Ire1 small molecule inhibitors

Abstract

To provide compounds for use in treating or ameliorating cancer in a subject.SOLUTION: Provided herein are specific small molecule inhibitors for the targeting of IRE1 protein family members. Binding may be direct or indirect. IRE1 small molecule inhibitors are for treatment of cancer, where the cancer is a solid cancer or hematologic cancer.SELECTED DRAWING: None

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 62 / 678,723, filed May 31, 2018, and U.S. Provisional Patent Application No. 62 / 584,575, filed November 10, 2017, which are incorporated by reference in their entireties.

[0002] Sequence Listing This application contains a Sequence Listing, which has been submitted electronically in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy, created on October 29, 2018, is named 51089-715_601_SL.txt and is 28,620 bytes in size. [Background technology]

[0003] background Malignant tumors have evolved strategies that allow them to proliferate under certain adverse conditions. For example, cancer cells respond to hypoxia, nutrient starvation, oxidative stress, and high metabolic demands by regulating their protein folding capacity through the endoplasmic reticulum (ER) stress response pathway. There is a need for improved methods and compositions for targeting cancer cells and countering their survival mechanisms. Summary of the Invention

[0004] overview In one aspect, there is provided a compound of formula (I), or a pharmaceutically acceptable salt, solvate thereof: TIFF2024156774000001.tif38128 formula, Each Z is independently N or CR 1 with the proviso that at least one Z is N; Each R 1 are independently H, halogen, -CN, -OR 8 , -SR 8 , -S(=O)R 9 , -S(=O)2R9 , -S(=O)2N(R 8 )2, -NR 8 S(=O)2R 9 , -C(=O)R 9 , -OC(=O)R 9 , -C(=O)OR 8 , -OC(=O)OR 9 , -N(R 8 )2, -OC(=O)N(R 8 )2, -NR 8 C(=O)R 9 , -NR 8 C(=O)OR 9 , optionally substituted C1-C4 alkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 3 -CN, -OR 8 , -SR 8 , optionally substituted C1-C4 alkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted —O—C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted —O—C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted —O—C3-C6 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 4 is halogen, -CN, -OR 8 , optionally substituted C1-C4 alkyl, optionally substituted C1-C4 fluoroalkyl, or optionally substituted C1-C4 heteroalkyl; Each R 5 are independently H, halogen, -CN, -OR 8 , -SR 8 , -N(R 8)2, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; Each R 2 are independently H, halogen, -CN, -OR 8 , -SR 8 , -S(=O)R 9 , -S(=O)2R 9 , -S(=O)2N(R 8 )2, -NR 8 S(=O)2R 9 , -C(=O)R 9 , -OC(=O)R 9 , -C(=O)OR 8 , -OC(=O)OR 9 , -N(R 8 )2, -OC(=O)N(R 8 )2, -NR 8 C(=O)R 9 , -NR 8 C(=O)OR 9 , optionally substituted C1-C4 alkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 6 is H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C2-C6 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 7is an optionally substituted C1-C4 alkyl, an optionally substituted C1-C4 heteroalkyl, an optionally substituted C1-C4 fluoroalkyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted C3-C6 cycloalkylalkyl, an optionally substituted C2-C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; Or, R 6 and R 7 together with the N atom to which they are attached form an optionally substituted heterocycle; Each R 8 are independently H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; Or, two R's 8 together with the N atom to which they are attached form an optionally substituted heterocycle; Each R 9 are independently an optionally substituted C1-C4 alkyl, an optionally substituted C1-C4 heteroalkyl, an optionally substituted C1-C4 fluoroalkyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted C2-C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R A1 and R A2 are each independently H, halogen, or -OR 9 , optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 fluoroalkyl, or optionally substituted aryl; provided that R A1 and R A2 Not both are H; n is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4.

[0005] In another aspect, there is provided a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof: TIFF2024156774000002.tif38128 formula, Each Z is independently N or CR 1 with the proviso that at least one Z is N; Each R 1 are independently H, halogen, -CN, -OR 8 , -SR 8 , -S(=O)R 9 , -S(=O)2R 9 , -S(=O)2N(R 8 )2, -NR 8 S(=O)2R 9 , -C(=O)R 9 , -OC(=O)R 9 , -C(=O)OR 8 , -OC(=O)OR 9 , -N(R 8 )2, -OC(=O)N(R 8 )2, -NR 8 C(=O)R 9 , -NR 8 C(=O)OR 9 , optionally substituted C1-C4 alkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 3 -CN, -OR 8 , -SR 8, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted —O—C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted —O—C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted —O—C3-C6 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 4 is halogen, -CN, -OR 8 , optionally substituted C1-C4 alkyl, optionally substituted C1-C4 fluoroalkyl, or optionally substituted C1-C4 heteroalkyl; Each R 5 are independently H, halogen, -CN, -OR 8 , -SR 8 , -N(R 8 )2, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; Each R 2 are independently H, halogen, -CN, -OR 8 , -SR 8 , -S(=O)R 9 , -S(=O)2R 9 , -S(=O)2N(R 8 )2, -NR 8 S(=O)2R 9 , -C(=O)R 9 , -OC(=O)R 9 , -C(=O)OR 8 , -OC(=O)OR 9 , -N(R 8 )2, -OC(=O)N(R 8 )2, -NR 8 C(=O)R 9 , -NR 8C(=O)OR 9 , optionally substituted C1-C4 alkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 6 is H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C2-C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 7 is an optionally substituted C-C cycloalkylalkyl, or R 7 is methyl, ethyl, -CH2CF3, -CH2-cyclopropyl, or -CH2CH2OCH3; Each R 8 are independently H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; Or, two R's 8 together with the N atom to which they are attached form an optionally substituted heterocycle; Each R 9 are independently an optionally substituted C1-C4 alkyl, an optionally substituted C1-C4 heteroalkyl, an optionally substituted C1-C4 fluoroalkyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted C2-C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; RA1 and R A2 are each independently H, halogen, or -OR 9 , optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 fluoroalkyl, or optionally substituted aryl; provided that R A1 and R A2 Not both are H; n is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4.

[0006] Any combination of the groups described above or below for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof will be chosen by one skilled in the art to provide stable moieties and compounds.

[0007] Provided herein are compounds, or pharmaceutically acceptable salts or solvates thereof, that selectively bind to IRE1a at one or more binding sites. In some embodiments, IRE1a comprises an RNase domain, a kinase domain, or any combination thereof. In some embodiments, the kinase domain is an autotransphosphorylating kinase domain. In some embodiments, the kinase domain comprises an ATP-binding pocket. In some embodiments, the kinase domain comprises an activation loop. In some embodiments, at least one binding site is within the RNase domain. In some embodiments, at least one binding site is within the kinase domain. In some embodiments, at least one binding site is within the ATP-binding pocket of the kinase domain. In some embodiments, at least one binding site is within the activation loop of the kinase domain. In some embodiments, binding occurs at a first binding site. In some embodiments, the first binding site is located within the RNase domain, the kinase domain, the ATP-binding pocket, or the activation loop. In some embodiments, the first binding site comprises at least one amino acid residue within amino acid residues 465-977 of SEQ ID NO: 1. In some embodiments, the first binding site comprises at least one amino acid residue within amino acid residues 568-833 of SEQ ID NO: 1. In some embodiments, the first binding site comprises at least one amino acid residue within amino acid residues 577-586, 597, 599, 626, 642-643, 645, 648, 688, 692-693, 695, or 711 of SEQ ID NO: 1. In some embodiments, the first binding site comprises at least one amino acid residue within amino acid residues 710-725 or 729-736 of SEQ ID NO: 1. In some embodiments, the first binding site comprises at least one amino acid residue within amino acid residues 835-963 of SEQ ID NO: 1. In some embodiments, binding further occurs at a second binding site. In some embodiments, the second binding site is located within the RNase domain, the kinase domain, the ATP-binding pocket, or the activation loop.In some embodiments, the second binding site comprises at least one amino acid residue within amino acid residues 465-977 of SEQ ID NO: 1. In some embodiments, the second binding site comprises at least one amino acid residue within amino acid residues 568-833 of SEQ ID NO: 1. In some embodiments, the second binding site comprises at least one amino acid residue within amino acid residues 577-586, 597, 599, 626, 642-643, 645, 648, 688, 692-693, 695, or 711 of SEQ ID NO: 1. In some embodiments, the second binding site comprises at least one amino acid residue within amino acid residues 710-725 or 729-736 of SEQ ID NO: 1. In some embodiments, the second binding site comprises at least one amino acid residue within amino acid residues 835-963 of SEQ ID NO: 1. In some embodiments, binding occurs when IRE1a is in a homodimerized conformation. In some embodiments, binding occurs when IRE1a is in an oligomerized conformation. In some embodiments, binding occurs when IRE1a is in a non-oligomerized or non-dimerized conformation. In some embodiments, binding occurs when IRE1a is in an ATP-bound state. In some embodiments, binding occurs when IRE1a is in an unATP-bound state. In some embodiments, the compound selectively binds to a first IRE1a. In some embodiments, selective binding to a first IRE1a blocks dimerization of the first IRE1a to a second IRE1a. In some embodiments, selective binding to a first IRE1a blocks autotransphosphorylation of the first IRE1a. In some embodiments, selective binding to a first IRE1a blocks autotransphosphorylation of a second IRE1a to which the first IRE1a dimerizes. In some embodiments, selective binding to the first IRE1a blocks activation of the first IRE1a. In some embodiments, selective binding to the first IRE1a blocks activation of a second IRE1a with which the first IRE1a dimerizes.In some embodiments, selective binding to the first IRE1a blocks the kinase activity of the first IRE1a. In some embodiments, selective binding to the first IRE1a blocks the kinase activity of a second IRE1a with which the first IRE1a dimerizes. In some embodiments, selective binding to the first IRE1a blocks the RNase activity of the first IRE1a. In some embodiments, selective binding to the first IRE1a blocks the RNase activity of a second IRE1a with which the first IRE1a dimerizes.

[0008] In another aspect, provided herein are compounds that selectively bind to a first IRE1a at two or more sites, wherein when the compound is bound to the first IRE1a protein, the compound binds to the ATP-binding pocket of the first IRE1a and blocks ATP binding to the first IRE1a. In some embodiments, the ATP-binding pocket is comprised within the kinase domain. In some embodiments, the ATP-binding pocket is comprised within amino acid residues 465-977 of SEQ ID NO: 1. In some embodiments, the ATP-binding pocket is comprised within amino acid residues 568-833 of SEQ ID NO: 1. In some embodiments, the ATP-binding pocket comprises one or more of amino acid residues 577-586, 597, 599, 626, 642-643, 645, 648, 688, 692-693, 695, or 711 of SEQ ID NO: 1.

[0009] In another aspect, provided herein is a pharmaceutical composition comprising any one of the compounds described herein, or its pharmaceutically acceptable salt or solvate.In some embodiments, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

[0010] In another aspect, provided herein is a method for treating or ameliorating the effects of a disease associated with altered IRE1 signaling, the method comprising administering a pharmaceutical composition to a subject in need thereof, wherein the pharmaceutical composition comprises any one of the compounds described herein. In some embodiments, the disease is cancer. In some embodiments, the cancer is a solid cancer or a blood cancer. In some embodiments, the cancer is ovarian cancer, bladder cancer, breast cancer, or lung cancer. In some embodiments, the breast cancer is triple-negative breast cancer (TNBC). In some embodiments, the cancer is leukemia, lymphoma, or multiple myeloma. In some embodiments, the pharmaceutical composition is administered intravenously or orally to the subject.

[0011] In another aspect, provided herein is a method for treating or ameliorating a cell proliferative disorder, the method comprising administering a pharmaceutical composition comprising a compound that selectively binds to at least one amino acid residue of an IRE1 family protein, including an RNase domain and a kinase domain, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the IRE1 family protein is IRE1a. In some embodiments, the compound binds to the ATP-binding site of IRE1a. In some embodiments, the cell proliferative disorder is cancer. In some embodiments, the cancer is a solid cancer or a blood cancer. [The present invention 1001] A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof: TIFF2024156774000003.tif38128 formula, Each Z is independently N or CR 1 with the proviso that at least one Z is N; Each R 1 are independently H, halogen, -CN, -OR 8 , -SR 8 , -S(=O)R 9 , -S(=O)2R 9 , -S(=O)2N(R 8)2, -NR 8 S(=O)2R 9 , -C(=O)R 9 , -OC(=O)R 9 , -C(=O)OR 8 , -OC(=O)OR 9 , -N(R 8 )2, -OC(=O)N(R 8 )2, -NR 8 C(=O)R 9 , -NR 8 C(=O)OR 9 , optionally substituted C1-C4 alkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 3 But, -CN, -OR 8 , -SR 8 , optionally substituted C1-C4 alkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted —O—C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted —O—C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted —O—C3-C6 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 4 But halogen, -CN, -OR 8 , optionally substituted C1-C4 alkyl, optionally substituted C1-C4 fluoroalkyl, or optionally substituted C1-C4 heteroalkyl; Each R 5 are independently H, halogen, -CN, -OR 8 , -SR 8 , -N(R 8)2, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; Each R 2 are independently H, halogen, -CN, -OR 8 , -SR 8 , -S(=O)R 9 , -S(=O)2R 9 , -S(=O)2N(R 8 )2, -NR 8 S(=O)2R 9 , -C(=O)R 9 , -OC(=O)R 9 , -C(=O)OR 8 , -OC(=O)OR 9 , -N(R 8 )2, -OC(=O)N(R 8 )2, -NR 8 C(=O)R 9 , -NR 8 C(=O)OR 9 , optionally substituted C1-C4 alkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 6 is H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C2-C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 7is an optionally substituted C3-C6 cycloalkylalkyl, or R 7 is methyl, ethyl, -CH2CF3, -CH2-cyclopropyl, or -CH2CH2OCH3; Each R 8 are independently H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; Or, two R's 8 together with the N atom to which they are attached form an optionally substituted heterocycle; Each R 9 are independently selected from optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R A1 and R A2 each independently represents H, halogen, or -OR 9 , optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 fluoroalkyl, or optionally substituted aryl; provided that R A1 and R A2 Not both are H; n is 0, 1, 2, 3, or 4; and A compound, or a pharmaceutically acceptable salt, or solvate thereof, wherein q is 0, 1, 2, 3, or 4. [The present invention 1002] R 7is methyl, ethyl, -CH2CF3, -CH2-cyclopropyl, or -CH2CH2OCH3, or a pharmaceutically acceptable salt, or solvate thereof. [The present invention 1003] R 7 is an optionally substituted C3-C6 cycloalkylalkyl, or a pharmaceutically acceptable salt, or solvate thereof. [The present invention 1004] R 6 is hydrogen, an optionally substituted C1-C4 alkyl, an optionally substituted C1-C4 heteroalkyl, an optionally substituted C1-C4 fluoroalkyl, an optionally substituted C3-C6 cycloalkyl (C3-C6 cyclooalkyl), or an optionally substituted C3-C6 cycloalkylalkyl, or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1005] R 6 is an optionally substituted C1-C4 alkyl, an optionally substituted C1-C4 heteroalkyl, an optionally substituted C1-C4 fluoroalkyl, an optionally substituted C3-C6 cycloalkyl, or an optionally substituted C3-C6 cycloalkylalkyl, or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1006] R 6 1004. The compound of the present invention, or a pharmaceutically acceptable salt, or solvate thereof, wherein is methyl. [The present invention 1007] A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof: TIFF2024156774000004.tif38128 formula, Each Z is independently N or CR 1 with the proviso that at least one Z is N; Each R 1 are independently H, halogen, -CN, -OR 8 , -SR8 , -S(=O)R 9 , -S(=O)2R 9 , -S(=O)2N(R 8 )2, -NR 8 S(=O)2R 9 , -C(=O)R 9 , -OC(=O)R 9 , -C(=O)OR 8 , -OC(=O)OR 9 , -N(R 8 )2, -OC(=O)N(R 8 )2, -NR 8 C(=O)R 9 , -NR 8 C(=O)OR 9 , optionally substituted C1-C4 alkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 3 But, -CN, -OR 8 , -SR 8 , optionally substituted C1-C4 alkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted —O—C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted —O—C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted —O—C3-C6 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 4 But halogen, -CN, -OR 8 , optionally substituted C1-C4 alkyl, optionally substituted C1-C4 fluoroalkyl, or optionally substituted C1-C4 heteroalkyl; Each R 5 are independently H, halogen, -CN, -OR 8 , -SR 8 , -N(R 8)2, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; Each R 2 are independently H, halogen, -CN, -OR 8 , -SR 8 , -S(=O)R 9 , -S(=O)2R 9 , -S(=O)2N(R 8 )2, -NR 8 S(=O)2R 9 , -C(=O)R 9 , -OC(=O)R 9 , -C(=O)OR 8 , -OC(=O)OR 9 , -N(R 8 )2, -OC(=O)N(R 8 )2, -NR 8 C(=O)R 9 , -NR 8 C(=O)OR 9 , optionally substituted C1-C4 alkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 6 is H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, Optionally substituted C1-C4 fluoroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C2-C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 7is optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C2-C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; Or, R 6 and R 7 together with the N atom to which they are attached form an optionally substituted heterocycle; Each R 8 are independently H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; Or, two R's 8 together with the N atom to which they are attached form an optionally substituted heterocycle; Each R 9 are independently selected from optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R A1 and R A2 each independently represents H, halogen, or -OR 9 , optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 fluoroalkyl, or optionally substituted aryl; provided that R A1 and R A2 Not both are H; n is 0, 1, 2, 3, or 4; and A compound, or a pharmaceutically acceptable salt, or solvate thereof, wherein q is 0, 1, 2, 3, or 4. [The present invention 1008] R 7 is an optionally substituted C1-C4 alkyl, an optionally substituted C1-C4 heteroalkyl, an optionally substituted C1-C4 fluoroalkyl, an optionally substituted C3-C6 cycloalkyl, or an optionally substituted C3-C6 cycloalkylalkyl, or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1009] R 7 is methyl, ethyl, -CH2CF3, -CH2-cyclopropyl, or -CH2CH2OCH3, or a pharmaceutically acceptable salt, or solvate thereof. [The present invention 1010] R 7 is optionally substituted C1-C4 alkyl, or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1011] R 7 is an optionally substituted C1-C4 heteroalkyl, or a pharmaceutically acceptable salt, or solvate thereof. [The present invention 1012] R 7 is an optionally substituted C3-C6 cycloalkyl, or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1013] R 7 is optionally substituted C1-C4 alkyl, or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1014] R 7 is an optionally substituted C3-C6 cycloalkylalkyl, or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1015] R 6 is H, an optionally substituted C1-C4 alkyl, an optionally substituted C1-C4 heteroalkyl, an optionally substituted C1-C4 fluoroalkyl, an optionally substituted C3-C6 cycloalkyl, or an optionally substituted C3-C6 cycloalkylalkyl, or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1016] R 6 The compound of the present invention 1004 or 1015, or a pharmaceutically acceptable salt or solvate thereof, wherein is optionally substituted C1-C4 alkyl. [The present invention 1017] R 6 1016. The compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, wherein is methyl. [The present invention 1018] R 6 The compound of the present invention 1004 or 1015, or a pharmaceutically acceptable salt or solvate thereof, wherein is optionally substituted C1-C4 heteroalkyl. [The present invention 1019] R 6 The compound of the present invention 1004 or 1015, or a pharmaceutically acceptable salt or solvate thereof, wherein is optionally substituted C1-C4 fluoroalkyl. [The present invention 1020] R 6 The compound of the present invention 1004 or 1015, or a pharmaceutically acceptable salt or solvate thereof, wherein is optionally substituted C3-C6 cycloalkyl. [The present invention 1021] R 6 The compound of the present invention 1004 or 1015, or a pharmaceutically acceptable salt or solvate thereof, wherein is optionally substituted C3-C6 cycloalkylalkyl. [The present invention 1022] R 6The compound of the present invention 1004 or 1015, or a pharmaceutically acceptable salt or solvate thereof, wherein is H. [The present invention 1023] Any one of compounds 1001 to 1022 of the present invention, which is TIFF2024156774000005.tif65128, or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1024] Any one of compounds 1001 to 1023 of the present invention, which is TIFF2024156774000006.tif37128, or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1025] Any of compounds 1001 to 1023 of the present invention, which is TIFF2024156774000007.tif36128, or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1026] Any of the compounds of the present invention 1001 to 1024, or a pharmaceutically acceptable salt or solvate thereof, which is TIFF2024156774000008.tif38128. [The present invention 1027] Each R 1 are independently H, halogen, -CN, -OR 8 , optionally substituted C1-C4 alkyl, optionally substituted C1-C4 fluoroalkyl, or optionally substituted C1-C4 heteroalkyl, or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1028] Each R 1 are independently H, halogen, -OR 8 , optionally substituted C1-C4 alkyl, or optionally substituted C1-C4 heteroalkyl, or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1029] R 3 But, -CN, -OR 8, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted —O—C3-C6 cycloalkyl, or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1030] R 3 But, -OR 8 , optionally substituted C1-C4 alkyl, optionally substituted C1-C4 fluoroalkyl, or optionally substituted C1-C4 heteroalkyl, or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1031] R 3 is an optionally substituted C1-C4 alkyl, or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1032] R 3 is methyl, ethyl, propyl, or butyl, or a pharmaceutically acceptable salt, or solvate thereof. [The present invention 1033] R 3 -OR 8 The compound of any one of the present inventions 1001 to 1030, or a pharmaceutically acceptable salt or solvate thereof, wherein [The present invention 1034] R 8 is an optionally substituted C1-C4 alkyl, an optionally substituted C1-C4 heteroalkyl, an optionally substituted C1-C4 fluoroalkyl, or an optionally substituted C3-C6 cycloalkyl, or a pharmaceutically acceptable salt or solvate thereof. [This invention 1035] R 4 But halogen, -CN, -OR 8, optionally substituted C1-C4 alkyl, or optionally substituted C1-C4 fluoroalkyl, or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1036] R 4 is halogen, optionally substituted C1-C4 alkyl, or optionally substituted C1-C4 fluoroalkyl, or a pharmaceutically acceptable salt or solvate thereof. [This invention 1037] R 4 The compound of the present invention 1035, or a pharmaceutically acceptable salt or solvate thereof, wherein is halogen. [The present invention 1038] R 4 The compound of the present invention 1037, or a pharmaceutically acceptable salt or solvate thereof, wherein is -Cl, -Br, -F, or -I. [This invention 1039] R 4 -OR 8 1035, or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1040] R 8 is H, an optionally substituted C1-C4 alkyl, or an optionally substituted C1-C4 fluoroalkyl, or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1041] R 4 is optionally substituted C1-C4 alkyl, or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1042] R 4 is methyl, ethyl, propyl, or butyl, or a pharmaceutically acceptable salt, or solvate thereof. [This invention 1043] R 4is an optionally substituted C1-C4 fluoroalkyl, or a pharmaceutically acceptable salt or solvate thereof. [This invention 1044] R 4 is -CF3, -CF2CH3, or -CH2CF3, or a pharmaceutically acceptable salt or solvate thereof. [This invention 1045] R 5 H, halogen, -CN, -OR 8 , -SR 8 , -N(R 8 )2, optionally substituted C1-C4 alkyl, or optionally substituted C1-C4 fluoroalkyl, or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1046] R 5 The compound of the present invention 1045, or a pharmaceutically acceptable salt or solvate thereof, wherein is H. [This invention 1047] R 5 The compound of the present invention 1045, or a pharmaceutically acceptable salt or solvate thereof, wherein is halogen. [This invention 1048] R 5 1047. The compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, wherein is -Cl, -Br, -F, or -I. [This invention 1049] R 5 -OR 8 1045, or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1050] R 8 is H, optionally substituted C1-C4 alkyl, or optionally substituted C1-C4 fluoroalkyl, the compound of the present invention 1049, or a pharmaceutically acceptable salt or solvate thereof. [This invention 1051] R 5is optionally substituted C1-C4 alkyl, or a pharmaceutically acceptable salt or solvate thereof. [This invention 1052] R 5 is methyl, ethyl, propyl, or butyl, or a pharmaceutically acceptable salt, or solvate thereof. [This invention 1053] R 5 is an optionally substituted C1-C4 fluoroalkyl, or a pharmaceutically acceptable salt or solvate thereof. [This invention 1054] R 5 is -CF3, -CF2CH3, or -CH2CF3, or a pharmaceutically acceptable salt, or solvate thereof. [This invention 1055] The compound has the structure of formula (Ia): Any of the compounds of the present invention 1001 to 1022, or a pharmaceutically acceptable salt or solvate thereof, having TIFF2024156774000009.tif32128. [This invention 1056] The compound has the structure of formula (Ib): Any of the compounds of the present invention 1001 to 1022, or a pharmaceutically acceptable salt or solvate thereof, having TIFF2024156774000010.tif32128. [This invention 1057] Each R 2 are independently H, halogen, -OR 8 , optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, or optionally substituted C1-C4 fluoroalkyl, or a pharmaceutically acceptable salt or solvate thereof. [This invention 1058] The compound of any one of claims 1001 to 1057, or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0, 1, or 2. [This invention 1059] R A1 is H, an optionally substituted C1-C4 alkyl, an optionally substituted C1-C4 heteroalkyl, or an optionally substituted C1-C4 fluoroalkyl, or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1060] R A1 is H, or a pharmaceutically acceptable salt, or solvate thereof. [The present invention 1061] R A1 is optionally substituted C1-C4 alkyl, or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1062] R A2 is H, an optionally substituted C1-C4 alkyl, an optionally substituted C1-C4 heteroalkyl, or an optionally substituted C1-C4 fluoroalkyl, or a pharmaceutically acceptable salt or solvate thereof. [This invention 1063] R A2 is optionally substituted C1-C4 alkyl, or a pharmaceutically acceptable salt or solvate thereof. [This invention 1064] R A2 is methyl, ethyl, propyl, or butyl, or a pharmaceutically acceptable salt or solvate thereof. [This invention 1065] R A2 The compound of the present invention 1064, or a pharmaceutically acceptable salt or solvate thereof, wherein is ethyl. [The present invention 1066] R A2 is an optionally substituted C1-C4 heteroalkyl, or a pharmaceutically acceptable salt or solvate thereof. [This invention 1067] R A2 is an optionally substituted C1-C4 fluoroalkyl, or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1068] R A2 The compound of the present invention 1062, or a pharmaceutically acceptable salt or solvate thereof, wherein is H. [This invention 1069] R 4 The compound of any one of the present inventions 1001 to 1034 and 1045 to 1068, or a pharmaceutically acceptable salt or solvate thereof, wherein is chlorine. [The present invention 1070] The compound has the structure of formula (Ic), (Id), or (Ie): A compound of the present invention 1001 or 1007 having TIFF2024156774000011.tif108128, or a pharmaceutically acceptable salt or solvate thereof. [This invention 1071] R 7 The compound of any one of the present invention 1003, 1006, 1008, and 1015 to 1070, or a pharmaceutically acceptable salt or solvate thereof, wherein is -CH2-cyclobutyl. [This invention 1072] The compound of any one of the present inventions 1001 to 1071, or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0. [This invention 1073] Each R 8 are independently H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C2-C 10 heterocycloalkyl, and each R 9 are independently optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C2-C 10The compound of any one of 1001 to 1072 of the present invention, or a pharmaceutically acceptable salt or solvate thereof, which is heterocycloalkyl. [This invention 1074] The optional substituents are independently D, halogen, —CN, —NH, —NH(CH), —N(CH), —OH, —COH, —CO(C-C alkyl), —CHNH, —C(═O)NH, —C(═O)NH(C-C alkyl), —C(═O)N(C-C alkyl), —S(═O)NH, —S(═O)NH(C-C alkyl), —S(═O)N(C-C alkyl). A compound of any one of claims 1001 to 1073 of the present invention, selected from -S(=O)C1-C4 alkyl, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 fluoroalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, -S(=O)C1-C4 alkyl, and -S(=O)2C1-C4 alkyl, or a pharmaceutically acceptable salt or solvate thereof. [This invention 1075] Any of compounds 1001 to 1074 of the present invention, or a pharmaceutically acceptable salt or solvate thereof, wherein the optional substituents are independently selected from D, halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CH2NH2, -CF3, -OCH3, and -OCF3. [This invention 1076] A compound of any one of 1001 to 1073 of the present invention, or a pharmaceutically acceptable salt or solvate thereof, having no optional substituents. [This invention 1077] 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide; 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-fluoro-6-methylpyridin-2-yl)benzenesulfonamide; and 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide A compound selected from: or a pharmaceutically acceptable salt or solvate thereof. [This invention 1078] 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-7-methylquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide; 2-chloro-N-(5-(8-ethyl-2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)quinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide; 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-ethylpyridin-2-yl)benzenesulfonamide; N-(5-(8-ethyl-2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)quinazolin-6-yl)-6-methoxypyridin-2-yl)-2-methylbenzenesulfonamide; N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2-methylbenzenesulfonamide; 2-chloro-N-(5-(8-ethyl-2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)quinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide; 2-chloro-N-(5-(8-(1,1-difluoroethyl)-2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide; 2-chloro-N-(5-(8-ethyl-2-(((1r,4r)-4-(ethyl(methyl)amino)cyclohexyl)amino)quinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide; 2-chloro-N-(5-(8-ethyl-2-(((1r,4r)-4-(methyl(2,2,2-trifluoroethyl)amino)cyclohexyl)amino)quinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide; 2-chloro-N-(5-(8-ethyl-2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)quinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide; 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide; 2-chloro-N-(5-(2-(((1r,4r)-4-((cyclobutylmethyl)(methyl)amino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide; 2-chloro-N-(5-(8-(1,1-difluoroethyl)-2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide; 2-chloro-N-(5-(8-ethyl-2-(((1r,4r)-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)amino)quinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide; 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-methylquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide; 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-(trifluoromethyl)quinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide; 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-(methoxymethyl)quinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide; 2-chloro-N-(5-(2-(((1s,4s)-4-(dimethylamino)cyclohexyl)amino)-8-methylquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide; 2-chloro-N-(5-(2-(((1s,4s)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide; 2-chloro-N-(5-(2-(((1s,4s)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide; 2-chloro-N-(5-(2-(((1s,4s)-4-(dimethylamino)-4-methylcyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide; 2-chloro-N-(5-(2-(((1s,4s)-4-(dimethylamino)-4-methylcyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide; 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-methylquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide; and 2-chloro-N-(5-(2-(((1s,4s)-4-(dimethylamino)cyclohexyl)amino)-8-methylquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide A compound selected from: or a pharmaceutically acceptable salt or solvate thereof. [This invention 1079] N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-4-methylpyrimidin-2-yl)-2-chlorobenzenesulfonamide; N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide; N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)pyrazin-2-yl)-2-chlorobenzenesulfonamide; N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)phenyl)-2-chlorobenzenesulfonamide; N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)pyridin-2-yl)-2-chlorobenzenesulfonamide; N-(6-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)pyridin-3-yl)-2-chlorobenzenesulfonamide; N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-1H-pyrazol-3-yl)-2-chlorobenzenesulfonamide; N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-hydroxyquinazolin-6-yl)-3-methylphenyl)-2-chloro-N-methylbenzenesulfonamide; N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-methylphenyl)-2-chloro-N-methylbenzenesulfonamide; N-(6-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)pyridazin-3-yl)-2-chlorobenzenesulfonamide; N-(2-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)pyrimidin-5-yl)-2-chlorobenzenesulfonamide; N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-ethylphenyl)-2-chlorobenzenesulfonamide; N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-fluorophenyl)-2-chlorobenzenesulfonamide; N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-methoxyquinazolin-6-yl)-3-methylphenyl)-2-chlorobenzenesulfonamide; N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide; N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-4-methylthiazol-2-yl)-2-chlorobenzenesulfonamide; N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)pyrimidin-2-yl)-2-chlorobenzenesulfonamide; N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-isopropylquinazolin-6-yl)-1-methyl-1H-pyrazol-3-yl)-2-chlorobenzenesulfonamide; N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)thiazol-2-yl)-2-chlorobenzenesulfonamide; N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-2-fluoro-5-methoxyphenyl)-2-chlorobenzenesulfonamide; N-(1-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-1H-pyrazol-4-yl)-2-chlorobenzenesulfonamide; N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)isoxazol-3-yl)-2-chlorobenzenesulfonamide; N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-methoxyquinazolin-6-yl)-1-methyl-1H-pyrazol-3-yl)-2-chlorobenzenesulfonamide; N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-4-methoxypyrimidin-2-yl)-2-chlorobenzenesulfonamide; N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-propylquinazolin-6-yl)-1-methyl-1H-pyrazol-3-yl)-2-chlorobenzenesulfonamide; N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)-3-fluorophenyl)-2-chlorobenzenesulfonamide; N-(6-(2-(((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)pyridazin-3-yl)-2-chlorobenzenesulfonamide; N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide; N-(6-(2-(((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)-5-fluoropyridin-3-yl)-2-chlorobenzenesulfonamide; N-(6-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-5-fluoropyridin-3-yl)-2-chlorobenzenesulfonamide; N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)-2,5-difluorophenyl)-2-chlorobenzenesulfonamide; N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)-3-fluoropyridin-2-yl)-2-chlorobenzenesulfonamide; N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-fluoropyridin-2-yl)-2-chlorobenzenesulfonamide; N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)-2,3-difluorophenyl)-2-chlorobenzenesulfonamide; N-(4-(3-(((1r,4r)-4-aminocyclohexyl)amino)isoquinolin-7-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide; (S)-2-amino-N-((1r,4S)-4-((6-(4-((2-chlorophenyl)sulfonamido)-3-fluorophenyl)-8-ethylquinazolin-2-yl)amino)cyclohexyl)-3-methylbutanamide; N-((1r,4r)-4-((6-(4-((2-chlorophenyl)sulfonamido)-3-fluorophenyl)-8-ethylquinazolin-2-yl)amino)cyclohexyl)acetamide; 2-chloro-N-(4-(8-ethyl-2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)quinazolin-6-yl)-2-fluorophenyl)benzenesulfonamide; 2-chloro-N-(6-(8-ethyl-2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)quinazolin-6-yl)pyridazin-3-yl)benzenesulfonamide; N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)-3,5-difluorophenyl)-2-chlorobenzenesulfonamide; N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-2,6-difluorophenyl)-2-chlorobenzenesulfonamide; 2-chloro-N-(6-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)pyridazin-3-yl)benzenesulfonamide; N-(6-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-5-methoxypyridazin-3-yl)-2-chlorobenzenesulfonamide; N-(6-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-4-methoxypyridazin-3-yl)-2-chlorobenzenesulfonamide; N-(6-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-5-methylpyridazin-3-yl)-2-chlorobenzenesulfonamide; N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)-4-methylpyrimidin-2-yl)-2-chlorobenzenesulfonamide; 2-chloro-N-(4-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-2-fluorophenyl)benzenesulfonamide; N-(4-(2-(((1R,3R,4S)-4-amino-3-methylcyclohexyl)amino)-8-ethylquinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide; N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-2-fluoro-3-methylphenyl)-2-chlorobenzenesulfonamide; N-(4-(2-(((1R,3S)-3-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide; (S)-2-chloro-N-(4-(8-ethyl-2-(piperidin-3-ylamino)quinazolin-6-yl)-2-fluorophenyl)benzenesulfonamide; N-(4-(2-(((1R,3R,4R)-4-amino-3-methylcyclohexyl)amino)-8-ethylquinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide; N-(4-(2-(((1R,3S)-3-aminocyclohexyl)amino)quinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide; (S)-2-chloro-N-(2-fluoro-4-(2-(piperidin-3-ylamino)quinazolin-6-yl)phenyl)benzenesulfonamide; N-(4-(2-(((1R,3R)-3-aminocyclopentyl)amino)quinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide; N-(4-(2-(((1R,3R)-3-aminocyclopentyl)amino)-8-ethylquinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide; N-(4-(2-(((1R,3S)-3-aminocyclopentyl)amino)-8-ethylquinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide; N-(4-(2-(((1R,3S)-3-aminocyclopentyl)amino)quinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide; N-(4-(2-((4-aminobicyclo[2.2.2]octan-1-yl)amino)quinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide; N-(4-(2-(((2r,5r)-5-aminooctahydropentalen-2-yl)amino)-8-ethylquinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide; N-(4-(2-(((2r,5r)-5-aminooctahydropentalen-2-yl)amino)-8-ethylquinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide; N-(4-(2-(((2s,5s)-5-aminooctahydropentalen-2-yl)amino)-8-ethylquinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide; N-(4-(2-(((2s,5s)-5-aminooctahydropentalen-2-yl)amino)quinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide; N-(4-(2-((4-aminobicyclo[2.2.1]heptan-1-yl)amino)quinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide; N-(4-(2-((4-aminobicyclo[2.2.2]octan-1-yl)amino)-8-ethylquinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide; 2-chloro-N-(4-(8-ethyl-2-(((1r,4r)-4-(pyrrolidin-1-yl)cyclohexyl)amino)quinazolin-6-yl)-2-fluorophenyl)benzenesulfonamide; N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)-1,3,4-thiadiazol-2-yl)-2-chlorobenzenesulfonamide; N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-7-methylquinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide; N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-4-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide; N-(6-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-5-methoxypyridin-3-yl)-2-chlorobenzenesulfonamide; N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methylpyrazin-2-yl)-2-chlorobenzenesulfonamide; 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-fluoropyridin-2-yl)benzenesulfonamide; N-(6-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-5-ethylpyridazin-3-yl)-2-chlorobenzenesulfonamide; and N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methoxypyrazin-2-yl)-2-chlorobenzenesulfonamide A compound selected from: or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1080] 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-fluoroquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide; 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide; 2-chloro-N-(3-fluoro-6-methoxy-5-(2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)quinazolin-6-yl)pyridin-2-yl)benzenesulfonamide; 2-chloro-N-(5-(2-(((1S,2S,4S)-4-(dimethylamino)-2-fluorocyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide; 2,3-Dichloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide; 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-3-fluoro-6-methylpyridin-2-yl)benzenesulfonamide; 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-4-methoxypyrimidin-2-yl)benzenesulfonamide; 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-fluoroquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide; 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-fluoroquinazolin-6-yl)-3-fluoro-6-methylpyridin-2-yl)benzenesulfonamide; 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methoxypyrazin-2-yl)benzenesulfonamide; 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methylpyridin-2-yl)-3-fluorobenzenesulfonamide; 2-chloro-N-(6-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-5-methoxypyridazin-3-yl)benzenesulfonamide; 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methylpyridin-2-yl)-3-methylbenzenesulfonamide; 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethyl-7-fluoroquinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide; 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethyl-7-fluoroquinazolin-6-yl)-3-fluoro-6-methylpyridin-2-yl)benzenesulfonamide; and 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethyl-7-fluoroquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide A compound selected from: or a pharmaceutically acceptable salt or solvate thereof. [This invention 1081] Formula (I * ): TIFF2024156774000012.tif38128, wherein Each Z is independently N or CR 1 with the proviso that at least one Z is N; Each R 1 are independently hydrogen, fluorine, chlorine, or cyano; R 3 is -CN, optionally substituted C1-C3 alkyl, optionally substituted C3-C4 cycloalkyl, optionally substituted -O-C3-C4 cycloalkyl, or optionally substituted -O-C1-C3 alkyl; R 4 is chlorine, -CH3, cyano, -OCH3, or CF3; Each R 5 are independently hydrogen, chlorine, -CH3, cyano, -OCH3, or CF3; Each R 2 are independently hydrogen, fluorine, -CH3, or -OH; R 6 is H, or C1-C3 alkyl; R 7is optionally substituted C1-C3 alkyl; C1-C3 fluoroalkyl, C1-C3 heteroalkyl, or C3-C4 cycloalkyl-C1-C3 alkyl; Or, R 6 and R 7 together with the N atom to which they are attached form an optionally substituted 4- to 6-membered ring, the remainder of the ring atoms being carbon; R A1 and R A2 are each independently H, optionally substituted C-C alkyl, C-C fluoroalkyl, optionally substituted C-C heteroalkyl, or optionally substituted C-C cycloalkyl-C-C alkyl, with the proviso that R A1 and R A2 are not both hydrogen; n is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4; The compound of the present invention 1007, or a pharmaceutically acceptable salt or solvate thereof. [This invention 1082] R A1 and R A2 are each independently H, C-C fluoroalkyl, C-C heteroalkyl, C-C cycloalkyl-C-C alkyl, or optionally substituted C-C alkyl, with the proviso that R A1 and R A2 The compound of the present invention 1081, or a pharmaceutically acceptable salt or solvate thereof, wherein both of are not hydrogen. [This invention 1083] The compound has the formula (Ib * ) structure: A compound of the present invention 1081 or 1082, or a pharmaceutically acceptable salt or solvate thereof, having TIFF2024156774000013.tif32128. [This invention 1084] The compound has the formula (Ic * ) structure: A compound of the present invention 1081 or 1082, or a pharmaceutically acceptable salt or solvate thereof, having TIFF2024156774000014.tif32128. [This invention 1085] R 6 is H or methyl and R 7 The compound of any one of claims 1081 to 1084, or a pharmaceutically acceptable salt or solvate thereof, wherein is methyl, ethyl, CH2CF3, CH2-cyclopropyl, or CH2CH2OCH3. [The present invention 1086] R 6 is methyl and R 7 The compound of any one of claims 1081 to 1084, or a pharmaceutically acceptable salt or solvate thereof, wherein is methyl, ethyl, CH2CF3, CH2-cyclopropyl, or CH2CH2OCH3. [This invention 1087] R 3 , R 7 , R A1 , and R A2 or a pharmaceutically acceptable salt or solvate thereof, wherein one or more of the optional substituents are each independently selected from fluorine, —OH, —OCH3, —OCH2CH3, —OCH2CH2CH3, —NH2, —NH(CH3), and —N(CH3)2. [This invention 1088] R 3 , R 7 , R A1 , and R A2 or a pharmaceutically acceptable salt or solvate thereof, wherein one or more of the optional substituents are each independently selected from fluorine, —OH, —OCH3, —OCH2CH3, —OCH2CH2CH3, —NH(CH3), and —N(CH3)2. [This invention 1089] R 7 , R A1 , and R A2or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1090] R A1 is H or C1-C3 alkyl, or a pharmaceutically acceptable salt or solvate thereof. [This invention 1091] The compound of any one of 1081 to 1090 of the present invention, wherein q is 0, or a pharmaceutically acceptable salt or solvate thereof. [This invention 1092] Each Z is independently N or CR 1 with the proviso that at least one Z is N; Each R 1 are independently hydrogen, fluorine, chlorine, or cyano; R 3 is C1-C3 alkyl or -OC1-C3 alkyl; R A1 is hydrogen, or C1-C3 alkyl; R A2 is C1-C3 alkyl, C1-C3 fluoroalkyl, or C1-C3 heteroalkyl; provided that R A1 and R A2 are not both hydrogen; R 4 is chlorine; Each R 5 are independently hydrogen, chlorine, -CH3, cyano, -OCH3, or CF3; n is 0, 1, 2, 3, or 4; and The compound of any one of 1081 to 1086 of the present invention, wherein q is 0, or a pharmaceutically acceptable salt or solvate thereof. [This invention 1093] Expression(Id * ): Any of the compounds of the present invention 1001 to 1022, or a pharmaceutically acceptable salt or solvate thereof, having TIFF2024156774000015.tif46128. [This invention 1094] R 3 is C1-C3 alkyl or -OC1-C3 alkyl; R A1 is fluorine, chlorine, hydrogen, or C1-C3 alkyl; R A2 is C1-C3 alkyl, -OC1-C3 alkyl, hydrogen, C1-C3 fluoroalkyl, fluorine, chlorine; Each Z is independently N or CR 1 with the proviso that at least one Z is N; Each R 5 are independently hydrogen, chlorine, fluorine, or C1-C3 alkyl; R 4 is chlorine or C1-C3 alkyl; C1-C3 heteroalkyl; provided that R A1 and R A2 are not both hydrogen; Each R 2 are independently hydrogen or fluorine; R 1 is hydrogen or fluorine, or a pharmaceutically acceptable salt or solvate thereof. [This invention 1095] The compound of the present invention 1093 or 1094, or a pharmaceutically acceptable salt or solvate thereof, wherein one Z is nitrogen. [This invention 1096] The compound of the present invention 1093 or 1094, or a pharmaceutically acceptable salt or solvate thereof, wherein two Z's are nitrogen. [This invention 1097] The compound of the present invention 1093 or 1094, or a pharmaceutically acceptable salt or solvate thereof, wherein three Z's are nitrogen. [This invention 1098] The compound of the present invention 1093 or 1094, which is TIFF2024156774000016.tif19128, or a pharmaceutically acceptable salt or solvate thereof. [This invention 1099] Each R 5 are independently hydrogen, chlorine, fluorine, or -CH3; R 4 is chlorine or -CH3; R 3 is -CH3, -CH2CH3, or -OCH3; R A1 is fluorine, chlorine, hydrogen, or -CH3; R A2 is hydrogen, -CH3, -CH2CH3, -OCH3, CF3, CF2CH3, CH2OCH3 or fluorine; provided that R A1 and R A2 are not both hydrogen; Each R 2 are independently hydrogen or fluorine; and R 1 The compound of any one of 1093 to 1098 of the present invention, or a pharmaceutically acceptable salt or solvate thereof, wherein is hydrogen or fluorine. [The present invention 1100] Each R 5 is hydrogen; R 4 is chlorine; Each R 2 is hydrogen; and R 1 The compound of any one of claims 1093 to 1099 of the present invention, or a pharmaceutically acceptable salt or solvate thereof, wherein is hydrogen. [The present invention 1101] A pharmaceutical composition comprising any one of the compounds of the present invention 1001 to 1100, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients. [The present invention 1102] A method for treating or ameliorating the effects of a disease associated with altered IRE1 signaling, comprising administering to a subject in need thereof any of the compounds of the present invention 1001 to 1100, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of the present invention 1101. [The present invention 1103] The method of claim 1102, wherein the disease is cancer. [The present invention 1104] The method of claim 1103, wherein the cancer is a solid cancer or a blood cancer. [This invention 1105] The method of claim 1104, wherein the cancer is ovarian cancer, bladder cancer, breast cancer, or lung cancer. [The present invention 1106] The method of claim 1105, wherein the breast cancer is triple-negative breast cancer (TNBC). [This invention 1107] The method of claim 1104, wherein the cancer is leukemia, lymphoma, or multiple myeloma. [This invention 1108] A compound of any one of the present inventions 1001 to 1100, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of the present invention 1101, for use as a medicine. [This invention 1109] A compound of any one of claims 1001 to 1100, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of claim 1101, for use in treating cancer.

[0012] BRIEF DESCRIPTION OF THE DRAWINGS The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings. [Brief explanation of the drawings]

[0013] [Figure 1]An illustration of the domain structure of IRE1a is shown, showing the signal peptide (P) and transmembrane (TM) regions. [Figure 2] Example alignments of C-terminal half-IRE1 orthologs from yeast (ScIre1), human (HsIre1), mouse (MmIre1), and rat (RnIRE1) are shown. Stars indicate kinase domain dimer interface residues. Circles indicate kinase extension nuclease (KEN) domain dimer interface residues. Triangles indicate putative nuclease active site residues. [Figure 3] Figure 3A depicts a comparison of mean plasma concentrations of Compound A of the present disclosure after intravenous (IV), oral (PO), and intraperitoneal (IP) dosing. Figure 3B depicts a comparison of mean plasma concentrations of Compound C of the present disclosure after intravenous (IV), oral (PO), and intraperitoneal (IP) dosing. [Figure 4] Figure 4A depicts a comparison of mean plasma concentrations of Compound B of the present disclosure after intravenous (IV), oral (PO), and intraperitoneal (IP) dosing. Figure 4B depicts a comparison of mean plasma concentrations of Compound D of the present disclosure after intravenous (IV), oral (PO), and intraperitoneal (IP) dosing. [Figure 5] 1 depicts plots of gene expression analysis in pancreatic tissue (top plot) and salivary tissue (bottom plot) after treatment with control, Compound B, Compound C or Compound D. [Figure 6] Figure 6A shows plots from a pharmacokinetic assay of the occurrence of XBP1 splicing events in 293T cells treated with Compound A or Compound C after stress induction. Figure 6B shows plots from a pharmacokinetic assay of the occurrence of XBP1 splicing events in 293T cells treated with Compound B or Compound D after stress induction. [Figure 7] 1 depicts plots of compound C-treated metastatic ovarian tumor cells, dendritic cells (DCs), and CD4+ T cells isolated by FACS and assayed for gene expression. [Figure 8]1 depicts immunoblot analysis of lysates from tunicamycin-treated 293T cells optionally treated with Compound C. Cells were stained for IRE1a, phosphorylated IRE1a, XBP1, and TBP. [Figure 9] 1 depicts plots of metastatic ovarian tumor cells and dendritic cells (DCs) treated with Compound D that were isolated by FACS and assayed for gene expression. DETAILED DESCRIPTION OF THE INVENTION

[0014] Detailed Description term Unless otherwise stated, the following terms used in this application have the definitions given below. The use of the term "including" as well as other forms such as "include," "includes," and "included" is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0015] As used herein and in the appended claims, the singular forms "a," "an," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to "an agent" includes a plurality of such agents; a reference to "the cell" includes a reference to one or more cells (or cells) and equivalents thereof known to those skilled in the art, etc. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulas, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about," when referring to a numerical value or numerical range, means that the referenced numerical value or numerical range is approximate within experimental variability (or within statistical experimental error), and thus the numerical value or numerical range may vary from 1% to 15% of the specified numerical value or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other specific embodiments, for example, any composition of matter, composition, method, or process described herein, etc., may "consist" or "consist essentially of" the described features.

[0016] definition As used in this specification and the appended claims, unless specified to the contrary, the following terms have the meanings indicated below.

[0017] "Amino" refers to the group -NH2.

[0018] "Cyano" refers to the group -CN.

[0019] "Nitro" refers to the -NO2 group.

[0020] "Oxa" refers to the group --O--.

[0021] "Oxo" refers to the group =O.

[0022] "Thioxo" refers to the =S group.

[0023] "Imino" refers to the =NH group.

[0024] "Oximo" refers to the =N-OH group.

[0025] As used herein, C1-C x C1-C2, C1-C3... C1-C x By way of example only, a group designated as "C1-C4" indicates that there are from 1 to 4 carbon atoms in the moiety, i.e., a group containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. Thus, by way of example only, "C1-C4 alkyl" indicates that there are from 1 to 4 carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.

[0026] An "alkyl" group refers to an aliphatic hydrocarbon group. An alkyl group may be branched or straight-chain. Unless otherwise specified, an "alkyl" group contains 1 to 10 carbon atoms, i.e., C1-C 10Alkyl preferably has 1 to 6 carbon atoms. Whenever it appears herein, a numerical range such as "1 to 10" refers to each integer within the given range; for example, "1 to 10 carbon atoms" means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, and so on, up to and including 10 carbon atoms, although this definition also encompasses the appearance of the term "alkyl" without a specified numerical range. In some embodiments, alkyl is C1-C6 alkyl. In one aspect, alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. Exemplary alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl. Alkyl includes alkenyl (one or more carbon-carbon double bonds) and alkynyl (one or more carbon-carbon triple bonds).

[0027] An "alkylene" group refers to a divalent alkyl group. Any of the monovalent alkyl groups described above may be alkylene by removing a hydrogen atom from the alkyl. Unless otherwise specified, alkylene is a C1-C6 alkylene. In other embodiments, alkylene is a C1-C4 alkylene. In some embodiments, alkylene contains 1 to 4 carbon atoms (e.g., a C1-C4 alkylene). In other embodiments, alkylene contains 1 to 3 carbon atoms (e.g., a C1-C3 alkylene). In other embodiments, alkylene contains 1 to 2 carbon atoms (e.g., a C1-C2 alkylene). In other embodiments, alkylene contains 1 carbon atom (e.g., a C1 alkylene). In other embodiments, alkylene contains 2 carbon atoms (e.g., a C2 alkylene). In other embodiments, alkylene contains 2 to 4 carbon atoms (e.g., a C2-C4 alkylene). Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like.

[0028] An "alkoxy" group refers to a (alkyl)O- group, where alkyl is as defined herein.

[0029] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2 π-electrons, where n is an integer. The term "aromatic" includes both carbocyclic aryl ("aryl", e.g., phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of carbon atoms) groups.

[0030] The term "carbocyclic" or "carbocycle" refers to a ring or ring system in which the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocycle from "heterocyclic" rings or "heterocycles," in which the ring backbone contains at least one atom other than carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. Carbocycles include cycloalkyl and aryl.

[0031] As used herein, the term "aryl" refers to an aromatic ring in which each atom forming the ring is a carbon atom. In one aspect, aryl is phenyl or naphthyl. In some embodiments, aryl is phenyl. Unless otherwise specified, aryl is C6-C 10 Depending on the structure, the aryl group may be a mono- or di-group (i.e., an arylene group).

[0032] The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic, non-aromatic group, wherein each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. In some embodiments, the cycloalkyl is a spirocyclic or bridged compound. In some embodiments, the cycloalkyl is optionally fused to an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom. Unless otherwise specified, a cycloalkyl group has 3 to 10 ring atoms, preferably 3 to 6 ring atoms. In some embodiments, the cycloalkyl group is selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl, and bicyclo[1.1.1]pentyl. In some embodiments, the cycloalkyl is a C3-C6 cycloalkyl. In some embodiments, the cycloalkyl is a monocyclic cycloalkyl. Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.

[0033] The term "cycloalkylalkyl" refers to a group of the formula -R b R d In the formula, R b is an alkylene group as defined herein, and R d is a cycloalkyl moiety as defined herein. In some embodiments, the cycloalkyl alkyl moiety is C3-C 10 In such cases, C3-C 10 Cycloalkylalkyl is C3-C 10 In some embodiments, the cycloalkylalkyl moiety is a C3-C6 cycloalkylalkyl moiety. In such cases, the C3-C6 cycloalkylalkyl comprises a C3-C6 cycloalkyl group.

[0034] The term "halo" or, alternatively, "halogen" or "halide" means fluoro, chloro, bromo, or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0035] The term "haloalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced by halogen atoms. In one aspect, the fluoroalkyl is a C1-C6 fluoroalkyl.

[0036] The term "fluoroalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced by fluorine atoms. In one aspect, the fluoroalkyl is a C1-C6 fluoroalkyl. In some embodiments, the fluoroalkyl is selected from trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc.

[0037] The term "heteroalkyl," unless otherwise specified, refers to a straight- or branched-chain alkyl group containing at least one carbon atom and at least one heteroatom, such as O, N (e.g., -NH-, -N(alkyl)-), P, Si, S, and Se. In some embodiments, one or more heteroatoms can be oxidized. The heteroatoms can be located within the alkyl moiety (e.g., -CH-O-CH-); at the point of attachment to the remainder of the molecule (e.g., -S(=O)CH(CH)CH-); or a combination thereof (e.g., -NHCHCHS(=O)CH-). In one aspect, the heteroalkyl is a C-C heteroalkyl.

[0038] As used herein, the term "heteroatom" refers to an atom of any element other than carbon or hydrogen. Unless otherwise specified, a heteroatom is nitrogen, oxygen, or sulfur. In some embodiments, a heteroatom is nitrogen or oxygen. In some embodiments, a heteroatom is nitrogen.

[0039] The term "heterocycle" or "heterocyclic" refers to aromatic heterocycles (also known as heteroaryls) and heterocycloalkyl rings (also known as heteroalicyclic groups) containing 1 to 4 heteroatoms in the ring, where each heteroatom in the ring is selected from O, S, and N, and where each heterocyclic group contains 3 to 14 atoms in its ring system, including 2 to 10 carbon atoms and 1 to 4 heteroatoms, provided that no ring contains two adjacent O or S atoms. In some embodiments, the heterocycle is a monocyclic, bicyclic, polycyclic, spirocyclic, or bridged compound. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) contain rings having 3 to 10 atoms in their ring system, and aromatic heterocyclic groups contain rings having 5 to 10 atoms in their ring system. Heterocyclic groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithio ranyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindolin-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl, isoindolin-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolidinyl.Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups are either C-attached or N-attached where possible. For example, groups derived from pyrrole include both pyrrol-1-yl (N-linked) and pyrrol-3-yl (C-linked).Further, groups derived from imidazole include imidazol-1-yl or imidazol-3-yl (both N-linked) or imidazol-2-yl, imidazol-4-yl, or imidazol-5-yl (all C-linked).Heterocyclic groups include benzo-fused ring systems.Non-aromatic heterocycles may be substituted with one or two oxo (=O) moieties; for example, pyrrolidin-2-one.In some embodiments, at least one of the two rings of a bicyclic heterocycle is aromatic.In some embodiments, both rings of a bicyclic heterocycle are aromatic.

[0040] The term "heteroaryl" or, alternatively, "heteroaromatic" refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. Illustrative examples of heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls. Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, the heteroaryl contains 0-4 N atoms in the ring. In some embodiments, the heteroaryl contains 1-4 N atoms in the ring. In some embodiments, the heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl is a C1-C9 heteroaryl. In some embodiments, the monocyclic heteroaryl is a C1-C5 heteroaryl. In some embodiments, the monocyclic heteroaryl is a 5- or 6-membered heteroaryl. In some embodiments, the bicyclic heteroaryl is a C6-C9 heteroaryl.

[0041] A "heterocycloalkyl" or "heteroalicyclic" group refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl is a spirocyclic or bridged compound. In some embodiments, the heterocycloalkyl is fused with an aryl or heteroaryl. In some embodiments, the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl. The term heteroalicyclic also includes all ring forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. In one aspect, a heterocycloalkyl is a C2-C 10 In another aspect, heterocycloalkyl is a C-C 10 Heterocycloalkyl. In some embodiments, heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms, and 0-1 S atoms in the ring.

[0042] The term "bond" or "single bond" refers to a chemical bond between two atoms, or between two moieties when the atoms connected by the bond are considered to be part of a larger substructure. In one aspect, when a group described herein is a bond, the referenced group is absent, thereby allowing a bond to be formed between the remaining specified groups.

[0043] The term "moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is often recognized as a chemical entity embedded in or appended to a molecule.

[0044] The term "optionally substituted" or "substituted" means that the referenced group is optionally substituted with one or more additional groups individually and independently selected from deuterium, halogen, -CN, -NH, -NH(alkyl), -CHN(alkyl), -N(alkyl), -OH, -COH, -COalkyl, -CHNH, -C(=O)NH, -C(=O)NH(alkyl), -C(=O)N(alkyl), -S(=O)NH, -S(=O)NH(alkyl), -S(=O)N(alkyl), alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, the optional substituents are independently selected from D, halogen, -CN, -NH, -NH(CH), -N(CH), -OH, -COH, -CO(C-C alkyl), -CHNH, -C(=O)NH, -C(=O)NH(C-C alkyl), -C(=O)N(C-C alkyl), -S(=O)NH, -S(=O)NH(C-C alkyl), -S(=O)N(C-C alkyl), C-C alkyl, C-C cycloalkyl, C-C fluoroalkyl, C-C heteroalkyl, C-C alkoxy, C-C fluoroalkoxy, -SC-C alkyl, -S(=O)C-C alkyl, and -S(=O)C-C alkyl. In some embodiments, optional substituents are independently selected from D, halogen, -CN, -NH, -OH, -NH(CH), -N(CH), -CH, -CHCH, -CHNH, -CF, -OCH, and -OCF. In some embodiments, substituted groups are substituted with one or two of the foregoing groups. In some embodiments, optional substituents on aliphatic carbon atoms (acyclic or cyclic) include oxo (=O).

[0045] "Tautomer" refers to a molecule in which a proton transfer from one atom of the molecule to another atom of the same molecule is possible. The compounds presented herein may, in certain embodiments, exist as tautomers. In situations where tautomerization is possible, a chemical equilibrium of tautomers will exist. The exact ratio of tautomers depends on several factors, including physical conditions, temperature, solvent, and pH. Some examples of tautomeric equilibrium include the following: TIFF2024156774000017.tif79128

[0046] "Optional" or "optionally" means that the subsequent description may or may not occur, and that the description includes cases where the event or circumstance occurs and cases where it does not. For example, "optionally substituted aryl" means that the aryl group may be substituted or unsubstituted, and that the description includes both substituted aryl groups and aryl groups with no substitution.

[0047] " Pharmaceutically acceptable salt " includes both acid addition salt and base addition salt.The pharmaceutically acceptable salt of any one of the pyrazole compounds described herein is intended to include any pharmaceutically suitable salt form.Preferred pharmaceutically acceptable salt of the compound described herein is pharmaceutically acceptable acid addition salt and pharmaceutically acceptable base addition salt.

[0048] "Pharmaceutically acceptable acid addition salts" refer to salts which are not biologically or otherwise unsuitable and which retain the biological effectiveness and properties of the free bases formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc. Also included are salts formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc., including, for example, formic acid, 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. Exemplary salts thus include sulfate, pyrosulfate, bisulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate, and the like. Salts of amino acids, such as arginate, gluconate, and galacturonate, are also contemplated (see, e.g., Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1997)). Acid addition salts of basic compounds can be prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt according to methods and techniques well known to those skilled in the art.

[0049] "Pharmaceutically acceptable base addition salts" refer to salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise unsuitable. These salts are prepared from the addition of inorganic or organic bases to the free acids. Pharmaceutically acceptable base addition salts can be formed with metals or amines, such as alkali or 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, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylmine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. See Berge et al., supra.

[0050] "Prodrug" is intended to refer to a compound that can be converted into a biologically active compound described herein under physiological conditions or by solvolysis. Thus, the term "prodrug" refers to a pharmaceutically acceptable precursor of a biologically active compound. A prodrug may be inactive when administered to a subject, but is converted into an active compound in vivo, for example, by hydrolysis. Prodrug compounds often offer the advantage of solubility, tissue compatibility, or delayed release in mammalian organisms (see, for example, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)).

[0051] A discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0052] The term "prodrug" is also intended to include any covalently bonded carrier that releases an active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of active compounds, as described herein, can be prepared by modifying functional groups present in the active compound such that the modifications are cleaved to the parent active compound, either in a routine operation or in vivo. Prodrugs include compounds in which a hydroxy, amino, or mercapto group is bonded to any group that is cleaved to form a free hydroxy, free amino, or free mercapto group, respectively, when the prodrug of the active compound is administered to a mammalian subject. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol or amine functional groups in the active compound.

[0053] The term "acceptable" as used herein with respect to a formulation, composition, or ingredient means having no lasting adverse effects on the overall health of the subject being treated.

[0054] The term "modulate," as used herein, means to interact with a target directly or indirectly to alter the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or prolonging the activity of the target.

[0055] The term "modulator" as used herein refers to a molecule that directly or indirectly interacts with a target. Interactions include, but are not limited to, agonist, partial agonist, inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, the modulator is an agonist.

[0056] The terms "administer," "administering," "administration," and the like, as used herein, refer to methods that can be used to deliver a compound or composition to a desired biological site of action. These methods include, but are not limited to, oral route, intraduodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical, and rectal administration. Those skilled in the art are familiar with the administration techniques that can be used with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0057] The term "co-administration" and the like, as used herein, is meant to encompass the administration of selected therapeutic agents to one patient and is intended to include treatment regimens in which the agents are administered by the same or different routes of administration or at the same or different times.

[0058] The term "effective amount" or "therapeutically effective amount," as used herein, refers to a sufficient amount of an agent or compound administered to relieve to some extent one or more symptoms of the disease or condition being treated. The result includes a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound as disclosed herein required to provide a clinically significant reduction in disease symptoms. The appropriate "effective" amount in any individual case is optionally determined using techniques, such as a dose escalation study.

[0059] The terms "enhance" or "enhancing," as used herein, means to increase or prolong either in potency or duration a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term "enhancing" refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An "enhancing-effective amount," as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.

[0060] The term "pharmaceutical combination" as used herein refers to a product resulting from mixing or combining two or more active ingredients, and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients, such as the compounds described herein or pharmaceutically acceptable salts thereof, and the co-drug are both administered to a patient at the same time in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, such as the compounds described herein or pharmaceutically acceptable salts thereof, and the co-drug are administered to a patient simultaneously, contemporaneously, or sequentially without a specific intervening time limit, as separate entities, where such administration provides effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy, for example, the administration of three or more active ingredients.

[0061] The terms "kit" and "article of manufacture" are used synonymously.

[0062] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates, such as chimpanzees, and other ape and monkey species; livestock, such as cows, horses, sheep, goats, and pigs; domestic animals, such as rabbits, dogs, and cats; and laboratory animals, such as rodents, such as rats, mice, and guinea pigs. In one aspect, the mammal is a human.

[0063] As used herein, "treatment" or "treating" or "alleviating" or "ameliorating" are used interchangeably herein. These terms refer to an approach to obtain beneficial or desired results, including, but not limited to, therapeutic benefit and / or preventative benefit. By "therapeutic benefit" is meant the eradication or amelioration of the underlying disorder being treated. Furthermore, therapeutic benefit is achieved by the eradication or amelioration of one or more physiological symptoms associated with the underlying disorder, such that an improvement is observed in the patient, even though the patient may still suffer from the underlying disorder. For preventative benefit, the composition can be administered to patients at risk of developing a particular disease or to patients who report one or more physiological symptoms of the disease, even if the disease may not have been diagnosed.

[0064] compound The compounds described herein, including pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof, directly or indirectly modulate IRE1-mediated signaling.

[0065] In one aspect, there is provided a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof: TIFF2024156774000018.tif38128 formula, Each Z is independently N or CR 1 with the proviso that at least one Z is N; Each R 1 are independently H, halogen, -CN, -OR 8 , -SR 8 , -S(=O)R 9 , -S(=O)2R 9 , -S(=O)2N(R 8 )2, -NR 8 S(=O)2R 9 , -C(=O)R 9 , -OC(=O)R 9 , -C(=O)OR 8 , -OC(=O)OR 9 , -N(R 8)2, -OC(=O)N(R 8 )2, -NR 8 C(=O)R 9 , -NR 8 C(=O)OR 9 , optionally substituted C1-C4 alkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 3 -CN, -OR 8 , -SR 8 , optionally substituted C1-C4 alkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted —O—C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted —O—C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted —O—C3-C6 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 4 is halogen, -CN, -OR 8 , optionally substituted C1-C4 alkyl, optionally substituted C1-C4 fluoroalkyl, or optionally substituted C1-C4 heteroalkyl; Each R 5 are independently H, halogen, -CN, -OR 8 , -SR 8 , -N(R 8 )2, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; Each R 2 are independently H, halogen, -CN, -OR 8 , -SR8 , -S(=O)R 9 , -S(=O)2R 9 , -S(=O)2N(R 8 )2, -NR 8 S(=O)2R 9 , -C(=O)R 9 , -OC(=O)R 9 , -C(=O)OR 8 , -OC(=O)OR 9 , -N(R 8 )2, -OC(=O)N(R 8 )2, -NR 8 C(=O)R 9 , -NR 8 C(=O)OR 9 , optionally substituted C1-C4 alkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 6 is H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C2-C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 7 is an optionally substituted C1-C4 alkyl, an optionally substituted C1-C4 heteroalkyl, an optionally substituted C1-C4 fluoroalkyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted C3-C6 cycloalkylalkyl, an optionally substituted C2-C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; Or, R 6 and R 7 together with the N atom to which they are attached form an optionally substituted heterocycle; Each R 8 are independently H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; Or, two R's 8 together with the N atom to which they are attached form an optionally substituted heterocycle; Each R 9 are independently an optionally substituted C1-C4 alkyl, an optionally substituted C1-C4 heteroalkyl, an optionally substituted C1-C4 fluoroalkyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted C2-C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R A1 and R A2 are each independently H, halogen, or -OR 9 , optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 fluoroalkyl, or optionally substituted aryl; provided that R A1 and R A2 Not both are H; n is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4.

[0066] In a second aspect, there is provided a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z, R 1 , R 3 , R 4 , R 5 , R 2 , R 8 , R 9 , R A1 , R A2, n and q are as provided in the preceding paragraph: R 6 is H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C2-C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and R 7 is an optionally substituted C-C cycloalkylalkyl, or R 7 is methyl, ethyl, -CHCF, -CH-cyclopropyl, or -CHCHOCH. 7 can be, for example, methyl, ethyl, —CHCF, —CH-cyclopropyl, or —CHCHOCH. Alternatively, R 7 R can be, for example, an optionally substituted C-C cycloalkylalkyl or -CH-cyclobutyl. 6 can be, for example, hydrogen, optionally substituted C-C alkyl, optionally substituted C-C heteroalkyl, optionally substituted C-C fluoroalkyl, optionally substituted C-C cycloalkyl, or optionally substituted C-C cycloalkylalkyl. Alternatively, R 6 can be, for example, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C6 cycloalkylalkyl. Alternatively, R 6 can be, for example, methyl.

[0067] In some embodiments, TIFF2024156774000019.tif62128. In such an embodiment, R 1 , R 3 , R 4 , R5 , R 2 , R 6 , R 7 , R 8 , R 9 , R A1 , R A2 , n, and q may be as defined above for formula (I), or may be as defined in any combination thereof in any of the embodiments described herein for those substituents.

[0068] In some embodiments, TIFF2024156774000020.tif41128. In such an embodiment, R 1 , R 3 , R 4 , R 5 , R 2 , R 6 , R 7 , R 8 , R 9 , R A1 , R A2 , n, and q may be as defined above for formula (I), or may be as defined in any combination thereof in any of the embodiments described herein for those substituents.

[0069] In some embodiments, TIFF2024156774000021.tif35128. In such an embodiment, R 1 , R 3 , R 4 , R 5 , R 2 , R 6 , R 7 , R 8 , R 9 , R A1 , R A2 , n, and q may be as defined above for formula (I), or may be as defined in any combination thereof in any of the embodiments described herein for those substituents.

[0070] In some embodiments, TIFF2024156774000022.tif39128. In such an embodiment, R 1 , R 3 , R 4 , R 5 , R 2 , R 6 , R 7 , R 8 , R 9 , R A1 , R A2 , n, and q may be as defined above for formula (I), or may be as defined in any combination thereof in any of the embodiments described herein for those substituents.

[0071] In some embodiments, each R 1 are independently H, halogen, -CN, -OR 8 , optionally substituted C1-C4 alkyl, optionally substituted C1-C4 fluoroalkyl, or optionally substituted C1-C4 heteroalkyl. 3 , R 4 , R 5 , R 2 , R 6 , R 7 , R 8 , R 9 , R A1 , R A2 , n, and q may be as defined above for formula (I), or may be as defined in any combination thereof in any of the embodiments described herein for those substituents.

[0072] In some embodiments, each R 1 are independently H, halogen, -OR 8 , optionally substituted C1-C4 alkyl, or optionally substituted C1-C4 heteroalkyl. 3 , R 4 , R 5 , R 2 , R 6 , R 7 , R 8 , R9 , R A1 , R A2 , n, and q may be as defined above for formula (I), or may be as defined in any combination thereof in any of the embodiments described herein for those substituents.

[0073] In some embodiments, each R 1 is independently H. In some embodiments, each R 1 is independently halogen. In some embodiments, each R 1 is independently -CN. In some embodiments, each R 1 are independently -OR 8 In some embodiments, each R 1 is independently an optionally substituted C1-C4 alkyl. In some embodiments, each R 1 is independently an optionally substituted C1-C4 fluoroalkyl. In some embodiments, each R 1 is independently an optionally substituted C1-C4 heteroalkyl. In all such embodiments, Z, R 3 , R 4 , R 5 , R 2 , R 6 , R 7 , R 8 , R 9 , R A1 , R A2 , n, and q may be as defined above for formula (I), or may be as defined in any combination thereof in any of the embodiments described herein for those substituents.

[0074] In some embodiments, R 3 -CN, -OR 8 , optionally substituted C1-C4 alkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted —O—C3-C6 cycloalkyl.1 , R 4 , R 5 , R 2 , R 6 , R 7 , R 8 , R 9 , R A1 , R A2 , n, and q may be as defined above for formula (I), or may be as defined in any combination thereof in any of the embodiments described herein for those substituents.

[0075] In some embodiments, R 3 -OR 8 , optionally substituted C1-C4 alkyl, optionally substituted C1-C4 fluoroalkyl, or optionally substituted C1-C4 heteroalkyl. 1 , R 4 , R 5 , R 2 , R 6 , R 7 , R 8 , R 9 , R A1 , R A2 , n, and q may be as defined above for formula (I), or may be as defined in any combination thereof in any of the embodiments described herein for those substituents.

[0076] In some embodiments, R 3 In some embodiments, R 3 HA-OR 8 In some embodiments, R 3 is an optionally substituted C1-C4 alkyl. In some embodiments, R 3 is an optionally substituted C1-C4 fluoroalkyl. In some embodiments, R 3 is an optionally substituted C1-C4 heteroalkyl. In some embodiments, R 3 is an optionally substituted C-C cycloalkyl. In some embodiments, R3 is optionally substituted -O-C3-C6 cycloalkyl. In all such embodiments, Z, R 1 , R 4 , R 5 , R 2 , R 6 , R 7 , R 8 , R 9 , R A1 , R A2 , n, and q may be as defined above for formula (I), or may be as defined in any combination thereof in any of the embodiments described herein for those substituents.

[0077] In some embodiments, R 8 is an optionally substituted C1-C4 alkyl, an optionally substituted C1-C4 heteroalkyl, an optionally substituted C1-C4 fluoroalkyl, or an optionally substituted C3-C6 cycloalkyl. 8 is an optionally substituted C1-C4 alkyl. In some embodiments, R 8 is an optionally substituted C1-C4 heteroalkyl. In some embodiments, R 8 is an optionally substituted C1-C4 fluoroalkyl. In some embodiments, R 8 is optionally substituted C3-C6 cycloalkyl. In all such embodiments, Z, R 1 , R 3 , R 4 , R 5 , R 2 , R 6 , R 7 , R 9 , R A1 , R A2 , n, and q may be as defined above for formula (I), or may be as defined in any combination thereof in any of the embodiments described herein for those substituents.

[0078] In some embodiments, R 4is halogen, -CN, -OR 8 , optionally substituted C1-C4 alkyl, or optionally substituted C1-C4 fluoroalkyl. 1 , R 3 , R 5 , R 2 , R 6 , R 7 , R 8 , R 9 , R A1 , R A2 , n, and q may be as defined above for formula (I), or may be as defined in any combination thereof in any of the embodiments described herein for those substituents.

[0079] In some embodiments, R 4 is halogen, -CN, -OR 8 , optionally substituted C1-C4 alkyl, or optionally substituted C1-C4 fluoroalkyl. 1 , R 3 , R 5 , R 2 , R 6 , R 7 , R 8 , R 9 , R A1 , R A2 , n, and q may be as defined above for formula (I), or may be as defined in any combination thereof in any of the embodiments described herein for those substituents.

[0080] In some embodiments, R 4 is halogen, optionally substituted C1-C4 alkyl, or optionally substituted C1-C4 fluoroalkyl. 1 , R 3 , R 5 , R 2 , R 6 , R 7 , R 8 , R 9 , R A1 , RA2 , n, and q may be as defined above for formula (I), or may be as defined in any combination thereof in any of the embodiments described herein for those substituents.

[0081] In some embodiments, R 4 is halogen. In some embodiments, R 4 is -Cl, -Br, -F, or -I. In all such embodiments, Z, R 1 , R 3 , R 5 , R 2 , R 6 , R 7 , R 8 , R 9 , R A1 , R A2 , n, and q may be as defined above for formula (I), or may be as defined in any combination thereof in any of the embodiments described herein for those substituents.

[0082] In some embodiments, R 4 HA-OR 8 In some embodiments, R 8 is H, optionally substituted C1-C4 alkyl, or optionally substituted C1-C4 fluoroalkyl. In all such embodiments, Z, R 1 , R 3 , R 5 , R 2 , R 6 , R 7 , R 8 , R 9 , R A1 , R A2 , n, and q may be as defined above for formula (I), or may be as defined in any combination thereof in any of the embodiments described herein for those substituents.

[0083] In some embodiments, R 4is an optionally substituted C1-C4 alkyl. In some embodiments, R 4 is methyl, ethyl, propyl, or butyl. In all such embodiments, Z, R 1 , R 3 , R 5 , R 2 , R 6 , R 7 , R 8 , R 9 , R A1 , R A2 , n, and q may be as defined above for formula (I), or may be as defined in any combination thereof in any of the embodiments described herein for those substituents.

[0084] In some embodiments, R 4 is an optionally substituted C1-C4 fluoroalkyl. In some embodiments, R 4 is -CF3, -CF2CH3, or -CH2CF3. In all such embodiments, Z, R 1 , R 3 , R 5 , R 2 , R 6 , R 7 , R 8 , R 9 , R A1 , R A2 , n, and q may be as defined above for formula (I), or may be as defined in any combination thereof in any of the embodiments described herein for those substituents.

[0085] In some embodiments, R 5 is H, halogen, -CN, -OR 8 , -SR 8 , -N(R 8 )2, optionally substituted C1-C4 alkyl, or optionally substituted C1-C4 fluoroalkyl. 1 , R 3 , R 4 , R 2 , R6 , R 7 , R 8 , R 9 , R A1 , R A2 , n, and q may be as defined above for formula (I), or may be as defined in any combination thereof in any of the embodiments described herein for those substituents.

[0086] In some embodiments, R 5 is H. In some embodiments, R 5 is halogen. In some embodiments, R 5 is -Cl, -Br, -F, or -I. In all such embodiments, Z, R 1 , R 3 , R 4 , R 2 , R 6 , R 7 , R 8 , R 9 , R A1 , R A2 , n, and q may be as defined above for formula (I), or may be as defined in any combination thereof in any of the embodiments described herein for those substituents.

[0087] In some embodiments, R 5 HA-OR 8 In some embodiments, R 8 is H, optionally substituted C1-C4 alkyl, or optionally substituted C1-C4 fluoroalkyl. In all such embodiments, Z, R 1 , R 3 , R 4 , R 2 , R 6 , R 7 , R 8 , R 9 , R A1 , R A2, n, and q may be as defined above for formula (I), or may be as defined in any combination thereof in any of the embodiments described herein for those substituents.

[0088] In some embodiments, R 5 is an optionally substituted C1-C4 alkyl. In some embodiments, R 5 is methyl, ethyl, propyl, or butyl. In all such embodiments, Z, R 1 , R 3 , R 4 , R 2 , R 6 , R 7 , R 8 , R 9 , R A1 , R A2 , n, and q may be as defined above for formula (I), or may be as defined in any combination thereof in any of the embodiments described herein for those substituents.

[0089] In some embodiments, R 5 is an optionally substituted C1-C4 fluoroalkyl. In some embodiments, R 5 is -CF3, -CF2CH3, or -CH2CF3. In all such embodiments, Z, R 1 , R 3 , R 4 , R 2 , R 6 , R 7 , R 8 , R 9 , R A1 , R A2 , n, and q may be as defined above for formula (I), or may be as defined in any combination thereof in any of the embodiments described herein for those substituents.

[0090] In some embodiments, the compound of formula (I) has the structure of formula (Ia): TIFF2024156774000023.tif32128

[0091] In some embodiments, the compound of formula (I) has the structure of formula (Ib): TIFF2024156774000024.tif32128

[0092] In some embodiments, each R 2 are independently H, halogen, -OR 8 , optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, or optionally substituted C1-C4 fluoroalkyl. 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R A1 , R A2 , n, and q may be as defined above for formula (I), or in any combination thereof in any of the embodiments described herein.

[0093] In some embodiments, q is 0, 1, 2, or 3. In some embodiments, q is 0, 1, or 2. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In all such embodiments, Z, R 1 , R 3 , R 4 , R 5 , R 2 , R 6 , R 7 , R 8 , R 9 , R A1 , R A2 and n may be as defined above for formula (I), or in any combination thereof in any of the embodiments described herein.

[0094] In some embodiments, R 6 is H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C6 cycloalkylalkyl. In such embodiments, Z, R 1 , R 3 , R 4 , R 5 , R 2 , R 7 , R 8 , R 9 , R A1 , R A2 , n, and q may be as defined above for formula (I), or in any combination thereof in any of the embodiments described herein.

[0095] In some embodiments, R 6 is an optionally substituted C1-C4 alkyl. In some embodiments, R 6 is methyl. In some embodiments, R 6 is ethyl. In some embodiments, R 6 is propyl. In all such embodiments, Z, R 1 , R 3 , R 4 , R 5 , R 2 , R 7 , R 8 , R 9 , R A1 , R A2 , n, and q may be as defined above for formula (I), or in any combination thereof in any of the embodiments described herein.

[0096] In some embodiments, R 6 is an optionally substituted C1-C4 heteroalkyl. In some embodiments, R 6is an optionally substituted C1-C4 fluoroalkyl. In some embodiments, R 6 is an optionally substituted C-C cycloalkyl. In some embodiments, R 6 is an optionally substituted C-C cycloalkylalkyl. In some embodiments, R 6 is H. In all such embodiments, Z, R 1 , R 3 , R 4 , R 5 , R 2 , R 7 , R 8 , R 9 , R A1 , R A2 , n, and q may be as defined above for formula (I), or in any combination thereof in any of the embodiments described herein.

[0097] In some embodiments, R 7 is optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C6 cycloalkylalkyl. In such embodiments, Z, R 1 , R 3 , R 4 , R 5 , R 2 , R 6 , R 8 , R 9 , R A1 , R A2 , n, and q may be as defined above for formula (I), or in any combination thereof in any of the embodiments described herein.

[0098] In some embodiments, R 7 is an optionally substituted C1-C4 alkyl. In some embodiments, R 7is an optionally substituted C1-C4 heteroalkyl. In some embodiments, R 7 is an optionally substituted C-C cycloalkyl. In some embodiments, R 7 is an optionally substituted C1-C4 alkyl. In some embodiments, R 7 is an optionally substituted C-C cycloalkylalkyl. In some embodiments, R 7 is selected from the group of methyl, ethyl, -CHCF, -CH-cyclopropyl, or -CHCHOCH. In all such embodiments, Z, R 1 , R 3 , R 4 , R 5 , R 2 , R 6 , R 8 , R 9 , R A1 , R A2 , n, and q may be as defined above for formula (I), or in any combination thereof in any of the embodiments described herein.

[0099] In some embodiments, R A1 is H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, or optionally substituted C1-C4 fluoroalkyl. 1 , R 3 , R 4 , R 5 , R 2 , R 6 , R 7 , R 8 , R 9 , R A2 , n, and q may be as defined above for formula (I), or in any combination thereof in any of the embodiments described herein.

[0100] In some embodiments, R A1 is H. In some embodiments, R A1is an optionally substituted C1-C4 alkyl. In some embodiments, R A1 is an optionally substituted C1-C4 heteroalkyl. In some embodiments, R A1 is optionally substituted C1-C4 fluoroalkyl. In all such embodiments, Z, R 1 , R 3 , R 4 , R 5 , R 2 , R 6 , R 7 , R 8 , R 9 , R A2 , n, and q may be as defined above for formula (I), or in any combination thereof in any of the embodiments described herein.

[0101] In some embodiments, R A2 is H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, or optionally substituted C1-C4 fluoroalkyl. 1 , R 3 , R 4 , R 5 , R 2 , R 6 , R 7 , R 8 , R 9 , R A1 , n, and q may be as defined above for formula (I), or in any combination thereof in any of the embodiments described herein.

[0102] In some embodiments, R A2 is an optionally substituted C1-C4 alkyl. In some embodiments, R A2 is methyl, ethyl, propyl, or butyl. A2 is ethyl. In some embodiments, R A2is an optionally substituted C1-C4 heteroalkyl. In some embodiments, R A2 is an optionally substituted C1-C4 fluoroalkyl. In some embodiments, R A2 is H. In all such embodiments, Z, R 1 , R 3 , R 4 , R 5 , R 2 , R 6 , R 7 , R 8 , R 9 , R A1 , n, and q may be as defined above for formula (I), or in any combination thereof in any of the embodiments described herein.

[0103] In some embodiments, the compound of formula (I) has the structure of formula (Ic): TIFF2024156774000025.tif32128

[0104] In some embodiments, the compound of formula (I) has the structure of formula (Id): TIFF2024156774000026.tif32128

[0105] In some embodiments, the compound of formula (I) has the structure of formula (Ie): TIFF2024156774000027.tif32128

[0106] In another aspect, the compound of formula (I * ), (Ib * ), or (Ic * Provided herein is a compound of the formula: TIFF2024156774000028.tif108128In formula, Each Z is independently N or CR 1 with the proviso that at least one Z is N; Each R 1are independently hydrogen, fluorine, chlorine, or cyano; R 3 is —CN, optionally substituted C1-C3 alkyl, optionally substituted C3-C4 cycloalkyl, optionally substituted —O—C3-C4 cycloalkyl, or optionally substituted —O—C1-C3 alkyl; R 4 is chlorine, -CH3, cyano, -OCH3, or CF3; Each R 5 are independently hydrogen, chlorine, -CH3, cyano, -OCH3, or CF3; Each R 2 are independently hydrogen, fluorine, -CH3, or -OH; R 6 is H, or C1-C3 alkyl; R 7 is an optionally substituted C1-C3 alkyl; C1-C3 fluoroalkyl, C1-C3 heteroalkyl, or C3-C4 cycloalkyl-C1-C3 alkyl; Or, R 6 and R 7 together with the N atom to which they are attached form an optionally substituted 4- to 6-membered ring, the remainder of the ring atoms being carbon; R A1 and R A2 are each independently H, optionally substituted C-C alkyl; C-C fluoroalkyl, C-C heteroalkyl, or C-C cycloalkyl-C-C alkyl, with the proviso that R A1 and R A2 are not both hydrogen; n is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4.

[0107] Formula (I * ), (Ib * ) or (Ic * In some such aspects of A1is H or C 1-3 Alkyl, and Z, R 1 , R 3 , R 4 , R 5 , R 2 , R 6 , R 7 , R 8 , R 9 , R A2 , n and q are represented by the formula (I * ), (Ib * ) or (Ic * ) or may be as defined above for formula (I * ), (Ib * ) or (Ic * ) may be as defined in any of the embodiments described herein in any combination thereof.

[0108] Formula (I * ), (Ib * ) or (Ic * In some such aspects of 3 , R 7 , R A1 , and R A2 one or more of may be substituted, wherein the optional substituents are each independently selected from fluorine, —OH, —OCH, —OCHCH, —OCHCH, —NH, —NH(CH), or —N(CH), and Z, R 1 , R 4 , R 5 , R 2 , R 6 , R 8 , R 9 , n and q are represented by the formula (I * ), (Ib * ) or (Ic * ) or may be as defined above for formula (I * ), (Ib * ) or (Ic * ) may be as defined in any of the embodiments described herein in any combination thereof.

[0109] Formula (I* ), (Ib * ) or (Ic * In some such aspects of 3 , R 7 , R A1 , and R A2 one or more of may be substituted, wherein the optional substituents are each independently selected from fluorine, —OH, —OCH, —OCHCH, —OCHCHCH, —NH(CH), or —N(CH), and Z, R 1 , R 4 , R 5 , R 2 , R 6 , R 8 , R 9 , n and q are represented by the formula (I * ), (Ib * ) or (Ic * ) or may be as defined above for formula (I * ), (Ib * ) or (Ic * ) may be as defined in any of the embodiments described herein in any combination thereof.

[0110] Formula (I * ), (Ib * ) or (Ic * In some such aspects of 7 , R A1 , and R A2 one or more of Z, R 1 , R 3 , R 4 , R 5 , R 2 , R 6 , R 8 , R 9 , n and q are represented by the formula (I * ), (Ib * ) or (Ic * ) or may be as defined above for formula (I * ), (Ib *) or (Ic * ) may be as defined in any of the embodiments described herein in any combination thereof.

[0111] Formula (I * ), (Ib * ) or (Ic * In some such aspects of 6 is H or methyl, and R 7 is methyl, ethyl, CH2CF3, CH2-cyclopropyl or CH2CH2OCH3, and Z, R 1 , R 3 , R 4 , R 5 , R 2 , R 8 , R 9 , R A1 , and R A2 , n and q are represented by the formula (I * ), (Ib * ) or (Ic * ) or may be as defined above for formula (I * ), (Ib * ) or (Ic * ) may be as defined in any of the embodiments described herein in any combination thereof.

[0112] Formula (I * ), (Ib * ) or (Ic * In some such aspects of 6 is methyl and R 7 is methyl, ethyl, CH2CF3, CH2-cyclopropyl or CH2CH2OCH3, and Z, R 1 , R 3 , R 4 , R 5 , R 2 , R 8 , R 9 , R A1 , and R A2 , n and q are represented by the formula (I * ), (Ib * ) or (Ic *) or may be as defined above for formula (I * ), (Ib * ) or (Ic * ) may be as defined in any of the embodiments described herein in any combination thereof.

[0113] Formula (I * ), (Ib * ) or (Ic * In some such aspects of (a), q is 0.

[0114] Formula (I * ), (Ib * ) or (Ic * In some such aspects of (a), each Z is independently N or CR 1 with the proviso that at least one Z is N; and each R 1 are independently hydrogen, fluorine, chlorine or cyano; R 3 is C1-C3 alkyl or -OC1-C3 alkyl; R A1 is hydrogen or C1-C3 alkyl; R A2 is C1-C3 alkyl, C1-C3 fluoroalkyl, or C1-C3 heteroalkyl; provided that R A1 and R A2 Not both of these are hydrogen; R 4 is chlorine; each R 5 are independently hydrogen, chlorine, —CH 3 , cyano, —OCH 3 , or CF 3 ; n is 0, 1, 2, 3, or 4; and q is 0.

[0115] Formula (I * ), (Ib * ) or (Ic * ) of formula (I * ), (Ib * ) or (Ic * In some such aspects of R 1 is fluorine; R 3 is methyl, ethyl, or -OCH3, R 4 is chlorine, or -CH3; R 6 is H, or methyl; R 7 is methyl, ethyl, CH2CF3, CH2-cyclopropyl or CH2CH2OCH3; R A2 is ethyl, hydrogen, CF2CH3, CF3, CH2OCH3, or CH3; R A2 is methyl or H; n is 0; and q is 0.

[0116] In another aspect, the compound of formula (Id * Provided herein is a compound of the formula: TIFF2024156774000029.tif40128 formula, Z, R 1 , R 3 , R 4 , R 5 , R 2 , R 6 , R 7 , R 8 , R 9 , R A1 , and R A2 is as described for formula (I). In some such embodiments, each Z is independently N or CR 1 with the proviso that at least one Z is N; and each R 5 are independently hydrogen, chlorine, fluorine, or C1-C3 alkyl; R 4 is chlorine or C1-C3 alkyl; R 3 is C1-C3 alkyl or -OC1-C3 alkyl; R A1 is fluorine, chlorine, hydrogen, or C1-C3 alkyl; R A2 is C1-C3 alkyl, —OC1-C3 alkyl, hydrogen, C1-C3 fluoroalkyl, fluorine, chlorine, or C1-C3 heteroalkyl; provided that R A1 and R A2are not both hydrogen; each R 2 are independently hydrogen or fluorine; and R 1 is hydrogen or fluorine; and wherein one, two or three Z are nitrogen. In an illustrative example, TIFF2024156774000030.tif19128. In some such cases, each R 5 are independently hydrogen, chlorine, fluorine, or -CH; R 4 is chlorine or -CH3; R 3 is -CH3, -CH2CH3, or -OCH3; R A1 is fluorine, chlorine, hydrogen, or -CH3; R A2 is hydrogen, -CH3, -CH2CH3, -OCH3, CF3, CF2CH3, CH2OCH3, or fluorine; provided that R A1 and R A2 are not both hydrogen; each R 2 are independently hydrogen or fluorine; and R 1 is hydrogen or fluorine. 6 and R 7 can be as described in any of the embodiments described herein. For example, R 7 can be an optionally substituted C-C cycloalkylalkyl, or R 7 may be selected from the group of methyl, ethyl, —CHCF, —CH-cyclopropyl, or —CHCHOCH, or R 7 may be selected from the group of methyl, ethyl, —CHCF, —CH-cyclopropyl, —CH-cyclobutyl, or —CHCHOCH; and R 6 is as described herein for any of the embodiments. For example, R 6 can be hydrogen or C alkyl, or R 6 can be hydrogen or methyl. In some such embodiments, each R 5 is hydrogen; R 4 is chlorine; each R 2 is hydrogen; and R1 is hydrogen.

[0117] In some embodiments, the compound described herein is selected from any one of the compounds from Table 1.

[0118] [Table 1] TIFF2024156774000032.tif225163TIFF2024156774000033.tif229163TIFF2024156774 000034.tif214163TIFF2024156774000035.tif241163TIFF2024156774000036.tif24316 3TIFF2024156774000037.tif225163TIFF2024156774000038.tif227163TIFF2024156774 000039.tif235163TIFF2024156774000040.tif225163TIFF2024156774000041.tif22716 3TIFF2024156774000042.tif232163TIFF2024156774000043.tif231163TIFF2024156774 000044.tif242163TIFF2024156774000045.tif218163TIFF2024156774000046.tif24116 3TIFF2024156774000047.tif210163TIFF2024156774000048.tif238163TIFF2024156774 000049.tif231163TIFF2024156774000050.tif231163TIFF2024156774000051.tif64163

[0119] In one aspect, provided herein are pharmaceutically acceptable salts or solvates of the compounds set forth in Table 1. Any combination of the groups described above or below for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof will be selected by one of ordinary skill in the art to provide stable moieties and compounds.

[0120] IRE1-like protein family In some embodiments, the compounds disclosed herein selectively bind to proteins of the serine / threonine-protein kinase / endoribonuclease inositol-requiring enzyme 1 (IRE1) protein family. In humans, IRE1 is encoded by the ERN1 gene. Exemplary IRE1 family proteins include the isoforms IRE1 and IRE1a. Other exemplary IRE1 family proteins include IRE1 homologs or orthologs in other organisms. Exemplary organisms include humans, non-human primates, mice, rats, chickens, Drosophila, yeast, etc., as listed in Table 2. In some embodiments, the IRE1 protein is human IRE1a.

[0121] [Table 2]

[0122] In some embodiments, the compounds disclosed herein selectively bind to IRE1 family proteins containing a kinase domain and / or an RNase domain. In some embodiments, the kinase domain is a trans-autophosphorylation kinase domain. In some embodiments, the IRE1 family protein is IRE1a. An example arrangement of domains within the IRE1a protein is depicted in Figure 1. An example alignment of IRE1 family protein orthologs is depicted in Figure 2.

[0123] In some embodiments, the compounds disclosed herein selectively bind to the trans-autophosphorylation kinase domain region of IRE1a, e.g., within amino acid residues 568-833 of SEQ ID NO: 1, or equivalent amino acid residues thereof.

[0124] In some embodiments, the compounds disclosed herein selectively bind to an ATP-binding pocket within the trans-autophosphorylation kinase domain region of IRE1a. In some embodiments, the compounds disclosed herein selectively bind to an ATP-binding pocket within the trans-autophosphorylation kinase domain region of IRE1a, e.g., one or more of amino acid residues 577-711, 577-586, 597, 599, 626, 642-643, 645, 648, 688, 692-693, 695, or 711 of SEQ ID NO: 1, or an equivalent amino acid residue thereof.

[0125] In some embodiments, the compounds disclosed herein selectively bind to an activation loop within the trans-autophosphorylation kinase domain region of IRE1a. In some embodiments, the compounds disclosed herein selectively bind to an activation loop within the trans-autophosphorylation kinase domain region of IRE1a, e.g., one or more of amino acid residues 710-736, 710-725, or 729-736 of SEQ ID NO: 1, or equivalent amino acid residues thereof.

[0126] In some embodiments, the compounds disclosed herein selectively bind to the RNase domain region of IRE1a, e.g., within amino acid residues 835-963 of SEQ ID NO: 1, or an equivalent amino acid residue thereof.

[0127] In some embodiments, the compounds disclosed herein selectively bind to kinase domain dimer interface amino acid residues, e.g., one or more of amino acid residues 569-701, 569, 591, 592, 594, 617, 620, 627, 628, 631, 674, 678, or 701 of SEQ ID NO: 1.

[0128] In some embodiments, the compounds disclosed herein selectively bind to the first IRE1a and block dimerization between the kinase domain dimer interface amino acid residues of the first IRE1a and the second IRE1a. In some embodiments, the compounds disclosed herein selectively bind to the first IRE1a and inhibit dimerization at one or more of amino acid residues 569-701, 569, 591, 592, 594, 617, 620, 627, 628, 631, 674, 678, or 701 of SEQ ID NO: 1.

[0129] In some embodiments, the compounds disclosed herein selectively bind to the kinase extension nuclease (KEN) domain dimer interface amino acid residues of IRE1a. In some embodiments, the compounds disclosed herein selectively bind to the KEN domain dimer interface amino acid residues, e.g., one or more of amino acid residues 840-925, 840, 844, 851, 908, 912, or 925 of SEQ ID NO: 1.

[0130] In some embodiments, the compounds disclosed herein selectively bind to amino acid residues in a nuclease active site, e.g., one or more of amino acid residues 847-910, 847, 850, 886, 888, 889, 890, 892, 902, 905, 906, or 910 of SEQ ID NO: 1.

[0131] In some embodiments, the compounds disclosed herein selectively bind to the RNase domain and trans-autophosphorylation kinase domain region of IRE1a. In some embodiments, the compounds disclosed herein selectively bind to an ATP-binding pocket within the RNase domain and trans-autophosphorylation kinase domain region of IRE1a. In some embodiments, the compounds disclosed herein selectively bind to an activation loop within the RNase domain and trans-autophosphorylation kinase domain region of IRE1a.

[0132] In some embodiments, the compounds disclosed herein selectively bind to IRE1a at two sites located in the RNase domain, the trans-autophosphorylation kinase domain region, the ATP-binding pocket, the activation loop, or any combination thereof. In some embodiments, the compounds disclosed herein selectively bind to IRE1a at two or more sites. In some embodiments, the compounds disclosed herein selectively bind to IRE1a at two or more sites located in the RNase domain, the trans-autophosphorylation kinase domain region, the ATP-binding pocket, the activation loop, or any combination thereof. In some embodiments, the compounds disclosed herein selectively bind to IRE1a at three sites located in the RNase domain, the trans-autophosphorylation kinase domain region, the ATP-binding pocket, the activation loop, or any combination thereof.

[0133] In some embodiments, the compounds disclosed herein selectively bind to IRE1a at a first site located in the RNase domain, the trans-autophosphorylation kinase domain region, the ATP-binding pocket, or the activation loop. In some embodiments, the first site comprises one or more of any amino acid residues within amino acid residues 465-977 of SEQ ID NO: 1. In some embodiments, the compounds disclosed herein selectively bind to IRE1a at a second site located in the RNase domain, the trans-autophosphorylation kinase domain region, the ATP-binding pocket, or the activation loop. In some examples, the first site is located in the same domain or region as the second site. In some examples, the first site is located in a different domain or region than the second site.

[0134] In some embodiments, the compounds disclosed herein selectively bind to a first IRE1a, thereby blocking dimerization of the first IRE1a to a second IRE1a. In some embodiments, the compounds disclosed herein selectively bind to a first IRE1a, thereby blocking autotransphosphorylation of the first IRE1a or a second IRE1a to which the first IRE1a dimerizes. In some embodiments, the compounds disclosed herein selectively bind to a first IRE1a, thereby blocking activation of the first IRE1a or a second IRE1a to which the first IRE1a dimerizes. In some embodiments, the compounds disclosed herein selectively bind to a first IRE1a, thereby blocking kinase activity of the first IRE1a or a second IRE1a to which the first IRE1a dimerizes. In some embodiments, the compounds disclosed herein selectively bind to a first IRE1a, thereby blocking the RNase activity of the first IRE1a or a second IRE1a with which the first IRE1a dimerizes.

[0135] In some embodiments, the compounds disclosed herein selectively bind to IRE1a when it is in a homodimerized conformation. In some embodiments, the compounds disclosed herein selectively bind to IRE1a when it is in an oligomerized conformation. In some embodiments, the compounds disclosed herein selectively bind to IRE1a when it is in a non-oligomerized or non-dimerized conformation. In some embodiments, the compounds disclosed herein selectively bind to IRE1a when it is in an ATP-bound state. In some embodiments, the compounds disclosed herein selectively bind to IRE1 family proteins when they are in a non-ATP-bound state. In some embodiments, the compounds are pharmaceutically acceptable salts or solvates thereof.

[0136] IRE1 signaling pathway In some embodiments, the compounds disclosed herein selectively bind to IRE1 family proteins and alter downstream signaling pathways. In some embodiments, the compounds disclosed herein selectively bind to IRE1 family proteins and alter signaling of immunoglobulin heavy chain-binding protein (BIP), protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), glucose-regulated protein 78 (Grp78), eukaryotic translation initiation factor 2α (eIF2α), X-box binding protein 1 (XBP1), activating transcription factor 6α (ATF6α), C / EBP homologous protein (CHOP), growth arrest and DNA damage-inducible protein 34 (GADD34), tumor necrosis factor receptor-associated factor 2 (TRAF2), JUN N-terminal kinase (JNK), regulated IRE1-dependent degradation (RIDD), transcriptionally active XBP1 (XBP1s), or unspliced ​​XBP1 (XBP1u). In some embodiments, the compounds disclosed herein selectively bind to IRE1 family proteins and alter downstream cellular processes. In some embodiments, the IRE1 family protein is IRE1, IRE1a, or ERN1.

[0137] In some embodiments, the compounds disclosed herein selectively bind to IRE1 family proteins and reduce or block downstream signaling pathways. In some embodiments, the compounds disclosed herein selectively bind to IRE1 family proteins and reduce or block the activity or signaling of TXNIP, caspase 1, interleukin 1β, JNK, Bim, cytochrome C, caspase 3, caspase 8, mRNA degradation, miRNA degradation, apoptosis-inducing proteins, or pro-inflammatory proteins. In some embodiments, the compounds disclosed herein selectively bind to IRE1 family proteins and reduce XBP1 mRNA levels. In some embodiments, the compounds disclosed herein selectively bind to IRE1 family proteins and reduce transcriptionally active XBP1 (XBP1s) mRNA levels. In some embodiments, the compounds disclosed herein selectively bind to IRE1 family proteins and reduce spliced ​​XBP1 mRNA levels. In some embodiments, the IRE1 family protein is IRE1, IRE1a, or ERN1.

[0138] In some embodiments, the compounds disclosed herein selectively bind to an IRE1 family protein and increase, activate, or remove the blockage of downstream signaling pathways. In some embodiments, the compounds disclosed herein selectively bind to an IRE1 family protein and increase, activate, or remove the blockage of the activity or signaling of Bcl2, Bcl-XL, Mcl-1, Bax, Bak, other anti-apoptotic proteins, or mRNA translocon proteins. In some embodiments, the IRE1 family protein is IRE1, IRE1a, or ERN1.

[0139] In some embodiments, the compounds disclosed herein selectively bind to an IRE1 family protein and interfere with its binding to an effector protein. In some cases, the effector protein binds to the IRE1 family protein when it is in a dimerized or oligomerized state. In some cases, the effector protein binds to the IRE1 family protein when it is in a non-dimerized or non-oligomerized state. In some cases, the effector protein is immunoglobulin heavy chain-binding protein (BIP), protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), glucose-regulated protein 78 (Grp78), tumor necrosis factor receptor-associated factor 2 (TRAF2), JUN N-terminal kinase (JNK), transcriptionally active XBP1 (XBP1s), unspliced ​​XBP1 (XBP1u), regulated IRE1-dependent degradation (RIDD), heat shock protein 90 kDa alpha (HSP 90-α), or a misfolded protein. In some embodiments, the IRE1 family protein is IRE1, IRE1a, or ERN1.

[0140] In some embodiments, the compounds disclosed herein selectively bind to IRE1 family proteins and alter the activity of a cellular process or function, such as regulated IRE1-dependent degradation (RIDD), RNA degradation, translation, autophagy, cell survival, ER protein folding, ERAD, reactive oxygen species production, trafficking, ER-associated protein degradation (ERAD), protein synthesis, or apoptosis. In some embodiments, when the alteration or lack of a cellular process or function is associated with a disease state, the selective binding of the compounds disclosed herein results in the suppression or alleviation of the disease state, or the inhibition of adverse activity associated with the disease state. In some embodiments, the IRE1 family protein is IRE1, IRE1a, or ERN1.

[0141] Diseases associated with altered IRE1 pathway signaling In some cases, the compounds disclosed herein, when administered to a subject in need thereof, are used to treat or ameliorate a disease associated with altered IRE1a pathway signaling. In some cases, the compounds disclosed herein, when administered to a subject in need thereof, are used to treat a disease associated with altered IRE1a pathway signaling or ameliorate the effects of the disease. Exemplary diseases associated with altered IRE1a signaling include cancer. In some cases, the compounds disclosed herein, when administered to a subject in need thereof, are used to treat or ameliorate cancer. Exemplary cancers include tumors, solid cancers, and blood cancers. In some cases, the compounds disclosed herein, when administered to a subject in need thereof, are used to treat or ameliorate a cell proliferative disorder. In some cases, the cell proliferative disorder is cancer. In some cases, the solid cancer is ovarian cancer, lung cancer, breast cancer, bladder cancer, or triple-negative breast cancer (TNBC). In some cases, the blood cancer is leukemia, lymphoma, and multiple myeloma.

[0142] The IRE1a pathway may be involved in a variety of pathological conditions, including neurodegenerative diseases, inflammation, metabolic disorders, liver dysfunction, cerebral ischemia, cardiac ischemia, autoimmune diseases, and cancer. In some cases, modulation of this pathway provides a useful therapeutic approach for treating such diseases.

[0143] In some cases, the compounds disclosed herein are used to enhance anti-tumor mechanisms. In some cases, the anti-tumor mechanism includes direct inhibition of tumor growth. In some cases, the anti-tumor mechanism includes induction of anti-tumor immunity. In some cases, the anti-tumor mechanism includes direct inhibition of tumor growth and simultaneous induction of anti-tumor immunity. In some cases, the compounds disclosed herein can prevent lipid accumulation in myeloid cells exposed to ascites supernatant from ovarian cancer. In some cases, the compounds disclosed herein can block myeloid cell immunosuppression mediated by tumor-associated factors. In some cases, the compounds disclosed herein can be used as therapeutic compounds to enhance dendritic cell and T cell anti-tumor activity in mammals. For example, the compounds disclosed herein can be used to treat mouse and human ovarian cancer.

[0144] Dosage and Treatment Regimen In one aspect, the compounds described herein, or their pharmaceutically acceptable salts, are used in the preparation of medicaments for the treatment of diseases or conditions in mammals that will benefit from the administration of any one of the disclosed compounds.The method for treating any of the diseases or conditions described herein in mammals that need such treatment involves administering to the mammal a therapeutically effective amount of a pharmaceutical composition comprising at least one compound described herein, or its pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate.

[0145] In some embodiments, compositions containing the compounds described herein are administered for preventive and / or therapeutic treatment. In some therapeutic applications, the compositions are administered to patients already suffering from a disease or condition in an amount sufficient to cure or at least partially prevent at least one of the symptoms of the disease or condition. The amount effective for this use depends on the severity and course of the disease or condition, previous treatments, the patient's health, weight, and response to drugs, and the judgment of the treating physician. The therapeutically effective amount is optionally determined by methods including, but not limited to, dose escalation and / or dose ranging clinical trials.

[0146] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition. Such an amount is defined to be a "prophylactically effective amount or dose." In this use, the precise amount also depends on the patient's health, weight, and the like. When used in a patient, the effective amount for this use will depend on the severity and course of the disease, disorder, or condition, previous treatments, the patient's health status and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatment involves administering a pharmaceutical composition containing a compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal that has previously experienced at least one symptom of the disease being treated and is now in remission, to prevent the recurrence of symptoms of the disease or condition.

[0147] In some embodiments where the patient's condition does not improve, at the physician's discretion, administration of the compound is administered chronically, i.e., for an extended period of time, including throughout the patient's lifespan, to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.

[0148] In some embodiments where the patient's condition improves, the dose of the administered drug is temporarily reduced or temporarily suspended for a period of time (e.g., a "drug holiday"). In certain embodiments, the length of the drug holiday is between 2 days and 1 year, for example, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. The dose reduction during the drug holiday can be, by way of example only, 10% to 100%, for example, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

[0149] Once improvement of the patient's condition occurs, a maintenance dose is administered as needed. Subsequently, in certain embodiments, the dosage or frequency of administration, or both, are reduced, depending on the symptoms, to a level at which the improved disease, disorder, or condition is maintained. In some embodiments, however, the patient requires intermittent treatment on a long-term basis upon recurrence of symptoms.

[0150] The amount of a given agent that corresponds to such an amount will vary depending on factors such as the particular compound, the disease state and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but will nevertheless be determined according to the particular circumstances surrounding the case, including, for example, the particular agent being administered, the route of administration, the condition being treated, and the subject or host being treated.

[0151] In general, however, dosages used for adult treatment typically range from 0.01 mg to 5000 mg per day. In one aspect, dosages used for adult treatment are from about 1 mg to about 1000 mg per day. In one embodiment, the desired dosage is conveniently presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, e.g., two, three, four or more subdoses per day.

[0152] In one embodiment, a suitable daily dosage for the compounds described herein, or their pharmaceutically acceptable salts, is about 0.01 mg / kg to about 50 mg / kg of body weight. In some embodiments, the daily dosage or amount of the active ingredient in the dosage form is lower or higher than the ranges set forth herein, depending on numerous variables related to the individual treatment regimen. In various embodiments, the daily and unit dosage amounts will vary depending on numerous variables, including, but not limited to, the activity of the compound used, the disease or condition being treated, the mode of administration, the individual subject's requirements, the severity of the disease or condition being treated, and the judgment of the practitioner.

[0153] The toxicity and therapeutic efficacy of such treatment regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, determining LD50 and ED50. The dose ratio between toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LD50 and ED50. In some embodiments, data obtained from cell culture assays and animal studies are used to formulate a therapeutically effective daily dosage range and / or a therapeutically effective unit dosage for use in mammals, including humans. In some embodiments, the daily dosage of the compounds described herein is within a circulating concentration range that includes the ED50 with minimal toxicity. In some embodiments, the daily dosage range and / or unit dosage will vary within this range depending on the dosage form used and the route of administration utilized.

[0154] In any of the foregoing aspects, there are further embodiments in which an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, is administered: (a) systemically to the mammal; and / or (b) orally to the mammal; and / or (c) intravenously to the mammal; and / or (d) by injection to the mammal; and / or (e) locally to the mammal; and / or (f) non-systemically or locally to the mammal.

[0155] In any of the foregoing aspects, there are further embodiments that include a single administration of an effective amount of the compound, including further embodiments in which (i) the compound is administered once daily; or (ii) the compound is administered to the mammal multiple times throughout the day, for example, two, three, four or more times daily.

[0156] In any of the above aspects, there are further embodiments that comprise multiple administrations of an effective amount of compound, including: (i) administering compound continuously or intermittently as a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) administering compound to mammal every 8 hours; (iv) administering compound to mammal every 12 hours; (v) administering compound to mammal every 24 hours.In further or alternative embodiments, the method comprises a drug holiday, wherein the administration of compound is temporarily stopped or the dose of administered compound is temporarily reduced; and at the end of the drug holiday, the administration of compound is resumed.In one embodiment, the length of the drug holiday varies from 2 days to 1 year.

[0157] In some cases, it is appropriate to administer at least one compound described herein or its pharmaceutically acceptable salt in combination with one or more other therapeutic agents.In one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by administering an adjuvant (i.e., the adjuvant has minimal therapeutic benefit by itself, but when combined with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).Alternatively, in some embodiments, the benefit experienced by the patient is increased by administering one of the compounds described herein together with another agent (including a treatment regimen) that also has therapeutic benefit.

[0158] It is understood that the dosage regimen for treating, preventing or ameliorating the condition for which relief is sought will be modified according to various factors (for example, the disease, disorder or condition that the subject suffers from; the subject's age, weight, sex, diet, and medical condition).Therefore, in some cases, the dosage regimen actually used will vary, and in some embodiments, will deviate from the dosage regimen described herein.

[0159] For the combination therapies described herein, the dosage of the co-administered compounds will vary depending on the type of co-drug used, the particular drug used, the disease or condition being treated, etc. In additional embodiments, when co-administered with one or more other therapeutic agents, the compounds provided herein are administered simultaneously with or sequentially with the one or more other therapeutic agents.

[0160] In combination therapy, multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or even simultaneously. When administration is simultaneous, the multiple therapeutic agents may be provided in a single, unified form or in multiple forms (e.g., as a single pill or as two separate pills), by way of example only.

[0161] The compounds described herein, or pharmaceutically acceptable salts thereof, and combination therapies are administered before, during, or after the onset of a disease or condition, and the timing of administering a composition containing the compound can vary. Thus, in one embodiment, the compounds described herein are used as prophylactic agents and are administered continuously to subjects prone to developing a condition or disease to prevent the onset of the disease or condition. In another embodiment, the compounds and compositions are administered to a subject during or as soon as possible after the onset of symptoms. In certain embodiments, the compounds described herein are administered as soon as possible after the onset of a disease or condition is detected or suspected, for the length of time necessary to treat the disease. In some embodiments, the length of treatment required varies, and the length of treatment is adjusted to suit the specific needs of each subject. For example, in certain embodiments, the compounds described herein or formulations containing the compounds are administered for at least 2 weeks, about 1 month to about 5 years.

[0162] Conjugates In some embodiments, the compounds described herein are conjugated to a molecule, optionally via a linker, that allows the compound to target. Exemplary targets include, but are not limited to, tumors, bacteria, fungi, viruses, or parasites. In some embodiments, the compounds described herein are conjugated to a molecule, optionally via a linker, that allows the compound to target a cell surface target. Exemplary cell surface targets include, but are not limited to, proteins, lipids, and sugars. In some embodiments, the molecule conjugated to the compounds described herein is a peptide, an antibody, or an antibody fragment. In some embodiments, immunoglobulins of the IgA, IgD, IgE, IgG, or IgM class are used. In some embodiments, the conjugated inhibitor / cell targeting composition provides targeting of the compound to a specific cell, internalization of the conjugated composition, separation of the compound from the vehicle in the cell, and then targeting of the compound to the intracellular target. In some embodiments, antibody fragments for use in the conjugate include, but are not limited to, half antibody molecules (single heavy / light chain pairs), Fab, Fab', (Fab')2 (monospecific, bispecific, or trispecific), scFv, bispecific diabody, trispecific diabody, scFv-Fc, or minibody fragments. In some embodiments, the compounds described herein are conjugated to a molecule that enables recruitment to the cellular machinery for degradation. For example, in some embodiments, a proteolysis-directed chimeric molecule (PROTAC) system is used. In such compositions, a ubiquitin E3 ligase-binding protein is linked to the compounds described herein by a linker. In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, is a compound described herein in Table 1.

[0163] Representative exemplary embodiments In a first exemplary embodiment, the present invention includes a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof: TIFF2024156774000053.tif38128 formula, Each Z is independently N or CR 1 with the proviso that at least one Z is N; Each R 1 are independently H, halogen, -CN, -OR 8 , -SR 8 , -S(=O)R 9 , -S(=O)2R 9 , -S(=O)2N(R 8 )2, -NR 8 S(=O)2R 9 , -C(=O)R 9 , -OC(=O)R 9 , -C(=O)OR 8 , -OC(=O)OR 9 , -N(R 8 )2, -OC(=O)N(R 8 )2, -NR 8 C(=O)R 9 , -NR 8 C(=O)OR 9 , optionally substituted C1-C4 alkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 3 -CN, -OR 8 , -SR 8 , optionally substituted C1-C4 alkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted —O—C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted —O—C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted —O—C3-C6 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 4 is halogen, -CN, -OR 8, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 fluoroalkyl, or optionally substituted C1-C4 heteroalkyl; Each R 5 are independently H, halogen, -CN, -OR 8 , -SR 8 , -N(R 8 )2, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; Each R 2 are independently H, halogen, -CN, -OR 8 , -SR 8 , -S(=O)R 9 , -S(=O)2R 9 , -S(=O)2N(R 8 )2, -NR 8 S(=O)2R 9 , -C(=O)R 9 , -OC(=O)R 9 , -C(=O)OR 8 , -OC(=O)OR 9 , -N(R 8 )2, -OC(=O)N(R 8 )2, -NR 8 C(=O)R 9 , -NR 8 C(=O)OR 9 , optionally substituted C1-C4 alkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 6is H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C2-C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 7 is an optionally substituted C1-C4 alkyl, an optionally substituted C1-C4 heteroalkyl, an optionally substituted C1-C4 fluoroalkyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted C3-C6 cycloalkylalkyl, an optionally substituted C2-C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; Or, R 6 and R 7 together with the N atom to which they are attached form an optionally substituted heterocycle; Each R 8 are independently H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; Or, two R's 8 together with the N atom to which they are attached form an optionally substituted heterocycle; Each R 9 are independently an optionally substituted C1-C4 alkyl, an optionally substituted C1-C4 heteroalkyl, an optionally substituted C1-C4 fluoroalkyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted C2-C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R A1 and R A2 are each independently H, halogen, or -OR 9 , optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 fluoroalkyl, or optionally substituted aryl; provided that R A1 and R A2 Not both are H; n is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4.

[0164] In a second embodiment, there is provided any of the compounds according to embodiment 1, or a pharmaceutically acceptable salt, or solvate thereof, wherein: TIFF2024156774000054.tif67128.

[0165] In a third aspect, there is provided any of the compounds according to aspect 1 or 2, or a pharmaceutically acceptable salt, or solvate thereof, wherein: The file is TIFF2024156774000055.tif23128.

[0166] In a fourth aspect, there is provided any of the compounds according to aspect 1 or 2, or a pharmaceutically acceptable salt, or solvate thereof, wherein: TIFF2024156774000056.tif19128.

[0167] In a fifth aspect, there is provided any of the compounds according to aspects 1 to 3, or a pharmaceutically acceptable salt, or solvate thereof, wherein: TIFF2024156774000057.tif19128.

[0168] In a sixth aspect, there is provided any of the compounds according to aspects 1-5, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 1 are independently H, halogen, -CN, -OR8 , optionally substituted C1-C4 alkyl, optionally substituted C1-C4 fluoroalkyl, or optionally substituted C1-C4 heteroalkyl.

[0169] In a seventh aspect, there is provided any of the compounds according to aspects 1-6, or a pharmaceutically acceptable salt, or solvate thereof, wherein each R 1 are independently H, halogen, -OR 8 , optionally substituted C1-C4 alkyl, or optionally substituted C1-C4 heteroalkyl.

[0170] In an eighth aspect, there is provided any of the compounds according to aspects 1 to 7, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 -CN, -OR 8 , optionally substituted C1-C4 alkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted —O—C3-C6 cycloalkyl.

[0171] In a ninth aspect, there is provided any of the compounds according to aspects 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 -OR 8 , optionally substituted C1-C4 alkyl, optionally substituted C1-C4 fluoroalkyl, or optionally substituted C1-C4 heteroalkyl.

[0172] In a tenth aspect, there is provided any of the compounds according to aspects 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is optionally substituted C1-C4 alkyl.

[0173] In an eleventh embodiment, there is provided any of the compounds according to embodiment 10, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3is methyl, ethyl, propyl, or butyl.

[0174] In a twelfth aspect, there is provided any of the compounds according to aspects 1-9, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 HA-OR 8 is.

[0175] In a thirteenth aspect, there is provided any of the compounds according to aspect 12, or a pharmaceutically acceptable salt or solvate thereof, wherein R 8 is optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 fluoroalkyl, or optionally substituted C3-C6 cycloalkyl.

[0176] In a fourteenth aspect, there is provided any of the compounds according to aspects 1 to 13, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is halogen, -CN, -OR 8 , optionally substituted C1-C4 alkyl, or optionally substituted C1-C4 fluoroalkyl.

[0177] In a fifteenth aspect, there is provided any of the compounds according to aspects 1 to 14, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is halogen, -CN, -OR 8 , optionally substituted C1-C4 alkyl, or optionally substituted C1-C4 fluoroalkyl.

[0178] In a sixteenth aspect, there is provided any of the compounds according to aspects 1 to 14, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is halogen, optionally substituted C1-C4 alkyl, or optionally substituted C1-C4 fluoroalkyl.

[0179] In a seventeenth embodiment, there is provided any of the compounds according to embodiment 15, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is a halogen.

[0180] In an eighteenth embodiment, there is provided any of the compounds according to embodiment 17, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is -Cl, -Br, -F, or -I, or where R 4 is -Cl.

[0181] In a nineteenth embodiment, there is provided any of the compounds according to embodiment 15, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 HA-OR 8 is.

[0182] In a twentieth aspect, there is provided any of the compounds according to aspect 19, or a pharmaceutically acceptable salt or solvate thereof, wherein R 8 is H, optionally substituted C1-C4 alkyl, or optionally substituted C1-C4 fluoroalkyl.

[0183] In a twenty-first embodiment, there is provided any of the compounds according to embodiment 15, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is optionally substituted C1-C4 alkyl.

[0184] In a twenty-second embodiment, there is provided any of the compounds according to embodiment 21, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is methyl, ethyl, propyl, or butyl.

[0185] In a twenty-third embodiment, there is provided any of the compounds according to embodiment 15, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is an optionally substituted C1-C4 fluoroalkyl.

[0186] In a twenty-fourth embodiment, there is provided any of the compounds according to embodiment 23, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is -CF3, -CF2CH3, or -CH2CF3.

[0187] In a twenty-fifth embodiment, there is provided any of the compounds according to embodiments 1 to 24, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is H, halogen, -CN, -OR 8 , -SR 8 , -N(R 8 )2, optionally substituted C1-C4 alkyl, or optionally substituted C1-C4 fluoroalkyl.

[0188] In a 26th embodiment, there is provided any of the compounds according to embodiment 25, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is H.

[0189] In a 27th embodiment, there is provided any of the compounds according to embodiment 25, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is a halogen.

[0190] In a 28th embodiment, there is provided any of the compounds according to embodiment 27, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is -Cl, -Br, -F, or -I.

[0191] In a 29th embodiment, there is provided any of the compounds according to embodiment 25, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 HA-OR 8 is.

[0192] In a 30th embodiment, there is provided any of the compounds according to embodiment 29, or a pharmaceutically acceptable salt or solvate thereof, wherein R 8is H, optionally substituted C1-C4 alkyl, or optionally substituted C1-C4 fluoroalkyl.

[0193] In a thirty-first embodiment, there is provided any of the compounds according to embodiment 25, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is optionally substituted C1-C4 alkyl.

[0194] In a thirty-second embodiment, there is provided any of the compounds according to embodiment 31, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is methyl, ethyl, propyl, or butyl.

[0195] In a thirty-third embodiment, there is provided any of the compounds according to embodiment 25, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is an optionally substituted C1-C4 fluoroalkyl.

[0196] In a thirty-fourth embodiment, there is provided any of the compounds according to embodiment 33, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is -CF3, -CF2CH3, or -CH2CF3.

[0197] In a 35th embodiment, the compound has the structure of formula (Ia) 10. The method of claim 1, wherein the compound has a structure similar to that of Example 1, or a pharmaceutically acceptable salt or solvate thereof.

[0198] In a 36th embodiment, the compound has the structure of formula (Ib) 10. The method of claim 1, wherein the compound has a structure similar to that of Example 1, or a pharmaceutically acceptable salt or solvate thereof.

[0199] In a thirty-seventh embodiment, there is provided any one of the compounds according to embodiments 1 to 36, or a pharmaceutically acceptable salt, or solvate thereof, wherein each R 2 are independently H, halogen, -OR 8 , optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, or optionally substituted C1-C4 fluoroalkyl, or alternatively where each R 2 is hydrogen.

[0200] In a thirty-eighth embodiment, there is provided any of the compounds according to embodiments 1 to 37, or a pharmaceutically acceptable salt, or solvate thereof, wherein q is 0, 1, or 2, or alternatively, wherein q is 0.

[0201] In a thirty-ninth embodiment, there is provided any one of the compounds according to embodiments 1 to 38, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C6 cycloalkylalkyl.

[0202] In a fortieth embodiment, there is provided any of the compounds according to embodiment 39, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is optionally substituted C1-C4 alkyl.

[0203] In a forty-first embodiment, there is provided any of the compounds according to embodiment 40, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is methyl.

[0204] In a forty-second embodiment, there is provided any of the compounds according to embodiment 39, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is an optionally substituted C1-C4 heteroalkyl.

[0205] In a forty-third embodiment, there is provided any of the compounds according to embodiment 39, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is an optionally substituted C1-C4 fluoroalkyl.

[0206] In a forty-fourth embodiment, there is provided any of the compounds according to embodiment 39, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is an optionally substituted C3-C6 cycloalkyl.

[0207] In a forty-fifth embodiment, there is provided any of the compounds according to embodiment 39, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is an optionally substituted C3-C6 cycloalkylalkyl.

[0208] In a forty-sixth embodiment, there is provided any of the compounds according to embodiment 39, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is H.

[0209] In a forty-seventh embodiment, there is provided any one of the compounds according to embodiments 1 to 46, or a pharmaceutically acceptable salt or solvate thereof, wherein R 7 is optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C6 cycloalkylalkyl.

[0210] In a 48th embodiment, there is provided any of the compounds according to embodiment 47, or a pharmaceutically acceptable salt or solvate thereof, wherein R 7 is optionally substituted C1-C4 alkyl.

[0211] In a 49th embodiment, there is provided any of the compounds according to embodiment 47, or a pharmaceutically acceptable salt or solvate thereof, wherein R 7 is an optionally substituted C1-C4 heteroalkyl.

[0212] In a 50th embodiment, there is provided any of the compounds according to embodiment 47, or a pharmaceutically acceptable salt or solvate thereof, wherein R 7 is an optionally substituted C3-C6 cycloalkyl.

[0213] In a fifty-first embodiment, there is provided any of the compounds according to embodiment 47, or a pharmaceutically acceptable salt or solvate thereof, wherein R 7 is optionally substituted C1-C4 alkyl.

[0214] In a 52nd embodiment, there is provided any of the compounds according to embodiment 47, or a pharmaceutically acceptable salt or solvate thereof, wherein R 7 is an optionally substituted C3-C6 cycloalkylalkyl.

[0215] In a fifty-third embodiment, there is provided any of the compounds according to embodiment 47, or a pharmaceutically acceptable salt or solvate thereof, wherein R 7 is selected from the group methyl, ethyl, -CH2CF3, -CH2-cyclopropyl, or -CH2CH2OCH3, or alternatively R 7 is CH2-cyclobutyl.

[0216] In a fifty-fourth embodiment, there is provided any one of the compounds according to embodiments 1 to 53, or a pharmaceutically acceptable salt or solvate thereof, wherein R A1 is H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, or optionally substituted C1-C4 fluoroalkyl.

[0217] In a 55th embodiment, there is provided any of the compounds according to embodiment 54, or a pharmaceutically acceptable salt or solvate thereof, wherein R A1 is H.

[0218] In a 56th embodiment, there is provided any of the compounds according to embodiment 54, or a pharmaceutically acceptable salt or solvate thereof, wherein R A1 is optionally substituted C1-C4 alkyl.

[0219] In a fifty-seventh embodiment, there is provided any one of the compounds according to embodiments 1 to 56, or a pharmaceutically acceptable salt, or solvate thereof, wherein R A2 is H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, or optionally substituted C1-C4 fluoroalkyl.

[0220] In a 58th embodiment, there is provided any of the compounds according to embodiment 57, or a pharmaceutically acceptable salt or solvate thereof, wherein R A2 is optionally substituted C1-C4 alkyl.

[0221] In a 59th embodiment, there is provided any of the compounds according to embodiment 58, or a pharmaceutically acceptable salt or solvate thereof, wherein R A2 is methyl, ethyl, propyl, or butyl.

[0222] In a 60th embodiment, there is provided any of the compounds according to embodiment 59, or a pharmaceutically acceptable salt or solvate thereof, wherein R A2 is ethyl.

[0223] In a sixty-first embodiment, there is provided any of the compounds according to embodiment 57, or a pharmaceutically acceptable salt or solvate thereof, wherein R A2 is an optionally substituted C1-C4 heteroalkyl.

[0224] In a 62nd embodiment, there is provided any of the compounds according to embodiment 57, or a pharmaceutically acceptable salt or solvate thereof, wherein R A2 is an optionally substituted C1-C4 fluoroalkyl.

[0225] In a 63rd embodiment, there is provided any of the compounds according to embodiment 57, or a pharmaceutically acceptable salt or solvate thereof, wherein R A2 is H.

[0226] In a 64th embodiment, the compound has the structure of formula (Ic), (Id), or (Ie): 64. The present invention provides any one of the compounds according to embodiments 1 to 63, or a pharmaceutically acceptable salt or solvate thereof, having the formula: TIFF2024156774000060.tif115128.

[0227] In a 65th embodiment, there is provided a compound according to any one of embodiments 1 to 64, or a pharmaceutically acceptable salt, or solvate thereof, wherein each R 8 are independently H, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C1-C4 fluoroalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C2-C 10 heterocycloalkyl, and each R 9 are independently an optionally substituted C1-C4 alkyl, an optionally substituted C1-C4 heteroalkyl, an optionally substituted C1-C4 fluoroalkyl, an optionally substituted C3-C6 cycloalkyl, or an optionally substituted C2-C 10 It is heterocycloalkyl.

[0228] In a sixty-sixth embodiment, there is provided a compound according to any one of embodiments 1 to 65, or a pharmaceutically acceptable salt, or solvate thereof, wherein the optional substituents are independently D, halogen, —CN, —NH, —NH(CH), —N(CH), —OH, —COH, —CO(C-C alkyl), —CHNH, —C(═O)NH, —C(═O)NH(C-C alkyl), —C(═O)N(C-C alkyl), —S(═O)NH, —S(═O)NH(C-C alkyl), —S(═O) and is selected from 2N(C1-C4 alkyl)2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 fluoroalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, —SC1-C4 alkyl, —S(═O)C1-C4 alkyl, and —S(═O)2C1-C4 alkyl (more preferably selected from D, halogen, —CN, —NH2, —OH, —NH(CH3), —N(CH3)2, —CH3, —CH2CH3, —CH2NH2, —CF3, —OCH3, and —OCF3).

[0229] In a 67th embodiment, there is provided a compound according to any one of embodiments 1 to 65, or a pharmaceutically acceptable salt or solvate thereof, wherein the optional substituents are absent.

[0230] In a 68th embodiment, a compound of formula (I *) or a pharmaceutically acceptable salt or solvate thereof: TIFF2024156774000061.tif38128 formula, Each Z is independently N or CR 1 with the proviso that at least one Z is N; Each R 1 are independently hydrogen, fluorine, chlorine, or cyano; R 3 is —CN, optionally substituted C1-C3 alkyl, optionally substituted C3-C4 cycloalkyl, optionally substituted —O—C3-C4 cycloalkyl, or optionally substituted —O—C1-C3 alkyl; R 4is chlorine, -CH3, cyano, -OCH3, or CF3; Each R 5 are independently hydrogen, chlorine, -CH3, cyano, -OCH3, or CF3; Each R 2 are independently hydrogen, fluorine, -CH3, or -OH; R 6 is H, or C1-C3 alkyl; R 7 is optionally substituted C1-C3 alkyl; C1-C3 fluoroalkyl, C1-C3 heteroalkyl, or C3-C4 cycloalkyl-C1-C3 alkyl; Or, R 6 and R 7 together with the N atom to which they are attached form an optionally substituted 4- to 6-membered ring, the remainder of the ring atoms being carbon; R A1 and R A2 are each independently H, optionally substituted C-C alkyl; optionally substituted C-C fluoroalkyl, optionally substituted C-C heteroalkyl, or optionally substituted C-C cycloalkyl-C-C alkyl, with the proviso that R A1 and R A2 are not both hydrogen; or alternatively, R A1 and R A2 are each independently H; C-C fluoroalkyl, C-C heteroalkyl, or C-C cycloalkyl-C-C alkyl or optionally substituted C-C alkyl, with the proviso that R A1 and R A2 are not both hydrogen; n is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4.

[0231] In a 69th embodiment, the compound has the formula (Ib * ) or (Ic * ) structure 69. The method of claim 68, wherein the compound has the formula: TIFF2024156774000062.tif74128, or a pharmaceutically acceptable salt or solvate thereof.

[0232] In a seventieth embodiment, there is provided any one of the compounds according to embodiments 68-69, or a pharmaceutically acceptable salt or solvate thereof, wherein R A1 is H or C1-C3 alkyl.

[0233] In a seventy-first embodiment, there is provided any one of the compounds according to embodiments 68 to 70, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 , R 7 , R A1 , and R A2 one or more of may be substituted, where the optional substituents are each independently selected from fluorine, —OH, —OCH, —OCHCH, —OCHCHCH, —NH, —NH(CH), or —N(CH).

[0234] In a seventy-second embodiment, there is provided any one of the compounds according to embodiments 68 to 70, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 , R 7 , R A1 , and R A2 one or more of may be substituted, where the optional substituents are each independently selected from fluorine, —OH, —OCH, —OCHCH, —OCHCHCH, —NH(CH), or —N(CH).

[0235] In a seventy-third embodiment, there is provided any one of the compounds according to embodiments 68 to 72, or a pharmaceutically acceptable salt or solvate thereof, wherein R 7 , R A1 , and R A2 One or more of is a C1-C3 heteroalkyl, where the heteroatom in the C1-C3 heteroalkyl is oxygen.

[0236] In a seventy-fourth embodiment, there is provided any one of the compounds according to embodiments 68 to 73, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is H or methyl, and R 7 is methyl, ethyl, CH2CF3, CH2-cyclopropyl, or CH2CH2OCH3.

[0237] In a seventy-fifth embodiment, there is provided any one of the compounds according to embodiments 68 to 74, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is methyl and R 7 is methyl, ethyl, CH2CF3, CH2-cyclopropyl, or CH2CH2OCH3.

[0238] In a seventy-sixth embodiment, there is provided a compound according to any one of embodiments 68 to 75, wherein q is 0.

[0239] In a 77th embodiment, there is provided a compound according to any of embodiments 68 to 76, wherein each Z is independently N or CR 1 with the proviso that at least one Z is N; and each R 1 are independently hydrogen, fluorine, chlorine or cyano; R 3 is C1-C3 alkyl or -OC1-C3 alkyl; R A1 is hydrogen or C1-C3 alkyl; R A2 is C1-C3 alkyl, C1-C3 fluoroalkyl, or C1-C3 heteroalkyl; provided that R A1 and R A2 Not both of these are hydrogen; R 4 is chlorine; each R 5 are independently hydrogen, chlorine, —CH 3 , cyano, —OCH 3 , or CF 3 ; n is 0, 1, 2, 3, or 4; and q is 0.

[0240] In a seventy-eighth embodiment, a compound of formula (Id * or a pharmaceutically acceptable salt or solvate thereof, wherein TIFF2024156774000063.tif39128 formula, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R A1 , and R A2 is as described for the compound according to embodiment 1.

[0241] In a 79th embodiment, there is provided a compound according to embodiment 78, or a pharmaceutically acceptable salt or solvate thereof: During the ceremony: Each R 5 are independently hydrogen, chlorine, fluorine, or C1-C3 alkyl (preferably hydrogen); R 4 is chlorine or C1-C3 alkyl (preferably chlorine); R 3 is C1-C3 alkyl or -OC1-C3 alkyl; R A1 is fluorine, chlorine, hydrogen, or C1-C3 alkyl; R A2 is C1-C3 alkyl, —OC1-C3 alkyl, hydrogen, C1-C3 fluoroalkyl, fluorine, chlorine, or C1-C3 heteroalkyl; provided that R A1 and R A2 are not both hydrogen; Each R 2 are independently hydrogen or fluorine (preferably hydrogen); R 1 is hydrogen or fluorine (preferably hydrogen); Z is independently N or CR 1 and; and wherein one Z is nitrogen, two Z are nitrogen, or three Z are nitrogen, or wherein: TIFF2024156774000064.tif19128.

[0242] In an 80th embodiment, there is provided a compound according to embodiment 79, or a pharmaceutically acceptable salt or solvate thereof, wherein: Each R 5 are independently hydrogen, chlorine, fluorine, or —CH (preferably hydrogen); R 4 is chlorine or —CH3 (preferably chlorine); R 3 is -CH3, -CH2CH3, or -OCH3; R A1 is fluorine, chlorine, hydrogen, or -CH3; R A2 is hydrogen, -CH3, -CH2CH3, -OCH3, CF3, CF2CH3, CH2OCH3, or fluorine; provided that R A1 and R A2 are not both hydrogen; Each R 2 are independently hydrogen or fluorine (preferably hydrogen); R 1 is hydrogen or fluorine (preferably hydrogen); and Z is as described for the compounds of embodiment 79.

[0243] In an 81st embodiment, there is provided a compound according to embodiment 78, 79, or 80, wherein R 6 and R 7 can be as described in any of the embodiments described herein. (e.g., R 7 can be an optionally substituted C-C cycloalkylalkyl, or R 7 may be selected from the group of methyl, ethyl, —CHCF, —CH-cyclopropyl, or —CHCHOCH, or R 7 may be selected from the group of methyl, ethyl, —CHCF, —CH-cyclopropyl, —CH-cyclobutyl, or —CHCHOCH; and R 6 can be as described herein for any of the embodiments (e.g., R 6may be hydrogen or C1-4 alkyl, more preferably hydrogen or methyl).

[0244] Also provided are pharmaceutical compositions comprising any of the compounds described herein, including pharmaceutically acceptable salts and solvates thereof, and one or more pharmaceutically acceptable excipients, as well as methods of using the compounds and compositions to treat or ameliorate the effects of diseases associated with altered IRE1 signaling. Such methods include administering a pharmaceutical composition or compound of the present invention to a subject in need thereof. The disease may be, for example, any of the diseases described herein.

[0245] The compounds and compositions provided herein can be for use as pharmaceuticals. Pharmaceuticals can be used, for example, to treat diseases, including any of the diseases described herein. [Example]

[0246] The following examples are intended to illustrate, but not limit, the disclosed embodiments.

[0247] I. Chemical synthesis Example 1A: Synthesis of tert-butyl ((1r,4r)-4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)amino)cyclohexyl)carbamate (1A) TIFF2024156774000065.tif53156

[0248] Step 1: 6-Bromoquinazolin-2-amine (1A-2) To a solution of 5-bromo-2-fluorobenzaldehyde (20.0 g, 98.5 mmol) in DMA (700 mL) was added guanidine-carbonate (26.6 g, 147.7 mmol). The mixture was stirred at 160 °C for 0.5 hours, cooled to room temperature, and concentrated. The residue was diluted with HO (300 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic layer was washed with brine (100 mL x 3), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was washed with DCM (300 mL) to give compound 1A-2 (4.0 g, crude).

[0249] Step 2: 6-Bromo-2-iodoquinazoline (1A-3) To a solution of compound 1A-2 (2.0 g, 8.9 mmol) in THF (20.0 mL) under N was added isoamyl nitrite (3.1 g, 26.8 mmol, 3.6 mL), diiodomethane (11.9 g, 44.7 mmol, 3.6 mL), and CuI (1.7 g, 8.9 mmol). The mixture was stirred at 80 °C for 2 hours, cooled to room temperature, quenched by the addition of ice water (100 mL), and extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with brine (100 mL x 3), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by column chromatography (SiO) to give compound 1A-3 (2.1 g, crude).

[0250] Step 3: 1-tert-butyl ((1r,4r)-4-((6-bromoquinazolin-2-yl)amino)cyclohexyl)carbamate (1A-4) To a solution of compound 1A-3 (4.0 g, 11.9 mmol) in IPA (120.0 mL) was added DIEA (4.6 g, 35.8 mmol, 6.2 mL) and tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate (7.6 g, 35.8 mmol). The mixture was stirred at 80 °C for 12 h, cooled to room temperature, and filtered. The collected solid was washed with dichloromethane / methanol (10 / 1, 60 mL). The combined filtrate was concentrated to give a residue, which was purified by column chromatography (SiO2) to give compound 1A-4 (3.6 g, 6.8 mmol, 57.2% yield). TIFF2024156774000066.tif26155

[0251] Step 4: tert-butyl ((1r,4r)-4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)amino)cyclohexyl)carbamate (1A) A mixture of compound 1A-4 (2.0 g, 4.7 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.3 g, 5.2 mmol), AcOK (1.4 g, 14.2 mmol), and Pd(dppf)Cl (347 mg, 474.6 umol) in dioxane (50 mL) was degassed and purged with N three times and heated at 90 °C under N for 12 hours. The reaction was cooled to room temperature and concentrated to give a residue. The residue was purified by column chromatography (SiO) to give compound 1A (2.7 g, crude). M+H + = 469.2 (LCMS).

[0252] Example 2A: Synthesis of tert-butyl ((1r,4r)-4-((8-ethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)amino)cyclohexyl)carbamate (2A) TIFF2024156774000067.tif79154

[0253] Step 1: 1-(5-bromo-2-fluorophenyl)ethan-1-ol (2A-2) A solution of 5-bromo-2-fluoro-benzaldehyde (55.0 g, 270.9 mmol) in THF (500.0 mL) was cooled to 0 °C. Then, MeMgBr (3 M, 94.8 mL) was added. The mixture was stirred at 0 °C for 0.5 hours, quenched with NH Cl (500 mL), and extracted with ethyl acetate (500 mL x 3). The combined organic layer was washed with brine (500 mL x 3), dried over Na SO , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO) to give compound 2A-2 (46.0 g, crude).

[0254] Step 2: 4-Bromo-2-ethyl-1-fluorobenzene (2A-3) To a solution of compound 2A-2 (46.0 g, 210.0 mmol) and triethylsilane (48.8 g, 420.0 mmol, 66.9 mL) in DCM (500.0 mL) was added BF3.Et2O (59.6 g, 420.0 mmol, 51.8 mL) at 0 °C. The mixture was stirred at 25 °C for 2 hours, concentrated, quenched by the addition of saturated NaHCO3 (200 mL) at 0 °C, and extracted with ethyl acetate (200 mL x 3). The combined organic layer was washed with brine (200 mL x 3), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2) to give compound 2A-3 (24.0 g, crude). TIFF2024156774000068.tif12152

[0255] Step 3: 5-Bromo-3-ethyl-2-fluorobenzaldehyde (2A-4) To a solution of compound 2A-3 (24.0 g, 82.7 mmol) in THF (500 mL) was added LDA (2 M, 49.6 mL) at −78° C. The mixture was stirred at −78° C. for 1 hour. Then, dimethylformamide (7.8 g, 107.5 mmol, 8.3 mL) was added and stirred at −78° C. for 1 hour. The reaction mixture was quenched by the addition of NH4Cl (100 mL), and the resulting mixture was extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2) to give compound 2A-4 (13.0 g, crude). TIFF2024156774000069.tif12143

[0256] Step 4: 6-Bromo-8-ethylquinazolin-2-amine (2A-5) To a solution of guanidine carbonate (3.5 g, 19.4 mmol) and DIEA (5.0 g, 38.9 mmol, 6.8 mL) in DMA (20 mL) was added a solution of compound 2A-4 (3.0 g, 12.98 mmol) in DMA (5 mL). The mixture was stirred at 160 °C for 1 hour, poured into ice water (30 mL), and extracted with ethyl acetate (40 mL x 3). The combined organic layer was washed with brine (30 mL x 3), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO) to give compound 2A-5 (1.2 g, crude). TIFF2024156774000070.tif12133

[0257] Step 5: 6-Bromo-8-ethyl-2-iodoquinazoline (2A-6) To a mixture of compound 2A-5 (1.2 g, 4.76 mmol) and CHCl (6.3 g, 23.8 mmol, 1.92 mL) in tetrahydrofuran (24.0 mL) was added CuI (906 mg, 4.7 mmol) and isoamyl nitrite (1.6 g, 14.3 mmol, 2.0 mL). The mixture was stirred under N at 80 °C for 2 h, and then NH.HO (30 mL) was added. The resulting mixture was extracted with ethyl acetate (50 mL x 3), and the combined organic layers were washed with brine (50 mL x 3), dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (SiO) to give compound 2A-6 (400 mg, crude).

[0258] Step 6: tert-Butyl ((1r,4r)-4-((6-bromo-8-ethylquinazolin-2-yl)amino)cyclohexyl)carbamate (2A-7) To a mixture of compound 2A-6 (350 mg, 964.2 umol) and DIEA (373 mg, 2.8 mmol, 505.2 uL) in isopropanol (10 mL) was added tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate (413 mg, 1.9 mmol). The mixture was stirred at 80 °C for 12 hours, cooled to room temperature, and concentrated. The residue was purified by prep-TLC (SiO2) to give compound 2A-7 (350 mg, crude).

[0259] Step 7: tert-butyl ((1r,4r)-4-((8-ethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)amino)cyclohexyl)carbamate (2A) To a mixture of compound 2A-7 (150 mg, 333.7 umol) and KOAc (98 mg, 1.0 mmol) in dioxane (2 mL), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (101 mg, 400.5 umol) and Pd(dppf)Cl (24 mg, 33.3 umol) were added. The mixture was stirred under N at 90 °C for 12 hours, cooled to room temperature, and concentrated. The residue was purified by prep-TLC (SiO) to give compound 2A (100 mg, crude).

[0260] Exemplary compounds were synthesized according to the procedures described herein. For compounds that do not have a specific synthetic scheme described herein, such compounds can be routinely synthesized by one of ordinary skill in the art with the guidance provided herein and skill in the art.

[0261] TIFF2024156774000071.tif122158TIFF2024156774000072.tif200158TIFF2024156774000073.tif19 6158TIFF2024156774000074.tif210158TIFF2024156774000075.tif228158TIFF2024156774000076.t if187158TIFF2024156774000077.tif242158TIFF2024156774000078.tif177158TIFF20241567740000 79.tif238158TIFF2024156774000080.tif233158TIFF2024156774000081.tif205158TIFF2024156774 000082.tif214158TIFF2024156774000083.tif191158TIFF2024156774000084.tif242158TIFF202415 6774000085.tif200158TIFF2024156774000086.tif206158TIFF2024156774000087.tif201158TIFF20 24156774000088.tif199158TIFF2024156774000089.tif229158TIFF2024156774000090.tif218158TI FF2024156774000091.tif189158TIFF2024156774000092.tif206158TIFF2024156774000093.tif77158

[0262] Example 1: Synthesis of 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide (91) TIFF2024156774000094.tif86157

[0263] Step 1: To a solution of guanidine (1.7 g, 13.8 mmol, H2CO3) and K2CO3 (5.7 g, 41.4 mmol) in DMA (60.0 mL) was added dropwise 5-bromo-3-ethyl-2-fluorobenzaldehyde (3.0 g, 13.8 mmol) in DMA (9.0 ml). The mixture was stirred at 160 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 → 10 / 1) to give 6-bromo-8-ethylquinazolin-2-amine (1.4 g, 3.4 mmol, 24.7% yield). M+H + = 257.8 (LCMS).

[0264] Step 2: To a solution of 6-bromo-8-ethylquinazolin-2-amine (10 g, 39.6 mmol) in pyridine (100.0 mL) was added pyridine hydrofluoride (220.0 g, 2.2 mol, 200.0 mL) at −40° C. The mixture was stirred at −40° C. for 15 minutes. Then, tert-butyl nitrite (8.2 g, 79.3 mmol, 9.4 mL) was added. The mixture was stirred at 20° C. for 12 hours. The mixture was poured into ice water, adjusted to pH = 7 with saturated NaHCO3, and extracted with ethyl acetate (500.0 mL x 3). The combined organic layer was washed with brine (200.0 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 → 10 / 1) to give 6-bromo-8-ethyl-2-fluoroquinazoline (11.4 g, 43.9 mmol, 55.4% yield). TIFF2024156774000095.tif19148

[0265] Step 3: To a solution of 6-bromo-8-ethyl-2-fluoroquinazoline (6.0 g, 23.5 mmol) and KOAc (3.5 g, 35.3 mmol) in dioxane (100.0 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (7.2 g, 28.2 mmol) and Pd(dppf)Cl (1.7 g, 2.3 mmol). The mixture was stirred at 90° C. under N for 12 hours. The mixture was concentrated to give the crude residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 → 3 / 1) to give 8-ethyl-2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline (7.1 g, 23.5 mmol, 99.9% yield).

[0266] Step 4: To a solution of 8-ethyl-2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline (7.1 g, 23.5 mmol) and KCO (9.7 g, 70.4 mmol) in dioxane (150.0 mL) and HO (15.0 mL) was added N-(5-bromo-6-methylpyridin-2-yl)-2-chlorobenzenesulfonamide (10.2 g, 28.2 mmol) and Pd(dppf)Cl (859 mg, 1.1 mmol). The mixture was stirred at 90 °C under N for 12 hours. The mixture was concentrated to give a crude residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 → 0 / 1) to give 2-chloro-N-(5-(8-ethyl-2-fluoroquinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide (8.5 g, 15.3 mmol, 65.2% yield). M+H + = 457.1 (LCMS).

[0267] Step 5: To a solution of 2-chloro-N-(5-(8-ethyl-2-fluoroquinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide (8.5 g, 18.6 mmol) in n-BuOH (60.0 mL) was added (1r,4r)-N1,N1-dimethylcyclohexane-1,4-diamine (13.3 g, 74.4 mmol, HCl) and DIEA (16.8 g, 130.2 mmol, 22.6 mL). The mixture was stirred at 100° C. for 12 hours. The mixture was concentrated to give a crude residue. The residue was purified by prep-HPLC (FA conditions) to give 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide (3.6 g, 5.7 mmol, 30.7% yield, formate (FA)). TIFF2024156774000096.tif33155

[0268] Example 2: Synthesis of 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-fluoropyridin-2-yl)benzenesulfonamide (95) TIFF2024156774000097.tif55143

[0269] Step 1: To a solution of 5-bromo-3-fluoropyridin-2-amine (815 mg, 4.2 mmol) in pyridine (20.0 mL) was added 2-chlorobenzene-1-sulfonyl chloride (1.4 g, 6.4 mmol, 871.5 uL). The mixture was stirred at 45 °C for 24 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2) to give N-(5-bromo-3-fluoropyridin-2-yl)-2-chlorobenzenesulfonamide (1.2 g, 2.0 mmol, 47.6% yield). M+H + = 366.8 (LCMS).

[0270] Step 2: To a solution of N-(5-bromo-3-fluoropyridin-2-yl)-2-chlorobenzenesulfonamide (1.2 g, 3.2 mmol) and 8-ethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine (1.2 g, 3.8 mmol) in dioxane (30.0 mL) and HO (3.0 mL) was added KCO (1.3 g, 9.6 mmol) and Pd(dppf)Cl (236 mg, 322.7 umol). The mixture was stirred at 90 °C under N for 12 h. The reaction mixture was concentrated in vacuo to give a residue. The residue was washed with HO (20.0 mL x 3) and ethyl acetate (20.0 mL x 3). To the residue, MeOH (30.0 mL) and THF (30.0 mL) were then added and stirred at 25° C. for 12 hours. The mixture was then filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO) to give N-(5-(2-amino-8-ethylquinazolin-6-yl)-3-fluoropyridin-2-yl)-2-chlorobenzenesulfonamide (429 mg, crude). M+H + = 458.2 (LCMS).

[0271] Step 3: To a solution of N-(5-(2-amino-8-ethylquinazolin-6-yl)-3-fluoropyridin-2-yl)-2-chlorobenzenesulfonamide (200 mg, 436.7 umol) and CuI (83 mg, 436.7 umol) in THF (5.0 mL) was added CHCl (584 mg, 2.1 mmol, 176.1 uL) and isopentyl nitrite (153 mg, 1.3 mmol, 176.4 uL). The mixture was stirred at 80 °C for 12 h. The reaction mixture was basified with NH.HO (25% solution) to pH 8-9. Water (20.0 mL) was then added to the mixture, which was then extracted with ethyl acetate (40.0 mL x 4). The combined organic phase was washed with brine (10.0 mL x 3), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (FA conditions) to give 2-chloro-N-(5-(8-ethyl-2-iodoquinazolin-6-yl)-3-fluoropyridin-2-yl)benzenesulfonamide (42 mg, 61.4 umol, 15.1% yield, FA). M+H + = 569.0 (LCMS).

[0272] Step 4: To a solution of 2-chloro-N-(5-(8-ethyl-2-iodoquinazolin-6-yl)-3-fluoropyridin-2-yl)benzenesulfonamide (37 mg, 65.0 umol) and (1r,4r)-N1,N1-dimethylcyclohexane-1,4-diamine (133 mg, 520.4 umol, TFA) in n-BuOH (2.0 mL) was basified with DIEA to pH 8, and DIEA (25 mg, 195.1 umol, 33.9 uL) was added. The mixture was placed in a microwave tube. The sealed tube was heated at 150° C. in a microwave for 6 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by pre-HPLC (FA conditions) to give 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-fluoropyridin-2-yl)benzenesulfonamide (5.2 mg, 7.6 μmol, 11.7% yield, FA). TIFF2024156774000098.tif33156

[0273] Example 3: Synthesis of N-(6-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-5-ethylpyridazin-3-yl)-2-chlorobenzenesulfonamide (96) TIFF2024156774000099.tif55156

[0274] Step 1: To a solution of 2-chlorobenzene-1-sulfonyl chloride (2.0 g, 9.5 mmol, 1.3 mL) in THF (20.0 mL) at 0 °C was added NH3.HO (3.3 g, 28.4 mmol, 3.7 mL, 25% solution). The mixture was stirred at 0 °C for 10 min and then warmed to 20 °C for 2 h. The reaction mixture was concentrated to give 2-chlorobenzenesulfonamide (1.8 g, 9.4 mmol, 99.1% yield). TIFF2024156774000100.tif11155

[0275] Step 2: A mixture of 3,6-dichloro-4-ethylpyridazine (500 mg, 2.8 mmol), 2-chlorobenzenesulfonamide (595 mg, 3.1 mmol), CsCO (2.7 g, 8.5 mmol), dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (132 mg, 282.4 umol), and [2-(2-aminoethyl)phenyl]chloropalladium; di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (194 mg, 282.4 umol) in THF (30.0 mL) was degassed and purged with N three times, and then the mixture was stirred at 80 °C under a N atmosphere for 12 h. The reaction was concentrated to give a residue. The residue was purified by column chromatography (SiO) to give the crude product (280 mg). The crude product was purified by prep-HPLC (TFA condition) to give 2-chloro-N-(6-chloro-5-ethylpyridazin-3-yl)benzenesulfonamide (20 mg, 54.2 umol, 1.9% yield). TIFF2024156774000101.tif19153; and 2-chloro-N-(6-chloro-4-ethylpyridazin-3-yl)benzenesulfonamide (100 mg, 270.9 umol, 10.7% yield) TIFF2024156774000102.tif19156 was obtained.

[0276] Step 3: A mixture of 2-chloro-N-(6-chloro-4-ethylpyridazin-3-yl)benzenesulfonamide (54 mg, 161.1 umol), tert-butyl ((1r,4r)-4-((8-ethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)amino)cyclohexyl)carbamate (80 mg, 161.1 umol), KPO (0.5 M, 644.6 uL), and [2-(2-aminophenyl)phenyl]-chloro-palladium; bis(1-adamantyl)-butyl-phosphane (11 mg, 16.1 umol) was degassed and purged with N three times and placed in a microwave tube in 2-methyltetrahydrofuran (2.5 mL). The sealed tube was heated in a microwave at 120° C. for 180 minutes. The reaction was concentrated to give a residue. The residue was purified by prep-TLC (SiO) to give tert-butyl ((1r,4r)-4-((6-(6-((2-chlorophenyl)sulfonamido)-4-ethylpyridazin-3-yl)-8-ethylquinazolin-2-yl)amino)cyclohexyl)carbamate (60 mg, crude). M+H + = 666.3 (LCMS).

[0277] Step 4: To a solution of tert-butyl ((1r,4r)-4-((6-(6-(2-chlorophenylsulfonamido)-4-ethylpyridazin-3-yl)-8-ethylquinazolin-2-yl)amino)cyclohexyl)carbamate (60 mg, 90.1 umol) in DCM (2.0 mL) was added TFA (1.0 mL). The mixture was stirred at 20° C. for 0.5 h. The reaction was concentrated to give a residue. The residue was dissolved in MeOH (1.0 mL) and basified to pH 7 with NH.H0 (25% solution). The residue was purified by prep-HPLC (FA conditions) to give N-(6-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-5-ethylpyridazin-3-yl)-2-chlorobenzenesulfonamide (5.1 mg, 7.9 µmol, 8.8% yield, FA). TIFF2024156774000103.tif33153

[0278] Example 4: Synthesis of 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-fluoro-6-methylpyridin-2-yl)benzenesulfonamide (97) TIFF2024156774000104.tif89147

[0279] Step 1: To a solution of 3-fluoro-6-methyl-pyridin-2-amine (500 mg, 3.9 mmol) in MeCN (15.0 mL) was added NBS (705 mg, 3.9 mmol) at 0 °C. After the addition, the resulting mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2) to give 5-bromo-3-fluoro-6-methylpyridin-2-amine (750 mg, 3.1 mmol, 78.4% yield). TIFF2024156774000105.tif12128

[0280] Step 2: A mixture of 5-bromo-3-fluoro-6-methylpyridin-2-amine (700 mg, 3.41 mmol) and 2-chlorobenzenesulfonyl chloride (720 mg, 3.4 mmol, 464.9 uL) in pyridine (20.0 mL) was stirred at 45 °C for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2) to give N-(5-bromo-3-fluoro-6-methylpyridin-2-yl)-2-chlorobenzenesulfonamide (500 mg, 1.1 mmol, 34.7% yield). TIFF2024156774000106.tif12146

[0281] Step 3: A mixture of N-(5-bromo-3-fluoro-6-methylpyridin-2-yl)-2-chlorobenzenesulfonamide (200 mg, 526.8 umol), 8-ethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine (131 mg, 439.0 umol), KCO (60 mg, 439.0 umol), and Pd(dppf)Cl (32 mg, 43.9 umol) in dioxane (3.0 mL) and HO (0.3 mL) was degassed and purged with N three times, and then the mixture was stirred at 90 °C under a N atmosphere for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2) to give N-(5-(2-amino-8-ethylquinazolin-6-yl)-3-fluoro-6-methylpyridin-2-yl)-2-chlorobenzenesulfonamide (116 mg, 196.6 umol, 44.7% yield).

[0282] Step 4: To a solution of N-(5-(2-amino-8-ethylquinazolin-6-yl)-3-fluoro-6-methylpyridin-2-yl)-2-chlorobenzenesulfonamide (116 mg, 245.8 umol), CuI (46 mg, 245.8 umol) in THF (5.0 mL) was added CHCl (329 mg, 1.2 mmol, 99.1 uL) and isoamyl nitrite (86 mg, 737.3 umol, 99.2 uL). The mixture was stirred at 80° C. for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2) to give 2-chloro-N-(5-(8-ethyl-2-iodoquinazolin-6-yl)-3-fluoro-6-methylpyridin-2-yl)benzenesulfonamide (46 mg, 62.5 umol, 25.4% yield). M+H + = 582.9 (LCMS).

[0283] Step 5: To a solution of 2-chloro-N-(5-(8-ethyl-2-iodoquinazolin-6-yl)-3-fluoro-6-methylpyridin-2-yl)benzenesulfonamide (46 mg, 78.9 umol), (1r,4r)-N1,N1-dimethylcyclohexane-1,4-diamine (161 mg, 631.4 umol, TFA) in n-BuOH (2.0 mL) was adjusted to pH 8-9 with DIEA. DIEA (30 mg, 236.7 umol, 41.2 uL) was then added. The mixture was stirred at 100° C. for 12 hours. (1r,4r)-N1,N1-dimethylcyclohexane-1,4-diamine (161 mg) was added. The reaction was stirred at 100° C. for an additional 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (FA conditions) to give 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-fluoro-6-methylpyridin-2-yl)benzenesulfonamide (2.1 mg, 3.1 umol, 4.0% yield, FA). TIFF2024156774000107.tif33156

[0284] Example 5: Synthesis of 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide (99) TIFF2024156774000108.tif56157

[0285] Step 1: A mixture of N-(5-bromo-6-methoxy-2-pyridyl)-2-chlorobenzenesulfonamide (2.5 g, 6.6 mmol), 8-ethyl-2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline (2.0 g, 6.6 mmol), KCO (2.7 g, 19.8 mmol), and Pd(dppf)Cl (484 mg, 661.9 umol) in HO (2.0 mL) and dioxane (20.0 mL) was degassed and purged with N three times, and then the mixture was stirred at 90 °C under a N atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 → 0 / 1) to give 2-chloro-N-(5-(8-ethyl-2-fluoroquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide (2.0 g, 3.6 mmol, crude). M+H + = 473.1 (LCMS).

[0286] Step 2: To a solution of 2-chloro-N-(5-(8-ethyl-2-fluoroquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide (1.5 g, 3.1 mmol) in n-BuOH (30.0 mL) was added DIEA (2.9 g, 22.2 mmol, 3.9 mL) and (1r,4r)-N1,N1-dimethylcyclohexane-1,4-diamine (2.3 g, 12.7 mmol, HCl). The mixture was stirred at 100° C. for 24 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA conditions) to give 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide (1.13 g, 1.6 mmol, 52.1% yield, FA). TIFF2024156774000109.tif40156

[0287] Example 6: Synthesis of 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-7-methylquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide (108) TIFF2024156774000110.tif55156

[0288] The title compound was synthesized according to the synthetic procedure reported for the preparation of N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-7-ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide (7.5 mg, 11.2 umol, 4.5% yield, FA). TIFF2024156774000111.tif40157

[0289] Example 7: Synthesis of 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-ethylpyridin-2-yl)benzenesulfonamide (117) TIFF2024156774000112.tif57156

[0290] Step 1: To a solution of 6-ethylpyridin-2-amine (1.8 g, 15.1 mmol) in CHCl (50.0 mL) was added NBS (2.7 g, 15.1 mmol) at 0 °C. The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO) to give 5-bromo-6-ethylpyridin-2-amine (3 g, 14.7 mmol, 97.5% yield). TIFF2024156774000113.tif12154

[0291] Step 2: To a solution of 5-bromo-6-ethylpyridin-2-amine (1.0 g, 5.0 mmol) in pyridine (20.0 mL) was added 2-chlorobenzene-1-sulfonyl chloride (1.3 g, 5.9 mmol, 812.7 uL). The mixture was stirred at 45 °C for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2) to give N-(5-bromo-6-ethylpyridin-2-yl)-2-chlorobenzenesulfonamide (1.0 g, 2.3 mmol, 47.5% yield). M+H + = 375.0 (LCMS).

[0292] Step 3: A mixture of N-(5-bromo-6-ethylpyridin-2-yl)-2-chlorobenzenesulfonamide (149 mg, 397.1 umol), 8-ethyl-2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline (100 mg, 330.9 umol), KCO (137.2 mg, 992.9 umol), and Pd(dppf)Cl (24 mg, 33.1 umol) in dioxane (4.0 mL) and HO (0.4 mL) was degassed and purged with N three times, and then the mixture was stirred at 90 °C under a N atmosphere for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2) to give 2-chloro-N-(6-ethyl-5-(8-ethyl-2-fluoroquinazolin-6-yl)pyridin-2-yl)benzenesulfonamide (110 mg, 217.2 umol, 65.6% yield). M+H + = 471.2 (LCMS).

[0293] Step 4: To a solution of 2-chloro-N-(6-ethyl-5-(8-ethyl-2-fluoroquinazolin-6-yl)pyridin-2-yl)benzenesulfonamide (110 mg, 233.6 umol) in n-BuOH (4.0 mL) was added DIEA (242 mg, 1.9 mmol, 325.5 uL) and (1r,4r)-N1,N1-dimethylcyclohexane-1,4-diamine (133 mg, 934.3 umol, HCl). The mixture was stirred at 100° C. for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (FA conditions) to give 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-ethylpyridin-2-yl)benzenesulfonamide (27.1 mg, 42.2 μmol, 18.1% yield, FA). TIFF2024156774000114.tif40157

[0294] Example 8: Synthesis of N-(5-(8-ethyl-2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)quinazolin-6-yl)-6-methoxypyridin-2-yl)-2-methylbenzenesulfonamide (118) TIFF2024156774000115.tif58156

[0295] Step 1: To a solution of N-(5-(8-ethyl-2-fluoroquinazolin-6-yl)-6-methoxypyridin-2-yl)-2-methylbenzenesulfonamide (0.4 g, 883.9 umol) in n-BuOH (5.0 mL), DIEA (799 mg, 6.1 mmol, 1.0 mL) and (1r,4r)-N1,N1-dimethylcyclohexane-1,4-diamine (403 mg, 1.7 mmol) were added. The mixture was stirred at 100° C. for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2) to give tert-butyl ((1r,4r)-4-((8-ethyl-6-(2-methoxy-6-(2-methylphenylsulfonamido)pyridin-3-yl)quinazolin-2-yl)amino)cyclohexyl)(methyl)carbamate (260 mg, 330.5 umol, 37.3% yield). M+H + = 661.3 (LCMS).

[0296] Step 2: To a solution of tert-butyl ((1r,4r)-4-((8-ethyl-6-(2-methoxy-6-(2-methylphenylsulfonamido)pyridin-3-yl)quinazolin-2-yl)amino)cyclohexyl)(methyl)carbamate (260 mg, 393.4 umol) in DCM (5.0 mL) was added TFA (2.0 mL). The mixture was stirred at 25° C. for 10 minutes. The reaction mixture was concentrated under reduced pressure. To the residue was added dichloromethane (2.0 mL) and NH3.H2O (25% solution) until pH 7 and again concentrated under reduced pressure. The residue was purified by prep-HPLC (FA conditions) to give N-(5-(8-ethyl-2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)quinazolin-6-yl)-6-methoxypyridin-2-yl)-2-methylbenzenesulfonamide (116.8 mg, 185.5 umol, 47.1% yield, FA). TIFF2024156774000116.tif40153

[0297] Example 9: Synthesis of N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2-methylbenzenesulfonamide (119) TIFF2024156774000117.tif60154

[0298] Step 1: A solution of 5-bromo-6-chloro-pyridin-2-amine (500 mg, 2.4 mmol) in NaOMe (7.0 mL, 30% solution) was stirred at 70° C. for 12 hours. Water (25.0 mL) was added to the residue and extracted with ethyl acetate (30.0 ml x 3). The combined organic phase was washed with brine (15.0 mL x 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give 5-bromo-6-methoxypyridin-2-amine (480 mg, crude).

[0299] Step 2: To a solution of 5-bromo-6-methoxypyridin-2-amine (1.0 g, 4.9 mmol) in DCM (20.0 mL) was added 2-methylbenzenesulfonyl chloride (1.1 g, 5.9 mmol, 853.6 uL) and pyridine (1.2 g, 14.8 mmol, 1.2 mL). The mixture was stirred at 45 °C for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 → 50 / 1) to give N-(5-bromo-6-methoxypyridin-2-yl)-2-methylbenzenesulfonamide (1.0 g, 2.5 mmol, 52.2% yield). M+H + = 357.0 (LCMS).

[0300] Step 3: A mixture of 8-ethyl-2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline (0.5 g, 1.6 mmol), N-(5-bromo-6-methoxypyridin-2-yl)-2-methylbenzenesulfonamide (591 mg, 1.6 mmol), KCO (686 mg, 4.9 mmol), and Pd(dppf)Cl (121 mg, 165.4 umol) in HO (1.0 mL) and dioxane (10.0 mL) was degassed and purged with N three times, and then the mixture was stirred under a N atmosphere at 90 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 → 0 / 1) to give N-(5-(8-ethyl-2-fluoroquinazolin-6-yl)-6-methoxypyridin-2-yl)-2-methylbenzenesulfonamide (0.6 g, 464.0 umol, 28.0% yield). M+H + =452.9 (LCMS).

[0301] Step 4: To a solution of N-(5-(8-ethyl-2-fluoroquinazolin-6-yl)-6-methoxypyridin-2-yl)-2-methylbenzenesulfonamide (200 mg, 441.9 umol) in n-BuOH (5.0 mL) was added DIEA (399 mg, 3.0 mmol, 538.8 uL) and (1r,4r)-N1,N1-dimethylcyclohexane-1,4-diamine (315 mg, 1.7 mmol, HCl). The mixture was stirred at 100° C. for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (FA conditions) to give N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2-methylbenzenesulfonamide (46.4 mg, 72.3 µmol, 16.3% yield, FA). TIFF2024156774000118.tif40155

[0302] Example 10: Synthesis of 2-chloro-N-(5-(8-ethyl-2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)quinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide (122) TIFF2024156774000119.tif56153

[0303] Step 1: To a solution of 2-chloro-N-(5-(8-ethyl-2-fluoroquinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide (0.6 g, 1.3 mmol) in n-BuOH (15.0 mL) was added DIEA (509 mg, 3.9 mmol, 686.0 uL) and tert-butyl ((1r,4r)-4-aminocyclohexyl)(methyl)carbamate (600 mg, 2.6 mmol). The mixture was stirred at 100° C. for 12 hours. The reaction was concentrated to give a residue. The residue was purified by flash silica gel chromatography (SiO) to give tert-butyl ((1r,4r)-4-((6-(6-(2-chlorophenylsulfonamido)-2-methylpyridin-3-yl)-8-ethylquinazolin-2-yl)amino)cyclohexyl)(methyl)carbamate (700 mg, 1.1 mmol, 80.1% yield).

[0304] Step 2: A mixture of tert-butyl ((1r,4r)-4-((6-(6-(2-chlorophenylsulfonamido)-2-methylpyridin-3-yl)-8-ethylquinazolin-2-yl)amino)cyclohexyl)(methyl)carbamate (700 mg, 1.1 mmol) in HCl / MeOH (4M, 15.0 mL) was stirred at 20° C. for 0.5 h. The reaction was concentrated to give a residue. The residue (30 mg) was dissolved in MeOH (2.0 mL), basified with NH.HO (25% solution) to pH 7, and then purified by prep-HPLC (FA conditions) to give 2-chloro-N-(5-(8-ethyl-2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)quinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide (19 mg, 31.2 umol, FA). The TIFF2024156774000120.tif33157 residue (500 mg) was dissolved in MeOH (10.0 mL), basified with NH3.HO (25% solution) to pH 7, and then purified by prep-HPLC (FA conditions) to give 2-chloro-N-(5-(8-ethyl-2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)quinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide (270 mg, 397.61 umol, 37.79% yield, FA).

[0305] Example 11: 2-chloro-N-(5-(8-ethyl-2-(((1r,4r)-4-(ethyl(methyl)amino)cyclohexyl)amino)quinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide (125) TIFF2024156774000121.tif87156

[0306] Step 1A: A mixture of 8-ethyl-2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline (2.0 g, 6.6 mmol), N-(5-bromo-6-methylpyridin-2-yl)-2-chlorobenzenesulfonamide (2.8 g, 7.9 mmol), KCO (2.7 g, 19.86 mmol), and Pd(dppf)Cl (484 mg, 661.9 umol) in dioxane (45.0 mL) and HO (4.5 mL) was degassed and purged with N three times, and then the mixture was stirred at 90 °C under a N atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2) to give 2-chloro-N-(5-(8-ethyl-2-fluoroquinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide (1.2 g, 1.8 mmol, 27.7% yield). M+H + = 457.1 (LCMS).

[0307] Step 1: To a solution of (1r,4r)-N1,N1-dibenzyl-N4-methylcyclohexane-1,4-diamine (447 mg, 1.4 mmol, HCl) in MeOH (15.0 mL) was added TEA (146 mg, 1.4 mmol, 201.7 uL) to adjust the pH to 7, and CH3COOH (87 mg, 1.4 mmol, 82.9 uL) to adjust the pH to 5. Then, acetaldehyde (798 mg, 7.2 mmol, 1.0 mL, 40% in HO) was added, and the mixture was stirred at 30 °C for 1 h. NaBH3CN (455 mg, 7.2 mmol) was then added, and the mixture was stirred at 30 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with NaHCO3 (10.0 mL) and extracted with ethyl acetate (5.0 mL x 3). The combined organic layers were concentrated under reduced pressure to give a residue, which gave crude (1r,4r)-N1,N1-dibenzyl-N4-ethyl-N4-methylcyclohexane-1,4-diamine (440 mg, crude).

[0308] Step 2: To a solution of (1r,4r)-N1,N1-dibenzyl-N4-ethyl-N4-methylcyclohexane-1,4-diamine (440 mg, 1.3 mmol) in THF (10.0 mL) was added Pd / C (0.4 g, 10% Pd basis) under a N2 atmosphere. The suspension was degassed and purged with H2 (50 psi) three times. The mixture was stirred at 60 °C for 24 h. The reaction mixture was filtered with methanol (60.0 mL), and the filtrate was concentrated under reduced pressure to give crude (1r,4r)-N1-ethyl-N1-methylcyclohexane-1,4-diamine (200 mg, crude).

[0309] Step 3: To a solution of (1r,4r)-N1-ethyl-N1-methylcyclohexane-1,4-diamine (51 mg, 328.2 umol) in n-BuOH (2.0 mL), DIEA (42 mg, 328.2 umol, 57.1 uL) and 2-chloro-N-(5-(8-ethyl-2-fluoroquinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide (50 mg, 109.4 umol) were added. The mixture was stirred at 100° C. for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (FA conditions) to give 2-chloro-N-(5-(8-ethyl-2-(((1r,4r)-4-(ethyl(methyl)amino)cyclohexyl)amino)quinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide (16.1 mg, 25.2 µmol, 23.0% yield, FA). TIFF2024156774000122.tif39156

[0310] Example 12: Synthesis of 2-chloro-N-(5-(8-ethyl-2-(((1r,4r)-4-(methyl(2,2,2-trifluoroethyl)amino)cyclohexyl)amino)quinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide (126) TIFF2024156774000123.tif54150

[0311] Step 1: To a solution of (1r,4r)-N1,N1-dibenzyl-N4-methylcyclohexane-1,4-diamine (0.7 g, 2.3 mmol, HCl) in MeCN (20.0 mL) was added NaHCO3 (763 mg, 9.1 mmol, 353.1 uL) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (790 mg, 3.4 mmol). The mixture was stirred at 70 °C for 12 hours. The reaction was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2) to give (1r,4r)-N1,N1-dibenzyl-N4-methyl-N4-(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine (800 mg, 1.1 mmol, 47.0% yield). M+H + = 391.3 (LCMS).

[0312] Step 2: To a solution of (1r,4r)-N1,N1-dibenzyl-N4-methyl-N4-(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine (0.8 g, 2.1 mmol) in THF (15.0 mL) was added Pd / C (0.8 g, 10% Pd basis) under a N2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred under H2 (50 Psi) at 60 °C for 24 h. The reaction was filtered and concentrated to give (1r,4r)-N1-methyl-N1-(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine (350 mg, crude).

[0313] Step 3: To a solution of (1r,4r)-N1-methyl-N1-(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine (69 mg, 328.3 umol) in n-BuOH (4.0 mL) was added 2-chloro-N-(5-(8-ethyl-2-fluoroquinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide (50 mg, 109.4 umol) and DIEA (42 mg, 328.3 umol, 57.2 uL). The mixture was stirred at 90° C. for 12 hours. The reaction was concentrated to give a residue. The residue was purified by prep-HPLC (FA conditions) to give 2-chloro-N-(5-(8-ethyl-2-(((1r,4r)-4-(methyl(2,2,2-trifluoroethyl)amino)cyclohexyl)amino)quinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide (29.8 mg, 42.4 umol, 38.8% yield, FA). TIFF2024156774000124.tif33156

[0314] Example 13: Synthesis of 2-chloro-N-(5-(8-ethyl-2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)quinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide (127) TIFF2024156774000125.tif62156

[0315] Step 1: To a solution of 2-chloro-N-(5-(8-ethyl-2-fluoroquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide (130 mg, 264.8 umol) in n-BuOH (6.0 mL) was added tert-butyl ((1r,4r)-4-aminocyclohexyl)(methyl)carbamate (181 mg, 794.4 umol) and DIEA (103 mg, 794.4 umol, 138.4 uL). The mixture was stirred at 90° C. for 12 hours. The reaction was concentrated to give a residue. The residue was purified by column chromatography (SiO2) to give tert-butyl ((1r,4r)-4-((6-(6-(2-chlorophenylsulfonamido)-5-fluoro-2-methoxypyridin-3-yl)-8-ethylquinazolin-2-yl)amino)cyclohexyl)(methyl)carbamate (170 mg, 243.12 umol, 91.81% yield).

[0316] Step 2: To a solution of tert-butyl ((1r,4r)-4-((6-(6-(2-chlorophenylsulfonamido)-5-fluoro-2-methoxypyridin-3-yl)-8-ethylquinazolin-2-yl)amino)cyclohexyl)(methyl)carbamate (170 mg, 243.1 umol) in DCM (3.0 mL) was added TFA (1.5 mL). The mixture was stirred at 20° C. for 0.5 h. The reaction was concentrated to give a residue. The residue was dissolved in MeOH (2.0 mL) and basified to pH 7 with NH.H0 (25% solution). The residue was purified by prep-HPLC (FA conditions) to give 2-chloro-N-(5-(8-ethyl-2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)quinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide (26.8 mg, 40.3 umol, 16.6% yield, FA). TIFF2024156774000126.tif26156

[0317] Example 14: Synthesis of 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide (128) TIFF2024156774000127.tif84156

[0318] Step 1: To a solution of 2,3,6-trifluoropyridine (2.4 g, 18.0 mmol) in dioxane (12.0 mL) was added NH3.H2O (12.0 mL, 25% solution). The mixture was stirred at 100 °C for 12 hours. The reaction was extracted with ethyl acetate (15.0 mL x 3). The combined organic phase was washed with brine (15.0 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated to give 3,6-difluoropyridin-2-amine (2.0 g, 15.4 mmol, 85.2% yield).

[0319] Step 2: A mixture of 3,6-difluoropyridin-2-amine (2.0 g, 15.4 mmol) in NaOMe (30.0 mL, 30% solution) was stirred at 70 °C for 1 hour. Water (30.0 mL) was added to the reaction mixture and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (30 mL x 3), dried over anhydrous NaSO, filtered, and concentrated to give a residue. The residue was purified by prep-HPLC (neutral condition) to give 3-fluoro-6-methoxypyridin-2-amine (0.8 g, 5.1 mmol, 33% yield). TIFF2024156774000128.tif12128

[0320] Step 3: To a solution of 3-fluoro-6-methoxypyridin-2-amine (300 mg, 2.1 mmol) in DMF (12.0 mL) was added NBS (376 mg, 2.1 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 hours. Cold HO (10.0 mL) was added to the reaction mixture, and it was extracted with ethyl acetate (10.0 mL x 3). The combined organic phase was washed with brine (10.0 mL x 3), dried over anhydrous NaSO, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO) to give 5-bromo-3-fluoro-6-methoxypyridin-2-amine (420 mg, 1.7 mmol, 81.0% yield). TIFF2024156774000129.tif12128

[0321] Step 4: To a solution of 5-bromo-3-fluoro-6-methoxypyridin-2-amine (400 mg, 1.8 mmol) in pyridine (10.0 mL) was added 2-chlorobenzenesulfonyl chloride (420 mg, 2.0 mmol, 271.1 uL). The mixture was stirred at 45° C. for 12 hours. The reaction was concentrated to give a residue. The residue was purified by column chromatography (SiO2) to give N-(5-bromo-3-fluoro-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide (680 mg). M+H + = 396.9 (LCMS).

[0322] Step 5: A mixture of 8-ethyl-2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline (300 mg, 992.9 umol), N-(5-bromo-3-fluoro-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide (471 mg, 1.2 mmol), KCO (206 mg, 1.5 mmol), and Pd(dppf)Cl (73 mg, 99.3 umol) in dioxane (15.0 mL) and HO (1.5 mL) was degassed and purged with N three times, and then the mixture was stirred at 90 °C under a N atmosphere for 12 hours. The reaction was concentrated to give a residue. The residue was purified by flash silica gel chromatography (SiO2) to give 2-chloro-N-(5-(8-ethyl-2-fluoroquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide (230 mg, 364.2 umol, 36.7% yield). M+H + = 491.2 (LCMS).

[0323] Step 6: To a solution of 2-chloro-N-(5-(8-ethyl-2-fluoroquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide (100 mg, 203.7 umol) in n-BuOH (4.0 mL) was added (1r,4r)-N1,N1-dimethylcyclohexane-1,4-diamine (109 mg, 611.1 umol, HCl) and DIEA (210.6 mg, 1.6 mmol, 283.9 uL). The mixture was stirred at 90° C. for 12 hours. The reaction was concentrated to give a residue. The residue was purified by prep-HPLC (FA conditions) to give 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide (37.2 mg, 54.6 umol, 26.8% yield, FA). TIFF2024156774000130.tif26155

[0324] Example 15: Synthesis of 2-chloro-N-(5-(2-(((1r,4r)-4-((cyclobutylmethyl)(methyl)amino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide (130) TIFF2024156774000131.tif25156

[0325] To a solution of 2-chloro-N-(5-(8-ethyl-2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)quinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide (60 mg, 98.2 umol, FA) in DCE (2.0 mL) and DCM (2.0 mL) was added TEA to basify the mixture to pH 7, followed by cyclobutanecarbaldehyde (33 mg, 294.5 umol, 128.6 uL). AcOH (0.05 mL) was added to the mixture to adjust the pH to 5, and the mixture was stirred at 30° C. for 2 hours. NaBH(OAc)3 (104 mg, 490.9 umol) was added to the mixture, and the reaction was stirred at 30° C. for 12 hours. The reaction was concentrated to give a residue. The residue was purified by prep-HPLC (FA conditions) to give 2-chloro-N-(5-(2-(((1r,4r)-4-((cyclobutylmethyl)(methyl)amino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide (34.8 mg, 51.2 umol, 52.1% yield, FA). TIFF2024156774000132.tif40156

[0326] Example 16: Synthesis of 2-chloro-N-(5-(8-(1,1-difluoroethyl)-2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide (131) TIFF2024156774000133.tif80156

[0327] Step 1: A solution of 1-(5-bromo-2-fluoro-phenyl)ethanone (1.0 g, 4.6 mmol) in DAST (12.2 g, 75.6 mmol, 10.0 mL) was stirred at 45 °C for 12 hours. The mixture was poured into ice-cold saturated NaHCO (100.0 mL) and extracted with ethyl acetate (10.0 mL x 3). The combined organic layers were washed with brine (10.0 mL x 3), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO) to give 4-bromo-2-(1,1-difluoroethyl)-1-fluorobenzene (1.0 g, 4.1 mmol, 90.8% yield). TIFF2024156774000134.tif12150

[0328] Step 2: To a solution of 4-bromo-2-(1,1-difluoroethyl)-1-fluorobenzene (450 mg, 1.8 mmol) in THF (10.0 mL) was added LDA (2 M, 1.2 mL) at −78° C. The mixture was stirred at −78° C. for 1 hour. Then, DMF (165 mg, 2.2 mmol, 173.8 uL) was added and stirred at −78° C. for 1 hour. The mixture was poured into saturated NH4Cl (10.0 mL) and extracted with ethyl acetate (10.0 mL x 3). The combined organic layers were washed with brine (10.0 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2) to give 5-bromo-3-(1,1-difluoroethyl)-2-fluorobenzaldehyde (0.4 g, 1.5 mmol, 79.5% yield). TIFF2024156774000135.tif12128

[0329] Step 3: To a solution of guanidine (181 mg, 1.5 mmol, H2CO3) and K2CO3 (621 mg, 4.4 mmol, 4.8 mL) in DMA (10.0 mL) was added a solution of 5-bromo-3-(1,1-difluoroethyl)-2-fluorobenzaldehyde (0.4 g, 1.5 mmol) in DMA (1.5 mL). The mixture was then stirred at 160 °C for 1 h. The mixture was concentrated to give a crude residue, and HO (30.0 mL) was added and extracted with ethyl acetate (30.0 mL x 3). The combined organic layers were washed with brine (20.0 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2) to give 6-bromo-8-(1,1-difluoroethyl)quinazolin-2-amine (0.4 g, 1.39 mmol, 92.69% yield).

[0330] Step 4: To a solution of 6-bromo-8-(1,1-difluoroethyl)quinazolin-2-amine (0.4 g, 1.3 mmol) in pyridine (3.5 mL) was added pyridine hydrofluoride (7.7 g, 77.7 mmol, 7.00 mL) at -40 °C. The mixture was stirred at -40 °C for 15 minutes. Then, tert-butyl nitrite (286 mg, 2.7 mmol, 330.2 uL) was added. The mixture was stirred at 20 °C for 12 hours. The mixture was poured into ice water, adjusted to pH = 7 with saturated NaHCO3, and extracted with ethyl acetate (50.0 mL x 3). The combined organic layer was washed with brine (20.0 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2) to give 6-bromo-8-(1,1-difluoroethyl)-2-fluoroquinazoline (0.3 g, 1.0 mmol, 74.2% yield). TIFF2024156774000136.tif12128

[0331] Step 5: To a solution of 6-bromo-8-(1,1-difluoroethyl)-2-fluoroquinazoline (0.3 g, 1.03 mmol) and KOAc (151 mg, 1.5 mmol) in dioxane (6.0 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (314 mg, 1.2 mmol) and Pd(dppf)Cl2 (75 mg, 103.0 umol). The mixture was stirred at 90 °C under N2 for 12 hours. The mixture was concentrated to give a crude residue. The residue was purified by column chromatography (SiO2) to give 8-(1,1-difluoroethyl)-2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline (0.3 g, crude).

[0332] Step 6: To a solution of 8-(1,1-difluoroethyl)-2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline (150 mg, 443.6 umol) and KCO (183 mg, 1.3 mmol) in dioxane (2.0 mL) and HO (0.2 mL) was added N-(5-bromo-6-methylpyridin-2-yl)-2-chlorobenzenesulfonamide (192 mg, 532.3 umol) and Pd(dppf)Cl (32 mg, 44.3 umol). The mixture was stirred at 90 °C under N for 12 hours. The mixture was concentrated to give a crude residue. The residue was purified by column chromatography (SiO 2 ) to give 2-chloro-N-(5-(8-(1,1-difluoroethyl)-2-fluoroquinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide (90 mg, crude).

[0333] Step 7: To a solution of 2-chloro-N-(5-(8-(1,1-difluoroethyl)-2-fluoroquinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide (90 mg, 182.5 umol) in n-BuOH (2.0 mL) was added (1r,4r)-N1,N1-dimethylcyclohexane-1,4-diamine (103 mg, 730.3 umol, HCl) and DIEA (188 mg, 1.4 mmol, 254.4 uL). The mixture was stirred at 100° C. for 12 hours. The mixture was concentrated to give the crude residue. The residue was purified by prep-HPLC (FA conditions) to give 2-chloro-N-(5-(8-(1,1-difluoroethyl)-2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide (6.8 mg, 10.4 μmol, 5.7% yield, FA). TIFF2024156774000137.tif26151

[0334] Example 17: Synthesis of 2-chloro-N-(5-(8-(1,1-difluoroethyl)-2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide (124) TIFF2024156774000138.tif31144

[0335] The title compound was synthesized according to the synthetic procedure reported for the preparation of 2-chloro-N-(5-(8-(1,1-difluoroethyl)-2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide (5.4 mg, 7.7 umol, 7.8% yield, FA). TIFF2024156774000139.tif33156

[0336] Example 18: Synthesis of 2-chloro-N-(5-(8-ethyl-2-(((1r,4r)-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)amino)quinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide (132) TIFF2024156774000140.tif88156

[0337] Step 1: To a solution of isoindoline-1,3-dione (10.0 g, 67.9 mmol), TEA (8.9 g, 88.3 mmol, 12.3 mL) in DMF (60.0 mL) was added ethyl carbonochloridate (8.8 g, 81.5 mmol, 7.7 mL). The mixture was stirred at 25 °C for 12 hours. The reaction mixture was filtered to give ethyl 1,3-dioxoisoindoline-2-carboxylate (700 mg, crude). TIFF2024156774000141.tif12146

[0338] Step 2: To a solution of ethyl 1,3-dioxoisoindoline-2-carboxylate (700 mg, 3.1 mmol), tert-butyl ((1r,4r)-4-aminocyclohexyl)(methyl)carbamate (875 mg, 3.8 mmol) in HO (20.0 mL) was added NaCO (406 mg, 3.8 mmol). The mixture was stirred at 15 °C for 12 h. The reaction mixture was filtered to give a cake, which was washed with MeOH (20.0 mL x 3) to give tert-butyl ((1r,4r)-4-(1,3-dioxoisoindolin-2-yl)cyclohexyl)(methyl)carbamate (800 mg, crude). TIFF2024156774000142.tif12160

[0339] Step 3: To a solution of tert-butyl ((1r,4r)-4-(1,3-dioxoisoindolin-2-yl)cyclohexyl)(methyl)carbamate (767 mg, 2.1 mmol) in HCl / MeOH (40.0 mL, 4M) was stirred for 30 minutes at 25° C. The reaction mixture was concentrated under reduced pressure to give 2-((1r,4r)-4-(methylamino)cyclohexyl)isoindoline-1,3-dione (600 mg, crude, HCl). TIFF2024156774000143.tif26156

[0340] Step 4: A solution of 1,1,2-trimethoxyethane (4.9 g, 40.8 mmol, 5.2 mL) in HO (40.0 mL) and HCl (1.0 mL, 1M) was stirred at 60 °C for 2 hours. The reaction mixture was then extracted with dichloromethane (30.0 mL x 3). The combined organic layers were washed with brine (30.0 mL x 3), dried over NaSO, and filtered to obtain a filtrate. To the filtrate was added a solution of 2-((1r,4r)-4-(methylamino)cyclohexyl)isoindoline-1,3-dione (600 mg, 2.0 mmol, HCl), to which TEA was added and adjusted to pH = 7 in MeOH (100.0 mL). CHCOOH (183 mg, 3.0 mmol, 175.0 uL) was then added to adjust the pH to 5. And then NaBHCN (256 mg, 4.0 mmol) was added to the reaction mixture. The mixture was stirred at 45 °C for 12 hours. The reaction mixture was extracted with dichloromethane (30.0 mL x 3). The combined organic layers were washed with brine (30.0 mL x 3), dried over NaSO, filtered, and concentrated under reduced pressure to give 2-((1r,4r)-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)isoindoline-1,3-dione (800 mg, crude). TIFF2024156774000144.tif19152

[0341] Step 5: To a solution of 2-((1r,4r)-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)isoindoline-1,3-dione (400 mg, 1.2 mmol) in EtOH (5.0 mL) was added N2H4.HO (645 mg, 12.6 mmol, 626.9 uL). The mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was washed with DCM (50.0 mL x 3). The combined organic layers were concentrated under reduced pressure to give (1r,4r)-N1-(2-methoxyethyl)-N1-methylcyclohexane-1,4-diamine (150 mg, crude).

[0342] Step 6: To a solution of 2-chloro-N-(5-(8-ethyl-2-fluoroquinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide (50 mg, 109.4 umol) in n-BuOH (2.0 mL) was added DIEA (42 mg, 328.2 umol, 57.1 uL) and (1r,4r)-N1-(2-methoxyethyl)-N1-methylcyclohexane-1,4-diamine (40.7 mg, 218.8 umol). The mixture was stirred at 100° C. for 12 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by pre-HPLC (FA conditions) to give 2-chloro-N-(5-(8-ethyl-2-(((1r,4r)-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)amino)quinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide (6.5 mg, 9.6 μmol, 8.8% yield, FA). TIFF2024156774000145.tif33157

[0343] Example 19: Synthesis of 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-methylquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide (133) TIFF2024156774000146.tif59156

[0344] Step 1: To a solution of 6-bromo-8-methylquinazolin-2-amine (0.5 g, 2.1 mmol) in pyridine (5.0 mL) was added pyridine hydrofluoride (11.0 g, 110.9 mmol, 10.0 mL) at −40° C. The mixture was stirred at −40° C. for 15 minutes. Then, tert-butyl nitrite (866 mg, 8.4 mmol, 999.1 uL) was added. The mixture was stirred at 20° C. for 4 hours. The reaction mixture was quenched by the addition of NaHCO (50.0 mL) to pH 7 and then diluted with ethyl acetate (20.0 mL x 3). The combined organic layers were washed with brine (20.0 mL x 3), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2) to give 6-bromo-2-fluoro-8-methylquinazoline (130 mg, 534.5 umol, 25.4% yield). M+H + = 243.1 (LCMS).

[0345] Step 2: A mixture of 6-bromo-2-fluoro-8-methylquinazoline (130 mg, 539.2 umol), 2-chloro-N-(6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)benzenesulfonamide (229 mg, 539.2 umol), KCO (223 mg, 1.6 mmol), and Pd(dppf)Cl (39 mg, 53.9 umol) in dioxane (4.0 mL) and HO (0.4 mL) was degassed and purged with N three times, and then the mixture was stirred at 90 °C under a N atmosphere for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2) to give 2-chloro-N-(5-(2-fluoro-8-methylquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide (130 mg, 181.3 umol, 33.6% yield). M+H + = 458.9 (LCMS).

[0346] Step 3: To a solution of 2-chloro-N-(5-(2-fluoro-8-methylquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide (130 mg, 283.2 umol) in n-BuOH (2.0 mL), DIEA (292 mg, 2.2 mmol, 394.7 uL) and (1r,4r)-N1,N1-dimethylcyclohexane-1,4-diamine (253 mg, 1.4 mmol, HCl) were added. The mixture was stirred at 100° C. for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (FA conditions) to give 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-methylquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide (25.7 mg, 39.9 μmol, 14.1% yield, FA). TIFF2024156774000147.tif33156

[0347] Example 20: Synthesis of 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-(trifluoromethyl)quinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide (135) TIFF2024156774000148.tif49156

[0348] Step 1: To a solution of 4-bromo-1-fluoro-2-(trifluoromethyl)benzene (5.0 g, 20.5 mmol, 2.9 mL) in THF (50.0 mL) at −78° C. was added LDA (2 M, 13.3 mL). The mixture was stirred at −78° C. for 1 hour. Then, DMF (1.8 g, 24.6 mmol, 1.9 mL) was added and stirred at −78° C. for 1 hour. The mixture was poured into saturated NH4Cl (20.0 mL) and extracted with ethyl acetate (20.0 mL x 3). The combined organic layers were washed with brine (20.0 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2) to give 5-bromo-2-fluoro-3-(trifluoromethyl)benzaldehyde (4 g, 14.7 mmol, 71.7% yield). TIFF2024156774000149.tif12128

[0349] Step 2: To a solution of guanidine (1.3 g, 11.0 mmol, H2CO3) and K2CO3 (4.5 g, 33.2 mmol) in DMA (60.0 mL) was added a solution of 5-bromo-2-fluoro-3-(trifluoromethyl)benzaldehyde (3.0 g, 11.0 mmol) in DMA (9.0 mL). The mixture was then stirred at 160 °C for 1 h. The mixture was concentrated to give a crude residue, to which HO (30.0 mL) was added and extracted with ethyl acetate (30.0 mL x 3). The combined organic layers were washed with brine (20.0 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2) to give 6-bromo-8-(trifluoromethyl)quinazolin-2-amine (1.6 g, 4.6 mmol, 42.0% yield). TIFF2024156774000150.tif12142

[0350] Step 3: To a solution of 6-bromo-8-(trifluoromethyl)quinazolin-2-amine (1.5 g, 5.1 mmol) in pyridine (13.0 mL) was added pyridine hydrofluoride (28.6 g, 288.5 mmol, 26.0 mL) at −40° C. The mixture was stirred at −40° C. for 15 minutes. Then, tert-butyl nitrite (1.0 g, 10.2 mmol, 1.2 mL) was added. The mixture was stirred at 20° C. for 12 hours. The mixture was poured into ice water, adjusted to pH = 7 with saturated NaHCO3, and extracted with ethyl acetate (50.0 mL × 3). The combined organic layer was washed with brine (20.0 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2) to give 6-bromo-2-fluoro-8-(trifluoromethyl)quinazoline (1.0 g, 3.3 mmol, 64.9% yield). + = 294.9 (LCMS).

[0351] Step 4: To a solution of 6-bromo-2-fluoro-8-(trifluoromethyl)quinazoline (0.5 g, 1.69 mmol) in n-BuOH (20.0 mL) was added (1r,4r)-N1,N1-dimethylcyclohexane-1,4-diamine (363 mg, 2.0 mmol, HCl) and DIEA (1.1 g, 8.4 mmol, 1.4 mL). The mixture was stirred at 100° C. for 4 hours. The mixture was concentrated to give a crude residue, and MTBE (20.0 mL) was added. The mixture was stirred at 25° C. for 1 hour. The mixture was then filtered to give (1r,4r)-N1-(6-bromo-8-(trifluoromethyl)quinazolin-2-yl)-N4,N4-dimethylcyclohexane-1,4-diamine (0.4 g, crude).

[0352] Step 5: To a solution of (1r,4r)-N1-(6-bromo-8-(trifluoromethyl)quinazolin-2-yl)-N4,N4-dimethylcyclohexane-1,4-diamine (0.2 g, 479.3 umol) and K2CO3 (198 mg, 1.4 mmol) in dioxane (2.0 mL) and HO (0.2 mL) was added 2-chloro-N-(6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)benzenesulfonamide (244 mg, 575.1 umol) and Pd(dppf)Cl2 (35 mg, 47.9 umol). The mixture was stirred at 90 °C under N2 for 12 hours. The mixture was concentrated to give the crude residue. The residue was purified by prep-HPLC (FA conditions) to give 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-(trifluoromethyl)quinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide (144 mg, 207.0 μmol, 43.2% yield, FA). TIFF2024156774000151.tif33153

[0353] Example 21: Synthesis of 2-chloro-N-(5-(8-ethyl-2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)quinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide (116) TIFF2024156774000152.tif51149

[0354] The title compound was synthesized according to the synthetic procedure reported for the preparation of 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-(trifluoromethyl)quinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide (114 mg, FA). TIFF2024156774000153.tif26156

[0355] Example 21A: Synthesis of (1r,4r)-N1,N1-dimethylcyclohexane-1,4-diamine TIFF2024156774000154.tif15147

[0356] The title compound was synthesized according to the synthetic procedure reported for the preparation of N1,N1-dimethylbicyclo[2.2.2]octane-1,4-diamine (8.3 g, 46.4 mmol, 99.6% yield, HCl). TIFF2024156774000155.tif19152

[0357] Example 21B: Synthesis of (1s,4s)-N1,N1-dimethylcyclohexane-1,4-diamine TIFF2024156774000156.tif15143

[0358] The title compound was synthesized according to the synthetic procedure reported for the preparation of N1,N1-dimethylbicyclo[2.2.2]octane-1,4-diamine (1.7 g, crude, HCl). TIFF2024156774000157.tif12153

[0359] Example 22: Synthesis of 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-(methoxymethyl)quinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide (137) TIFF2024156774000158.tif76163

[0360] Step 1: To a solution of 6-bromo-8-methylquinazolin-2-amine (6.6 g, 27.8 mmol) in BocO (100.0 mL) was added DMAP (3.4 g, 27.8 mmol). The mixture was stirred at 100 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO) to give tert-butyl N-(6-bromo-8-methyl-quinazolin-2-yl)-N-tert-butoxycarbonyl-carbamate (4.1 g, 6.6 mmol, 24.0% yield). TIFF2024156774000159.tif19154

[0361] Step 2: To a solution of tert-butyl N-(6-bromo-8-methyl-quinazolin-2-yl)-N-tert-butoxycarbonyl-carbamate (3.5 g, 8.1 mmol) and NBS (4.3 g, 24.5 mmol) in ACN (90.0 mL) was added AIBN (1.3 g, 8.1 mmol). The mixture was stirred at 90 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2) to give tert-butyl N-[6-bromo-8-(bromomethyl)quinazolin-2-yl]-N-tert-butoxycarbonyl-carbamate (2.3 g, 3.1 mmol, 38.1% yield).

[0362] Step 3: A solution of tert-butyl N-[6-bromo-8-(bromomethyl)quinazolin-2-yl]-N-tert-butoxycarbonyl-carbamate (0.5 g, 966.7 umol) in NaOMe (10.0 mL, 30% solution) was stirred for 12 hours at 30° C. The reaction mixture was added to HO (10 mL) and then filtered to afford the desired tert-butyl N-[6-bromo-8-(methoxymethyl)quinazolin-2-yl]carbamate (0.3 g, crude).

[0363] Step 4: To a solution of tert-butyl N-[6-bromo-8-(methoxymethyl)quinazolin-2-yl]carbamate (0.3 g, 814.7 umol) in HCl / EtOAc (10.0 mL, 4M) was stirred at 25° C. for 0.5 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added DCM (10.0 mL) and TFA (4.0 mL). The mixture was stirred at 25° C. for 4 hours. The reaction mixture was concentrated under reduced pressure. The reaction mixture was quenched by the addition of NaHCO (9.0 mL) and then extracted with ethyl acetate (3.0 mL x 3). The combined organic layers were washed with brine (3.0 mL x 3), dried over NaSO, filtered, and concentrated under reduced pressure to give 6-bromo-8-(methoxymethyl)quinazolin-2-amine (200 mg, crude).

[0364] Step 5: To a solution of 6-bromo-8-(methoxymethyl)quinazolin-2-amine (170 mg, 634.0 umol) in pyridine (2.0 mL) at −40° C. was added pyridine hydrofluoride (4.4 g, 44.4 mmol, 4.0 mL). The mixture was stirred at −40° C. for 15 minutes. Then, tert-butyl nitrite (261 mg, 2.5 mmol, 301.6 uL) was added. The mixture was stirred at 20° C. for 1 hour. The reaction mixture was quenched by the addition of NaHCO (5.0 mL) to pH 7 and then diluted with ethyl acetate (3.0 mL x 3). The combined organic layers were washed with brine (3.0 mL x 3), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2) to give 6-bromo-2-fluoro-8-(methoxymethyl)quinazoline (100 mg). + = 271.0 (LCMS).

[0365] Step 6: A mixture of 6-bromo-2-fluoro-8-(methoxymethyl)quinazoline (100 mg, 368.8 umol), 2-chloro-N-(6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)benzenesulfonamide (172 mg, 405.7 umol), KCO (152 mg, 1.1 mmol), and Pd(dppf)Cl (26 mg, 36.8 umol) in dioxane (2.0 mL) and HO (0.2 mL) was degassed and purged with N three times, and then the mixture was stirred at 90 °C under a N atmosphere for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2) to give 2-chloro-N-(5-(2-fluoro-8-(methoxymethyl)quinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide (0.1 g, 188.1 umol, 51.0% yield). M+H + = 489.0 (LCMS).

[0366] Step 7: To a solution of 2-chloro-N-(5-(2-fluoro-8-(methoxymethyl)quinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide (100 mg, 204.5 umol) in n-BuOH (2.0 mL) was added DIEA (158 mg, 1.2 mmol, 213.7 uL) and (1r,4r)-N1,N1-dimethylcyclohexane-1,4-diamine (73 mg, 409.0 umol, HCl). The mixture was stirred at 100° C. for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (FA conditions) to give 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-(methoxymethyl)quinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide (33.3 mg, 44.8 μmol, 21.9% yield, FA). TIFF2024156774000160.tif61156

[0367] Example 23: Synthesis of 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-methylquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide (145) TIFF2024156774000161.tif60156

[0368] Step 1: A mixture of 6-bromo-2-fluoro-8-methylquinazoline (500 mg, 2.0 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (632 mg, 2.4 mmol), KOAc (610 mg, 6.22 mmol), and Pd(dppf)Cl (151 mg, 207.4 umol) in dioxane (20.0 mL) was degassed and purged with N three times, and then the mixture was stirred under a N atmosphere at 90 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2) to give 2-fluoro-8-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline (590 mg, 1.9 mmol, 95.7% yield). M+H + = 289.2 (LCMS).

[0369] Step 2: A mixture of 2-fluoro-8-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline (349 mg, 1.2 mmol), N-(5-bromo-3-fluoro-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide (400 mg, 1.0 mmol), KCO (419 mg, 3.0 mmol), and Pd(dppf)Cl (73 mg, 101 umol) in dioxane (15.0 mL) and HO (1.5 mL) was degassed and purged with N three times, and then the mixture was stirred at 90 °C under a N atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2) to give 2-chloro-N-(3-fluoro-5-(2-fluoro-8-methylquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide (450 mg, 802 umol, 79.3% yield). M+H + = 477.2 (LCMS).

[0370] Step 3: To a solution of (1r,4r)-N1,N1-dimethylcyclohexane-1,4-diamine (281 mg, 1.5 mmol, HCl) in n-BuOH (7.0 mL), DIEA (325 mg, 2.5 mmol, 438.3 uL) and 2-chloro-N-(3-fluoro-5-(2-fluoro-8-methylquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide (150 mg, 314.5 umol) were added. The mixture was stirred at 100° C. for 24 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (FA conditions) to give 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-methylquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide (54.9 mg, 82.9 umol, 26.3% yield, FA). TIFF2024156774000162.tif26153

[0371] Example 24: Synthesis of 2-chloro-N-(5-(2-(((1s,4s)-4-(dimethylamino)cyclohexyl)amino)-8-methylquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide (139) TIFF2024156774000163.tif28156

[0372] The title compound was synthesized according to the synthetic procedure reported for the preparation of 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-methylquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide (64.6 mg, 100.7 umol, 29.6% yield, FA). TIFF2024156774000164.tif26153

[0373] Example 25: Synthesis of 2-chloro-N-(5-(2-(((1s,4s)-4-(dimethylamino)cyclohexyl)amino)-8-methylquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide (147) TIFF2024156774000165.tif25136

[0374] The title compound was synthesized according to the synthetic procedure reported for the preparation of 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-methylquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide (72.4 mg, 111.1 umol, 35.3% yield, FA). TIFF2024156774000166.tif26154

[0375] Example 26: Synthesis of 2-chloro-N-(5-(2-(((1s,4s)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide (142) TIFF2024156774000167.tif29157

[0376] Step 1: A mixture of 8-ethyl-2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline (100 mg, 331 umol), N-(5-bromo-3-fluoro-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide (131 mg, 331 umol), KCO (69 mg, 496.4 umol), and Pd(dppf)Cl (24 mg, 33.1 umol) in dioxane (15.0 mL) and HO (1.5 mL) was degassed and purged with N three times, and then the mixture was stirred at 90 °C under a N atmosphere for 12 hours. The reaction was concentrated to give a residue. The residue was purified by prep-TLC (SiO2) to give 2-chloro-N-(5-(8-ethyl-2-fluoroquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide (90 mg, 47.7 umol, 14.4% yield). M+H + = 491.0 (LCMS).

[0377] Step 2: To a solution of 2-chloro-N-(5-(8-ethyl-2-fluoroquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide (90 mg, 183.3 umol) in n-BuOH (4.0 mL) was added DIEA (190 mg, 1.5 mmol, 255.5 uL) and (1s,4s)-N1,N1-dimethylcyclohexane-1,4-diamine (131 mg, 733.3 umol, HCl). The mixture was stirred at 120° C. for 12 hours. The reaction was concentrated to give a residue. The residue was purified by prep-HPLC (FA conditions) to give 2-chloro-N-(5-(2-(((1s,4s)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide (60.3 mg, 85.3 umol, 46.5% yield, FA). TIFF2024156774000168.tif26153

[0378] Example 27: Synthesis of 2-chloro-N-(5-(2-(((1s,4s)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide (141) TIFF2024156774000169.tif30157

[0379] The title compound was synthesized according to the synthetic procedure reported for the preparation of 2-chloro-N-(5-(2-(((1s,4s)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide (51.8 mg, 74.5 umol, 17.6% yield, FA). TIFF2024156774000170.tif26155

[0380] Example 28: Synthesis of 2-chloro-N-(5-(2-(((1s,4s)-4-(dimethylamino)-4-methylcyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide (144) TIFF2024156774000171.tif80157

[0381] Step 1: To a solution of tert-butyl (1-methyl-4-oxocyclohexyl)carbamate (900 mg, 4 mmol) in EtOH (20.0 mL) at 0 °C, phenylmethanamine (509 mg, 4.7 mmol, 517.9 uL) and AcOH (238 mg, 4 mmol, 226.5 uL) were added. The resulting mixture was stirred at 0 °C for 15 minutes. NaBH3CN (498 mg, 7.9 mmol) was then added successively, and the mixture was stirred at 20 °C for 12 hours. The reaction was concentrated to give a residue. The residue was dissolved in saturated aqueous NaHCO3 (20.0 mL) and extracted with ethyl acetate (20.0 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated to give tert-butyl (4-(benzylamino)-1-methylcyclohexyl)carbamate (1.3 g, crude).

[0382] Step 2: To a solution of tert-butyl (4-(benzylamino)-1-methylcyclohexyl)carbamate (1.2 g, 3.7 mmol) in DMF (20.0 mL) was added K2CO3 (1.6 g, 11.3 mmol) and bromomethylbenzene (773 mg, 4.5 mmol, 537.1 uL). The mixture was stirred at 40 °C for 12 h. The reaction was quenched with HO (30.0 mL) and extracted with ethyl acetate (20 mL x 3). The combined organics were washed with brine (20 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The residue was purified by flash silica gel chromatography (SiO2) to give tert-butyl (4-(dibenzylamino)-1-methylcyclohexyl)carbamate (1.5 g, 3.4 mmol, 90% yield). TIFF2024156774000172.tif19157

[0383] Step 3: A mixture of tert-butyl (4-(dibenzylamino)-1-methylcyclohexyl)carbamate (500 mg, 1.2 mmol) in HCl / MeOH (4M, 10.0 mL) was stirred at 20° C. for 1 h. The reaction was concentrated and 1 ,N 1 -Dibenzyl-4-methylcyclohexane-1,4-diamine (400 mg, crude, HCl) was obtained.

[0384] Step 4: N in MeOH (10.0 mL) 1 ,N 1To a solution of -dibenzyl-4-methylcyclohexane-1,4-diamine (350 mg, 1 mmol, HCl) was added TEA to basify the pH to 7, followed by the addition of (HCHO)n (274 mg, 3 mmol). AcOH (61 mg, 1 mmol, 58 uL) was added to adjust the pH to 5, and the mixture was then stirred at 60°C for 2 hours. NaBH3CN (255 mg, 4.1 mmol) was added, and the mixture was stirred at 60°C for 12 hours. The reaction was concentrated to give a residue. The residue was dissolved in saturated NaHCO3 (10.0 mL) and extracted with ethyl acetate (10.0 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered, concentrated, and diluted with N 4 ,N 4 -Dibenzyl-N 1 ,N 1 , 1-trimethylcyclohexane-1,4-diamine (330 mg, crude) was obtained.

[0385] Step 5: N in THF (10.0 mL) and AcOH (0.1 mL) 4 ,N 4 -Dibenzyl-N 1 ,N 1 To a solution of 1,1-trimethylcyclohexane-1,4-diamine (330 mg, 980.6 umol) under a N atmosphere was added Pd(OH) / C (400 mg, 980.6 umol, 10% Pd basis). The suspension was degassed and purged with H three times. The mixture was stirred under H (50 Psi) at 50 °C for 12 h. The reaction was filtered, concentrated, and purified with N. 1 ,N 1 , 1-trimethylcyclohexane-1,4-diamine (150 mg, crude) was obtained.

[0386] Step 6: To a solution of 2-chloro-N-(5-(8-ethyl-2-fluoroquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide (30 mg, 61.1 umol) in n-BuOH (3.0 mL) was added DIEA (63 mg, 488.9 umol, 85.2 uL) and N 1 N 1 To the mixture was added 1-trimethylcyclohexane-1,4-diamine (38 mg, 244.4 umol). The mixture was stirred at 120° C. for 12 hours. The reaction was concentrated to give a residue. The residue was purified by prep-HPLC (FA conditions) to give 2-chloro-N-(5-(2-(((1s,4s)-4-(dimethylamino)-4-methylcyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide (3.7 mg, 5.4 umol, 8.9% yield, FA). TIFF2024156774000173.tif47156

[0387] Example 29: Synthesis of 2-chloro-N-(5-(2-(((1s,4s)-4-(dimethylamino)-4-methylcyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide (143) TIFF2024156774000174.tif30130

[0388] The title compound was synthesized according to the synthetic procedure reported for the preparation of 2-chloro-N-(5-(2-(((1s,4s)-4-(dimethylamino)-4-methylcyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide (6.4 mg, 9.4% yield). TIFF2024156774000175.tif26156

[0389] Example 30: Synthesis of 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-fluoroquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide (148) TIFF2024156774000176.tif59156

[0390] Step 1: A mixture of 6-bromo-2-chloro-8-fluoroquinazoline (90 mg, 344.2 umol), 2-chloro-N-(6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)benzenesulfonamide (146 mg, 344.2 umol), KCO (142 mg, 1.0 mmol), Pd(dppf)Cl (25 mg, 34.4 umol) in dioxane (4.0 mL) and HO (0.4 mL) was degassed and purged with N three times, and then the mixture was stirred at 90 °C under a N atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC. Purification by silica gel (SiO2) afforded 2-chloro-N-(5-(2-chloro-8-fluoroquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide (95 mg, 29.9% yield) as a yellow solid. M+H + = 479.1.

[0391] Step 2: To a solution of (1r,4r)-N1,N1-dimethylcyclohexane-1,4-diamine (55 mg, 312.9 umol, HCl) in n-BuOH (3.0 mL) was added DIEA (60 mg, 469.4 umol, 81.7 uL), 2-chloro-N-(5-(2-chloro-8-fluoroquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide (75 mg, 156.4 umol), and CsF (23 mg, 156.4 umol, 5.7 uL). The reaction vessel was sealed and heated at 140° C. in a microwave oven for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA conditions) to give 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-fluoroquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide (13.2 mg, 13.1% yield, FA) as a yellow solid. TIFF2024156774000177.tif33156

[0392] Example 31: Synthesis of 2-chloro-N-(3-fluoro-6-methoxy-5-(2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)quinazolin-6-yl)pyridin-2-yl)benzenesulfonamide (150) TIFF2024156774000178.tif60157

[0393] Step 1: To a solution of compound 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline (200 mg, 729.6 umol) and K3PO4 (0.5 M, 2.9 mL) in EtOH (12.0 mL), N-(5-bromo-3-fluoro-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide (317 mg, 802.6 umol) and [2-(2-aminophenyl)phenyl]-chloro-palladium; bis(1-adamantyl)-butyl-phosphane (48 mg, 72.9 umol) were added. The mixture was stirred under N2 at 80 ° C for 12 hours. The mixture was concentrated to give 2-chloro-N-(3-fluoro-5-(2-fluoroquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide (200 mg, crude) as a yellow oil.

[0394] Step 2: To a solution of compound 2-chloro-N-(3-fluoro-5-(2-fluoroquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide (150 mg, 324.0 umol) in n-BuOH (4.0 mL), DIEA (209 mg, 1.6 mmol, 282.2 uL) and compound 2A (147 mg, 648 1 umol) were added. The mixture was stirred at 100 °C for 12 hours. The mixture was concentrated, and the residue was purified by flash silica gel chromatography to give compound tert-butyl ((1r,4r)-4-((6-(6-((2-chlorophenyl)sulfonamido)-5-fluoro-2-methoxypyridin-3-yl)quinazolin-2-yl)amino)cyclohexyl)(methyl)carbamate (50 mg, 22.9% yield) as a yellow oil.

[0395] Step 3: A solution of tert-butyl ((1r,4r)-4-((6-(6-((2-chlorophenyl)sulfonamido)-5-fluoro-2-methoxypyridin-3-yl)quinazolin-2-yl)amino)cyclohexyl)(methyl)carbamate (50 mg, 74.5 umol) in DCM (2.0 mL) and TFA (1.0 mL) was stirred at 25° C. for 10 minutes. The mixture was concentrated to give a residue. The residue was dissolved in MeOH (2.0 mL), basified to pH 8 with NH.H0 (25% pure), and concentrated to give a residue. The residue was purified by prep-HPLC (FA conditions) to give 2-chloro-N-(3-fluoro-6-methoxy-5-(2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)quinazolin-6-yl)pyridin-2-yl)benzenesulfonamide (31.5 mg, 68.5% yield, FA) as a yellow solid. TIFF2024156774000179.tif26153

[0396] Example 32: Synthesis of 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide (149) TIFF2024156774000180.tif27152

[0397] The title compound was synthesized according to the synthetic procedure described in Example 31 to afford 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide (12.6 mg, 19.9 umol, 18.4% yield, FA) as a yellow solid. TIFF2024156774000181.tif33156

[0398] Example 33: Synthesis of 2-chloro-N-(5-(2-(((1R,2S,4R)-4-(dimethylamino)-2-fluorocyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide (151) TIFF2024156774000182.tif102162

[0399] Step 1: To a solution of cyclohex-3-enecarboxylic acid (20.0 g, 158.5 mmol) in toluene (360.0 mL) was added TEA (17.6 g, 174.3 mmol, 24.2 mL) and DPPA (45.8 g, 166.4 mmol, 36.0 mL). The mixture was degassed and purged with N three times, and it was stirred at 25 °C under a N atmosphere for 1.5 h. It was then warmed to 110 °C and stirred for an additional 2.5 h. BnOH (18.8 g, 174.3 mmol, 18.1 mL) was added to the mixture, and the resulting mixture was stirred at 110 °C for 12 h. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give benzyl cyclohex-3-en-1-ylcarbamate (33.0 g, 81.0% yield) as a white solid. TIFF2024156774000183.tif19153

[0400] Step 2: To a solution of benzyl cyclohex-3-en-1-ylcarbamate (15.0 g, 64.8 mmol) in DCM (180.0 mL) was added m-CPBA (18.1 g, 84.3 mmol, 80% purity) in portions at 25 °C. The mixture was stirred at 25 °C for 3 h. The reaction mixture was filtered, and the filtrated solution was washed with aqueous NaSO (100 mL x 2). The organic phase was then washed with saturated aqueous NaHCO (100 mL x 2), dried over NaSO, filtered, and concentrated to give a residue. The residue was purified by flash silica gel chromatography to give benzyl ((1R,3R,6S)-7-oxabicyclo[4.1.0]heptan-3-yl)carbamate (10.6 g, 52.8% yield) as a white solid. TIFF2024156774000184.tif12152

[0401] Step 3: A mixture of benzyl ((1R,3R,6S)-7-oxabicyclo[4.1.0]heptan-3-yl)carbamate (10.6 g, 42.8 mmol) and N,N-diethylethanamine trihydrofluoride (34.5 g, 214.3 mmol, 34.9 mL) was stirred at 100° C. for 2 hours. The reaction mixture was cooled to 20° C. and slowly poured into KCO (29.6 g, 214.3 mmol) in HO (600.0 ml). The mixture was then extracted with ethyl acetate (50 ml × 3). The combined organic layers were washed with saturated brine (50 ml × 2), dried over NaSO, filtered, and concentrated to give a residue. The residue was purified by HPLC (TFA condition) to obtain benzyl ((1R,3S,4S)-3-fluoro-4-hydroxycyclohexyl)carbamate (3 g) as a pale yellow oil.

[0402] Step 4: To a solution of isoindoline-1,3-dione (1.6 g, 11.2 mmol), benzyl ((1R,3S,4S)-3-fluoro-4-hydroxycyclohexyl)carbamate (3.0 g, 11.2 mmol), and PPh3 (3.8 g, 14.5 mmol) in THF (100.0 mL) was added DIAD (2.9 g, 14.5 mmol, 2.8 mL) under a N2 atmosphere. The mixture was stirred at 45 °C for 12 hours. The reaction was concentrated under reduced pressure to give a residue. MeCN (50 mL) was added to the residue. The resulting mixture was filtered, and the filter cake was washed with MeCN (20 mL X 3) and dried in vacuo to give benzyl ((1R,3S,4R)-4-(1,3-dioxoisoindolin-2-yl)-3-fluorocyclohexyl)carbamate (2.3 g, crude) as a white solid. M+Na + = 419.1 (LCMS). TIFF2024156774000185.tif19152

[0403] Step 5: To a solution of benzyl ((1R,3S,4R)-4-(1,3-dioxoisoindolin-2-yl)-3-fluorocyclohexyl)carbamate (0.8 g, 2.0 mmol) in EtOH (10.0 mL) was added N2H4.HO (2.5 mL, purity 98%). The mixture was stirred at 80 °C for 3 h. The reaction was concentrated under reduced pressure to give a residue. DCM (30.0 mL) was added to the residue. The resulting mixture was filtered, and the filter cake was washed with DCM (10 mL x 3). The combined organic layers were concentrated to give benzyl ((1R,3S,4R)-4-amino-3-fluorocyclohexyl)carbamate (530 mg, crude) as a white solid. TIFF2024156774000186.tif26153

[0404] Step 6: To a solution of benzyl ((1R,3S,4R)-4-amino-3-fluorocyclohexyl)carbamate (430 mg, 1.61 mmol) in DCM (15 mL) was added BocO (704 mg, 3.2 mmol, 741.8 uL) and TEA (490 mg, 4.8 mmol, 674.2 uL). The mixture was stirred at 25 °C for 3 hours. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give benzyl tert-butyl ((1R,2S,4R)-2-fluorocyclohexane-1,4-diyl)dicarbamate (530 mg, 1.1 mmol, 71.6% yield) as a white solid. TIFF2024156774000187.tif26153

[0405] Step 7: To a solution of benzyl tert-butyl ((1R,2S,4R)-2-fluorocyclohexane-1,4-diyl)dicarbamate (530 mg, 1.4 mmol) in MeOH (10.0 mL) and THF (10.0 mL) under a N atmosphere was added Pd(OH) / C (400 mg, 20% purity). The suspension was degassed and purged with H three times. The mixture was stirred under H (15 Psi) at 25 °C for 4 h. The suspension was filtered through a pad of Celite, and the filter cake was washed with MeOH (20.0 mL x 3). The combined filtrate was concentrated to dryness to give benzyl tert-butyl ((1R,2S,4R)-2-fluorocyclohexane-1,4-diyl)dicarbamate (330 mg, crude) as a yellow oil.

[0406] Step 8: To a solution of benzyl tert-butyl ((1R,2S,4R)-2-fluorocyclohexane-1,4-diyl)dicarbamate (330 mg, 1.4 mmol) in MeOH (15.0 mL) was added (HCHO)n (570 mg, 6.3 mmol) and AcOH (8 mg, 142.0 umol, 8.1 uL) at 25 °C for 1 h. NaBH3CN (446 mg, 7.1 mmol) was then added, and the mixture was stirred at 45 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with saturated aqueous NaHCO3 (20.0 mL) and extracted with DCM (10 x 3). The combined organic solution was dried over Na2SO4, filtered, and concentrated under reduced pressure to give tert-butyl ((1R,2S,4R)-4-(dimethylamino)-2-fluorocyclohexyl)carbamate (300 mg, crude) as a white solid. TIFF2024156774000188.tif26150

[0407] Step 9: A solution of tert-butyl ((1R,2S,4R)-4-(dimethylamino)-2-fluorocyclohexyl)carbamate (300 mg, 1.1 mmol) in HCl / EtOAc (5.0 mL, 4 M) was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give (1R,3S,4R)-3-fluoro-N1,N1-dimethylcyclohexane-1,4-diamine (226 mg, crude, HCl) as a white solid.

[0408] Step 10: To a solution of (1R,3S,4R)-3-fluoro-N1,N1-dimethylcyclohexane-1,4-diamine (50 mg, 254.2 umol, HCl) in n-BuOH (3.0 mL) was added DIEA (98 mg, 762.6 umol, 132.8 uL) and 2-chloro-N-(5-(8-ethyl-2-fluoroquinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide (116 mg, 254.2 umol). The mixture was stirred at 100° C. for 12 hours. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA conditions) to give 2-chloro-N-(5-(2-(((1R,2S,4R)-4-(dimethylamino)-2-fluorocyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide (37.7 mg, 55.8 umol, 21.9% yield, FA) as a white solid. TIFF2024156774000189.tif33152

[0409] Example 34: Synthesis of 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methylpyridin-2-yl)-3-fluorobenzenesulfonamide (158) TIFF2024156774000190.tif83151

[0410] Step 1: A mixture of 1-bromo-2-chloro-3-fluorobenzene (1 g, 4.7 mmol), phenylmethanethiol (712 mg, 5.7 mmol), Pd(dba) (875 mg, 954.9 umol), DIEA (1.9 g, 14.3 mmol), and Xantphos (552.5 mg, 954.9 umol) in dioxane (20.0 mL) was degassed and purged with N three times, and then the mixture was stirred at 100 °C under a N atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO) to afford benzyl(2-chloro-3-fluorophenyl)sulfane (800 mg, 46.4% yield) as a yellow oil. TIFF2024156774000191.tif12153

[0411] Step 2: To a solution of benzyl(2-chloro-3-fluorophenyl)sulfane (550 mg, 2.2 mmol) in MeCN (10.0 mL) was added TCCA (505 mg, 2.2 mmol), AcOH (13 mg, 217.6 umol), and HO (7 mg, 435.2 umol). The mixture was stirred at 0 °C for 1 hour. The reaction mixture was diluted with HO (10.0 mL) and extracted with ethyl acetate (10.0 mL x 3). The combined organic layers were washed with brine (5.0 mL x 2), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO) to give 2-chloro-3-fluorobenzenesulfonic acid (300 mg, 30.1% yield) as a colorless oil. MH + = 208.9 (LCMS).

[0412] Step 3: A solution of 2-chloro-3-fluorobenzenesulfonic acid (400 mg, 1.9 mmol) in SOCl (5.0 mL) was stirred for 12 h at 60° C. The reaction mixture was concentrated under reduced pressure to give 2-chloro-3-fluorobenzenesulfonyl chloride (360 mg, crude) as a brown oil.

[0413] Step 4: To a solution of 2-chloro-3-fluorobenzenesulfonyl chloride (100 mg, 436.6 umol) in pyridine (2.0 mL) was added 5-bromo-6-methyl-pyridin-2-amine (81 mg, 436.6 umol). The mixture was stirred at 45° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2) to give N-(5-bromo-6-methylpyridin-2-yl)-2-chloro-3-fluorobenzenesulfonamide (50 mg, 24.8% yield) as a yellow oil. M+H + = 381.0 (LCMS).

[0414] Step 5: A mixture of N-(5-bromo-6-methylpyridin-2-yl)-2-chloro-3-fluorobenzenesulfonamide (50 mg, 65.9 umol), 8-ethyl-2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline (29.9 mg, 988 umol), KCO (27 mg, 197.6 umol), Pd(dppf)Cl (4.8 mg, 6.6 umol), and HO (0.2 mL) in dioxane (2.0 mL) was degassed and purged with N three times, and then the mixture was stirred at 90 °C under a N atmosphere for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2) to give 2-chloro-N-(5-(8-ethyl-2-fluoroquinazolin-6-yl)-6-methylpyridin-2-yl)-3-fluorobenzenesulfonamide as a pale yellow solid (50 mg). M+H + = 475.1 (LCMS).

[0415] Step 6: To a solution of 2-chloro-N-(5-(8-ethyl-2-fluoroquinazolin-6-yl)-6-methylpyridin-2-yl)-3-fluorobenzenesulfonamide (50 mg, 105.3 umol) in n-BuOH (2.0 mL) was added DIEA (68.0 mg, 526.4 umol) and (1r,4r)-N1,N1-dimethylcyclohexane-1,4-diamine (37 mg, 210.6 umol, HCl). The mixture was stirred at 100° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA conditions) to give 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methylpyridin-2-yl)-3-fluorobenzenesulfonamide (9.9 mg, 14.7% yield, FA) as a white solid. TIFF2024156774000192.tif33157

[0416] Example 35: Synthesis of 2,3-dichloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide (152) TIFF2024156774000193.tif66162

[0417] The title compound was synthesized according to the synthetic procedure described in Example 34 to afford 2,3-dichloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide (37.7 mg, 31.1% yield, FA) as a pale yellow solid. TIFF2024156774000194.tif33156

[0418] Example 36: Synthesis of 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-3-fluoro-6-methylpyridin-2-yl)benzenesulfonamide (153) TIFF2024156774000195.tif57162

[0419] The title compound was synthesized according to the synthetic procedure described in Example 34 to afford 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-3-fluoro-6-methylpyridin-2-yl)benzenesulfonamide (18.9 mg, 16.9% yield, FA) as a pale yellow solid. TIFF2024156774000196.tif33154

[0420] Example 37: Synthesis of 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-4-methoxypyrimidin-2-yl)benzenesulfonamide (154) TIFF2024156774000197.tif61158

[0421] Step 1: To a solution of 5-bromo-4-methoxypyrimidin-2-amine (400 mg, 1.9 mmol) in pyridine (6.0 mL) was added 2-chlorobenzenesulfonyl chloride (620 mg, 2.9 mmol, 400.4 uL). The mixture was stirred at 45° C. for 16 hours. Additional 2-chlorobenzenesulfonyl chloride (827 mg, 3.9 mmol, 533.9 uL) was added, and the mixture was stirred at 45° C. for 5 hours. The reaction mixture was concentrated under reduced pressure. The crude product was triturated with MTBE (5.0 mL), ethyl acetate (5.0 mL), and methanol (2.0 mL) at 25° C. for 15 minutes. The mixture was then filtered to afford N-(5-bromo-4-methoxypyrimidin-2-yl)-2-chlorobenzenesulfonamide (170 mg, 17.7% yield) as a yellow solid. M+H+ = 379.8 (LCMS).

[0422] Step 2: A mixture of N-(5-bromo-4-methoxypyrimidin-2-yl)-2-chlorobenzenesulfonamide (90 mg, 237.7 μmol), 8-ethyl-2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline (71 mg, 237.7 μmol), KPO (0.5 M, 1.4 mL), and [2-(2-aminophenyl)phenyl]chloropalladium; bis(1-adamantyl)butylphosphane (15 mg, 23.7 μmol) in THF (5.0 mL) was degassed and purged with N three times, and then the mixture was stirred at 80° C. under a N atmosphere for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2) to give 2-chloro-N-(5-(8-ethyl-2-fluoroquinazolin-6-yl)-4-methoxypyrimidin-2-yl)benzenesulfonamide (104 mg, 28.2% yield) as a yellow solid. M+H + = 474.3 (LCMS).

[0423] Step 3: A mixture of (1r,4r)-N1,N1-dimethylcyclohexane-1,4-diamine (62 mg, 438.9 umol, HCl), 2-chloro-N-(5-(8-ethyl-2-fluoroquinazolin-6-yl)-4-methoxypyrimidin-2-yl)benzenesulfonamide (104 mg, 219.4 umol), DIEA (141.8 mg, 1.1 mmol, 191.1 uL) in n-BuOH (2.0 mL) was added, and the mixture was then stirred at 100° C. for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (FA conditions) to give 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-4-methoxypyrimidin-2-yl)benzenesulfonamide (10.2 mg, 7.1% yield, FA) as a pale yellow solid. TIFF2024156774000198.tif33156

[0424] Example 38: Synthesis of 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-fluoroquinazolin-6-yl)-3-fluoro-6-methylpyridin-2-yl)benzenesulfonamide (156) TIFF2024156774000199.tif74163

[0425] Step 1: To a solution of 2-amino-3-fluorobenzoic acid (10.0 g, 64.4 mmol) in DCM (100.0 mL) was added NBS (11.4 g, 64.4 mmol) portionwise at 20° C. The resulting mixture was stirred at 20° C. for 3 hours. The reaction mixture was filtered. The cake was collected and dried to give 2-amino-5-bromo-3-fluorobenzoic acid (14.9 g, crude) as a yellow solid. TIFF2024156774000200.tif12151

[0426] Step 2: To a solution of 2-amino-5-bromo-3-fluorobenzoic acid (1.0 g, 4.2 mmol) in THF (10.0 mL) was added BH3-Me2S (10 M, 10.0 mL) at 0 °C. The reaction mixture was stirred at 20 °C for 4 hours. The reaction mixture was quenched with MeOH (100.0 mL), and then the mixture was concentrated under reduced pressure. The residue was diluted with aqueous sodium bicarbonate (25.0 mL) and extracted with ethyl acetate (30.0 mL x 3). The combined organic layers were washed with brine (30.0 mL x 3), dried over Na2SO4, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2) to give (2-amino-5-bromo-3-fluorophenyl)methanol (740 mg) as a white solid. TIFF2024156774000201.tif19151

[0427] Step 3: To a solution of (2-amino-5-bromo-3-fluorophenyl)methanol (740 mg, 3.3 mmol) in DCM (50.0 mL) was added MnO (2.9 g, 33.6 mmol). The mixture was stirred at 20 °C for 12 h. The reaction mixture was filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO) to give 2-amino-5-bromo-3-fluorobenzaldehyde (585 mg, 71.8% yield) as a yellow solid. TIFF2024156774000202.tif19150

[0428] Step 4: A mixture of 2-amino-5-bromo-3-fluorobenzaldehyde (585 mg, 2.68 mmol) and urea (2.4 g, 40.2 mmol, 2.1 mL) was heated at 180 °C for 4 h. The reaction mixture was poured into HO (30.0 mL), and the resulting mixture was filtered. The cake was washed with HO (10.0 mL x 3) to give 6-bromo-8-fluoroquinazolin-2-ol (650 mg, crude) as a yellow solid.

[0429] Step 5: A solution of 6-bromo-8-fluoroquinazolin-2-ol (650 mg, 2.6 mmol) in POCl (7.0 mL) was stirred at 110 °C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with NaHCO (20.0 mL) and extracted with ethyl acetate (15.0 mL x 3). The combined organic layers were washed with brine (15.0 mL x 3), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give 6-bromo-2-chloro-8-fluoroquinazoline (370 mg, 51.3% yield) as a pale yellow solid. M+H + = 262.8 (LCMS).

[0430] Step 6: A mixture of 6-bromo-2-chloro-8-fluoroquinazoline (350 mg, 1.3 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (373 mg, 1.4 mmol), Pd(dppf)Cl (97 mg, 133.8 umol), and KOAc (394 mg, 4.0 mmol) in dioxane (12.0 mL) was degassed and purged with N three times, and then the mixture was stirred at 90 °C under a N atmosphere for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. EtOAc (20.0 mL) was added to the residue. The resulting mixture was filtered, and the filtrate was concentrated to give a residue. The residue was purified by flash silica gel chromatography to give (2-chloro-8-fluoroquinazolin-6-yl)boronic acid (300 mg, 88.1% yield) as a yellow solid. + = 227.2 (LCMS).

[0431] Step 7: A mixture of (2-chloro-8-fluoroquinazolin-6-yl)boronic acid (120 mg, 530.0 umol), N-(5-bromo-3-fluoro-6-methylpyridin-2-yl)-2-chlorobenzenesulfonamide (201 mg, 530.0 umol), Pd(dppf)Cl (38 mg, 53.0 umol), and NaHCO (133 mg, 1.5 mmol, 61.8 uL) in dioxane (4.0 mL) and HO (0.4 mL) was degassed and purged with N three times. The reaction mixture was stirred at 80 °C under a N atmosphere for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. Ethyl acetate (10.0 mL) was added to the residue. The resulting mixture was filtered, and the filtrate was concentrated to give a residue. The residue was purified by flash silica gel chromatography to give 2-chloro-N-(5-(2-chloro-8-fluoroquinazolin-6-yl)-3-fluoro-6-methylpyridin-2-yl)benzenesulfonamide (56 mg, 14.7% yield) as a yellow solid. M+H + = 481.2 (LCMS).

[0432] Step 8: To a solution of (1r,4r)-N1,N1-dimethylcyclohexane-1,4-diamine (41 mg, 232.7 umol, HCl) in n-BuOH (3.0 mL) was added DIEA (45 mg, 349.0 umol, 60.8 uL), 2-chloro-N-(5-(2-chloro-8-fluoroquinazolin-6-yl)-3-fluoro-6-methylpyridin-2-yl)benzenesulfonamide (56 mg, 116.3 umol), and CsF (17 mg, 116.3 umol). The reaction vessel was sealed and heated at 140° C. in a microwave oven for 4 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA conditions) to give 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-fluoroquinazolin-6-yl)-3-fluoro-6-methylpyridin-2-yl)benzenesulfonamide (12.9 mg, 17.7% yield) as a yellow solid. TIFF2024156774000203.tif33156

[0433] Example 39: Synthesis of 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-fluoroquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide (155) TIFF2024156774000204.tif57154

[0434] The title compound was synthesized according to the synthetic procedure described in Example 38 to afford 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-fluoroquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide (2.1 mg, 5.0% yield, FA) as a yellow solid. TIFF2024156774000205.tif26154

[0435] Example 40: Synthesis of 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methoxypyrazin-2-yl)benzenesulfonamide (157) TIFF2024156774000206.tif59162

[0436] Step 1: To a solution of 6-methoxypyrazin-2-amine (0.5 g, 4.0 mmol) in CHCl (25 mL) was added NCS (533 mg, 4.0 mmol). The reaction mixture was stirred at 40 °C for 12 h. The mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO) to give 5-chloro-6-methoxypyrazin-2-amine (95 mg, 14.9% yield) as a yellow solid. TIFF2024156774000207.tif5132

[0437] Step 2: To a solution of 5-chloro-6-methoxypyrazin-2-amine (95 mg, 595.3 umol) in DCM (8.0 mL) was added pyridine (141 mg, 1.7 mmol) and 2-chlorobenzenesulfonyl chloride (188 mg, 893.0 umol). The reaction mixture was stirred at 45°C for 12 hours. TLC showed that 5-chloro-6-methoxypyrazin-2-amine remained, so 2-chlorobenzenesulfonyl chloride (62 mg, 293.7 umol) was added, and the mixture was stirred at 45°C for 12 hours. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2) to give 2-chloro-N-(5-chloro-6-methoxypyrazin-2-yl)benzenesulfonamide (131 mg, 59.4% yield) as a yellow solid. M+H + = 333.9 (LCMS).

[0438] Step 3: A mixture of 2-chloro-N-(5-chloro-6-methoxypyrazin-2-yl)benzenesulfonamide (50 mg, 149.6 umol), 8-ethyl-2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline (45 mg, 149.6 umol), KPO (0.5 M, 598.4 uL), and [2-(2-aminophenyl)phenyl]-chloropalladium; bis(1-adamantyl)-butyl-phosphane (10 mg, 14.9 umol) in THF (2.0 mL) was degassed and purged with N three times. The mixture was stirred at 80 °C under a N atmosphere for 12 hours. The reaction mixture was concentrated to give a residue. The residue was purified by prep-TLC (SiO 2 ) to give 2-chloro-N-(5-(8-ethyl-2-fluoroquinazolin-6-yl)-6-methoxypyrazin-2-yl)benzenesulfonamide (44 mg, crude) as a yellow solid.

[0439] Step 4: To a solution of 2-chloro-N-(5-(8-ethyl-2-fluoroquinazolin-6-yl)-6-methoxypyrazin-2-yl)benzenesulfonamide (44 mg, 92.8 umol) in n-BuOH (3.0 mL) was added (1r,4r)-N1,N1-dimethylcyclohexane-1,4-diamine (26 mg, 185.7 umol, HCl) and DIEA (60 mg, 464.2 umol). The reaction mixture was stirred at 100° C. for 12 hours. Additional (1r,4r)-N1,N1-dimethylcyclohexane-1,4-diamine (26 mg, 185.7 umol, HCl) and DIEA (60 mg, 464.2 umol) were added. The reaction mixture was stirred at 100° C. for an additional 20 hours. The reaction mixture was concentrated under reduced pressure to provide a residue. The residue was purified by prep-HPLC (FA conditions) to give 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methoxypyrazin-2-yl)benzenesulfonamide (5.1 mg, 7.8% yield, FA) as a pale yellow solid. TIFF2024156774000208.tif33156

[0440] Example 41: Synthesis of 2-chloro-N-(6-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-5-methoxypyridazin-3-yl)benzenesulfonamide (159) TIFF2024156774000209.tif60162

[0441] Step 1: To a solution of 2-chlorobenzenesulfonamide (1.0 g, 5.4 mmol) in THF (40.0 mL) was added 3,6-dichloro-4-methoxypyridazine (0.6 g, 3.6 mmol), [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (288 mg, 363.1 umol), and CsCO (2.3 g, 7.2 mmol). The reaction mixture was stirred at 80 °C for 12 hours. The reaction mixture was concentrated to give a residue. The residue was diluted with HO (20.0 mL) and extracted with EtOAc (20.0 mL x 3). The combined organic layers were washed with brine (20.0 mL x 3), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (TFA condition) to obtain 2-chloro-N-(6-chloro-5-methoxypyridazin-3-yl)benzenesulfonamide (75 mg, 6.1% yield) as a red solid. TIFF2024156774000210.tif12146

[0442] Step 2: A mixture of 2-chloro-N-(6-chloro-5-methoxypyridazin-3-yl)benzenesulfonamide (50 mg, 149.6 umol), 8-ethyl-2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline (54 mg, 179.5 umol), KPO (0.5 M, 598.4 uL), and [2-(2-aminophenyl)phenyl]-chloro-palladium; bis(1-adamantyl)-butyl-phosphane (10 mg, 14.9 umol) in THF (2.0 mL) was placed in a microwave tube and then degassed and purged with N three times. The sealed tube was heated at 120 °C in a microwave for 4 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2) to give 2-chloro-N-(6-(8-ethyl-2-fluoroquinazolin-6-yl)-5-methoxypyridazin-3-yl)benzenesulfonamide (14 mg, 16.6% yield) as a yellow solid. M+H + = 474.1 (LCMS).

[0443] Step 3: To a solution of 2-chloro-N-(6-(8-ethyl-2-fluoroquinazolin-6-yl)-5-methoxypyridazin-3-yl)benzenesulfonamide (21 mg, 44.3 umol) in n-BuOH (1.0 mL) was added (1r,4r)-N1,N1-dimethylcyclohexane-1,4-diamine (15 mg, 88.6 umol, HCl) and DIEA (28 mg, 221.5 umol). The reaction mixture was stirred at 100° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA conditions) to give 2-chloro-N-(6-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-5-methoxypyridazin-3-yl)benzenesulfonamide (3.8 mg, 12.8% yield, FA) as a pale yellow solid. TIFF2024156774000211.tif33154

[0444] Example 42: Synthesis of 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methylpyridin-2-yl)-3-methylbenzenesulfonamide (160) TIFF2024156774000212.tif87162

[0445] Step 1: A mixture of 1-bromo-2-chloro-3-methyl-benzene (3.0 g, 14.6 mmol), phenylmethanethiol (2.1 g, 17.5 mmol, 2.0 mL), (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium (2.6 g, 2.9 mmol), DIEA (5.6 g, 43.8 mmol, 7.6 mL), and (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane (1.6 g, 2.9 mmol) in dioxane (60.0 mL) was degassed and purged with N three times, and then the mixture was stirred under a N atmosphere at 100 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2) to give benzyl(2-chloro-3-methylphenyl)sulfane (2.6 g, 53.6% yield) as a yellow solid. TIFF2024156774000213.tif19150

[0446] Step 2: To a solution of benzyl(2-chloro-3-methylphenyl)sulfane (0.5 g, 2.0 mmol) in MeCN (5.0 mL) was added HO (7 mg, 401.9 umol, 7.2 uL) and AcOH (12 mg, 200.9 umol, 11.4 uL), followed by trichloroisocyanuric acid (TCCA) (467 mg, 2.0 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (basic conditions) to afford 2-chloro-3-methylbenzenesulfonic acid (70 mg, 16.8% yield) as a white solid.

[0447] Step 3: A solution of 2-chloro-3-methylbenzenesulfonic acid (100 mg, 483.9 umol) in SOCl (4.0 mL) and DMF (0.1 mL) was stirred for 12 hours at 70° C. The reaction mixture was concentrated under reduced pressure to give 2-chloro-3-methylbenzenesulfonyl chloride (100 mg, crude) as a yellow oil.

[0448] Step 4: To a solution of 5-bromo-6-methyl-pyridin-2-amine (80 mg, 427.7 umol) in pyridine (2.0 mL) was added 2-chloro-3-methylbenzenesulfonyl chloride (96 mg, 427.7 umol). The reaction mixture was stirred at 45° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (FA conditions) to give N-(5-bromo-6-methylpyridin-2-yl)-2-chloro-3-methylbenzenesulfonamide (16 mg, 8.8% yield, FA) as a white solid.

[0449] Step 5: A mixture of N-(5-bromo-6-methylpyridin-2-yl)-2-chloro-3-methylbenzenesulfonamide (6 mg, 14.2 umol FA), 8-ethyl-2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline (4. mg, 14.2 umol), KCO (5 mg, 42.6 umol), and Pd(dppf)Cl (1 mg, 1.4 umol) in dioxane (2.0 mL) and HO (0.2 mL) was degassed and purged with N three times, and then the mixture was stirred at 90 °C under a N atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was combined with another 10 mg batch and purified by prep-TLC (SiO2) to give 2-chloro-N-(5-(8-ethyl-2-fluoroquinazolin-6-yl)-6-methylpyridin-2-yl)-3-methylbenzenesulfonamide (20 mg) as a white solid. M+H + = 471.2 (LCMS).

[0450] Step 6: To a solution of 2-chloro-N-(5-(8-ethyl-2-fluoroquinazolin-6-yl)-6-methylpyridin-2-yl)-3-methylbenzenesulfonamide (20 mg, 42.4 umol) in n-BuOH (2.0 mL) was added DIEA (27 mg, 212.3 umol, 36.9 uL) and (1r,4r)-N1,N1-dimethylcyclohexane-1,4-diamine (15 mg, 84.9 umol, HCl). The reaction mixture was stirred at 100° C. for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (FA conditions) to give 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methylpyridin-2-yl)-3-methylbenzenesulfonamide (4.7 mg, 16.6% yield, FA) as a pale yellow solid. TIFF2024156774000214.tif33156

[0451] Example 43: Synthesis of 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethyl-7-fluoroquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide (163) TIFF2024156774000215.tif87163

[0452] Step 1: To a solution of 3-bromo-2,6-difluorobenzaldehyde (20 g, 90.5 mmol) in THF (320.0 mL) at −78° C. under a N atmosphere, MeMgBr (3 M, 42.2 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 30 minutes and then at 0° C. for 1.5 hours. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl (300.0 mL) and extracted with ethyl acetate (80.0 mL × 3). The combined organic layers were washed with brine (80.0 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give 1-(3-bromo-2,6-difluorophenyl)ethan-1-ol (21.0 g, 78.3% yield) as a yellow oil. TIFF2024156774000216.tif19150

[0453] Step 2: To a solution of 1-(3-bromo-2,6-difluorophenyl)ethan-1-ol (21.0 g, 88.5 mmol) and EtSiH (20.6 g, 177.1 mmol, 28.3 mL) in DCM (800.0 mL) was added BF.EtO (44.9 g, 310.0 mmol, 39.0 mL, 98% purity) at 0 °C under a N atmosphere. The reaction mixture was stirred at 35 °C for 72 h. The reaction mixture was quenched at 0 °C by the addition of saturated aqueous NaHCO (500.0 mL) and extracted with DCM (100.0 mL x 3). The combined organic layers were washed with brine (100.0 mL x 3), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give 1-bromo-3-ethyl-2,4-difluorobenzene (9.8 g, 40.0% yield) as a colorless oil. TIFF2024156774000217.tif20148

[0454] Step 3: To a solution of 1-bromo-3-ethyl-2,4-difluorobenzene (9.8 g, 44.3 mmol) in THF (100.0 mL) was added dropwise LDA (2 M, 26.6 mL) at −78° C. After the addition, the mixture was stirred at this temperature for 1 hour, and then DMF (4.2 g, 57.6 mmol, 4.4 mL) was added dropwise at −78° C. The resulting mixture was stirred at −78° C. for 1 hour. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl (100.0 mL) and extracted with ethyl acetate (50.0 mL x 3). The combined organic layers were washed with brine (50.0 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give 5-bromo-3-ethyl-2,4-difluorobenzaldehyde (3.3 g, 20.9% yield) as a yellow oil. TIFF2024156774000218.tif19155

[0455] Step 4: To a solution of 5-bromo-3-ethyl-2,4-difluorobenzaldehyde (3.3 g, 13.2 mmol) in DMA (65.0 mL) was added guanidine (1.6 g, 13.2 mmol, H2CO3) and DIEA (1.7 g, 13.2 mmol, 2.3 mL). The mixture was stirred at 160 °C for 1 h. The reaction mixture was quenched by the addition of HO (200.0 mL) and extracted with ethyl acetate (30.0 mL x 3). The combined organic layers were washed with brine (30.0 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give 6-bromo-8-ethyl-7-fluoroquinazolin-2-amine (318 mg, 7.1% yield) as a yellow oil. TIFF2024156774000219.tif12128

[0456] Step 5: To a solution of 6-bromo-8-ethyl-7-fluoroquinazolin-2-amine (318 mg, 1.1 mmol) in pyridine (3.0 mL) at −40° C. was added pyridine hydrofluoride (6.6 g, 66.6 mmol, 6.0 mL). The mixture was stirred at −40° C. for 15 minutes. Then, tert-butyl nitrite (242 mg, 2.3 mmol, 280.0 uL) was added. The mixture was stirred at 25° C. for 1 hour. The reaction mixture was quenched by the addition of saturated NaHCO (400.0 mL) and extracted with EtOAc (50.0 mL x 3). The combined organic layers were washed with brine (50.0 mL x 3), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to give 6-bromo-8-ethyl-2,7-difluoroquinazoline (180 mg, 54.3% yield) as a yellow solid. TIFF2024156774000220.tif12130

[0457] Step 6: A mixture of 6-bromo-8-ethyl-2,7-difluoroquinazoline (40 mg, 146.4 umol), (6-((2-chlorophenyl)sulfonamido)-5-fluoro-2-methoxypyridin-3-yl)boronic acid (105 mg, 292.9 umol), K2CO3 (60 mg, 439.4 umol), Pd(dppf)Cl2 (10 mg, 14.6 umol), and HO (0.1 mL) in dioxane (1.0 mL) was degassed and purged with N2 three times. The reaction mixture was stirred at 90 °C under a N2 atmosphere for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2) to give 2-chloro-N-(5-(8-ethyl-2,7-difluoroquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide (27 mg, 21.2% yield) as a yellow oil. M+H + = 509.1 (LCMS).

[0458] Step 7: To a solution of 2-chloro-N-(5-(8-ethyl-2,7-difluoroquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide (27 mg, 53.0 umol) in n-BuOH (2.0 mL) was added DIEA (34 mg, 265.2 umol, 46.2 uL) and (1r,4r)-N1,N1-dimethylcyclohexane-1,4-diamine (18 mg, 106.1 umol, HCl). The reaction mixture was stirred at 100° C. for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (FA conditions) to give 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethyl-7-fluoroquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide (3.0 mg, 7.8% yield, FA) as a yellow solid. TIFF2024156774000221.tif33156

[0459] Example 44: Synthesis of 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethyl-7-fluoroquinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide (161) TIFF2024156774000222.tif68148

[0460] The title compound was synthesized according to the synthetic procedure described in Example 43 to afford 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethyl-7-fluoroquinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide (7.9 mg, 12.6% yield, FA) as a pale yellow solid. M+H + = 597.3 (LCMS). TIFF2024156774000223.tif33155

[0461] Example 45: Synthesis of 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethyl-7-fluoroquinazolin-6-yl)-3-fluoro-6-methylpyridin-2-yl)benzenesulfonamide (162) TIFF2024156774000224.tif68148

[0462] The title compound was synthesized according to the synthetic procedure described in Example 43 to afford 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethyl-7-fluoroquinazolin-6-yl)-3-fluoro-6-methylpyridin-2-yl)benzenesulfonamide (3.4 mg, 6.4% yield, FA) as a white solid. TIFF2024156774000225.tif33154

[0463] II. Biological Evaluation Example 1: In vitro FRET assay In vitro FRET assays were performed to evaluate the ability of selected compounds to inhibit IRE1, and the results are summarized in Table 3. To perform the in vitro FRET assays, SignalChem IRE1a protein was diluted to a final concentration of 2 nM using 1× complete assay buffer (CAB; 1 M DTT, 50 mM sodium citrate pH 7.15, 1 mM magnesium acetate, 0.02% Tween 20). Selected compounds were serially diluted with DMSO in a non-binding black 384-well plate (15 μl total in each well). 2 μl of the serially diluted compound or DMSO control was then added to new wells containing 98 μl of 1× CAB (total volume 100 μl), of which 10 μl was then transferred to wells in a new plate. 5 μl of diluted IRE1a was then added to each well. 5 μl of 400 mM XBP1 RNA probe was then added to each well. Fluorescence was then read in kinetic mode (485 / 515 nm) over a period of 30 minutes.

[0464] Two RNA probes were used: XBP1 wild-type (SEQ ID NO: 2), which can be spliced ​​by active IRE1a; and XBP1 mutant (SEQ ID NO: 3), which cannot be spliced. Each probe contained a 5' 6-FAM modification and a 3' IOWA Black FQ modification.

[0465] A second FRET assay was performed to evaluate ATP-mediated inhibition. In this case, compounds and IRE1a were prepared as described above and combined, and ATP was added to a final concentration of up to 1 mM. The mixture was incubated at room temperature for 60 minutes, followed by the addition of 5 μL of 400 nM XBP1 wild-type or mutant RNA probe. The plate was then read in kinetic mode (485 / 515 nm) for 30 minutes.

[0466] [Table 3] TIFF2024156774000227.tif24468TIFF2024156774000228.tif23868TIFF2024156774000229.tif24668Note: Biochemical assay average IC 50 Specify the data within the following ranges: A:≦5 nM; B:>5 nM~≦50 nM; C:>50 nM~≦100 nM; and D:>100 nM~≦10 uM.

[0467] Example 2: In vitro luciferase assay The compounds disclosed herein were evaluated for disruption of IRE1 signaling using the IRE1a endoribonuclease nanoluciferase assay. Briefly, 2.5 x 10 6 293T cells in 10 cm 2The cells were seeded in tissue culture dishes. Approximately 24 hours later, the cells were transfected with Effectene. The following was added to a 15 mL tube: 2 μg XBP1 luciferase reporter plasmid (PGK-Luc2-P2A-XBP1u-nanoluciferase-PEST); 300 μl EC buffer; and 16 μl enhancer, followed by incubation at room temperature for 5 minutes. Next, 60 μl Effectene (Qiagen 301427) was added, followed by incubation at room temperature for 10 minutes. 2.6 mL cDMEM medium was added. The old medium was aspirated from the cells, followed by the addition of 7 mL of fresh medium. The complete transfection mixture was added dropwise to the cells. The cells were incubated for 6 hours, then trypsinized, centrifuged, and resuspended in 11 mL of fresh cDMEM medium. 100 μL of cells were plated per well in a 96-well plate. One day later, the optimal ER stressor + / - inhibitor was added. To harvest, the medium was completely aspirated from the cells, and then 50 μL of 1x passive lysis buffer (Promega: E1941) was added per well and placed on a shaker (300 rpm) at room temperature for 30 minutes. The cells were centrifuged, and 15 μL of sample per well was added to a new opaque 384-well plate (Corning 3570). 15 μL of OneGlo (nanoluciferase kit, Promega N1630) was added. The plate was spun down and placed on a shaker (300 rpm) for 10 minutes. The plate was read in a luminometer with a 1000 ms integration time per well. 15 μL of Stop and Glo (nanoluciferase kit) was added. The plate was spun down and placed on a shaker (300 rpm) for 10 minutes. The plate was read in a luminometer with a 1000 ms second integration time per well. The records are provided in Table 4 below.

[0468] [Table 4] TIFF2024156774000231.tif24476TIFF2024156774000232.tif23876TIFF2024156774000233.tif188128Note: Biochemical assay average EC 50 Specify the data within the following ranges: A:≦5 nM; B:>5 nM~≦50 nM; C:>50 nM~≦100 nM; and D:>100 nM~≦10 uM.

[0469] Example 3: Proliferation assay A proliferation assay was performed to evaluate the cytotoxicity of the compounds disclosed herein. Briefly, 5,000,000 293T cells were resuspended in 18 mL of cDMEM to a final concentration of 277,777 cells / mL. As shown in Table 5, 180 μL (50,000 cells) of cDMEM was seeded per well in a 96-well flat-bottom plate, with the "medium" wells left empty. In a separate 96-well dilution plate, 199 μL of cDMEM and 1 μL of DMSO or one of the compounds disclosed herein (shown below as test compounds 1, 2, 3, 4, 5, or 6) were added to wells A4, A8, C4, C8, E4, E8, G4, and G8. 133.3 μL of cDMEM was added to wells 1, 2, 3, 5, 6, and 7 in rows A, C, E, and G of the dilution plate. Compounds were serially diluted leftward in 3-fold dilutions (66.7 μL into 133.3 μL of cDMEM). 20 μL of each dilution was transferred in duplicate (duplicates in perpendicular pairs of wells) to cells plated in a 96-well plate as shown in Table 5, to the total concentrations shown below. 200 μL of cDMEM was added to the medium wells (wells G5-H8). The plates were then placed in a humidified chamber for incubation for 2 days and then photographed (the medium was more yellow in wells with strong cell growth). Absorbance was then measured at approximately 535 nM (lower for more acidic medium) and approximately 450 nM (higher for more acidic medium). The results of the proliferation assay are shown in Table 6.

[0470] [Table 5]

[0471] [Table 6] Note: Specify % proliferation data within the following ranges: A:≦25%; B:>25%~≦50%; C:>50%~≦75%; D:>75%~≦100%.

[0472] Example 4: ELISA assay Total human or mouse CD4 T cells are isolated by negative selection with Miltenyi MACS beads. Mouse CD4 T cells were isolated from mouse spleens, while human CD4 T cells were isolated from human PBMCs. CD4 T cells are washed and then mixed with CD3 / CD28 activator Dynabeads at 8 pm. After 36 hours of incubation, the selected IRE1a inhibitor compound or IRE1a inhibitor control is added and incubated for 2 hours.

[0473] After a 2-hour incubation, mouse or human cell-free malignant ascites supernatant or cRPMI control is added. After a 10-hour incubation, the supernatant is isolated and used in an IFN-g ELISA assay. To isolate RNA, Trizol is added to each ELISA well containing T cells. ELISA assays are performed using the eBioscience Ready-Set-Go IFN-g ELISA kit according to the manufacturer's recommended protocol.

[0474] Example 5: T cell metabolic assay Total human or mouse CD4 T cells are isolated by negative selection with Miltenyi MACS beads. Mouse CD4 T cells are isolated from mouse spleens, while human CD4 T cells are isolated from human PBMCs. 1.5 million CD4 T cells are washed and then mixed with CD3 / CD28 activator Dynabeads at a 1:1 bead:cell ratio and plated in complete RPMI in a 6-well plate. After 24 hours of incubation, the selected IRE1a inhibitor compound or IRE1a inhibitor control compound is added and incubated for 2 hours. After 2 hours of incubation, mouse or human cell-free malignant ascites supernatant or cRPMI control is added. After 16 hours of incubation, the Dynabeads are removed by magnetic separation, and the mitochondrial oxygen consumption rate (OCR) and glycolytic extracellular acidification rate (ECAR) are measured using a Seahorse XFe96 Analyzer (Agilent). Samples are assayed in triplicate with 150,000 viable cells plated in each well of the assay plate. The supernatant is then isolated and used in downstream IFN-g ELISA assays. IRE1a activity is also measured by quantifying XBP1 splicing with quantitative PCR or by intracellular flow cytometry staining with an XBP1s-specific monoclonal antibody (clone: ​​Q3-695; BD Pharmingen).

[0475] Example 6: Inflammatory cytokine production assay Ap...

Claims

1. A compound of formula (I) or a pharma- ceutically acceptable salt thereof: During the ceremony, R 3 But, C 1 -C 4 Alkyl, or -OC 1 -C 4 is alkyl; R 4 is a halogen; Each R 5 is independently H or halogen; Each R 2 are independently H or C 1 -C 4 is alkyl; R 6 But H or C 1 -C 4 is alkyl; R 7 But, C 1 -C 4 is alkyl; R A1 and R A2 are each independently H or C 1 -C 4 alkyl; A1 and R A2 are not both H; However, the compound of formula (I) is 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide; 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide; 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-7-methylquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide; 2-chloro-N-(5-(8-ethyl-2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)quinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide; 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-ethylpyridin-2-yl)benzenesulfonamide; 2-chloro-N-(5-(8-ethyl-2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)quinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide; 2-chloro-N-(5-(8-ethyl-2-(((1r,4r)-4-(ethyl(methyl)amino)cyclohexyl)amino)quinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide; 2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-methylquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide; 2-chloro-N-(5-(2-(((1s,4s)-4-(dimethylamino)cyclohexyl)amino)-8-methylquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide; 2-chloro-N-(5-(2-(((1s,4s)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide; and 2,3-Dichloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide; isn't it, The compound, or a pharma- ceutically acceptable salt, or solvate thereof.

2. R 3 But, C 1 -C 3 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein: R is an alkyl group;

3. R 3 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein:

4. R 4 The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof, wherein is chlorine.

5. At least 3 R's 5 The compound of any one of claims 1 to 4, wherein is H, or a pharma- ceutically acceptable salt thereof.

6. All R 5 The compound of any one of claims 1 to 4, wherein is H, or a pharma- ceutically acceptable salt thereof.

7. R 6 But, C 1 -C 3 7. The compound of any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof, wherein:

8. R 6 and R 7 C 1 -C 3 7. The compound of any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof, wherein:

9. R 6 and R 7 The compound according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof, wherein is methyl.

10. R A1 is H, or a pharma- ceutically acceptable salt thereof.

11. R A2 But, C 1 -C 3 10. The compound of any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof, wherein: R is an alkyl group;

12. R A2 The compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof, wherein is ethyl.

13. R A1 is H and R A2 The compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof, wherein is ethyl.

14. R 3 But, C 1 -C 3 is alkyl; R A1 is H; R A2 But, C 1 -C 3 is alkyl; R 4 is chlorine, 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

15. R A2 15. The compound of claim 14, or a pharma- ceutically acceptable salt thereof, wherein is ethyl.

16. R 6 and R 7 But, C 1 -C 3 16. The compound of claim 15, or a pharma- ceutically acceptable salt thereof, wherein: R is an alkyl group;

17. R 6 and R 7 16. The compound of claim 15, or a pharma- ceutically acceptable salt thereof, wherein is methyl.

18. 18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17, or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients.

19. 20. A pharmaceutical composition for the treatment of cancer comprising a compound according to any one of claims 1 to 17 or a pharma- ceutically acceptable salt thereof, wherein the cancer is a solid cancer or a hematological cancer.

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