), or (Aa-1), are provided in substantially pure stereoisomer form. In some embodiments, the stereoisomer is provided in an enantiomeric excess of at least 80%, such as at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.9%.

[0182] In some embodiments, the compounds described herein are present in the form of their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts as a pharmaceutical composition.

[0183] In some embodiments, the compounds described herein have acidic or basic groups and thus react with any of a number of inorganic or organic bases or inorganic or organic acids to form pharmaceutically acceptable salts. In some embodiments, such salts are prepared in situ during the final isolation and purification of the compounds described herein, or by reacting the purified compound in its free form with a suitable acid or base and isolating the resulting salt.

[0184] In some embodiments, the compounds described herein are present in the form of solvates. In some embodiments, methods of treating a disease are performed by applying such solvates. Methods of treating a disease by applying such solvates as pharmaceutical compositions are also described herein.

[0185] The solvates contain stoichiometric or non-stoichiometric amounts of solvent and, in some embodiments, are formed during a crystallization process using pharmaceutically acceptable solvents such as water, ethanol, etc. When the solvent is water, a hydrate is formed, or when the solvent is an alcohol, an alcohol is formed. The solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. By way of example only, the hydrates of the compounds described herein are conveniently prepared by recrystallization from an aqueous solvent / organic solvent mixture using an organic solvent, including but not limited to dioxane, tetrahydrofuran, or MeOH. Furthermore, the compounds provided herein exist in both unsolvated and solvated forms. Generally, for the purposes of the compounds and methods provided herein, the solvated form is considered equivalent to the unsolvated form.

[0186] The chemical entities described herein can be synthesized according to one or more illustrative schemes herein and / or techniques known in the art. The materials used herein are commercially available or prepared by synthetic methods generally known in the art. These schemes are not limited to the compounds listed in the examples or any particular substituents used for illustrative purposes. Although various steps are described and depicted in Schemes 1-16, in some cases these steps may be performed in a different order than that shown in Schemes 1-16. Various modifications can be made to these synthetic reaction schemes, and various modifications to these synthetic reaction schemes will occur to those skilled in the art upon reference to this disclosure. Unless otherwise stated, the numbers or R groups in each scheme generally have the same meaning as defined elsewhere herein.

[0187] Unless otherwise stated, the reactions described herein are carried out at atmospheric pressure, generally in a temperature range of -10°C to 200°C. Furthermore, unless otherwise stated, reaction times and conditions are intended to be approximate, for example, carried out in a temperature range of about -10°C to about 110°C, over a period of about 1 to about 24 hours, at approximately atmospheric pressure; reactions left to run overnight last an average of about 16 hours.

[0188] Generally, the compounds disclosed herein can be prepared by the following reaction scheme: Option 1

[0189] In some embodiments, compounds of formula 1e can be prepared according to scheme 1. For example, heteroarylamine 1b can be formed from chloride 1a via a nucleophilic aromatic substitution reaction. Substitution of the lactam can be carried out under basic conditions to give diene 1c, which can undergo a cross-metathesis reaction (such as the Grubbs cross-metathesis reaction) to form macrocycle 1d. Optionally, 1d can undergo one or more subsequent reactions (such as hydrogenation) to provide compounds of formula 1e.

[0190] Option 2

[0191] Similarly, in some embodiments, compounds of formula 2e can be prepared according to scheme 2. For example, heteroarylamine 2b can be formed from chloride 2a via a nucleophilic aromatic substitution reaction. Substitution of the lactam can be carried out under basic conditions to give diene 2c, which can undergo a cross-metathesis reaction (such as the Grubbs cross-metathesis reaction) to form macrocycle 2d. Optionally, 2d can undergo one or more subsequent reactions (such as hydrogenation) to provide compounds of formula 2e.

[0192] Option 3

[0193] In some embodiments, compounds of formula 3e can be prepared according to scheme 3. For example, heteroarylamine 3b can be formed from chloride 3a via a substitution reaction. Substitution of a lactam can yield a protected amine 3c. Hydrolysis of an ester can form a carboxylic acid 3d, which can undergo deprotection and peptide coupling reactions to yield a macrocyclic compound of formula 3e.

[0194] Option 4

[0195] Similarly, in some embodiments, compounds of formula 4e can be prepared according to scheme 4. For example, heteroarylamine 4b can be formed from chloride 4a via a substitution reaction. Substitution of a lactam can yield a protected amine 4c. Hydrolysis of an ester can form a carboxylic acid 4d, which can undergo deprotection and peptide coupling reactions to yield a macrocyclic compound of formula 4e.

[0196] Option 5

[0197] In some embodiments, compounds of formula 5g can be prepared according to scheme 5. For example, heteroarylamine 3c can be formed by coupling chloride 5a with amine 5b. Oxidation of the alcohol can yield aldehyde 5d, which is then substituted with phenol to yield 5e. Removal of the amine protecting group yields 5f, which can undergo reductive amination to form a macrocyclic compound of formula 5g.

[0198] Option 6

[0199] In some embodiments, compounds of formula 6f can be prepared according to scheme 6. For example, heteroarylamine 6c can be formed by coupling chloride 1a with amine 6b. After phenol is substituted into alkene 6d, a second alkene can be attached to give diene 6e. The resulting double bond can be hydrogenated after a cross-metathesis reaction (such as the Grubbs cross-metathesis reaction) to provide a macrocyclic compound of formula 6f.

[0200] Option 7

[0201] In some embodiments, compounds of formula 7e can be prepared according to scheme 7. For example, heteroarylamine 7b can be formed by coupling chloride 7a with amine 5b. Substitution of phenol can yield 7c. Ester hydrolysis and deprotection of amine can yield 7d, which can be cyclized via peptide coupling to form macrocyclic compounds of formula 7e.

[0202] Option 8

[0203] In some embodiments, compounds of formula 8g can be prepared according to scheme 8. For example, substituting lactam 8a with a suitable bromide dioxolane (8b) yields acetal 8c. Nucleophilic aromatic substitution of amine 8d provides heteroarylamine 8e, which can be treated with a suitable acid such as HCl to remove the Boc protecting group and reveal an aldehyde. Finally, cyclization of 8f can be carried out via reductive amination conditions to yield macrocyclic compounds of formula 8g.

[0204] Option 9

[0205] Option 10

[0206] Option 11

[0207] Option 12

[0208] Option 13

[0209] Option 14

[0210] Option 15

[0211] Option 16

[0212] Synthetic procedures for certain compounds can be found in PCT / US2022 / 018584, U.S. Patent No. 11,648,254, PCT / US2023 / 065963, and U.S. Application No. 18 / 328,109, all of which are incorporated herein by reference in their entirety, including any compounds, formulas, descriptions of compound variables, and synthetic methods disclosed therein. In some embodiments, the SOS1 inhibitors of this disclosure are compounds described in U.S. Patent No. 11,648,254, which is incorporated herein by reference in its entirety. In some embodiments, the SOS1 inhibitors of this disclosure are compounds described in U.S. Patent No. 11,912,708, which is incorporated herein by reference in its entirety.

[0213] In some embodiments, the compounds of this disclosure, such as those of the formulas given in Table 1 or Table 2, are synthesized according to one of the general routes outlined in Schemes 1-16 or by methods generally known in the art. In some embodiments, exemplary compounds may include, but are not limited to, compounds selected from Tables 1 and 2, or their salts or solvates.

[0214] Table 1

[0215]

[0216]

[0217]

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246] Table 2

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295] In some embodiments, the compounds of this disclosure exhibit one or more functional properties described herein. For example, the subject compounds are capable of reducing Ras signaling output. In some cases, the subject compounds are capable of disrupting Ras-SOS interactions, including disrupting the interaction or binding between mutant Kras (e.g., Kras G12C) and SOS1 or between wild-type Kras and SOS1, thereby reducing Ras signaling output. In some embodiments, the subject compounds specifically bind to SOS proteins, including SOS1. In some embodiments, the subject compounds (including those shown in Table 1) have IC50 values ​​for SOS proteins of less than about 5 μM, less than about 1 μM, less than about 50 nM, less than about 10 nM, less than about 1 nM, less than about 0.5 nM, less than about 100 pM, or less than about 50 pM, as measured in in vitro assays known in the art or exemplified herein.

[0296] A reduction in Ras signaling output can be demonstrated by one or more of the following: (i) increased homeostatic levels of GDP-bound Ras proteins; (ii) decreased homeostatic levels of GTP-bound Ras proteins; (iii) reduced phosphorylated AKTs473; (iv) reduced phosphorylated ERKT202 / y204; (v) reduced phosphorylated S6S235 / 236; (vi) reduced (e.g., inhibited) Ras-driven tumor cell growth (e.g., tumor cells derived from the tumor cell lines disclosed herein); and (vii) interference with or disruption of the interaction or binding between SOS proteins (e.g., SOS1) and Ras proteins (e.g., wild-type or mutant Ras). In some cases, a reduction in Ras signaling output can be demonstrated by two, three, four, five, six, or all of the above (i)-(vii).

[0297] It should be understood that different aspects of the invention can be understood individually, jointly, or in combination with each other. The various aspects of the invention described herein can be applied to any particular application disclosed herein. Compositions of substances comprising compounds of any chemical formula disclosed in the compound portion of this disclosure can be used in the method portion, including the methods of use and production disclosed herein, and vice versa.

[0298] method The SOS1 inhibitors and pharmaceutical compositions disclosed herein are particularly suitable for the treatment of Philadelphia chromosome-positive (Ph+) diseases and related symptoms. Philadelphia chromosome abnormalities caused by t(9;22)(q34;qll) reciprocal translocations have led to fusions associated with several cancers. BCR-ABLGenes. These include blood cancers (including leukemia and lymphoma) and secondary cancers in other body tissues and organs resulting from metastasis of primary Ph+ cancers. Chronic myeloid leukemia (CML) is the most common Ph+ disease, followed by Ph+ acute lymphoblastic leukemia (Ph+ ALL) and Ph+ lymphoblastic lymphoma (Ph+ LBL). The compositions and methods disclosed herein open a new avenue for remission or treatment-free response (TFR) of (Ph+) blood cancers, including CML.

[0299] In one aspect, this disclosure provides a method for treating one or more of these Philadelphia chromosome-positive (Ph+) blood cancers or for improving symptoms in a subject in need. The method may include administering to the subject a pharmaceutical composition comprising an effective amount of a small molecule SOS1 inhibitor, wherein the subject has been treated with a tyrosine kinase inhibitor (TKI) targeting BCR-ABL tyrosine kinase prior to the administration of the SOS1 inhibitor.

[0300] In another aspect, methods for treating Philadelphia chromosome-positive (Ph+) leukemia in subjects of need include administering a pharmaceutical composition containing an effective amount of a small molecule SOS1 inhibitor, wherein the subject is identified as having a BCR-ABL genetic aberration.

[0301] In some embodiments, the subject of the treatment method has been previously treated with one or more TKIs. In some embodiments, the subject of the treatment method disclosed herein has been treated with one or more known TKIs, including first-generation TKIs (e.g., imatinib), second-generation TKIs (e.g., dasatinib), and / or third-generation TKIs (e.g., aciminib or ponatinib). Available TKIs can bind to the ATP-binding site in BCR-ABL tyrosine kinase and reduce its enzyme activity and / or expression level. In some embodiments, exemplary TKIs exhibit IC50 values ​​of less than 1 μM, 0.5 μM, 100 nM, 10 nM, 1 nM, 100 pM, or even lower against BCR-ABL. Non-limiting examples of TKIs include imatinib, dasatinib, nilotinib, bosutinib, raldotinib, flumatinib, ponatinib, olaribatinib, and aciminib. In some embodiments, this disclosure provides a method for treating blood cancers in patients who are resistant to and / or intolerant of dasatinib treatment, the method comprising administering an SOS1 inhibitor to the patient. In some embodiments, the method further comprises administering dasatinib to the patient. In some embodiments, this disclosure provides a method for treating blood cancers such as chronic phase (CP) Ph+CML, wherein the blood cancer is resistant to, intolerant of, or has progressed on at least two TKIs, the method comprising administering an SOS1 inhibitor to the patient. In some embodiments, the blood cancer is relapsed and / or refractory Ph+CML-CP. In some embodiments, the at least two TKIs are selected from second-generation TKIs (e.g., dasatinib, nilotinib, or bosutinib) and third-generation TKIs (e.g., aciminib or ponatinib). In some embodiments, the method further comprises administering a TKI, such as dasatinib, to the patient. In some embodiments, this disclosure provides a method for treating CML-CP (such as CML-CP with warnings or failures according to the ELN 2020 guidelines) while taking dasatinib, the method comprising administering (a) an SOS1 inhibitor and (b) dasatinib to the subject. (For the ELN 2020 guidelines, see Hochhaus et al., Leukemia, 2020, 34(4), 966-984 (doi:10.1038 / s41375-020-0776-2), incorporated herein by reference).

[0302] Despite remarkable progress made with the advent of several generations of TKIs, resistance and / or intolerance to earlier generations of TKIs severely limit treatment options for patients who have relapsed or are resistant to one or more TKIs. The characteristics of a TKI-resistant subject can be... BCR-ABL Genes with one or more mutations or overexpression BCR-ABLChanges in gene and drug transporter activity (e.g., increased efflux and decreased influx of TKIs), activation of compensatory signaling pathways (e.g., PI3K / AKT / JAK / STAT and RAS / MAPK), changes in cell metabolism (e.g., changes in leukemia stem cell metabolism, as evidenced by metabolic shifts, hypoxia / HIF-1α, and Alox5 / β-catenin), epigenetic alterations (e.g., mutations in epigenetic regulatory genes (such as DNMT3A) and / or increased methylation of p15 and EBF2 genes), changes in microenvironment and immune status (e.g., increased MDSCs and Tregs in the immunosuppressive bone marrow microenvironment (BMM) and T cell exhaustion), altered expression of microRNAs (e.g., miR-17 and miR-203), and / or alterations in DNA damage repair and genomic instability (e.g., increased additional chromosomal abnormalities (ACA) and point mutations). The combination therapies disclosed herein (e.g., comprising (a) a small molecule SOS1 inhibitor and (b) a tyrosine kinase inhibitor (TKI) targeting BCR-ABL tyrosine kinase) result in greater inhibition of signal transduction downstream of BCR-ABL, such as greater inhibition of one or more of STAT5, GAB1 / 2, ERK, AKT, and S6, than the signal transduction inhibition observed after treatment with the TKI alone, optionally assessed by measuring the levels of phosphorylated proteins (e.g., p-BCR-ABL, p-STAT5, p-GAB1 / 2, p-ERK, p-AKT, and p-S6).

[0303] In some implementations, objects resistant to TKIs include BCR-ABL One or more mutations in the gene result in a decreased affinity of the TKI for the BCR-ABL tyrosine kinase. In some embodiments, TKI-resistant objects include mutations in the P ring (ATP binding site), the C ring (catalytic domain), the A ring on the activation domain, the myristic acid pocket, and / or mutations that directly affect TKI binding (drug contact site). In some embodiments, TKI-resistant objects include... BCR-ABL Mutations in the gene include, but are not limited to, point mutations selected from T315I, F359V, Y253H, E255K, M351T, G250E, F359I, and H396R. In some implementations, TKI-resistant objects include the BCR-ABL mutation described in Cancer (Basel) October 2021; 13(19): 4820, which is incorporated herein by reference.

[0304] In some implementations, subjects suited for the subject treatment show intolerance to TKIs. TKIs are known to affect multiple organs of the body, including the lungs, liver, gastrointestinal tract, kidneys, thyroid, blood, and skin. Cardiac involvement is a cause of some of the most serious complications. Subjects intolerant to TKIs may experience cardiovascular side effects, including high blood pressure, atrial fibrillation, decreased cardiac function, heart failure, and sudden death. Subjects may also experience other side effects, including nausea, vomiting and / or diarrhea, muscle cramps and bone pain, fatigue, rash and / or edema, any one or all of which can lead to intolerance to TKI treatment. In some implementations, subjects experience one or more side effects selected from the following: fluid retention, headache, diarrhea, fatigue, dyspnea, musculoskeletal pain, nausea, rash, myalgia, arthralgia, infection, abdominal pain, bleeding, pruritus, pain, constipation, bone marrow suppression, bleeding-related events, cardiovascular toxicity, pulmonary hypertension, QT prolongation, skin reactions, Stevens-Johnson syndrome, erythema multiforme, tumor lysis syndrome, and hepatotoxicity.

[0305] Despite receiving TKI treatment, individuals resistant to TKIs may exhibit progression of Philadelphia chromosome-positive (Ph+) blood cancers. Exemplary Philadelphia chromosome-positive (Ph+) blood cancers include chronic myeloid leukemia (CML), Ph+ acute lymphoblastic leukemia (Ph+ ALL), and Ph+ lymphoblastic lymphoma (Ph+ LBL). These blood cancers present with one or more symptoms, including fatigue or weakness (such as shortness of breath during daily activities), fever, pallor, bruising, excessive sweating (especially at night), weight loss, nausea and vomiting, headache, blurred vision, abnormal blood cell counts, abdominal swelling or discomfort due to splenomegaly, itching, bone pain, and bleeding. Ph+ ALL subjects may also exhibit hepatomegaly, splenomegaly, and lymphadenopathy.

[0306] Other symptoms associated with Ph+ blood cancer include hematological abnormalities, such as abnormal levels of red blood cells, white blood cells, or platelets detected in the subject. A hematological marker of CML is the uncontrolled production of mature and maturing granulocytes or blast cells in the subject's bone marrow (e.g., an elevated granulocyte count, such as exceeding 50,000 / mcL (≤50 × 10⁻⁶)). 9 / L), or 200,000 / mcL (200×10 9 / L) to 1,000,000 / mcL (1,000×10 9In some embodiments, the subject's CML to be treated by the subject-specific approach is in the chronic phase (e.g., the subject typically has less than 10% blast cells in their blood or bone marrow). In some embodiments, the subject's CML relapse enters the accelerated phase (e.g., typically has 15% or more but less than 30% blast cells). In some embodiments, the subject's CML relapse enters the terminal blast crisis phase (e.g., typically has more than 30% blast cells, which may have spread to tissues and organs outside the bone marrow).

[0307] Other symptoms associated with Ph+ blood cancer include abnormal molecular responses. Abnormal molecular responses include, but are not limited to, the presence of [unclear - possibly a substance or substance] in the subject's biological samples (including blood, bone marrow, and cerebrospinal fluid). BCR-ABL Genes. In some cases, more than 10%, 20%, 30%, 50%, 60%, 70%, 80%, or 90% of blood cells contain genes. BCR-ABL Gene.

[0308] Other symptoms associated with Ph+ leukemia include abnormal cytogenetic responses, one hallmark of which is the presence of the Philadelphia chromosome (Ph+ chromosome) in the patient's cells. In some cases, patients requiring treatment have the Ph+ chromosome in more than 95%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, or 1% of their blood cells. In other cases, patients requiring treatment have the Ph+ chromosome in more than 95% of their blood cells, approximately 66%–95% of their blood cells, approximately 36%–65% of their blood cells, or approximately 1%–35% of their blood cells.

[0309] Progression can be determined if any or some of the symptoms associated with Ph+ blood cancer disclosed herein or known in the art do not improve. In some embodiments, progression can be determined if one or more symptoms do not improve after 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or more following initial TKI treatment.

[0310] In some implementations, the subject of the treatment regimen has relapsed Philadelphia chromosome-positive (Ph+) leukemia. In some implementations, the subject has relapsed CML. In some implementations, the subject has relapsed Ph+ALL. In some implementations, the subject has relapsed Ph+LBL. Relapse can be identified by the recurrence of any symptoms previously diagnosed in the subject that are associated with Philadelphia chromosome-positive (Ph+) leukemia. Relapse can occur after initial TKI treatment, for example, at 3, 5, 7, 8, 9, 10, 11, 12, 15, 18, 24, 25, 26, 27, 28, 29, 30, 36 months or more. Relapse can be identified by one or more of the following: (a) loss of complete hematologic response (CHR), (b) loss of complete response (CCyR), (c) loss of partial response (PCyR), (d) development of a new mutation, (e) loss of major molecular response (MMR), (f) clonal chromosomal abnormality (CCA), and (g) Ph+.

[0311] Various techniques exist in this field for assessing recurrence or progression of Ph+ hematologic malignancies. Specifically, techniques have been developed for detecting abnormal hematological, molecular, and / or cytogenetic responses. Blood tests on a subject's blood sample can reveal abnormal levels of white blood cells, red blood cells, or platelets, as well as the presence of blast cells. Bone marrow tests can be applied to bone marrow aspiration or biopsy to detect the type and maturation stage of leukemia cells (B or T lymphocytes). Imaging studies, including X-rays, computed tomography (CT) scans, magnetic resonance imaging (MRI), and ultrasound scans, can detect signs of cancer metastasis to the brain, spinal cord, or other parts of the body. Cerebrospinal fluid tests can be performed to detect any spread of cancer into the cerebrospinal fluid.

[0312] On one hand, this disclosure provides a method for treating Philadelphia chromosome-positive (Ph+) leukemia in a subject. The method includes: (1) assessing the presence of genetic aberrations in a biological sample containing nucleic acid molecules from the subject that are associated with resistance to a tyrosine kinase inhibitor (TKI) against BCR-ABL tyrosine kinase; and (2) upon detection of… BCR-ABL Following the presence of the genetic aberration, a pharmaceutical composition containing an effective amount of a small molecule SOS1 inhibitor is administered to the subject.

[0313] It can be determined through various nucleic acid assays BCR-ABLThe presence of Ph+ chromosomal or genetic aberrations. Exemplary nucleic acid assays include, but are not limited to, genotyping and sequencing methods. Sequencing methods may include next-generation sequencing, targeted sequencing, exome sequencing, whole-genome sequencing, massively parallel sequencing, etc. Several platforms for next-generation sequencing are commercially available, including those sold by Illumina and Pacific Biosciences. Other nucleic acid assays include, but are not limited to, in situ hybridization (e.g., FISH), polymerase chain reaction (PCR), quantitative PCR (qPCR), quantitative real-time PCR (qRT-PCR), and ligase chain reaction (LCR), all of which are suitable for detecting... BCR-ABL Genetic abnormalities in the body. If necessary, one or more nucleic acids can be used to detect the underlying cause. BCR-ABL Genetic aberrations that lead to gene formation, including but not limited to translational aberrations, as well as those occurring through point mutations, insertions, deletions, or frameshifts. BCR-ABL Gene mutations within a gene.

[0314] In some implementations, the step of assessing the presence of genetic aberrations associated with TKI resistance is detected. BCR-ABL Gene overexpression. In some embodiments, the evaluation step detects mutations in the P loop (ATP binding site), C loop (catalytic domain), A loop (activation loop), or myristic acid pocket. In some embodiments, the evaluation step detects genetic aberrations associated with: (i) changes in drug transporter activity (e.g., increased efflux and decreased influx of TKIs, thus confirming drug resistance), (ii) activation of compensatory signaling pathways (e.g., PI3K / AKT / JAK / STAT and RAS / MAPK), (iii) changes in cellular metabolism (e.g., changes in leukemia stem cell metabolism, demonstrated by metabolic shifts, hypoxia / HIF-1α, Alox5 / β-catenin), and (iv) epigenetics. Alterations (e.g., mutations in epigenetic regulatory genes such as DNMT3A and / or increased methylation of p15 and EBF2 genes), (v) changes in the microenvironment and immune status (e.g., increased MDSCs and Tregs in the immunosuppressive bone marrow microenvironment (BMM) and T cell exhaustion), (vi) altered expression of microRNAs (e.g., miR-17 and miR-203), and / or (vii) alterations in DNA damage repair and genomic instability (e.g., increased additional chromosomal abnormalities (ACA) and point mutations).

[0315] In some embodiments, the evaluation step detects mutations in BCR-ABL, including but not limited to point mutations selected from T315I, F359V, Y253H, E255K, M351T, G250E, F359I, and H396R. In some embodiments, the evaluation step detects one or more mutations in BCR-ABL described in Cancer (Basel) October 2021; 13(19): 4820, which is incorporated herein by reference. In some embodiments, the evaluation step detects one or more mutations in BCR-ABL associated with reduced binding affinity of TKIs to BCR-ABL tyrosine kinases.

[0316] Various protein analysis techniques can be applied to assess the presence and / or overexpression of BCR-ABL or its mutants, as well as the expression of other proteins associated with TKI resistance. Suitable protein assays include, but are not limited to, immunohistochemistry (IHC), ELISA (enzyme-linked immunosorbent assay), sandwich immunoassay, immunoradiography, in situ immunoassay, Western blot analysis, immunoprecipitation assay, immunofluorescence assay, flow cytometry, confocal microscopy, enzyme assays, surface plasmon resonance, and PAGE-SDS. One or more of these protein assays utilize antibodies or fragments thereof that exhibit specific binding to the BCR-ABL peptide. A large number of anti-BCR-ABL antibodies are available, including those provided by Thermofisher and Abcam. Commercially available antibodies can also be used in immunoassays to determine the presence and / or overexpression of BCR-ABL due to TKI resistance. BCR-ABL The reduced affinity of TKI for binding to BCR-ABL is caused by gene mutation.

[0317] Protein assays are interested in detecting proteins involved in changes in drug transporter activity (increased efflux or decreased efflux of TKIs), activation of compensatory signaling pathways, changes in cell metabolism, epigenetic alterations, microenvironment and immune status, changes in microRNA expression, or alterations in DNA damage repair and genomic instability.

[0318] When implementing the subject-specific approach, any biological sample containing target cells (e.g., cancer cells from the study subject) or its components (e.g., components such as cfDNA from tumor tissue or cancer cells) can be used to determine the Ph+ chromosome. BCR-ABL Gene, BCR-ABLThe presence of mutations within the gene or other genetic aberrations associated with TKI resistance. Biological samples can be liquid or solid biological samples from a research or treatment subject (in the case of transfer to other tissues). Biological samples can be fixed, paraffin-embedded, fresh, or frozen biopsy samples. Biological samples can be obtained by any suitable means, including but not limited to blood collection, needle aspiration, fine-needle aspiration, core needle biopsy, vacuum-assisted biopsy, large-core biopsy, incisional biopsy, excisional biopsy, puncture biopsy, curettage biopsy, skin biopsy, surgical specimens, and venipuncture.

[0319] Depending on the tumor tissue or cancer cells to be treated, biological samples may be obtained from, but are not limited to, the subject's blood or plasma, skin, heart, lungs, kidneys, bone marrow, breast, pancreas, liver, muscle, smooth muscle, bladder, gallbladder, colon, intestine, brain, prostate, esophagus, thyroid, serum, saliva, urine, gastric juice and digestive juices, tears, feces, semen, vaginal fluid, interstitial fluid derived from tumor tissue, eye discharge, sweat, mucus, earwax, oil, glandular secretions, cerebrospinal fluid, hair, nails, plasma, nasal swabs or nasopharyngeal irrigation fluid, cerebrospinal fluid, cerebrospinal fluid, tissue, pharyngeal swabs, biopsy, placental fluid, amniotic fluid, umbilical cord blood, emphatic fluid, cavity fluid, sputum, pus, microbiota, meconium, breast milk and / or other excretions or body tissues.

[0320] In some implementations, the biological sample contains cell-free DNA (cfDNA) derived from whole blood or plasma of the subject. The contents of the sample can be analyzed directly, or the sample can be processed to purify one or more of its contents for analysis. In some implementations, one or more components are purified from the sample for the detection of Ph+ chromosomes. BCR-ABL Gene, BCR- ABL The presence of mutations within the gene or other genetic aberrations associated with TKI resistance. In some embodiments, the purified component of the biological sample is a protein (e.g., total protein, cytoplasmic protein, or membrane protein). In some embodiments, the purified component of the sample is a nucleic acid, such as DNA (e.g., genomic DNA, cDNA, ctDNA, or cfDNA) or RNA (e.g., total RNA, mRNA, or microRNA).

[0321] In practicing the methods disclosed herein, administering an SOS1 inhibitor or a pharmaceutical composition containing an effective amount of an SOS1 inhibitor typically involves contacting cells with the SOS1 inhibitor disclosed herein. The SOS1 inhibitor may be a small molecule, a nucleic acid agent, or a peptide (e.g., an endonuclease). As disclosed herein, contact may occur in vitro, ex vivo, or in vivo.

[0322] In some embodiments, cells are contacted with (i) the SOS1 inhibitor disclosed herein and (ii) at least one additional agent. Contact with (i) and (ii) can be simultaneous. For example, the SOS1 inhibitor can be administered before, after, or simultaneously with the administration of at least one additional agent. For simultaneous contact, the SOS1 inhibitor and at least one additional inhibitor can be present in the same composition (e.g., as a formulation or unit dose) or in different compositions (e.g., exposing cells to two different compositions simultaneously). For sequential contact, the SOS1 inhibitor and at least one additional agent can be present in the same composition (e.g., a single composition exhibiting different release profiles or in different compositions). For sequential exposure, the first exposure of cells (e.g., exposure to an SOS1 inhibitor or at least one other agent) and the second exposure of cells (e.g., exposure to at least one other agent or an SOS1 inhibitor) may be spaced at least about 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 12 hours, 16 hours, 24 hours, 1 day, 3 days, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months or longer. The first exposure and the second exposure may be spaced at most about 1 month, 1 week, 24 hours, 20 hours, 16 hours, 12 hours, 11 hours, 10 hours, 9 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 60 minutes or less.

[0323] Suitable agents that can be used in combination with the subject SOS1 inhibitor include, but are not limited to, the TKIs disclosed herein, other anticancer agents, anti-allergy agents, anti-nausea agents (or antiemetics), analgesics, cell protectants, immunomodulators, chemotherapeutic agents, and combinations thereof.

[0324] Exemplary immunomodulators include, but are not limited to, immunostimulants, checkpoint immune blockers (e.g., blockers or inhibitors of immune checkpoint genes such as PD-1, PD-L1, CTLA-4, IDO, TIM3, LAG3, TIGIT, BTLA, VISTA, ICOS, KIR, and CD39), radiotherapy agents, chemotherapeutic agents, and combinations thereof. In some embodiments, the immunostimulant is selected from IL-12, agonist-co-stimulating monoclonal antibodies, and combinations thereof. In one embodiment, the immunostimulant is IL-12. In some embodiments, the agonist-co-stimulating monoclonal antibody is selected from anti-4-1BB antibodies (e.g., urelumab, PF-05082566), anti-OX40 antibodies (pogalizumab, taboliziumab, PF-04518600), anti-ICOS antibodies (BMS986226, MEDI-570, GSK3359609, JTX-2011), and combinations thereof. In one embodiment, the agonist co-stimulatory monoclonal antibody is an anti-4-1BB antibody. In some embodiments, the checkpoint immune blocker is selected from anti-PD-L1 antibodies (atezolizumab, avelumab, durvalumab, BMS-936559), anti-CTLA-4 antibodies (e.g., tremelimumab, ipilimumab), anti-PD-1 antibodies (e.g., pembrolizumab, nivolumab), anti-LAG3 antibodies (e.g., C9B7W, 410C9), anti-B7-H3 antibodies (e.g., DS-5573a), anti-TIM3 antibodies (e.g., F38-2E2), and combinations thereof. In one embodiment, the checkpoint immune blocker is an anti-PD-L1 antibody.

[0325] Exemplary chemotherapeutic agents include anthracycline (e.g., doxorubicin, liposomal doxorubicin), vinblastine alkaloids (e.g., vincristine, vinorelbine, vinorelbine), alkylating agents (e.g., cyclophosphamide, decarbazine, melphalan, ifosfamide, temozolomide), and immune cell antibodies (e.g., aleemtuzumab). b) gemtuzumab, rituximab, ofatumumab, tositumomab, brentuximab, antimetabolites (including, for example, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors (e.g., fludarabine)), TNFR glucocorticoid-induced TNFR-associated protein (GITR) agonists, proteasome inhibitors (e.g., aclacinomycin A, gliotoxin or bortezomib), and immunomodulators such as thalidomide or thalidomide derivatives (e.g., lenalidomide). Other chemotherapy agents considered for combination use include Myleran®, Busulfex®, Leustatin® (cladribine), Cytoxan® or Neosar®, Cytarabine, Cytosine arabinoside (Cytosar-U®), DepoCyt® (cytarabine liposome injection), Cerubidine® (daunorubicin hydrochloride), DaunoXome® (daunorubicin citrate liposome injection), Dexamethasone, Adriamycin® or Rubex® (doxorubicin hydrochloride), Vepesid® (etoposide), Fludara® (fludarabine phosphate), Hydrea® (hydroxyurea), and Idarubicin. (Idamycin®), mitoxantrone (Novantrone®), gemtuzumab ozogamicin (Mylotarg®), anastrozole (Arimidex®), bicalutamideCasodex®, Bleomycin sulfate (Blenoxane®), Busulex®, Capecitabine (Xeloda®), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, Paraplatin®, Carmustine (BiCNU®), Leukeran®, Platinol®, Dacarbazine (DTIC-Dome®), Dactinomycin (Actinomycin D), Cosmegan, Dexamethasone, Docetaxel (Taxotere®), 5-Fluorouracil (Adrucil®, Efudex®), Flutamide (Eulexin®), Tezacitibine, Gemcitabine (difluorodeoxycytidine), Ifosfamide (IFEX®), Irinotecan (Camptosar®), L-asparaginase (ELSPAR®), leucovorin calcium, melphalan (Alkeran®), 6-mercaptopurine (Purinethol®), methotrexate (Folex®), mitoxanone (Novantrone®), mylotarg, paclitaxel (Taxol®), phoenix (Yttrium 90 / MX-DTPA), pentostatin, polyphenylprotein 20 and carmustine implant (Gliadel®), tamoxifencitrate (Nolvadex®), teniposide (Vumon®), 6-thioguanine, thiotepa, tirapazamine (Tirazone®), topotecan hydrochloride for injection (Hycamptin®), vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine (Navelbine®).

[0326] In some embodiments, the methods described herein include administering (a) an SOS1 inhibitor and optionally (b) a TKI, such as dasatinib, and further include administering (c) an additional agent selected from: (1) an SHP2 inhibitor (e.g., 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine, RMC-4630, ERAS-601, TNO155, JAB-3068, IACS-13909 / BBP-398, SHP099, RMC-4550), (2) an inhibitor of wild-type or mutant RAS, such as wild-type KRAS, wild-type HRAS, wild-type NRAS, mutant KRAS, mutant HRAS, mutant NRAS, KRAS G12C, KRAS G12D, KRAS G12S, KRAS G12V, KRAS G13D, KRAS G13C, KRAS G13V or KRAS Q61H (e.g., LY3537982, JAB-21822, BBO-8520, D-1553, BI-1823911, RMC-9805, MRTX1133, MRTX849, AMG510, GDC-6036, AZD4625, JDQ443, RMC-6291, RMC-6236, BI-2493, MK-1084, RMC-8839, SHR1127, JAB-21822, GFH925, IBI351, BPI-421286, JMKX1899, HBI-2438, D3S-001, GFH375, VS-7375, RMC-7977, RMC-5127, FMC-376), and (3) MET inhibitors (e.g., foretinib, AMG-458, tivantinib, crizotinib, cabozantinib, tepotinib, capmatinib, savolitinib, glesatinib).

[0327] Practice of any treatment method disclosed herein may involve the combined or concurrent administration of an SOS1 inhibitor with other therapies. Therapies applicable to the treatment of Ph+ diseases (including Ph+ blood cancers) include surgery, radiation therapy, cell therapy, chemotherapy, bone marrow transplantation, and radiation.

[0328] In some embodiments, the subject SOS1 inhibitor is administered as a monotherapy to the recipient. As used herein, the term "monotherapy" means administering only one therapy to the recipient for the intended purpose (e.g., treating cancer, or specifically for treating Ph+ cancer) during a treatment cycle. In some embodiments, the SOS1 inhibitor is administered without a TKI. In some embodiments, the SOS1 inhibitor is administered without anticancer agents, including chemotherapy agents. However, in some embodiments, other therapies may be administered to the recipient for other purposes. For example, an anti-inflammatory agent or other agent that treats symptoms associated with Ph+ cancer but does not treat the underlying cancer itself may be administered to a recipient with cancer during monotherapy treatment, including, for example, inflammation, pain, nausea, weight loss, and general malaise. Recipients of this treatment may have completed any prior treatment (e.g., surgery, chemotherapy, bone marrow transplant, or treatment with some other anticancer agent) before monotherapy treatment, or received additional therapy after monotherapy treatment. In one aspect, this disclosure provides a method for treating Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (Ph+ALL) in a subject of need, comprising administering a pharmaceutical composition containing an effective amount of a small molecule SOS1 inhibitor.

[0329] In another aspect, this disclosure provides a method of combination therapy comprising administering (a) a small molecule SOS1 inhibitor and (b) a tyrosine kinase inhibitor (TKI) targeting BCR-ABL tyrosine kinase to a subject in need, wherein administration (a) occurs before, simultaneously with, or after administration (b), and wherein the combination therapy synergistically slows the progression of Philadelphia chromosome-positive (Ph+) cancers (e.g., blood cancers) and / or reduces undesirable side effects associated with the TKI. The combination therapy may be used to treat chronic myeloid leukemia (CML), Ph+ acute lymphoblastic leukemia (Ph+ ALL), and Ph+ lymphoblastic lymphoma (Ph+ LBL).

[0330] The synergistic effect of combination therapies containing multiple agents, as disclosed herein, can be characterized by a synergistic value determined by the “BLISS Independence” or “BLISS” independence criterion. The BLISS independence criterion can be used to screen candidate drug combinations. This criterion compares the observed combination response to a predicted combination response, which is obtained based on the assumption that there are no drug-interaction effects. When the observed combination response is greater than the predicted combination response (e.g., greater than a threshold), the combination effect can be determined to be synergistic. To determine the synergistic value of a combination therapy containing an inhibitor (a) (e.g., an SOS1 inhibitor) and an inhibitor (b) (e.g., a TKI disclosed herein or exemplified) for inducing inhibition of target cell (e.g., Ph+ cell) growth, the BLISS independence criterion can be used with the following formula: Y AB,O -Y AB,P (1) in: Y AB,O It is the percentage of growth inhibition of target cells observed by the combination of dose A (a) and dose B (b); and Y AB,P It is the predicted percentage of growth inhibition of target cells by the combination of dose A (a) and dose B (b), where: Y AB,P = Y A + Y B – Y A Y B (2) Further, including: Y A It is the percentage of growth inhibition of target cells observed at dose A alone (a); Y B This is the observed percentage of growth inhibition of target cells at dose B alone (b); and Y A Y B It is Y A and Y B The product of.

[0331] According to equation (1), the observed combined inhibition percentage Y AB,O Compared with the predicted percentage of growth inhibition Y AB,P Comparisons are made. Comparisons can determine whether the combination therapy promotes synergistic, additive, or antagonistic effects, as described in equation (3). When Y AB,O >Y AB,P When Y is in a state of combination therapy, it can be determined that the combination therapy is more effective than expected (e.g., synergistic effect). AB,O <Y AB,P When Y is in a state of adverse reaction, it can be determined that the combination therapy is worse than expected (e.g., antagonistic effect). AB,O =Y AB,P In this case, it can be determined that combination therapy is essentially the same as the simple addition of two individual drugs (e.g., independent or additive effects).

[0332]

[0333] When using the BLISS independent criteria, the percentage of target cell growth inhibition can be provided on a percentage scale (e.g., about 0% to about 100%) or a fractional scale (e.g., about 0 to 1). For example, to perform analysis according to the BLISS independent criteria, 75% growth inhibition of target cells can be expressed as 0.75. For example, when using a fractional scale, the observed combined inhibition percentage Y is calculated according to equation (1) (e.g., based on one or more in vitro experiments). AB,O Compared with the predicted percentage of growth inhibition Y AB,P Differences between individuals can be identified as additive (or antagonistic) when the difference is less than or equal to zero. Differences greater than zero can be identified as synergistic. Here, synergy can be divided into several sub-ranges, for example, a first synergistic sub-range with a difference between about 0.05 and about 0.1 (e.g., mild synergy), a second synergistic sub-range with a difference between about 0.1 and about 0.2 (e.g., moderate synergy), and a third synergistic sub-range with a difference greater than or equal to 0.2 (e.g., strong synergy).

[0334] In some implementations, combination therapy comprising multiple agents (e.g., SOS1 inhibitors and TKIs disclosed or exemplified herein) can be used to reduce the growth or proliferation of target cells (such as Ph+ cells) in vitro or in vivo. The therapeutic effect of the combination therapy can be characterized by a synergistic value greater than 0.1 as determined by the Bliss Independent Criteria. The therapeutic efficacy of the combination therapy can be characterized by a synergistic value of at least about 0.1, 0.2, 0.3, 0.4, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 9, 10, 11, 12, 13, 14, 15, or greater as determined by the Bliss Independent Criteria. The therapeutic efficacy of the combination therapy can be characterized by a synergistic value of about 0.1 to about 1, about 1.0-5, about 5 to about 10, or about 10-15.

[0335] Combination therapies comprising multiple different therapeutic agents (e.g., SOS1 inhibitors and TKIs) can synergistically achieve one or more desired therapeutic effects or outcomes, including but not limited to slowing the progression of chronic myeloid leukemia (CML), Ph+ acute lymphoblastic leukemia (Ph+ ALL), or Ph+ lymphoblastic lymphoma (Ph+ LBL). In some embodiments, slowing the progression of Philadelphia chromosome-positive (Ph+) blood cancer is demonstrated by improvements in the response of the treated subject, such as hematological, molecular, and cytogenetic responses. In some embodiments, improvements in hematological responses are characterized by the restoration or partial restoration of the subject's blood cell count to normal levels. In some embodiments, improvements in hematological responses are characterized by one or more of the following: <10 × 10⁻⁶ 9 White blood cell count <450×10⁹ / L9 / L platelet count, <5% peripheral blood myeloblasts and metamyelocytes, <20% peripheral blood basophils, no blasts or promyelocytes in peripheral blood, no extramedullary involvement, no differentiating immature granulocytes, and an unpalpable spleen. In some embodiments, improvement in hematologic response is characterized by peripheral blood blasts <10%, such as <9%, <8%, <7%, <6%, <5%, <4%, <3%, <2%, or <1%. In some embodiments, improvement in molecular response is characterized by the presence of [unspecified substance] in the target blood as determined by nucleic acid assay. BCR-ABL1 The amount of genes is reduced. In some implementations, the improvement in molecular response is characterized by the presence of proteins in the blood of the target organism, as determined by protein assays. BCR-ABL1 A decrease in gene expression levels. In some implementations, the improvement in molecular responses is characterized by... BCR-ABL1 Levels less than 10%, such as less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.1%, less than 0.01%, or less than 0.0032%. In some embodiments, the improvement in the molecular response is characterized by the presence of [a specific substance] in the target blood, optionally as determined by qPCR. BCR-ABL1 At least three log reductions at the gene level, such as those present in the subject's blood. BCR-ABL1 The gene level is reduced by at least 4, 4.5, or 5 log units. In some embodiments, the improvement in cytogenetic response is characterized by a reduction in the number of blood cells containing the Philadelphia chromosome, as determined by, for example, FISH, PCR, sequencing, or other techniques. In some embodiments, the improvement in cytogenetic response is characterized by the presence of <40% Ph+ metaphases in at least 20 metaphases, such as <35% Ph+ metaphases, <30% Ph+ metaphases, <25% Ph+ metaphases, <20% Ph+ metaphases, <15% Ph+ metaphases, <10% Ph+ metaphases, <5% Ph+ metaphases, or no detectable (0%) Ph+ metaphases in at least 20 metaphases. In some embodiments, the improvement in cytogenetic response is characterized by less than 40%, such as less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 5% of cells containing the Ph chromosome, or no detectable cells containing the Ph chromosome.

[0336] The hematological, molecular, and / or cytogenetic response of the subject to the treatment methods described herein shall last for at least one month, such as at least two months, at least three months, at least four months, at least five months, at least six months, at ...

Claims

1. A method of treating Philadelphia chromosome-positive (Ph+) leukemia in a subject of need, comprising administering to the subject a pharmaceutical composition comprising an effective amount of a small molecule SOS1 inhibitor, wherein the subject has been treated with a tyrosine kinase inhibitor (TKI) targeting BCR-ABL tyrosine kinase prior to the administration of the SOS1 inhibitor.

2. The method according to claim 1, wherein the Philadelphia chromosome-positive (Ph+) blood cancer is chronic myeloid leukemia (CML), Ph+ acute lymphoblastic leukemia (Ph+ALL), or Ph+ lymphoblastic lymphoma (Ph+LBL).

3. The method according to any one of the preceding claims, wherein the object exhibits relapse of CML, Ph+ALL, or Ph+LBL.

4. The method according to any one of the preceding claims, wherein the object exhibits resistance or intolerance to the TKI.

5. The method according to claim 4, wherein resistance to the TKI is characterized by being selected from one or more of the following: (1) progression of Philadelphia chromosome-positive (Ph+) leukemia, (2) BCR-ABL Gene mutation, (3) BCR-ABL (4) Changes in drug transporter activity, (5) Activation of compensatory signaling pathways, (6) Changes in cell metabolism, (7) Epigenetic changes, (8) Changes in microenvironment and immune status, (9) Changes in microRNA expression, and (10) Changes in DNA damage repair and genomic instability.

6. The method of claim 4, wherein the resistance to the TKI is characterized by: BCR-ABL One or more mutations in the gene that reduce the binding affinity of TKI to BCR-ABL tyrosine kinase.

7. The method according to claim 4, wherein resistance to the TKI is characterized by mutations in the P ring (ATP binding site), mutations in the C ring (catalytic domain), mutations on the activation (A) ring, mutations in the myristic acid pocket, and / or mutations that directly affect the binding of the TKI (drug contact site).

8. The method according to claim 4, wherein the resistance to TKI is characterized by a mutation in the BCR-ABL gene, the mutation being selected from T315I, F359V, Y253H, E255K, M351T, G250E, F359I, and H396R.

9. The method according to any one of claims 1-3, wherein the object exhibits recurrence of CML, characterized in that... Recurrence of abnormal hematological, molecular and / or cytogenetic reactions.

10. The method according to any one of the preceding claims, wherein the TKI is selected from imatinib, dasatinib, nilotinib, bosutinib, radiutinib, flumatinib, ponatinib, olabatinib, and aciminib.

11. The method of claim 10, wherein the TKI is selected from dasatinib, nilotinib, bosutinib, raditinib, flumatinib, ponatinib, olabatitinib, and aciminib.

12. The method of claim 10, wherein the TKI is dasatinib.

13. The method according to any one of the preceding claims, wherein the SOS1 inhibitor is administered as a single therapy.

14. The method according to any one of claims 1-12, wherein the SOS1 inhibitor is administered in combination with another agent or another therapy.

15. The method of claim 14, wherein the additional agent is selected from TKIs, immunomodulators, antinausea (or antiemetics), analgesics, and chemotherapeutic agents.

16. The method of claim 15, wherein the additional agent is the same TKI as the TKI previously administered to the subject.

17. The method of claim 15, wherein the additional agent is a different TKI from the TKI previously administered to the subject.

18. The method of claim 15, wherein the additional agent is the same TKI as that previously administered to the subject, but at a different dose than the dose previously administered to the subject.

19. The method of claim 15, wherein the additional agent is a different TKI from the TKI previously administered to the subject, and wherein the additional agent is administered to the subject at a subtherapeutic dose.

20. The method of claim 15, wherein the additional agent is an immunomodulator, cytokine, or checkpoint immunoblocker.

21. The method of claim 15, wherein the additional agent is selected from anti-PD-L1 antibody, anti-CTLA-4 antibody, anti-PD-1 antibody, anti-LAG3 antibody, anti-TIM3 antibody, and combinations thereof.

22. The method of claim 14, wherein the additional agent is selected from dasatinib, nilotinib, bosutinib, raditinib, flumatinib, ponatinib, olabatitinib, and aciminib.

23. The method of claim 14, wherein the additional therapy is selected from surgery, cell therapy, chemotherapy, bone marrow transplantation, and radiation.

24. A method of treating Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (Ph+ALL) in a subject of need, comprising administering a pharmaceutical composition containing an effective amount of a small molecule SOS1 inhibitor.

25. A method of treating Philadelphia chromosome-positive (Ph+) leukemia in a subject of need, comprising administering a pharmaceutical composition containing an effective amount of a small molecule SOS1 inhibitor, wherein the subject is identified as having a genetic aberration of BCR-ABL.

26. The method of claim 25, wherein the genetic aberration is a mutation in BCR-ABL associated with resistance to a tyrosine kinase inhibitor (TKI) against BCR-ABL tyrosine kinase.

27. The method of claim 26, wherein the genetic aberration is characterized by mutations in the P loop (ATP binding site), mutations in the C loop (catalytic domain), mutations on the activation (A) loop, mutations in the myristic acid pocket, and / or mutations that directly affect the binding of TKIs (drug contact site).

28. The method of claim 25, wherein the resistance to the TKI is characterized by: BCR-ABL The mutations are selected from T315I, F359V, Y253H, E255K, M351T, G250E, F359I and H396.

29. The method according to any one of claims 25-28, wherein the Ph+ blood cancer is selected from chronic myeloid leukemia (CML), Ph+ acute lymphoblastic leukemia (Ph+ALL), and Ph+ lymphoblastic lymphoma (Ph+LBL).

30. The method according to any one of claims 24-29, wherein the SOS1 inhibitor is administered as a single therapy.

31. The method according to any one of claims 24-29, wherein the SOS1 inhibitor is administered in combination with another agent or another therapy.

32. The method of claim 31, wherein the additional agent is selected from TKIs targeting BCR-ABL tyrosine kinases, immunomodulators, antinausea agents (or antiemetics), analgesics, and chemotherapeutic agents.

33. The method of claim 31, wherein the additional agent is an immunomodulator, cytokine, or checkpoint immunoblocker.

34. The method of claim 31, wherein the additional agent is selected from anti-PD-L1 antibody, anti-CTLA-4 antibody, anti-PD-1 antibody, anti-LAG3 antibody, anti-TIM3 antibody, and combinations thereof.

35. The method of claim 31, wherein the additional agent is selected from dasatinib, nilotinib, bosutinib, raditinib, flumatinib, ponatinib, olabatitinib, and aciminib.

36. The method of claim 31, wherein the additional therapy is selected from surgery, cell therapy, chemotherapy, bone marrow transplantation, and radiation.

37. A method of combination therapy comprising administering (a) a small molecule SOS1 inhibitor and (b) a tyrosine kinase inhibitor (TKI) targeting BCR-ABL tyrosine kinase to a subject in need, wherein the administration of (a) occurs before, simultaneously with, or after the administration of (b), and wherein the combination therapy synergistically slows the progression of Philadelphia chromosome-positive (Ph+) blood cancer and / or reduces undesirable side effects associated with said TKI.

38. The method of claim 37, wherein one or both of (a) and (b) are administered at a subtherapeutic dose, but when (a) or (b) is administered at its therapeutically effective dose, the therapeutic effect achieved is at least equivalent to that achieved by administering (a) or (b) alone.

39. The method according to any one of claims 37-38, wherein the combination therapy exhibits a synergistic effect in slowing the progression of chronic myeloid leukemia (CML), Ph+ acute lymphoblastic leukemia (Ph+ALL), or Ph+ lymphoblastic lymphoma (Ph+LBL).

40. The method according to any one of claims 37-39, wherein slowing the progression of Philadelphia chromosome-positive (Ph+) leukemia is demonstrated by improvement in a selection of hematologic, molecular, and cytogenetic responses of the subject.

41. The method of claim 40, wherein the improvement in hematological response is characterized by the restoration of the subject's blood cells to normal levels.

42. The method of claim 40, wherein the improvement in the molecular reaction is characterized by the presence of [something] in the blood of the target, as determined by nucleic acid assay. BCR-ALB1 The amount of genes has decreased.

43. The method of claim 40, wherein the improvement in cytogenetic response is characterized by a reduction in the number of bone marrow cells containing the Philadelphia chromosome.

44. The method according to any one of claims 37-43, wherein the combination therapy exhibits a synergistic effect in reducing side effects associated with the TKI, the side effects being selected from cardiotoxicity, nausea, vomiting, diarrhea, muscle cramps, bone pain, fatigue, rash, and edema.

45. The method according to any one of claims 37-44, wherein the TKI is dasatinib, administered at the following sub-therapeutic doses: less than 100 mg daily for the treatment of chronic phase CML or less than 140 mg daily for the treatment of accelerated and blast crisis CML or Ph+ALL.

46. ​​The method according to any one of claims 37-44, wherein the TKI is imatinib, administered at the following sub-therapeutic doses: less than 400 mg daily for the treatment of chronic phase CML or less than 600 mg daily for the treatment of accelerated and blast crisis CML or Ph+ALL.

47. The method according to any one of claims 37-44, wherein the TKI is nilotinib, which is administered in the following sub-therapeutic doses: less than 300 mg twice daily for chronic phase CML or less than 400 mg twice daily for resistant (second-line) and accelerated or blast crisis CML.

48. The method according to any one of claims 37-44, wherein the TKI is acimenil, which is administered in the following sub-therapeutic doses: less than 80 mg daily or less than 40 mg twice daily, or less than 200 mg twice daily for Ph+ blood cancers with T315I mutation.

49. The method according to any one of claims 37-44, wherein the TKI is ponatinib, administered at a subtherapeutic dose of less than 45 mg daily.

50. The method according to any one of claims 37-44, wherein the Ph+ blood cancer is selected from chronic myeloid leukemia (CML), Ph+ acute lymphoblastic leukemia (Ph+ALL), and Ph+ lymphoblastic lymphoma (Ph+LBL).

51. A method of treating a subject with Philadelphia chromosome-positive (Ph+) leukemia, comprising administering to the subject a pharmaceutical composition comprising an effective amount of a small molecule SOS1 inhibitor, wherein the SOS1 inhibitor inhibits the growth of CML cell lines with an IC50 of less than about 50 nM, as determined in a growth inhibition assay of CML cell lines.

52. The method of claim 51, wherein the SOS1 inhibitor, in combination with a tyrosine kinase inhibitor (TKI) targeting BCR-ABL tyrosine kinase, synergistically inhibits the growth of CML cell lines.

53. The method according to claim 51 or 52, wherein the TKI is selected from imatinib, dasatinib, nilotinib, bosutinib, radiutinib, flumatinib, ponatinib, olabatitinib, and aciminib.

54. The method according to any one of claims 51-53, wherein the SOS1 inhibitor is administered as a single therapy.

55. The method according to any one of claims 51-53, wherein the SOS1 inhibitor is administered in combination with another agent or another therapy.

56. The method of claim 55, wherein the additional agent is selected from TKIs, immunomodulators, antinausea (or antiemetics), analgesics, and chemotherapeutic agents.

57. The method of claim 55, wherein the additional agent is an immunomodulator, cytokine, or checkpoint immunoblocker.

58. The method of claim 55, wherein the additional agent is selected from anti-PD-L1 antibody, anti-CTLA-4 antibody, anti-PD-1 antibody, anti-LAG3 antibody, anti-TIM3 antibody, and combinations thereof.

59. The method of claim 55, wherein the additional therapy is selected from surgery, cell therapy, chemotherapy, bone marrow transplantation, and radiation.

60. The method according to any one of claims 51-59, wherein the Ph+ blood cancer is selected from chronic myeloid leukemia (CML), Ph+ acute lymphoblastic leukemia (Ph+ALL), and Ph+ lymphoblastic lymphoma (Ph+LBL).

61. A method for reducing the proliferation of cells containing the Philadelphia chromosome, the method comprising administering (a) a small molecule SOS1 inhibitor and (b) at least one tyrosine kinase inhibitor (TKI) targeting BCR-ABL tyrosine kinase to the cells, wherein the administration of (a) and (b) synergistically inhibits the growth of CML cells, as demonstrated by the following: when (1) less than half the amount of the SOS1 inhibitor is administered compared to the amount required for administration of the SOS1 inhibitor alone; or (2) less than half the amount of the TKI is administered compared to the amount required for administration of the TKI alone, a comparable or greater degree of growth inhibition is achieved.

62. The method of claim 61, wherein the TKI applied in (b) is less than about 25% of the amount required to achieve a comparable or higher degree of growth inhibition.

63. The method of claim 61, wherein the TKI applied in (b) is less than about 15% of the amount required to achieve a comparable or higher degree of growth inhibition.

64. The method according to any one of claims 61-63, wherein the TKI is selected from imatinib, dasatinib, nilotinib, bosutinib, radiutinib, flumatinib, ponatinib, olabatitinib, and aciminib.

65. The method according to any one of claims 61-64, wherein the reduction of proliferation of cells containing the Philadelphia chromosome occurs in vitro, in vitro, or in vivo.

66. The method according to any one of claims 61-65, wherein the cell containing the Philadelphia chromosome is a Ph+ chronic myeloid leukemia (CML) cell, a Ph+ ALL cell, or a Ph+ LBL cell.

67. A method for treating Philadelphia chromosome-positive (Ph+) leukemia in a subject, the method comprising: (1) Assess the presence of genetic aberrations associated with resistance to tyrosine kinase inhibitors (TKIs) against BCR-ABL tyrosine kinases in biological samples containing nucleic acid molecules from the subject; and (2) Upon detection of the presence of the genetic aberration, administer to the subject a pharmaceutical composition comprising an effective amount of a small molecule SOS1 inhibitor.

68. The method of claim 67, wherein the genetic aberration is a mutation in BCR-ABL associated with resistance to the TKI.

69. The method according to claim 67 or claim 68, wherein the genetic aberration is a mutation in BCR-ABL, the mutation being selected from T315I, F359V, Y253H, E255K, M351T, G250E, F359I, and H396R.

70. The method according to any one of claims 67-69, wherein the TKI is selected from imatinib, dasatinib, nilotinib, bosutinib, radiutinib, flumatinib, ponatinib, olabatinib, and aciminib.

71. The method according to any one of claims 67-70, wherein the Ph+ blood cancer is selected from chronic myeloid leukemia (CML), Ph+ acute lymphoblastic leukemia (Ph+ALL), and Ph+ lymphoblastic lymphoma (Ph+LBL).

72. A method for reducing the proliferation of cells containing the Philadelphia chromosome, the method comprising administering (a) a small molecule SOS1 inhibitor and (b) at least one tyrosine kinase inhibitor (TKI) against BCR-ABL to the cells, wherein the administration of (a) and (b) synergistically inhibits the growth of CML cells, with a synergistic value of at least about 0.1 as determined by the Bliss Independent Criterion.

73. The method of claim 72, wherein the synergy value is determined by the Bliss independence criterion according to the following formula: Y AB,O -Y AB,P in: Y AB,O is the percent growth inhibition of the cancer cells observed by applying (a) at dose A and (b) at dose B; and Y AB,P Y is the percentage of cancer cell growth inhibition predicted by applying (a) and (b) containing (a) at dose A and (b) at dose B, where Y AB,P = Y A + Y B – Y A Y B , Further, including: Y A The percentage of cancer cell growth inhibition observed by using dose A alone (a); Y B The percentage of cancer cell growth inhibition observed by using dose B alone (b); and Y A Y B It is Y A and Y B The product of.

74. The method of claim 72 or claim 73, wherein the synergistic value is at least about 0.

4.

75. The method of claim 72 or claim 73, wherein the cooperating value is at least about 1.

76. The method of claim 72 or claim 73, wherein the synergistic value is at least about 5.

77. The method according to any one of claims 1-76, wherein the SOS1 inhibitor has formula (I-1) or formula (A-1).

78. The method according to any one of claims 1-77, wherein the SOS1 inhibitor is a compound of formula (I-1): (I-1)， Or a pharmaceutically acceptable salt or solvate thereof, wherein: Selected from C 5-7 Carbon rings and 5- to 7-membered heterocycles, each of which is optionally bounded by one or more R 11 replace; Does not exist or selected from C 3-8 Carbon rings and 3 to 8-membered heterocycles, each of which is optionally bounded by one or more R 11a replace; L 1 Selected from key, C 1-6 Alkylene and C 1-6 Halogenated alkylene; L 2 Selected from C 5-25 Alkylene, C 5-25 imidene group, C 5-25 5- to 25-membered heteroalkyl and 5- to 25-membered heteroalkylene, each of which is optionally divided by one or more R 11b Replace, where L 2 Covalently bound to W 3 W 4 W 5 W 6 or W 7 one of; W 3 Selected from N(R) 3b ), N, C(R) 3 ) and C(O); W 4 Selected from N(R) 4b ), N, C(R) 4 ) and C(O); W 5 Selected from N(R) 5b ), N and C(R) 5 ); W 6 Selected from C(R) 6 ) and C(O); W 7 It is C(R) 7 ); R 1 It is optionally controlled by one or more R 11c Replacement C 1-3 alkyl; R 8 Selected from hydrogen, halogens, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 -S(=O)(=NH)N(R) 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 and -CH2S(O)2N(R 12 (R) 13 ), where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are independently and optionally separated by one, two, or three R... 20 replace; R 3 R 4 R 5 R 6 and R 7 Each independently selected from L 2 bonds, hydrogen, halogens, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 -S(=O)(=NH)N(R) 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 and -CH2S(O)2N(R 12 (R) 13 ), where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are independently and optionally separated by one, two, or three R... 20 replace; R 3b R 4b and R 5b Each independently selected from L 2 bonds, hydrogen, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -SR 12 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 -S(=O)(=NH)N(R) 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 and -CH2S(O)2N(R 12 (R) 13 ), where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are independently and optionally separated by one, two, or three R... 20 replace; R 11 and R 11a Each time it appears, it is independently selected from halogen, -CN, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 -S(=O)(=NH)N(R) 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 -CH2S(O)2N(R) 12 (R) 13 ), -CH2N(R 12 )S(O)2(R 13 ) and -P(O)(R 17 (R) 17a ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 replace; R 11b Each time it appears, it is independently selected from halogen, oxo, -CN, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 -S(=O)(=NH)N(R) 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 -CH2S(O)2N(R) 12 (R) 13 ), -CH2N(R 12 )S(O)2(R 13 ) and -P(O)(R 17 (R) 17a ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 replace; R 11c Each time it appears, it is independently selected from halogen, -OR 12 and -N(R) 12 (R) 13 ); R 12 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 replace; R 13 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl; or R 12 and R 13 Together with the nitrogen atoms they are attached to, they form a structure optionally bounded by one, two, or three R atoms. 20 Replaced 3- to 10-membered heterocycles; R 14 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R 15 Each time it appears, it is independently selected from C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. 20 replace; R 17 and R 17a Each time it appears, it is independently selected from C. 1-6 Alkyl and C 3-6 cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl groups are optionally surrounded by one, two, or three R groups. 20 Replace; or R 17 and R 17a Together with the phosphorus atoms they are attached to, they form 3 to 10-membered heterocycles; R 20 Each time it appears, it is independently selected from halogen, oxo, =NH, -CN, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon ring, -CH2-(C 3-10 Carbon rings), 3- to 10-membered heterocycles, -CH2- (3- to 10-membered heterocycles), -OR 21 -SR 21 -N(R) 22 (R) 23 -C(O)OR 22 -C(O)N(R) 22 (R) 23 -C(O)C(O)N(R) 22 (R) 23 ), -OC(O)N(R 22 (R) 23 ), -N(R 24 )C(O)N(R 22 (R) 23 ), -N(R 24 )C(O)OR 25 -N(R) 24 )C(O)R 25 -N(R) 24 )S(O)2R 25 -C(O)R 25 -S(O)2R 25 -S(O)2N(R) 22 (R) 23 -OCH2C(O)OR 22 and -OC(O)R 25 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon ring, -CH2-(C 3-10 The carbocyclic ring (3 to 10-membered heterocycle) and -CH2- (3 to 10-membered heterocycle) are optionally substituted by one, two, or three independent groups selected from the following: halogen, oxo, =NH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -OR 21 -SR 21 -N(R) 22 (R) 23 -C(O)OR 22 -C(O)N(R) 22 )(R 23 )、 -C(O)C(O)N(R 22 )(R 23 )、 -OC(O)N(R 22 )(R 23 )、 -N(R 24 )C(O)N(R 22 )(R 23 )、 -N(R 24 )C(O)OR 25 、 -N(R 24 )C(O)R 25 、 -N(R 24 )S(O)2R 25 、 -C(O)R 25 、 -S(O)2R 25 、 -S(O)2N(R 22 )(R 23 ) and -OC(O)R 25 ; R 21 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 3-10 The carbide ring and the 3 to 10-membered heterocycle are optionally substituted by one, two, or three independent groups selected from the following: halogen and C. 1-6 alkyl; R 22 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 3-10 The carbide ring and the 3 to 10-membered heterocycle are optionally substituted by one, two, or three independent groups selected from the following: halogen and C. 1-6 alkyl; R 23 Each time it appears, it is independently selected from H and C. 1-6 alkyl; R 24 Each time it appears, it is independently selected from H and C. 1-6 alkyl; R 25 Each time it appears, it is independently selected from C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 1-6 Alkyl, C 3-10 The carbide ring and the 3 to 10-membered heterocycle are optionally substituted by one, two, or three independent groups selected from the following: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-10 Carbon rings and 3 to 10-membered heterocycles; and This indicates a single or double bond, such that all valences are satisfied.

79. The method according to any one of claims 1-76, wherein the SOS1 inhibitor is selected from BI-3406, MRTX0902, BAY 293, RMC-5845 and BI-1701963.

80. A kit for reducing the proliferation of cells containing the Philadelphia chromosome, the kit comprising: (1) A composition comprising a small molecule SOS1 inhibitor of formula (I-1) or formula (A-1); and (2) Instructions for contacting cells with the composition.

81. The kit of claim 80, wherein the contact occurs in vitro, ex vivo, or in vivo.

82. The kit according to claim 80 or claim 81, comprising at least one TKI selected from imatinib, dasatinib, nilotinib, bosutinib, raditinib, flumatinib, ponatinib, olabatitinib, and aciminib.

83. The kit according to any one of claims 80-82, wherein the SOS1 inhibitor and the at least one TKI are formulated in the same unit dosage form.

84. The kit according to any one of claims 80-82, wherein the SOS1 inhibitor and the at least one TKI are in different unit dosage forms.

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