Malt1 and BTK dual inhibitors

Abstract

The present disclosure provides compounds having the structure of Formulae (I) and (II): which act as dual inhibitors of MALT1 and BTK, as well as uses of these compounds for treating diseases including cancer, autoimmune disorders, and inflammatory disorders. In certain embodiments, the present disclosure provides a method of treating a disease or disorder in a subject comprising administering a compound of any one of the formulae (I), (II), or an enantiomer, diastereomer, stereoisomer, or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof.

Description

MALT1 AND BTK DUAL INHIBITORSCROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 63 / 553,073, filed February 13, 2024. The content of the prior application is considered part of and is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION

[0002] The present disclosure relates generally to small molecule protein inhibitors and more specifically to dual inhibitors of MALT1 and BTK and their associated uses for treating diseases including cancer, autoimmune diseases, and inflammatory diseases.BACKGROUND INFORMATION

[0003] Mantle cell lymphoma (MCL) is an incurable subtype of non-Hodgkin lymphoma with aberrant activation of the B-cell receptor (BCR) pathway. Upon BCR stimulation, Bruton’s tyrosine kinase (BTK) is activated, which in turn regulates the downstream NF-KB pathway and the PI3K / AKT / mTOR pathway. Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is an essential regulator of BCR-activated NF-KB signaling and serves two intrinsic functions, as a scaffold protein and as the sole human paracaspase. As a scaffold protein, MALT1 binds to CARD 11 and BCL10 to form the CARD11-BCL10-MALT1 complex, which activates IKK and NF-KB signaling. As a paracaspase, MALT1 cleaves substrates that include itself, BCL10, RelB, A20, and CYLD to dramatically upregulate NF-KB activation. MALT1 also regulates non-classical NF-KB signaling by physically interacting with TRAF3. However, the roles of MALT 1 in lymphomagenesis and resultant drug resistance are poorly understood.

[0004] Pharmacological BTK inhibitors (BTKi) like ibrutinib (IBN, covalent) and pirtobrutinib (PBN, non-covalent) have been proven effective in MCL treatment. However, MCL patients frequently relapse from these treatments. Nevertheless, PBN was recently shown to overcome resistance to covalent BTKi in 52% of MCL patients, indicating that BTK is still targetable in this cohort. Recent studies have shown that non-canonical NF-KB signaling is associated with IBN resistance, and PI3K-AKT-mTOR and integrin signaling also confer tumor microenvironment- driven IBN resistance in MCL. However, the role of MALT 1 in BTKi resistance is not well defined, and novel means to overcome BTKi resistance are needed.SUMMARY OF THE INVENTION

[0005] The present disclosure is based on the seminal discovery that dual inhibitors of MALT 1 and BTK exhibit enhanced therapeutic activity relative to combinations of inhibitors that individually target MALT1 and BTK. Leveraging this discovery, the present disclosure provides compounds that simultaneously target MALT1 and BTK, as well as uses of these compounds for treating diseases and disorders including cancers, autoimmune diseases, and inflammatory disorders.

[0006] In one embodiment, the present disclosure provides a compound according to Formula I:or an enantiomer, diastereomer, stereoisomer, or a pharmaceutically acceptable salt or solvate thereof, wherein:Z1is N or CR1, Z2is N or CR2, and at most one of Z1and Z2is N;R1and R2are independently hydrogen, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, halogen, cyano, NH2, or hydroxyl;R3is hydrogen, halogen, NH2, or aminocarbonyl;X1and X2are each independently selected from a bond,Z3is N or CR5, Z4is N or CR6, and at most one of Z3and Z4is N;R4, R5, and R6are independently hydrogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, halogen, cyano, NH2, hydroxyl, C1-6 alkoxyalkyl, C1-6alkoxycarbonyl, Ci-6 alkylcarbonyl, aminocarbonyl, Ci-6 alkylaminocarbonyl, Ci-6 aminoalkyl, or Ci-6 hydroxyalkyl;Z5is N or CR9, Z6is N or CR10, and Z7is N or CR11, wherein at most one ofZ5, Z6, and Z7is N;R7, R8, R9, R10, and R11are each independently hydrogen, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy, halogen, cyano, NH2, hydroxyl, C1-6 alkoxyalkyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyl, C1-6 aminocarbonyl, C1-6 alkylaminocarbonyl, C1-6 aminoalkyl, or C1-6 hydroxyalkyl;X3is a bondR12and R13are each independently hydrogen, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, halogen, cyano, NH2, or hydroxyl; andR14is hydrogen or C1-3 alkyl.

[0007] In some aspects, Z1is N. In certain aspects, Z2is CR2. In particular aspects, Z1is N and Z2is CR2. In further aspects, Z1is N and Z2is CCF3. In other aspects, Z1is CR1and Z2is N. In a specific aspect, Z1is CNH2 and Z2is N.

[0008] In a further aspect, R1and R2are independently selected from hydrogen, C1-C3 alkyl, Ci- C3 haloalkyl, halogen, or cyano. In another aspect, R1and R2are independently selected from hydrogen or C1-C3 haloalkyl. In an additional aspect, R1and R2are independently selected from hydrogen, Ci haloalkyl, or methyl. In a particular aspect, R1and R2are independently selected from hydrogen or CF3.

[0009] In another aspect, R3is selected from hydrogen or NH2. In a specific aspect, R3is hydrogen.

[0010] In an additional aspect, X1is a bond or . In a further aspect, X1is

[0011] In one aspect,certainV '"u aspects, X is

[0012] In some aspects, Z3CR5. In particular aspects, Z3CH. In additional aspects, Z4CR6. In further aspects, Z4CH.

[0013] In certain aspects, R4, R5, and R6are independently hydrogen, C1-3 alkyl, C1-3 alkoxy, Cn 3 haloalkyl, halogen, cyano, NH2, or hydroxyl. In further aspects, two of R4, R5, and R6are hydrogen and the remaining instance of R4, R5, and R6is C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, halogen, cyano, NH2, or hydroxyl. In additional aspects, R4, R5, and R6are independently selected from hydrogen, methyl, OCH3, CF3, halogen, or hydroxyl. In a particular aspect, R4, R5, and R6are each hydrogen.

[0014] In certain aspects, Z5is CR9, Z6is CR10, and Z7is CR11. In a number of aspects, two of R9, R10, and R11are hydrogen. In a further aspect, Z5is CH, Z6is CR10, and Z7is CH. In a specific aspect, R10is halogen. In another aspect, Z5, Z6, and Z7are each CH.

[0015] In certain aspects, R7, R8, R9, R10, and R11are each independently hydrogen, C1-3 alkyl, Cn 3 alkoxy, C1-3 haloalkyl, halogen, cyano, NH2, or hydroxyl. In further aspects, R7, R8, R9, R10, and R11are each independently selected from hydrogen, methyl, OCH3, CF3, halogen, or hydroxyl. In a specific aspect, R7is H and R8is C1-C3 alkoxy. In a particular aspect, R7is H and R8is OCH3. In a specific aspect,

[0016] In many aspects, X3is a bond.

[0017] In an additional aspect, R12and R13are each independently hydrogen, methyl, OCH3, CF3, halogen, or hydroxyl. In a specific aspect, R12and R13are each hydrogen.

[0018] In another aspect, R14is hydrogen.

[0019] In particular aspects, the compound is selected from

[0020] In another embodiment, the present disclosure provides a compound according toFormula II:or an enantiomer, diastereomer, stereoisomer, or a pharmaceutically acceptable salt or solvate thereof, wherein:is a divalent group or a bond;Z21is N or CR21, Z22is N or CR22, Z23is N or CR23, Z24is N or CR24, Z25is N or CR25, at most one of Z21and Z22is N, and at most one of Z23, Z24, and Z25is N; each instance of R21, R22, R23, R24, R25, R28, R29, and R30is independently hydrogen, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy, halogen, cyano, NH2, hydroxyl, C1-6 alkoxyalkyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyl, C1-6 aminocarbonyl, C1-6 alkylaminocarbonyl, C1-6 aminoalkyl, or C1-6 hydroxyalkyl;R31and R32are each independently C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, halogen, cyano, NH2, or hydroxyl;R33is H or C1-3 alkyl;Z26is CR26or N, Z27is CR27or N, and at most one of Z26and Z27is N;R26and R27are independently hydrogen, C1-6 alkyl, C1-6 alkoxyl, C1-6 haloalkyl, C1-6 haloalkoxy, halogen, cyano, or hydroxyl;Ring A is selected fromR34and R35are independently selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy,C1-6 haloalkyl, C1-6 haloalkoxy, halo, NH2, C1-6 alkoxyalkyl, C1-6 aminoalkyl, hydroxyl, C1-6 aminocarbonyl, or C1-6 hydroxyalkyl.In some aspects,is selected fromRing C is a C2-8 N-heterocycle, C4-12 N-heterobicycle, or C3-8 cycloalkyl, wherein Ring C is optionally substituted with one or more groups independently selected from amine, C2-8 N- heterocycle, C3-C8 cycloalkyl, or C1-6 aminoalkyl;is selected fromis selected fromeach instance of n is independently an integer from 1 to 10; and each instance of m is independently an integer from 1 to 10.

[0021] In one aspect,is selected from

[0022] In another aspect, Ring B is selected from. In a further. al aspect, is selected from. In another aspect, each instance of n is independently an integer from 1 to5. In a further aspect, each instance of m is independently an integer from 1 to 5.

[0023] In some aspects, Ring C is selected from. In certain aspects, Ring C is selected fromparticular aspect, Ring C is

[0024] In some aspects, X4is selected from. In a particular aspect, X is

[0025] In certain aspects, Z21and Z22are independently selected from N, CH, CF, CC1, CBr, CI, CCH3, CCF3, COH, COCH3, or CCN, wherein at most one of Z21and Z22is N. In further aspects, Z21and Z22are each independently selected from N or CH, wherein at most one of Z21and Z22is N. In a particular aspect, Z21and Z22are each CH.

[0026] In some aspects, Z23, Z24, and Z25are each independently selected from N, CH, CF, CC1, CBr, CI, CCH3, CCF3, COH, COCH3, or CCN, wherein at most one of Z23, Z24, and Z25is N. In other aspects, Z23, Z24, and Z25are each independently selected from CH, CF, CC1, CBr, CI, CCH3, CCF3, COH, COCH3, or CCN. In a specific aspect, Z23is CH. In a further aspect, Z24is COCH3. In an additional aspect, Z25is CH.

[0027] In one aspect, each instance of R28, R29, and R30is independently selected from hydrogen, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, halogen, cyano, NH2, or hydroxyl. In some aspects, R28is H.In further aspects, R29is OCH3. In additional aspects, R30is H. In many aspects,

[0028] In certain aspects, R31and R32are each independently selected from hydrogen, methyl, OCH3, CF3, halogen, or hydroxyl. In further aspects, R31and R32are each hydrogen. In additional aspects, R33is hydrogen.

[0029] In one aspect, Z26is N. In another aspect, Z27is CR27. In a further aspect, R26and R27are each independently selected from hydrogen, C1-3 alkyl, C1-3 haloalkyl, halogen, or cyano. In a particular aspect, Z26is N and Z27is CCF3.

[0030] In some aspects, R34and R35are each independently selected from hydrogen, NH2, C1-3 alkyl, and C1-3 aminocarbonyl. In particular aspects, Ring A is selected from

[0031] In a specific aspect, the compound is selected from

[0032] Further embodiments of the present disclosure provide a pharmaceutical composition that includes a compound of the present disclosure.

[0033] In some aspects, the pharmaceutical composition further includes a pharmaceutically acceptable excipient. In particular aspects, the pharmaceutically acceptable excipient is selected from a buffer, an antioxidant, a preservative, a peptide, a protein, a hydrophilic polymer, an amino acid, a sugar, a polysaccharide, a chelating agent, a salt-forming counter-ion, a non-ionic surfactant, an anti-adherent, a binder, a synthetic polymer, a lubricant, a vitamin, selenium, or a paraben.

[0034] In further aspects, the pharmaceutical composition includes a pharmaceutically acceptable carrier. In some aspects, the pharmaceutically acceptable carrier includes a liposome, ananoparticle, a microparticle, a polysaccharide, a protein, a hydrogel, an ointment, a micelle, a microsphere, a cream, an emulsion, or a gel. In particular aspects, the compound is coupled to the pharmaceutically acceptable carrier.

[0035] Further aspects of the present disclosure provide a method of treating a disease or disorder in a subject that includes administering a compound or a pharmaceutical composition of the present disclosure to the subject, thereby treating the disease or disorder in the subject.

[0036] In some aspects, the disease is cancer. In particular aspects, the cancer is selected from activated B-cell type diffuse large B-cell lymphoma (ABC-DLBCL), acute myeloid leukemia (AML), bile duct cancer, bladder cancer, brain cancer, breast cancer, carcinoma, cervical cancer, chronic lymphocytic leukemia (CLL), colorectal cancer, endometrial cancer, epitheloid carcinoma of the bone, esophageal cancer, follicular lymphoma (FL), gallbladder cancer, gastric cancer, glioblastoma, head and neck cancer, hepatocellular cancer, large B-cell lymphoma (LBCL), large cell lung carcinoma, leukemia, lung cancer, lymphoma, mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), medulloblastoma, melanoma, mucosa assisted lymphoid tissue (MALT), myelodysplastic syndrome (MDS), non-Hodgkin’s lymphoma (NHL), ovarian cancer, non-small cell lung cancer, pancreatic cancer, prostate cancer, renal cell cancer, small lymphocytic lymphoma (SLL), thyroid cancer, or Waldenstrom macroglobulinemia (WM).

[0037] In another aspect, the disorder is an inflammatory disorder. In a particular aspect, the inflammatory disorder is selected from rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, ankylosing spondylitis, graft-versus-host disease, stroke, spinal cord injury, chronic renal disease; allergies, type 1 diabetes, inflammatory bowel disorder, Crohn's disease, ulcerative colitis; myasthenia gravis, fibromyalgia; psoriasis, vitiligo, dermatitis, or systemic lupus.

[0038] In a further aspect, the disease is an autoimmune disease. In particular aspects, the autoimmune disease is selected from type I diabetes, Crohn's disease, ulcerative colitis, myasthenia gravis, vitiligo, Graves' disease, Hashimoto's disease, Addison's disease, autoimmune gastritis, autoimmune hepatitis, rheumatoid disease, systemic lupus erythematosus, progressive systemic sclerosis, polymyositis, dermatomyositis, pernicious anemia, autoimmune gastritis, primary biliary cirrhosis, autoimmune thrombocytopenia, Sjogren's syndrome, multiple sclerosis, or psoriasis.

[0039] In another embodiment, the present disclosure provides a compound selected from

[0040] In another embodiment, the present disclosure provides a compound selected from:c) , wherein n is an integer from 1 to 10;0;x)wherein n is an integer from 1 to 10.

[0041] In a further embodiment, the present disclosure provides a method of treating a disease or condition in a subject in need thereof comprising administering to the subject a compound that includes: i) a first moiety that inhibits BTK and ii) a second moiety that inhibits MALT1; thereby treating the disease or condition in the subject.BRIEF DESCRIPTION OF THE DRAWINGS

[0042] FIG. 1A-1F is a set of plots that show that MALT1 is overexpressed in ibrutinib-resistant (IBN-R) MCL cell lines and primary MCL cells. FIG. 1A is a set of dot plots of IC50 values for ibrutinib (upper panel) and venetoclax (bottom panel) in 9 MCL cell lines. FIG. IB is a heatmap with MALT1 highlighted in the right as one of the top DEGs in IBN-R MCL cells compared to IBN-S cells. FIG. 1C is a volcano plot shows MALT1 was upregulated in IBN-R group. FIG. ID is a set of box plots that show MALT1 mRNA expression in IBN-R vs IBN-S and DuaLR vs DuaL S groups. FIG. IE is a volcano plot of DEGs involved in NF-KB signaling, comparing IBN-R vs IBN-S cells. FIG. IF is a heatmap of DEGs involved in NF-KB signaling, comparing IBN-R vs IBN-S cells.

[0043] FIG. 2A-2I is a set of plots that show that MALT1 expression correlates with ibrutinib resistance and poor patient survival and that NF-kB signaling is enriched in ibrutinib-resistant MCL cells. FIG. 2A is a violin plot shows MALT1 mRNA expression in IBN-R (n = 17) vs IBN-S (n = 4) MCL cells at single-cell resolution determined by single-cell RNA sequencing. Statistical significance was calculated using Wilcoxon rank sum test. FIG. 2B is a plot of MALT1 mRNA expression determined by quantitative PCR in MCL patients (n = 24) and PBMC samples (n = 3) from healthy donors (as controls), with MALT1 mRNA expression normalized to that of PBMC samples. FIG. 2C is a plot of MALT1 mRNA expression determined by qPCR in IBN-R (n = 9), DuaLR (n = 4), and IBN-S (n = 13) cells. FIG. 2D is a plot showing progress-free survival in MCL patients with high and low MALT1 mRNA expression. FIG. 2E is a plot showing survival probability in MCL patients with high, intermediate, and low MALT1 mRNA expression. FIG. 2F is a plot showing survival probability in MCL patients with high, intermediate, and low MALT1 mRNA expression. FIG. 2G is a set of plots of the top 10 cancer hallmarks upregulated in IBN-Rcells compared to IBN-S cells (left) or in Dual-R cells compared to Dual-S cells (right) identified with GSEA. FIG. 2H is a set of plots showing NF-KB signaling pathways as top cancer hallmarks that were upregulated in IBN-R cells compared to IBN-S cells, with FDRs (false discovery rates) generated using the Benjamini-Hochberg method. FIG. 21 is a set of plots showing NF-KB activity of all five NF-KB family members in each cell line.

[0044] FIG. 3A-3H is a set of plots that show that MALT1 acts as an oncogenic tumor driver in ibrutinib-resistant MCL cells. FIG. 3A is a Western blot that shows expression of MALT1, CARD11, and BCL10, and cleavage of MALT1 substrates, in JeKo-1, JeKo-R, and JeKo BTK KD_1 and _2 cell lines. FIG. 3B is a plot of endogenous MALT1 cleavage activity detected in JeKo-1 and JeKo BTK KD_2 cells. FIG. 3C is a Western blot that shows expression of MALT1, CARD11, BCL10, and cleavage of MALT1 substrates in seven additional MCL cell lines. FIG. 3D is a Western blot that shows expression of MALT 1, CARD11, and BCL-10, and cleavage of MALT1 substrates, in IBN-R and IBN-S primary MCL cells. FIG. 3E is a Western blot that shows expression of MALT1 in JeKo-1, JeKo BTK KD_2, Maver and Z138 cells, with or without MALT1 or CARD 11 knockdown by shRNA. FIG. 3F is a set of plots that show MALT1 knockdown resulted in cell proliferation inhibition in JeKo-1, JeKo BTK KD_2, Maver and Z138 cells. FIG. 3G is a Western blot of JeKo-1 and JeKo-MALTl cells were treated by doxycycline at 1 pg / ml for 24 hours and MALT 1 -Flag expression was detected by anti -Flag antibody cells. FIG. 3H is a plot of cell proliferation in JeKo-1 and JeKo-MALTl cells with induced MALT1- Flag expression.

[0045] FIG. 4A-4H is a set of plots that show that genetic knockout of MALT1 leads to defective cell growth in both ibrutinib-sensitive and -resistant cells. FIG. 4A is a Western blot that shows expression of MALT1, CARD11, and BTK in JeKo-1 and JeKo BTK KD_2 cells with or without MALT1 knockout (KO), CARD11 KO or BTK KD. FIG. 4B is a plot that shows proliferation for JeKo-1, JeKo-1 MALT1 KO, and JeKo-1 CARD11 KO. FIG. 4C is a plot of cell proliferation for JeKo BTK KD_2 cells with or without MALT1 or CARD11 KO. FIG. 4D is a plot of tumor volumes for JeKo-1, JeKo-1 MALT1 KO, and JeKo-1 CARD11 KO cells. FIG. 4E is a plot of tumor volumes in JeKo-1 BTK KD 2, JeKo-1 MALT1 / BTKDK, and JeKo-1 CARD11 / BTK DK cells. FIG. 4F is a plot of B2M levels in JeKo-1, JeKo-1 MALT1 KO, and JeKo-1 CARD 11 KO cells. FIG. 4G is a plot of B2M levels in JeKo-1 BTK KD_2, JeKo-1 MALT1 / BTK DK, and JeKo-1 CARD11 / BTKDK cells. FIG. 4H is a set of images and weights of subcutaneous tumors.

[0046] FIG. 5A-5J is a set of plots and images that show that MALT1 inhibition by MI-2 decreases MALT1 paracaspase activity and suppresses cell proliferation in MCL cells. FIG. 5A is a set of plots of endogenous MALT1 cleavage activity detected in JeKo-1, JeKo BTK KD_2and Mino cells upon MALT1 inhibition by MI-2 at the indicated concentrations and treatment times. FIG. 5B is a plot of cell viabilities for various MCL cell lines treated with MI-2. FIG. 5C is a plot of cell viabilities for various MCL cell lines treated with MI-2. FIG. 5D is a set of IC50 values for ibrutinib (left panel) and MI-2 (right panel) in IBN-R and IBN-S cells. FIG. 5E is a set of plots of cell viabilities for primary patient samples ex vivo treated with ibrutinib or MI-2. FIG. 5F is a set of cell viability plots that show that MI-2 effectively inhibited cell viability in JeKo-1 cells and JeKo BTK KD_2 cells, but not their counterparts with stable MALT1 knockdown. FIG. 5G is a plot that shows cell apoptosis as a function of MI-2 concentration for multiple MCL cell lines. FIG. 5H is a set of Western blots that show that MI-2 induced cleavage of PARP and caspase 3 in JeKo BTK KD_2 cells and primary patient cells. FIG. 51 is a set of images of mice bearing luciferase-expressing JeKo BTK KD_2-derived subcutaneous xenografts treated with vehicle or MI-2 at 25 mg / kg daily via intraperitoneal injection for 24 d. FIG. 5 J is a plot of luminescence values from mice bearing luciferase-expressing JeKo BTK KD_2-derived subcutaneous xenografts treated with vehicle or MI -2 at 25 mg / kg daily via intraperitoneal injection as a function of days post treatment.

[0047] FIG. 6A-6F is a set of plots that show that MALT1 inhibition by MI-2 suppresses NF- KB signaling in MCL cells. FIG. 6 A is a set of plots of elevated pathways triggered upon MALT1 inhibition by MI-2 in JeKo-1 and JeKo BTK KD cells. FIG. 6B is a set of plots of enrichment scores of TNFa Signaling via NF-KB (upper panels) and NIK NF-KB signaling (bottom panels) in JeKo-1 (left panels) and JeKo BTK KD_2 (right panels) cells. FIG. 6C is a plot of activities of all five NF-KB family members as a function of MI-2 concentration in JeKo-1 cells. FIG. 6D is a plot of activities of all five NF-KB family members as a function of MI-2 concentration in JeKo BTKKD 2 cells. FIG. 6E is a plot of ROS production in JeKo-1, Mino, JeKo BTKKD 2, Maver- 1, and Z-138 cells treated with MI-2 at 0 and 2 pM for 6 h. FIG. 6F is a plot of ATm in JeKo-1, Mino, JeKo BTK KD_2, Maver-1, and Z-138 cells treated with MI-2 at 0 and 2 pM 10 h.

[0048] FIG. 7A-7I is an illustration and set of images and plots that show that MALT1, but not CARD11, is critical for MCL cell dissemination to mouse spleen, liver, and bone marrow. FIG. 7A is a schematic illustration of disseminated cell line-derived CDX or PDX models. FIG. 7B is a plot of tumor cell percentages in PB from JeKo-1 and JeKo BTK KD_2 models with or without MALT1 or CARD11 KO as determined by flow cytometry. FIG. 7C is a plot of tumor cell percentages in BM from JeKo-1 and JeKo BTK KD_2 models with or without MALT1 or CARD11 KO as determined by flow cytometry. FIG. 7D is a plot of spleen weights from JeKo-1 and JeKo BTK KD_2 models with or without MALT1 or CARD11 KO. FIG. 7E is a plot of tumor cell percentages in spleens from JeKo-1 and JeKo BTK KD_2 models with or without MALT1 orCARD11 KO as determined by flow cytometry. FIG. 7F is a set of images of spleens from JeKo- 1 and JeKo BTK KD_2 models with or without MALT1 or CARD11 KO. FIG. 7G is a plot of liver weights from JeKo- 1 and JeKo BTK KD_2 models with or without MALT1 or CARD11 KO. FIG. 7H is a plot of tumor cell percentages in livers from JeKo-1 and JeKo BTK KD_2 models with or without MALT1 or CARD 11 KO as determined by flow cytometry. FIG. 71 is a set of images of spleens from JeKo-1 and JeKo BTK KD_2 models with or without MALT1 or CARD11 KO.

[0049] FIG. 8A-8F is a set of plots that show that MALT1 inhibition suppresses MCL cell dissemination in mouse peripheral blood (PB), spleen, and bone marrow (BM). FIG. 8A is a plot of MCL cell frequencies in PB 1 hour post- injection of vehicle or MI-2. FIG. 8B is a plot of MCL cell frequencies in PB 4 days post- injection of vehicle or MI-2. FIG. 8C is a plot of spleen MCL cell frequencies 4 days post-injection of vehicle or MI-2. FIG. 8D is a plot of bone marrow MCL cell frequencies 4 days post-injection of vehicle or MI-2. FIG. 8E is a plot of spleen weights following four weeks of daily injection with vehicle, ibrutinib (50 mg / kg), or MI-2 (25 mg / kg). FIG. 8F is a set of plots of spleen, bone marrow, and PB tumor cell frequencies following four weeks of daily injection with vehicle, ibrutinib (50 mg / kg), or MI -2 (25 mg / kg).

[0050] FIG. 9A-9D is a heatmap, plot, and set of images of Western blots that show that MALT1 inhibition leads to suppressed PI3K-AKT-mTOR signaling. FIG. 9A is a heatmap generated from RPPA analysis for MCL cell lines treated with MI-2 at 0, 1, or 2 mM for 6 hours that shows proteins whose expression is altered by MI-2 treatment. FIG. 9B is a set of images of Western blot analyses that show the phosphorylation of AKT, S6, and p90RSK was upregulated in JeKo- R and JeKo BTK KD_1 and _2 cells. FIG. 9C is a set of images of Western blot analyses that show that phosphorylation of PLCy2, BTK, AKT, and ERK was reduced upon MI -2 pretreatment followed by IgM stimulation in JeKo-1 cells. FIG. 9D is a plot of ATP levels in various models treated with 0, 1, or 2 pM MI-2.

[0051] FIG. 10A-10I is a set of plots and diagrams that show that MALT1 inhibition suppresses cell adhesion and cell migration. FIG. 10A is a set of plots of GSEA analysis that show that cell adhesion molecules, adhesions junction, focal adhesion, and apical junction were significantly suppressed by MALT inhibition by MI-2 in JeKo-1 and JeKo BTK KD_2 cells. FIG. 10B is a Venn diagram showing common DEGs involved in cell adhesion molecules and focal junction downregulated upon MI-2 treatment in JeKo-1 cells. FIG. 10C is a Venn diagram showing common DEGs involved in cell adhesion molecules and focal junction downregulated upon MI-2 treatment in JeKo BTK KD_2 cells. FIG. 10D is a plot of integrin molecules altered upon MI-2 treatment identified in a screen for ECM using ECM array in JeKo-1, JeKo-R, JeKo BTK KD_1 and _2, and Mino cells. FIG. 10E is a plot of cell titers from a fibronectin adhesion assay for cellspretreated with DMSO, ibrutinib at 5 tM, or MI-2 at 0.5 tM for 30 min. FIG. 10F is a plot of cell titers from a laminin adhesion assay for cells pretreated with DMSO, ibrutinib at 5 tM, or MI-2 at 0.5 tM for 30 min. FIG. 10G is a plot of cell titers from an FBS adhesion assay in which JeKo-1, JeKo-R, JeKo BTK KD_1 and _2 were pretreated with DMSO, ibrutinib at 5 tM, or MI-2 at 0.5 tM for 30 min and incubated in plates pro-coated with fetal bovine serum (FBS) for 4 h. FIG. 10H is a plot of cell titers from a cell migration assay in which MCL cells were pretreated with DMSO, ibrutinib at 5 tM, or MI-2 at 1 tM for 30 min, added in Transwell inserts, and incubated in plates pre-seeded with monolayer of stromal cells (HS-5) for 6 h. FIG. 101 is a plot of cell titers from a cell migration assay in which MCL cells were added in Transwell inserts and incubated in plates with pre-seeded (overnight) monolayers of stromal cells (HS-5) or with only the supernatants harvested from cultured stromal cells (overnight).

[0052] FIG. 11A-11H is a set of plots, heatmaps, and images of Western blots that show that dual targeting of BTK and MALT1 by ibrutinib and MI-2 promotes potent anti-MCL activity in MCL cells with resistance to BTK inhibitors. FIG. 11 A is a plot of combination indices from a combinatorial screen for MI-2 using two ibrutinib-resistant primary patient samples. FIG. 1 IB is a plot of combination indices from a combinatorial screen for MI -2 using a PDX sample. FIG. 11C is a set of plots of cell viabilities for JeKo-1, JeKo BTKKD 2 and Z 138 cells treated with DMSO, ibrutinib, MI-2 or the combination of ibrutinib and MI-2. FIG. 11D is a set of plots of cell viabilities for primary PDX cells and primary patient cells treated with DMSO, ibrutinib, MI-2 or the combination of ibrutinib and MI -2. FIG. HE is a set of plots of cell apoptosis frequencies in JekO-1, Jeko BTK KD_1, and JeKo BTK KD_2 cells treated with DMSO, ibrutinib, MI-2 or the combination of ibrutinib and MI-2. FIG. HF is a set of heatmaps of RPPA analyses for JeKo-1 and JeKo BTK KD_1 and _2 cells treated with MI-2 and ibrutinib, alone or in combination, for 6 h. FIG. 11G is a plot of gene set enrichment scores that show the top cancer hallmarks altered by the combination of MI-2 plus ibrutinib compared to DMSO control. FIG. 11H is a set of images of Western blot analyses for JeKo-1 and JeKo BTK KD_2 cells treated with MI-2 and ibrutinib, alone or in combination, for 6 h.

[0053] FIG. 12A-12F is a set of plots that show that dual targeting of BTK and MALT1 by pirtobrutinib and safimlatib promotes potent anti-MCL activity in MCL cells with resistance to BTK inhibitors in vitro and in vivo. FIG. 12A is a plot of cell viabilities for multiple cell lines treated with DMSO, pirtobrutinib, MI-2, and the combination of pirtobrutinib and MI-2. FIG. 12B is a set of plots of cell viability for multiple cell lines treated with pirtobrutinib (left) or safimaltib (right). FIG. 12C is a set of plots of cell viability for cells treated with pirtobrutinib, safimaltib, or pirtobrutinib and safimaltib. FIG. 12D is a plot of tumor volumes for micesubcutaneously injected with PDX cells and treated with vehicle, pirtobrutinib, safimaltib, or pirtobrutinib and safimaltib. FIG. 12E is a plot of survival probabilities for mice subcutaneously injected with PDX cells and treated with vehicle, pirtobrutinib, safimaltib, or pirtobrutinib and safimaltib. FIG. 12F is a plot of body weights for mice subcutaneously injected with PDX cells and treated with vehicle, pirtobrutinib, safimaltib, or pirtobrutinib and safimaltib.

[0054] FIG. 13 is a schematic that shows the design and chemical structure of BTK-MALT1 dual inhibitors MZ0150-1 and MZ0170-1 via two design strategies. The top portion of FIG. 13 shows MZO 150-1 via merging the BTK pharmacophore from pirtobrutinib and the MALT1 pharmacophore from safimaltib. The bottom portion of FIG. 13 shows MZ0170-1 via connecting BTK and MALT1 pharmacophores with a linker.

[0055] FIG. 14A-14G is a set of plots from a drug efficacy screen of BTK-MALT1 dual inhibitors. FIG. 14A is a plot of cell viabilities for a 3-dose drug screen of multiple BTK-MALT1 dual inhibitors in JeKo-1 cells at 72 hours post-treatment. FIG. 14B is a plot of cell viabilities for an 8-dose drug screen of pirtobrutinib, safimaltib, pirtobrutinib and safimaltib, MZO 150-1, MZ0170-1, and MZ0264. FIG. 14C is a summary of IC50 values for MZ0150-1, MZ0170-1, MZ0264, and the combination of pirtobrutinib and safimaltib in multiple cell lines. FIG. 14D is a set of images of Western blots for P-BTK, BTK, MALT1, CYLD, CYLD cl, and GAPDH in cells treated with 0, 5, or 10 pM MZ0150-1, MZ0170-1, or MZ0264. FIG. 14E is a plot of dose and time-dependent inhibition of cell viability in JeKo-1 cells at 24 hours post treatment of MZO 150- 1 and MZ0170-1. FIG. 14F is a plot of dose and time-dependent induction of apoptosis in JeKo- 1 cells at 24 hours post treatment of MZ0150-1 and MZ0170-1. FIG. 14G is a plot of cell cycle stages for cells treated with various inhibitors.

[0056] FIG. 15A-15B is a set of plots that show the drug efficacy of BTK-MALT1 dual inhibitor MZO 150 in patient-derived organoid (PDO) models. FIG. 15A is a plot of cell viabilities for BTKi-resistant PDOs treated with vehicle, PBN, MZO 150-1, or DOX. FIG. 15B is a plot of cell viabilities for PBN-sensitive PDOs treated with DMSO, pirtobrutinib, or MZO150-1.

[0057] FIG. 16A-16B is a set of plots that show the off-target toxicities of BTK-MALT1 dual inhibitors / / ? vitro and in vivo. FIG. 16A is a plot of normal cell viability for healthy PBMC treated with pirtobrutinib, safimaltib, MZO150-1, or MZO170-1. FIG. 16B is a plot of body weights for mice treated with 10-50 mg / kg MZO 150-1.

[0058] FIG. 17 is an illustration that shows the mechanism of action of targeting BTK and MALT1 via the combination of BTKi and MALTli or via novel compounds of BTK-MALT1 dual inhibitors.DETAILED DESCRIPTION OF THE INVENTION

[0059] Before the present compositions and methods are described, it is to be understood that this invention is not limited to particular compositions, methods, and experimental conditions described, as such compositions, methods, and conditions may vary. It is also to be understood that the terminology used herein is for purposes of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only in the appended claims.

[0060] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0061] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, it will be understood that modifications and variations are encompassed within the spirit and scope of the instant disclosure. The preferred methods and materials are now described.

[0062] As used in this specification and the appended claims, the singular forms “a,” “an”, and “the” include plural references unless the context clearly dictates otherwise. Thus, for example, references to “the method” include one or more methods, and / or steps of the type described herein which will become apparent to those persons skilled in the art upon reading this disclosure and so forth.

[0063] As used herein, the term “and / or” includes any and all combinations of one or more of the associated listed items.

[0064] As used herein, the term “alkyl” denotes a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl, pentyl, and the like.

[0065] As used herein, the term “alkoxy” denotes a -OR radical where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, and the like.

[0066] As used herein, the term “alkoxyalkyl” denotes a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one alkoxy group, as defined above, e.g., 2-methoxyethyl, 1-, 2-, or 3- methoxypropyl, and the like.

[0067] As used herein, C(O) denotes a carbon double bonded to an oxygen. For example, -C(O)- denotes, while -C(O)R denotes.

[0068] As used herein, the term “alkylcarbonyl” denotes a -C(O)R radical where R is alkyl as defined herein, e.g., methylcarbonyl, ethylcarbonyl, and the like.

[0069] As used herein, the term “alkoxycarbonyl” denotes a -C(O)OR radical where R is alkyl as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, and the like.

[0070] As used herein, the term “alkylsulfonyl” denotes a -S(O)2R radical where R is alkyl as defined above, e.g., methylsulfonyl, ethylsulfonyl, and the like.

[0071] As used herein, the term “alkylamino” denotes an -NHR radical where R is alkyl as defined above, e.g., methylamino, ethylamino, propylamino, or 2-propylamino, and the like.

[0072] As used herein, the term “aminoalkyl” denotes a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with -NR'R" where R' and R" are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or alkylcarbonyl, each as defined herein, e.g., aminomethyl, aminoethyl, methylaminomethyl, and the like.

[0073] As used herein, the term “alkylaminocarbonyl” denotes a -C(O)NHR group where R is alkyl as defined above, e.g., methylaminocarbonyl, ethylaminocarbonyl and the like.

[0074] As used herein, the term “aminocarbonyl” denotes a -C(O)NH2 group.

[0075] As used herein, the term “cycloalkyl” denotes a monocyclic hydrocarbon radical of three to eight carbon atoms or a bicyclic hydrocarbon radical of six to fifteen carbon atoms, which may be saturated or contain one double bond. Cycloalkyl may be unsubstituted or substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxyl, or cyano. Examples include but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1- cyanocycloprop-l-yl, 1-cyanomethylcycloprop-l-yl, and the like.

[0076] As used herein, the term “halo” denotes fluoro, chloro, bromo, or iodo.

[0077] As used herein, the term “haloalkyl” denotes an alkyl group as defined above, which is substituted with one to five halogen atoms, such as fluorine or chlorine, including those substituted with different halogens, e.g., - CH2CI, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)2, and the like.

[0078] As used herein, the term “haloalkoxy” denotes an a -OR group where R is haloalkyl as defined above, e.g., -OCF3, -OCHF2, and the like.

[0079] As used herein, the term “hydroxyalkyl” denotes a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one or two hydroxy groups, provided that if two hydroxy groups arepresent they are not both on the same carbon atom Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxy-ethyl, 2-hydroxypropyl, 3 -hydroxypropyl, 1- (hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3 -hydroxybutyl, 4-hydroxybutyl, 2,3- dihydroxypropyl, l-(hydroxymethyl)-2-hydroxyethyl.

[0080] Disclosed herein are compounds with dual inhibitory activity towards Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) and Bruton's tyrosine kinase (BTK). It was surprisingly determined that MALT1 is hyperactive and drives BTKi resistance by bypassing upstream BTK-CARD11 signaling. Pirtobrutinib is effective for treating over half of patients with primary or acquired resistance to prior BTKi, which demonstrates that BTK is still functional and targetable in BTKi-resistant patients.

[0081] Building from these observations, the potential of dual targeting of BTK and MALT1 was investigated with separate MALT1 and BTK inhibitors and with single compounds that inhibit MALT1 and BTK. Surprisingly, these dual targeting inhibitors of MALT1 and BTK achieved better efficacy than combinations of separate BTK and MALT1 inhibitors in preclinical MCL models. These studies demonstrated that dual -targeted agents that simultaneously inhibit MALT1 and BTK achieve greater clinical efficacy and are more cost-effective in overcoming drug resistance and promoting improved patient outcomes. In particular, compounds disclosed herein (including MZ0150-1) showed better anti-MCL activity than pirtobrutinib and safimaltib (the first- in-class MALTli under clinical investigation) administered alone or in combination.

[0082] Leveraging these discoveries, in one embodiment, the present disclosure provides a compound according to Formula I:or an enantiomer, diastereomer, stereoisomer, or a pharmaceutically acceptable salt or solvate thereof, wherein:Z1is N or CR1, Z2is N or CR2, and at most one of Z1and Z2is N;R1and R2are independently hydrogen, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, halogen, cyano, NH2, or hydroxyl;R3is hydrogen, halogen, NH2, or aminocarbonyl;X1and X2are each independently selected from a bond,y |Z3is N or CR5, Z4is N or CR6, and at most one of Z3and Z4is N;R4, R5, and R6are independently hydrogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, halogen, cyano, NH2, hydroxyl, C1-6 alkoxyalkyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, C1-6 aminoalkyl, or C1-6 hydroxyalkyl;Z5is N or CR9, Z6is N or CR10, and Z7is N or CR11, wherein at most one ofZ5, Z6, and Z7is N;R7, R8, R9, R10, and R11are each independently hydrogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, halogen, cyano, NH2, hydroxyl, C1-6 alkoxyalkyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyl, C1-6 aminocarbonyl, C1-6 alkylaminocarbonyl, C1-6 aminoalkyl, or C1-6 hydroxyalkyl;X is a bondR12and R13are each independently hydrogen, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, halogen, cyano, NH2, or hydroxyl; andR14is hydrogen or C1-3 alkyl.

[0083] In many aspects, these compounds exhibit strong inhibitory activities for MALT1 and for BTK. Without being bound by theory, a basis for enhanced therapeutic activity by dual MALT1 / BTK inhibitors is presented in FIG. 17. In BTKi-sensitive MCL cells, BTK is critical in activating downstream CARD1 l / MALTl / BCL10-mediated MCL cell survival and growth. Therefore, inhibitors against BTK or MALT1 are effective in targeting MCL cells for cell killing. In patients with primary resistance to BTKi or those relapsed from BTKi therapies, expression of MALT1, but not its binding partners CARD11 or BCL10, is significantly upregulated in MCL cells leading to hyperactive MALT1 activity, which employs a bypass compensatory mechanism to support cell survival, proliferation, and development of BTKi resistance. In patients with primaryresistance to BTKi, BTK function does not appear to be critical for MCL cell survival and growth and therefore, they are resistant to other BTKi therapies such as pirtobrutinib. In patients relapsed from BTKi therapies with initial response, pirtobrutinib is efficacious in treating over half of these patients, indicating that BTK is still functional and targetable to treat these patients. Importantly, dual targeting of BTK and MALT1 achieved better efficacy that the single agents in preclinical MCL models. The BTK-MALT1 dual inhibitors disclosed herein are configured to simultaneously inhibit both BTK and MALT1 inside the same cell, and achieve greater efficacy than single BTKi, MALTli or their combination.

[0084] In some aspects, Z1is N. In certain aspects, Z2is CR2. In particular aspects, Z1is N and Z2is CR2. In further aspects, Z1is N and Z2is CCF3. In other aspects, Z1is CR1and Z2is N. In a specific aspect, Z1is CNH2 and Z2is N.

[0085] In a further aspect, R1and R2are independently selected from hydrogen, C1-C3 alkyl, Ci- C3 haloalkyl, halogen, or cyano. In another aspect, R1and R2are independently selected from hydrogen or C1-C3 haloalkyl. In an additional aspect, R1and R2are independently selected from hydrogen, Ci haloalkyl, or methyl. In a particular aspect, R1and R2are independently selected from hydrogen or CF3.

[0086] In another aspect, R3is selected from hydrogen or NH2. In a specific aspect, R3is hydrogen.11

[0087] In an additional aspect, X is a bond or . In a further aspect, X isAA V X yVy

[0088] In one aspect, X2is , , , * , orH. In certain aspects,

[0089] In some aspects, Z3CR5. In particular aspects, Z3CH. In additional aspects, Z4CR6. In further aspects, Z4CH.

[0090] In certain aspects, R4, R5, and R6are independently hydrogen, C1-3 alkyl, C1-3 alkoxy, Ci- 3 haloalkyl, halogen, cyano, NH2, or hydroxyl. In further aspects, two of R4, R5, and R6are hydrogen and the remaining instance of R4, R5, and R6is C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, halogen, cyano, NH2, or hydroxyl. In additional aspects, R4, R5, and R6are independently selected from hydrogen, methyl, OCH3, CF3, halogen, or hydroxyl. In a particular aspect, R4, R5, and R6are each hydrogen.

[0091] In certain aspects, Z5is CR9, Z6is CR10, and Z7is CR11. In a number of aspects, two of R9, R10, and R11are hydrogen. In a further aspect, Z5is CH, Z6is CR10, and Z7is CH. In a specific aspect, R10is halogen. In another aspect, Z5, Z6, and Z7are each CH.

[0092] In certain aspects, R7, R8, R9, R10, and R11are each independently hydrogen, C1-3 alkyl, Cn 3 alkoxy, C1-3 haloalkyl, halogen, cyano, NH2, or hydroxyl. In further aspects, R7, R8, R9, R10, and R11are each independently selected from hydrogen, methyl, OCH3, CF3, halogen, or hydroxyl. In a specific aspect, R7is H and R8is C1-C3 alkoxy. In a particular aspect, R7is H and R8is OCH3. In a specific aspect,

[0093] In many aspects,

[0094] In an additional aspect, R12and R13are each independently hydrogen, methyl, OCH3, CF3, halogen, or hydroxyl. In a specific aspect, R12and R13are each hydrogen.

[0095] In another aspect, R14is hydrogen.

[0096] In particular aspects, the compound is selected from

[0097] In another embodiment, the present disclosure provides a compound according toFormula II:or an enantiomer, diastereomer, stereoisomer, or a pharmaceutically acceptable salt or solvate thereof, wherein:is a divalent group or a bond;Z21is N or CR21, Z22is N or CR22, Z23is N or CR23, Z24is N or CR24, Z25is N or CR25, at most one of Z21and Z22is N, and at most one of Z23, Z24, and Z25is N;each instance of R21, R22, R23, R24, R25, R28, R29, and R30is independently hydrogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, halogen, cyano, NH2, hydroxyl, C1-6 alkoxyalkyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyl, C1-6 aminocarbonyl, C1-6 alkylaminocarbonyl, C1-6 aminoalkyl, or C1-6 hydroxyalkyl;R31and R32are each independently C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, halogen, cyano, NH2, or hydroxyl;R33is H or C1-3 alkyl;Z26is CR26or N, Z27is CR27or N, and at most one of Z26and Z27is N;R26and R27are independently hydrogen, C1-6 alkyl, C1-6 alkoxyl, C1-6 haloalkyl, C1-6 haloalkoxy, halogen, cyano, or hydroxyl;Ring A is selected fromR34and R35are independently selected from hydrogen, Ci-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, halo, NH2, C1-6 alkoxyalkyl, C1-6 aminoalkyl, hydroxyl, C1-3 aminocarbonyl, or C1-6 hydroxyalkyl.

[0098] In some aspects,- is selected fromRing B is selected fromRing C is a C2-8 N-heterocycle, C4-12 N-heterobicycle, or C3-8 cycloalkyl, wherein Ring C is optionally substituted with one or more groups independently selected from amine, C2-8 N- heterocycle, C3-C8 cycloalkyl, or C1-6 aminoalkyl;- is selected fromis selected fromeach instance of n is independently an integer from 1 to 10; and each instance of m is independently an integer from 1 to 10..

[0099] In one aspect, -1is selected from

[0100] In another aspect, Ring B is selected fromor . In a further. In another aspect, each instance of n is independently an integer from 1 to 5. In a further aspect, each instance of m is independently an integer from 1 to 5.

[0101] In some aspects, Ring C is substituted with one or two groups independently selected from amine, C2-8 N-heterocycle, C3-C8 cycloalkyl, or C1-6 aminoalkyl. In some aspects, Ring C is substituted with one group selected from amine, C2-8 N-heterocycle, C3-C8 cycloalkyl, or C1-6 aminoalkyljn some aspects, Ring C is selected fromparticular aspect, Ring C is

[0102] In some aspects, X4is selected from, or. In a particular aspect, X4is

[0103] In certain aspects, Z21and Z22are independently selected from N, CH, CF, CC1, CBr, CI, CCH3, CCF3, COH, COCH3, or CCN, wherein at most one of Z21and Z22is N. In further aspects, Z21and Z22are each independently selected from N or CH, wherein at most one of Z21and Z22is N. In a particular aspect, Z21and Z22are each CH.

[0104] In some aspects, Z23, Z24, and Z25are each independently selected from N, CH, CF, CC1, CBr, CI, CCH3, CCF3, COH, COCH3, or CCN, wherein at most one of Z23, Z24, and Z25is N. In other aspects, Z23, Z24, and Z25are each independently selected from CH, CF, CC1, CBr, CI, CCH3, CCF3, COH, COCH3, or CCN. In a specific aspect, Z23is CH. In a further aspect, Z24is COCH3. In an additional aspect, Z25is CH.

[0105] In one aspect, each instance of R28, R29, and R30is independently selected from hydrogen, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, halogen, cyano, NH2, or hydroxyl. In some aspects, R28is H.In further aspects, R29is OCH3. In additional aspects, R30is H. In many aspects,

[0106] In certain aspects, R31and R32are each independently selected from hydrogen, methyl, OCH3, CF3, halogen, or hydroxyl. In further aspects, R31and R32are each hydrogen. In additional aspects, R33is hydrogen.

[0107] In one aspect, Z26is N. In another aspect, Z27is CR27. In a further aspect, R26and R27are each independently selected from hydrogen, C1-3 alkyl, C1-3 haloalkyl, halogen, or cyano. In a particular aspect, Z26is N and Z27is CCF3.

[0108] In some aspects, R34and R35are each independently selected from hydrogen, NH2, C1-3 alkyl, and C1-3 aminocarbonyl. In particular aspects, Ring A is selected from

[0109] In a specific aspect, the compound is selected from

[0110] TABLE 1 lists examples of compounds of the present disclosure (e.g., compounds of Formula I or Formula II).TABLE 1

[0111] In another embodiment, the present disclosure provides a compound selected from

[0112] In another embodiment, the present disclosure provides a compound selected from:o 10;n) ; wherein n is an integer from 1 to 10;0;wherein n is an integer from 1 to 10.

[0113] Further disclosed herein are intermediates useful for synthesizing dual MALT1-BTK inhibitors of the present disclosure. Exemplary intermediates for these syntheses are listed in TABLE 2.TABLE 2

[0114] Further aspects of the present invention provide a pharmaceutical composition with a compound disclosed herein (e.g., a compound of Formula I or Formula II). By “pharmaceutical composition” it is meant that the compounds described herein are formulated with a “pharmaceutically acceptable” carrier, diluent or excipient that is compatible with the other ingredients of the composition and not deleterious to the recipient thereof, nor to the activity of the compound or additional active ingredients.

[0115] The pharmaceutical composition may also contain other therapeutic agents, and may be formulated, for example, by employing conventional vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example,excipients, preservatives, etc.) according to techniques known in the art of pharmaceutical formulation.

[0116] The pharmaceutical compositions can also include one or more pharmaceutically acceptable salts. The term “pharmaceutically acceptable salts” refers to physiologically and pharmaceutically acceptable salts of the compounds of the invention, e.g., salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects thereto.

[0117] In particular aspects, a compound disclosed herein is formulated as a pharmaceutically acceptable salt. The term “pharmaceutically acceptable salt” refers to a form of a compound in which the compound is charged and associated with a counterion of an opposite charge. A pharmaceutically acceptable salt can be a base addition salt that is formed by contacting a compound with a suitable amount of base to abstract a proton from the compound. Salts derived from bases include, sodium, potassium, lithium, ammonium, calcium, magnesium, and amine salts. A pharmaceutically acceptable salt can also be an acid addition salt that is formed by contacting a compound with a suitable amount of acid to protonate the compound. Salts derived from acids include halogen, nitrate, nitrite, glutamate, and aspartate salts.

[0118] In a further aspect, the present invention provides a pharmaceutical compound with a compound disclosed herein and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers, excipients or stabilizers are well known in the art, and include those disclosed in Remington’s Pharmaceutical Sciences, 16thedition, Osol, A. Ed. (1980). Pharmaceutically acceptable carriers, excipients, or stabilizers are typically nontoxic to recipients at the dosages and concentrations employed, and may include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (for example, Zn-protein complexes); and / or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). Examples of carriers include, but are not limited to, liposomes, nanoparticles, microparticles, polysaccharides, hydrogels (e.g.,alginates), ointments, micelles, microspheres, creams, emulsions, and gels. Examples of excipients include, but are not limited to, anti-adherents such as magnesium stearate, binders such as saccharides and their derivatives (sucrose, lactose, starches, cellulose, sugar alcohols and the like) proteins like gelatin and synthetic polymers, lubricants such as talc and silica, and preservatives such as antioxidants, vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium, cysteine, methionine, citric acid, sodium sulfate and parabens. Examples of diluents include, but are not limited to, water, alcohol, saline solution, glycol, mineral oil, and dimethyl sulfoxide (DMSO). In particular aspects, the pharmaceutical composition includes a pharmaceutically acceptable excipient. As non-limiting examples, the pharmaceutically acceptable excipient can be selected from a buffer, an antioxidant, a preservative, a peptide, a protein, a hydrophilic polymer, an amino acid, a sugar, a polysaccharide, a chelating agent, a salt-forming counter-ion, a non-ionic surfactant, an anti-adherent, a binder, a synthetic polymer, a lubricant, a vitamin, selenium, or a paraben.

[0119] In further aspects, the pharmaceutical composition includes a pharmaceutically acceptable carrier. In some aspects, the pharmaceutically acceptable carrier includes a liposome, a nanoparticle, a microparticle, a polysaccharide, a protein, a hydrogel, an ointment, a micelle, a microsphere, a cream, an emulsion, or a gel. In particular aspects, the compound is coupled to the pharmaceutically acceptable carrier.

[0120] Further aspects of the present disclosure provide a method of treating a disease or disorder in a subject that includes administering a compound or a pharmaceutical composition of the present disclosure to the subject, thereby treating the disease or disorder in the subject.

[0121] The term “subject” as used herein refers to any individual or patient to which the disclosed methods are performed or from whom a biological material is obtained. Generally, the subject is human, although as will be appreciated by those in the art, the subject may be a nonhuman animal. Thus, other animals, including vertebrates such as rodents (including mice, rats, hamsters, and guinea pigs), cats, dogs, rabbits, farm animals including cows, horses, goats, sheep, pigs, chickens, etc., and primates (including monkeys, chimpanzees, orangutans and gorillas) are included within the definition of subject.

[0122] The term "treatment" is used interchangeably herein with the term "therapeutic activity," “therapy,” or “treatment” and refers to 1) therapeutic treatments or measures that cure, slow down, lessen symptoms of, and / or halt progression of a diagnosed pathologic conditions or disorder, and / or 2) prophylactic / preventative measures. Those in need of treatment may include individuals already having a particular medical disorder as well as those who may ultimately acquire the disorder (i.e., those needing preventive measures).

[0123] The terms “administration of’ and or “administering” should be understood to mean providing a pharmaceutical composition in a therapeutically effective amount to the subject in need of treatment. Administration routes can be enteral, topical, or parenteral. As such, administration routes include but are not limited to intracutaneous, subcutaneous, intravenous, intraperitoneal, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, transdermal, transtracheal, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal and intrasternal, oral, sublingual buccal, rectal, vaginal, nasal ocular administrations, as well infusion, inhalation, and nebulization. The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration.

[0124] Routes of administration may include but are not limited to inhalation, otic, buccal, conjunctival, dental, endocervical, endosinusial, endotracheal, enteral, epidural, extra-amniotic, extracorporeal, hemodialysis, infiltration, interstitial, intraabdominal, intraamniotic, intraarterial, intraarticular, intrabiliary, intrabronchial, intrabursal, intracardiac, intracartilaginous, intracaudal, intracavernous, intracavitary, intracerebroventricular, intracistemal, intracorneal, intracoronal, intracoronary, intracorpous cavernaosum, intradermal, intradiscal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intrahippocampal, intraileal, intralesional, intraluminal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraocular, intraovarian, intrapericardial, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratendinous, intratesticular, intrathoracic, intratubular, intratumor, intratympanic, intrauterine, intravascular, intravenous, intravenous bolus, intravenous drip, intravesical, intravitreal, iontophoresis, irrigation, laryngeal, nasal, nasogastric, ophthalmic, oral, oropharyngeal, parenteral, percutaneous, periarticular, peridural, perineural, periodontal, rectal, retrobulbar, subarachnoid, subconjunctival, subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transplacental, transtracheal, transtympanic, ureteral, urethral, vaginal, infraorbital, intraparenchymal, intrathecal, intraventricular, stereotactic administration, or any combination thereof.

[0125] The pharmaceutical compositions can be administered in a variety of unit dosage forms depending upon the method of administration. Suitable unit dosage forms, include, but are not limited to powders, tablets, pills, capsules, lozenges, suppositories, patches, nasal sprays, injectables, implantable sustained-release formulations, lipid complexes.

[0126] In some aspects, the disease is cancer. As used herein, the term “cancer” refers to a group of diseases characterized by abnormal and uncontrolled cell proliferation starting at one site (primary site) with the potential to invade and to spread to other sites (secondary sites, metastases).Virtually all organs can be affected by cancer, reflected by the fact that more than 100 types of cancer affect humans. Cancers can result from many causes including genetic predisposition, viral infection, exposure to ionizing radiation, exposure to environmental pollutants, tobacco and or alcohol use, obesity, poor diet, lack of physical activity or any combination thereof. Early detection of cancer and cancer stage, as enabled by the BNC methods and systems of the present disclosure, can greatly improve the prospects for successful cancer treatment and survival. As non-limiting examples, cancer can be selected from activated B-cell type diffuse large B-cell lymphoma (ABC-DLBCL), acute myeloid leukemia (AML), bile duct cancer, bladder cancer, brain cancer, breast cancer, carcinoma, cervical cancer, chronic lymphocytic leukemia (CLL), colorectal cancer, endometrial cancer, epitheloid carcinoma of the bone, esophageal cancer, follicular lymphoma (FL), gallbladder cancer, gastric cancer, glioblastoma, head and neck cancer, hepatocellular cancer, large B-cell lymphoma (LBCL), large cell lung carcinoma, leukemia, lung cancer, lymphoma, mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), medulloblastoma, melanoma, mucosa assisted lymphoid tissue (MALT), myelodysplastic syndrome (MDS), non-Hodgkin’s lymphoma (NHL), ovarian cancer, non-small cell lung cancer, pancreatic cancer, prostate cancer, renal cell cancer, small lymphocytic lymphoma (SLL), thyroid cancer, or Waldenstrom macroglobulinemia (WM).

[0127] In another aspect, the disorder is an inflammatory disorder.

[0128] As used herein the “inflammatory disorder” term refers to a condition in which the body's immune system overreacts to an external or internal trigger, leading to inflammation. Examples of inflammatory disorders include, but are not limited to, Acute disseminated encephalomyelitis (ADEM), Addison's disease, Agammaglobulinemia, Alopecia areata, Amyotrophic lateral sclerosis (aka Lou Gehrig's disease), Ankylosing Spondylitis, Antiphospholipid syndrome, Antisynthetase syndrome, Arthritis, Asthma; Atherosclerosis Atopic allergy, Atopic dermatitis, Autoimmune aplastic anemia, Autoimmune cardiomyopathy, Autoimmune enteropathy, Autoimmune hemolytic anemia, Autoimmune hepatitis, Autoimmune inner ear disease, Autoimmune lymphoproliferative syndrome, Autoimmune pancreatitis, Autoimmune peripheral neuropathy, Autoimmune polyendocrine syndrome, Autoimmune progesterone dermatitis, Autoimmune thrombocytopenic purpura, Autoimmune urticaria, Autoimmune uveitis, Balo disease / Balo concentric sclerosis, Behget's disease, Berger's disease, Bickerstaffs encephalitis, Blau syndrome, Bullous pemphigoid, Cancer, Castleman's disease, Celiac disease, Chagas disease, Chronic inflammatory demyelinating polyneuropathy, Chronic inflammatory demyelinating polyneuropathy, Chronic obstructive pulmonary disease, Chronic recurrent multifocal osteomyelitis, Churg-Strauss syndrome, Cicatricial pemphigoid, Cogan syndrome,Cold agglutinin disease, Complement component 2 deficiency, Contact dermatitis, Cranial arteritis, CREST syndrome, Crohn's disease, Cushing's Syndrome, Cutaneous leukocytoclastic angiitis, Dego's disease, Dercum's disease, Dermatitis herpetiformis, Dermatomyositis, Diabetes mellitus type 1, Diffuse cutaneous systemic sclerosis, Discoid lupus erythematosus, Diverticulitis, Dressier's syndrome, Drug-induced lupus, Eczema, Endometriosis, Eosinophilic fasciitis, Eosinophilic gastroenteritis, Eosinophilic pneumonia, Epidermolysis bullosa acquisita, Erythema nodosum, Erythroblastosis fetalis, Essential mixed cryoglobulinemia, Evan's syndrome, Fibrodysplasia ossificans progressiva, Fibrosing alveolitis (or Idiopathic pulmonary fibrosis), Gastritis, Gastrointestinal pemphigoid, Glomerulonephritis, Goodpasture's syndrome, graft versus host disease, Gout , Graves' disease, Guillain-Barre syndrome, Hashimoto's encephalopathy, Hashimoto's thyroiditis, Henoch-Schonlein purpura, Hepatitis, Herpes gestationis aka Gestational Pemphigoid, Hidradenitis suppurativa, Hughes-Stovin syndrome, Hypogammaglobulinemi, Idiopathic inflammatory demyelinating diseases, Idiopathic pulmonary fibrosis, Idiopathic thrombocytopenic purpura, IgA nephropathy, Inclusion body myositis, Interstitial cystitis, Irritable bowel syndrome, Juvenile idiopathic arthritis aka Juvenile rheumatoid arthritis, Kawasaki's disease, Lambert-Eaton myasthenic syndrome, Laryngitis, Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Linear IgA disease, Lupoid hepatitis aka Autoimmune hepatitis, Lupus erythematosus, Majeed syndrome, Microscopic colitis, Microscopic polyangiitis, Miller-Fisher syndrome, Mixed connective tissue disease, Morphea, Mucha-Habermann disease aka Pityriasis lichenoides et varioliformis acuta, Multiple sclerosis, Myasthenia gravis, Myositis, Myopathies, Meniere's disease, Narcolepsy, Nephritis, Neuromyelitis optica, Neuromyotonia, Occular cicatricial pemphigoid, Opsoclonus myoclonus syndrome, Ord's thyroiditis, Palindromic rheumatism, PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcus), Paraneoplastic cerebellar degeneration, Paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Pars planitis, Parsonage-Turner syndrome, Pelvic inflammatory disease, Pemphigus vulgaris, Perivenous encephalomyelitis, Pernicious anemia, Pharyngitis, Pleurisy, POEMS syndrome, Polyarteritis nodosa, Polymyalgia rheumatica, Polymyositis, Primary biliary cirrhosis, Primary sclerosing cholangitis, Progressive inflammatory neuropathy, Prostatitis, Psoriasis, Psoriatic arthritis, Pure red cell aplasia, Pyoderma gangrenosum, Rasmussen's encephalitis, Raynaud phenomenon, Reiter's syndrome, Relapsing polychondritis, Restless leg syndrome, Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schizophrenia, Schmidt syndrome, Schnitzler syndrome, Scleritis, Scleroderma, Seborrheic dermatitis, Serum Sickness, Sinusitis, Sjogren's syndrome, Splenitis, Spondyloarthropathy, Stiff person syndrome, Still's disease, Subacute bacterial endocarditis(SBE), Susac's syndrome, Sweet's syndrome, Sydenham chorea, Sympathetic ophthalmia, Systemic lupus erythematosus, Takayasu's arteritis, Temporal arteritis, Thrombocytopenia, thyroiditis, Tolosa-Hunt syndrome, Transverse myelitis, Ulcerative colitis, Undifferentiated spondyloarthropathy, Urticarial vasculitis, Vasculitis, Vitiligo, Wegener's granulomatosis, Familial Mediterranean fever (FMF), Hyperimmunoglobulinemia D with recurrent fever (HIDS), TNF receptor associated periodic syndrome (TRAPS), Muckle-Wells syndrome (CAPS, urticaria deafness amyloidosis), Spinal cord injury Familial cold urticarial, a condition in which the body's immune system overreacts to an external or internal trigger, Juvenile arthritis Neonatal onset multisystem inflammatory disease, Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA syndrome), Stroke, Chronic renal disease Blau syndrome, Pyogenic sterile arthritis, fibromyalgia, pyoderma gangrenosum, allergies, acne (PAPA), Deficiency of the interleukin- 1- receptor antagonist (DIRA), Allergic reactions, Crohn’s disease and Gout.

[0129] In a particular aspect, the inflammatory disorder is selected from rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, ankylosing spondylitis, graft-versus-host disease, stroke, spinal cord injury, chronic renal disease; allergies, type 1 diabetes, inflammatory bowel disorder, Crohn's disease, ulcerative colitis; myasthenia gravis, fibromyalgia; psoriasis, vitiligo, dermatitis, or systemic lupus.

[0130] In a further aspect, the disease is an autoimmune disease.

[0131] “Autoimmune disorder” or “autoimmune disease” refer to any medical conditions characterized by a dysfunction of the immune system. Autoimmune diseases are characterized by the abnormal activation and proliferation of self-reactive T- and B- cells, capable of being reactive against substances and tissues normally present in the body (autoimmunity). Self-antigen reactivity can induce damage to or destruction of tissues, alteration of organ growth, and / or alteration of organ function. These disorders can be characterized in several different ways: by the component(s) of the immune system affected; by whether the immune system is overactive or underactive and by whether the condition is congenital or acquired. A major understanding of the underlying pathophysiology of autoimmune diseases has been the application of genome wide association scans that have identified a striking degree of genetic sharing among the autoimmune diseases.

[0132] Examples of autoimmune diseases include, but are not limited to, Acute disseminated encephalomyelitis (ADEM), Addison's disease, Agammaglobulinemia, Alopecia areata, Amyotrophic lateral sclerosis (aka Lou Gehrig's disease), Ankylosing Spondylitis, Antiphospholipid syndrome, Antisynthetase syndrome, Atopic allergy, Atopic dermatitis, Autoimmune aplastic anemia, Autoimmune cardiomyopathy, Autoimmune enteropathy,Autoimmune hemolytic anemia, Autoimmune hepatitis, Autoimmune inner ear disease, Autoimmune lymphoproliferative syndrome, Autoimmune pancreatitis, Autoimmune peripheral neuropathy, Autoimmune polyendocrine syndrome, Autoimmune progesterone dermatitis, Autoimmune thrombocytopenic purpura, Autoimmune urticaria, Autoimmune uveitis, Balo disease / Balo concentric sclerosis, Behget's disease, Berger's disease, Bickerstaffs encephalitis, Blau syndrome, Bullous pemphigoid, Cancer, Castleman's disease, Celiac disease, Chagas disease, Chronic inflammatory demyelinating polyneuropathy, Chronic inflammatory demyelinating polyneuropathy, Chronic obstructive pulmonary disease, Chronic recurrent multifocal osteomyelitis, Churg-Strauss syndrome, Cicatricial pemphigoid, Cogan syndrome, Cold agglutinin disease, Complement component 2 deficiency, Contact dermatitis, Cranial arteritis, CREST syndrome, Crohn's disease, Cushing's Syndrome, Cutaneous leukocytoclastic angiitis, Dego's disease, Dercum's disease, Dermatitis herpetiformis, Dermatomyositis, Diabetes mellitus type 1, Diffuse cutaneous systemic sclerosis, Discoid lupus erythematosus, Dressier's syndrome, Drug-induced lupus, Eczema, Endometriosis, Eosinophilic fasciitis, Eosinophilic gastroenteritis, Eosinophilic pneumonia, Epidermolysis bullosa acquisita, Erythema nodosum, Erythroblastosis fetalis, Essential mixed cryoglobulinemia, Evan's syndrome, Fibrodysplasia ossificans progressiva, Fibrosing alveolitis (or Idiopathic pulmonary fibrosis), Gastritis, Gastrointestinal pemphigoid, Glomerulonephritis, Goodpasture's syndrome, graft versus host disease, Graves' disease, Guillain-Barre syndrome, Hashimoto's encephalopathy, Hashimoto's thyroiditis, Henoch-Schonlein purpura, Herpes gestationis aka Gestational Pemphigoid, Hidradenitis suppurativa, Hughes-Stovin syndrome, Hypogammaglobulinemi, Idiopathic inflammatory demyelinating diseases, Idiopathic pulmonary fibrosis, Idiopathic thrombocytopenic purpura, IgA nephropathy, Inclusion body myositis, Interstitial cystitis, Juvenile idiopathic arthritis aka Juvenile rheumatoid arthritis, Kawasaki's disease, Lambert-Eaton myasthenic syndrome, Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Linear IgA disease, Lupoid hepatitis aka Autoimmune hepatitis, Lupus erythematosus, Majeed syndrome, Microscopic colitis, Microscopic polyangiitis, Miller-Fisher syndrome, Mixed connective tissue disease, Morphea, Mucha-Habermann disease aka Pityriasis lichenoides et varioliformis acuta, Multiple sclerosis, Myasthenia gravis, Myositis, Meniere's disease, Narcolepsy, Neuromyelitis optica, Neuromyotonia, Occular cicatricial pemphigoid, Opsoclonus myoclonus syndrome, Sjogren's syndrome, Ord's thyroiditis, Palindromic rheumatism, PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcus), Paraneoplastic cerebellar degeneration, Paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Pars planitis, Parsonage-Turner syndrome, Pemphigus vulgaris, Perivenous encephalomyelitis, Perniciousanemia, POEMS syndrome, Polyarteritis nodosa, Polymyalgia rheumatica, Polymyositis, Primary biliary cirrhosis, Primary sclerosing cholangitis, Progressive inflammatory neuropathy, Psoriasis, Psoriatic arthritis, Progressive systemic sclerosis, Pure red cell aplasia, Pyoderma gangrenosum, Rasmussen's encephalitis, Raynaud phenomenon, Reiter's syndrome, Relapsing polychondritis, Restless leg syndrome, Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schizophrenia, Schmidt syndrome, Schnitzler syndrome, Scleritis, Scleroderma, Serum Sickness, Sjogren's syndrome, Spondyloarthropathy, Stiff person syndrome, Still's disease, Subacute bacterial endocarditis (SBE), Susac's syndrome, Sweet's syndrome, Sydenham chorea, Sympathetic ophthalmia, Systemic lupus erythematosus, Takayasu's arteritis, Temporal arteritis, Thrombocytopenia, Tolosa-Hunt syndrome, Transverse myelitis, Ulcerative colitis, Undifferentiated spondyloarthropathy, Urticarial vasculitis, Vasculitis, Vitiligo, Wegener's granulomatosis.

[0133] In particular aspects, the autoimmune disease is selected from type I diabetes, Crohn's disease, ulcerative colitis, myasthenia gravis, vitiligo, Graves' disease, Hashimoto's disease, Addison's disease, autoimmune gastritis, autoimmune hepatitis, rheumatoid disease, systemic lupus erythematosus, progressive systemic sclerosis, polymyositis, dermatomyositis, pernicious anemia, primary biliary cirrhosis, autoimmune thrombocytopenia, Sjogren's syndrome, multiple sclerosis, or psoriasis.

[0134] The following examples are provided to further illustrate the embodiments of the present invention but are not intended to limit the scope of the invention. While they are typical of those that might be used, other procedures, methodologies, or techniques known to those skilled in the art may alternatively be used.EXAMPLESEXAMPLE 1SYNTHESIS OF INTERMEDIATE MZ0142SCHEME 1

[0135] Reagents and conditions: (a) POCI3, pyridine, DCM, 0 °C-r.t., overnight, 89%; (b) pyridine, 130 °C, overnight, 93%; (c) TFA, DCM, 0 °C-rt, overnight, 93%.EXAMPLE 2SYNTHETIC ROUTES 1 AND 2SCHEME 2

[0136] Reagents and conditions: (a) CS2CO3, DMF, 80 °C, 1-4 h, 66%-79%; (b) TFA, DCM, 0 °C-r.t., overnight, 95%-quant. yield; (c) HATU, HOBt, DIPEA, DMF, rt, overnight, 10-60%.EXAMPLE 3SYNTHETIC ROUTES 3 AND 4SCHEME 3R&a&e 3

[0137] Reagents and conditions: (a) CS2CO3, DMF, 80 °C, 1-4 h; (b) TFA, DCM, 0 °C-r.t., overnight; (c) HATU, HOBt, DIPEA, DMF, rt, overnight.EXAMPLE 4SYNTHETIC ROUTE 5SCHEME 4

[0138] Reagents and conditions: (a) Cs2CO3, DMF, 80 °C; (b)Zn, NH4C1, MeOH / H2O; (c) TFA, DCM, 0 °C-rt, overnight; (d) EDCI, pyridine, DCM, rt, overnight; (e) HATU, HOBt, DIPEA, DMF, rt, overnight.EXAMPLE 5SYNTHESIS OF MZ0142A-(2-Chloro-6-(trifluoromethyl)pyridin-4-yl)-l-(l-oxo-l,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)- 17 / -pyrazole-4-carboxamide (MZ0124)

[0139] To a solution of 1-(1 -oxo- l,2-dihydroisoquinolin-5-yl)-5 -(trifluoromethyl)- l / / -pyrazolc-4- carboxylic acid (compound 1) (1.62 g, 5 mmol, 1 equiv.) and 2-chloro-6-(trifluoromethyl)pyridin-4- amine (1.08 g, 5.5 mmol, 1.1 equiv.) in DCM (35 mL) and pyridine (15 mL) was added POCI3 (0.93 mL, 6 mmol, 2 equiv.) at 0 °C, then stirred at rt overnight. The reaction mixture was concentratedand diluted with DCM. The organic layer was washed with a saturated NaHCO, solution. The aqueous solution was extracted with DCM, and the organic layer was separated, washed by brine, dried with Na2SO4, and concentrated. The residue was purified by column chromatography (DCM / MeOH = 30 / 1 to 10 / 1) to afford MZ0124 (2.2 g, 89% yield) as a yellow solid. HPLC purity 99.1% (tR= 17.93 min). 'HNMR QOO MHz, CDCh / MeOD) 5 8.60 (d, J= 8.1 Hz, 1H), 8.25 (s, 1H), 8.11 (s, 1H), 8.03 (d,J= 2.6 Hz, 1H), 7.75 (d, .7= 7.6 Hz, 1H), 7.65 (t, .7= 7.9 Hz, 1H), 7.14 (d, J= 7.4 Hz, 1H), 5.90 (d, J= 7.3 Hz, 1H).13C NMR (75 MHz, CDCh / MeOD) 5 162.9, 160.8, 153.3, 149.5, 149.1 (q, J= 35.6 Hz), 148.4, 140.4, 136.1, 134.3, 134.3 (q, J= 40.0 Hz), 131.9, 130.5, 127.7, 126.6, 121.1 (q, .7= 273.9 Hz), 119.8, 119.3 (q, J= 271.2 Hz), 116.6, 110.5 (q, .7= 3.2 Hz), 100.4. HRMS (ESI) calcd for C20H11CIF6N5O2 502.0500 [M + H]+; found, 502.0599.EXAMPLE 6 SYNTHESIS OF MZ0137-1 tert- Butyl 4-(4-(l-(l -oxo- l,2-dihydroisoquinolin-5-yl)-5 -(trifluoromethyl)- 177-pyrazole-4- carboxamido)-6-(trifluoromethyl)pyridin-2-yl)piperazine-l -carboxylate (MZ0137-1)

[0140] To a solution of MZ0124 (501.8 mg, 1 mmol, 1 equiv.) in pyridine (10 mL) was added tert-butyl piperazine- 1 -carboxylate (1.8625g, 10 mmol, 10 equiv.) in a pressure tube. The reaction mixture was heated at 130 °C and stirred overnight. Then the reaction mixture was concentrated and purified by column chromatography (DCM / MeOH = 10 / 1) to afford MZ0137-1 (604.6 mg, 93% yield) as a yellow solid. HPLC purity 98.3% (tR = 18.74 min). 'H NMR (300 MHz, CDCh / MeOD) 5 8.60 (dt, J= 7.9, 1.1 Hz, 1H), 8.23 (d, J= 0.7 Hz, 1H), 7.75 (dd, J= 7.6, 1.4 Hz, 1H), 7.64 (t, .7= 7.9 Hz, 1H), 7.57 (d, J= 1.5 Hz, 1H), 7.22 (d,J= 1.4 Hz, 1H), 7.15 (d,J= 7.4 Hz, 1H), 5.92 (dd, J= 7.4, 0.8 Hz, 1H), 3.65 (dd, J= 6.5, 3.4 Hz, 4H), 3.57 (dd, J= 7.1, 3.9 Hz, 4H), 1.50 (s, 9H).13C NMR (75 MHZ, CDCh / MeOD) 5 162.9, 160.7, 160.4, 155.5, 148.0, 147.5 (q, J= 34.0 Hz), 140.2, 136.1, 134.3, 133.8 (q, J= 39.9 Hz), 131.9, 130.4, 130.4, 127.6, 126.5, 121.8 (q, J= 274.0 Hz), 120.5 (q, J= 1.5 Hz), 119.3 (q, J= 271.2 Hz), 101.8 (q, J= 3.3 Hz), 100.4, 99.1, 80.8, 45.1, 43.6, 28.5.EXAMPLE 7SYNTHESIS OF MZ01421 -( 1 -Oxo- 1 ,2-dihydroisoqui nol i n-5-y 1 )- / V-(2 -(p i perazi n- 1 -yl)-6-(trifluoromethyl)pyridin-4-yl)-5- (trifluoromethyl)- 177-pyrazole-4-carboxamide (MZ0142)

[0141] To a solution of MZ0137-1 (600 mg, 0.92 mmol) in DCM (10 mL) was added TFA (1 mL) at 0 °C, then stirred at rt overnight. Then the reaction mixture was concentrated and diluted with MeOH (20 mL). The NHvMcOH (20 mL) was added at 0 °C slowly and stirred for 1 h. The reaction mixture was concentrated and purified by column chromatography (DCM / NHvMcOH = 10 / 1) to afford MZ0142 (471.4 mg, 93% yield) as a yellow solid. HPLC purity 99.6% (fe = 14.88 min). 'H NMR (300 MHz, CDCh / MeOD) 5 8.59 (d, J= 8.0 Hz, 1H), 8.22 (s, 1H), 7.75 (d, J= 7.5 Hz, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.55 (s, 1H), 7.21 (s, 1H), 7.14 (d, J= 7.4 Hz, 1H), 5.92 (d, J = 7.4 Hz, 1H), 3.63 (t, .7= 5.1 Hz, 4H), 2.99 (t, .7= 5.1 Hz, 4H).13C NMR (75 MHz, CDCh / MeOD) 5 162.9, 160.7, 160.6, 147.9, 147.4 (q, J= 34.0 Hz), 140.3, 136.1, 134.3, 133.8 (q, J= 39.9 Hz),131.9, 130.4, 127.5, 126.5, 121.8 (q, .7= 274.0 Hz), 120.5 (q, J= 1.3 Hz), 119.1 (q, J= 271.3 Hz),113.9, 101.7 (q, J = 3.2 Hz), 100.4, 99.0, 45.7, 45.3. HRMS (ESI) calcd for C24H20F6N7O2 552.1577 [M + H]+; found, 552.1579.EXAMPLE 8GENERAL SYNTHESIS PROCEDURESGeneral Procedure A

[0142] To a solution of nitro aromatic compounds (1 equiv.) in MeOH (25 mL) were added Zn powder (5 equiv.) and NH4CI saturated solution (5 mL). After addition, the reaction mixture was stirred at rt for 2 h. Then the reaction mixture was filtered and concentrated. The aqueous solution was extracted with DCM (25 x 3 mL), and the organic layer was separated, washed by brine (50 mL), dried with Na2SO4, and concentrated. The residue was purified by column chromatography to afford the title compound.General Procedure B

[0143] To a solution of compound 2 (766.8 mg, 2 mmol, 1 equiv.) and cesium carbonate (977.5 mg, 3 mmol, 1.5 equiv.) in DMF (20 mL) were added bromo tert-butyl ester or carbamate (2.4 mmol, 1.2 equiv.). After addition, the reaction mixture was stirred at 80 °C for 1-4 h. Then the reaction mixture was filtered, concentrated, and purified by column chromatography to afford the title compound.General Procedure C

[0144] To a solution of tert-butyl esters or carbamates in DCM was added TFA at 0 °C, then stirred at rt overnight. Then the reaction mixture was concentrated to afford the title compounds without further purification.General Procedure D

[0145] To a solution of amine (0.05 mmol, 1 equiv.) and acid (0.05 mmol, 1 equiv.) in DMF (1 mL) were added HATU (38.0 mg, 0.1 mmol, 2 equiv.), HOBt (13.5 mg, 0.1 mmol, 2 equiv.) and DIPEA (35pL, 0.2 mmol, 4 equiv.). The reaction mixture was stirred at rt overnight. Then the reaction mixture was concentrated and purified by column chromatography to afford the title compounds.General Procedure E

[0146] To a solution of amine (0.1 mmol, 1 equiv.) and acid (0.1 mmol, 1 equiv.) in pyridine / DCM (3:7) (1-2 mL) was added EDCI (38.3 mg, 0.2 mmol, 2 equiv.). The reaction mixture was stirred at rt overnight. Then the reaction mixture was concentrated and purified by column chromatography to afford the title compound.General Procedure F

[0147] To a solution of 3 -amino-5 -methoxyphenol (695.8 mg, 5 mmol, 1 equiv.) and cesium carbonate (3.26 g, 10 mmol, 2 equiv.) in MeCN (50 mL) were added te / 7-butyl bromo ester (6 mmol, 1.2 equiv.). After addition, the reaction mixture was stirred at 80 °C for 24-72h. Then the reaction mixture was filtered, concentrated, and purified by column chromatography to afford the title compound.EXAMPLE 9SYNTHESIS OF MZ0229-1 te / 7- Butyl 2-(5-amino-4-carbamoyl-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-177- pyrazol-l-yl)acetate (MZ0229-1)

[0148] General Procedure B. Purification via column chromatography (DCM / MeOH = 30 / 1 to 20 / 1) afforded MZ0229-1 (647.0 mg, 65% yield) as a yellow solid. 'H NMR (300 MHz, CDC13) 5 8.31 (t, J= 5.7 Hz, 1H), 7.93 (dd, J= 9.5, 3.3 Hz, 1H), 7.54 (d, J= 7.9 Hz, 2H), 7.42 (d, J= 7.9 Hz, 2H), 7.14 (ddd, J= 8.9, 7.2, 3.3 Hz, 1H), 6.94 (dd, J= 9.1, 4.1 Hz, 1H), 5.71 (s, 2H), 5.51 (s, 2H), 4.71 (d, J= 5.8 Hz, 2H), 4.69 (s, 2H), 3.91 (s, 3H), 1.48 (s, 9H).13C NMR (75 MHz, CDC13) 5 167.0, 166.7, 164.3 (d, J= 1.9 Hz), 157.2 (d, J= 240.0 Hz), 153.7 (d, J= 2.2 Hz), 152.0, 149.4, 139.6, 132.3, 129.5, 127.9, 122.7 (d, J = 6.7 Hz), 119.2 (d, J = 23.5 Hz), 118.6 (d, J = 25.1 Hz), 112.9 (d, J= 7.7 Hz), 96.2, 83.4, 56.6, 50.3, 43.5, 28.0.EXAMPLE 10SYNTHESIS OF MZ02312-(5-Amino-4-carbamoyl-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)- 1 / / -pyrazol- 1 - yl)acetic acid (MZ0231)

[0149] General Procedure C. 0.63 mmol scale, afforded MZ0231 (318.9 mg, 98% yield) as a white solid.EXAMPLE 11SYNTHESIS OF MZ02375-Amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-l-(2-oxo-2-(4-(4-(l-(l-oxo-l,2- dihydroisoquinolin-5-yl)-5 -(trifluoromethyl)- l / / -pyrazolc-4-carboxamiclo)-6- (trifluoromethyl)pyridin-2-yl)piperazin- 1 -y I )cthy I )- 1 / / -pyrazol c-4-carboxam ide (MZ0237)

[0150] General Procedure D. Purification via column chromatography (DCM / NHa’MeOH = 10 / 1) afforded MZ0237 (22.5 mg, 46% yield) as a white solid. HPLC purity 98.3% (fe = 16.93 min). 'H NMR (300 MHz, CDCh / MeOD) 5 8.59 (dt, J= 8.1, 1.1 Hz, 1H), 8.55 (t, J= 5.6 Hz, 1H), 8.22 (s, 1H), 7.83 (dd, J= 9.3, 3.3 Hz, 1H), 7.75 (dd, J= 7.6, 1.4 Hz, 1H), 7.64 (t, J= 7.9 Hz, 1H), 7.60 (d, J= 1.6 Hz, 1H), 7.55 (d, J= 8.2 Hz, 2H), 7.47 (d, J= 8.5 Hz, 2H), 7.24 (d, J= 1.4 Hz, 1H), 7.23 - 7.15 (m, 1H), 7.13 (d, J= 7.4 Hz, 1H), 7.02 (dd, J= 9.1, 4.1 Hz, 1H), 5.91 (d, J= 7.4 Hz, 1H), 4.95 (s, 2H), 4.72 (d, J= 5.8 Hz, 2H), 3.96 (s, 3H), 3.84 - 3.72 (m, 6H), 3.71 - 3.60 (m, 2H).13C NMR (201 MHz, CDCh / MeOD) 5 167.4, 165.8, 165.3, 165.2, 162.8, 160.7, 160.0, 157.4 (d, J= 240.1 Hz), 154.1, 152.8, 150.0, 148.1, 147.4 (q, J= 34.0 Hz), 140.2, 139.9, 139.9, 136.0, 134.2, 133.8 (q, J= 39.8 Hz), 132.1, 131.8, 130.4, 130.3, 129.7, 128.2, 127.6, 126.5, 122.6, 122.5, 122.5, 121.7 (q, J= 274.0 Hz), 120.4, 119.8 (d, J= 23.4 Hz), 119.3 (q, .7= 271.3 Hz), 118.4 (d, J= 25.0 Hz), 113.3 (d, .7 = 7.7 Hz), 102.1 (q, .7= 2.9 Hz), 100.3, 99.1, 95.7, 56.8, 45.3, 44.9, 44.9, 43.8, 43.6, 42.1.EXAMPLE 12SYNTHESIS OF MZ02395-Amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-l-(2-oxo-2-(4-(4-(l-(l-oxo-l,2- dihydroisoquinolin-5-yl)-5 -(trifluoromethyl)- l / / -pyrazolc-4-carboxamiclo)-6-(trifluoromethyl)pyridin-2-yl)- 1 ,4-diazepan- 1 -yl)ethyl)- 1 / / -pyrazolc-4-carboxam ide (MZ0239)

[0151] General Procedure D. Purification via column chromatography (DCM / NH3’MeOH = 10 / 1) afforded MZ0239 (22.5 mg, 46% yield) as a white solid. HPLC purity 99.9% (fe = 17.19 min). 'H NMR (300 MHz, CDCh / MeOD) 5 8.59 (dt, J= 8.1, 1.2 Hz, 1H), 8.55 (dd, J= 6.9, 2.1 Hz, 1H), 8.21 (d, J= 2.7 Hz, 1H), 7.83 (dd, J= 9.4, 3.3 Hz, 1H), 7.75 (dd, J= 7.6, 1.4 Hz, 1H), 7.64 (t, J= 7.9 Hz, 1H), 7.56 - 7.45 (m, 5H), 7.26 - 7.10 (m, 3H), 7.02 (dd, J= 9.1, 4.1 Hz, 1H), 5.91 (d, J= 7.4 Hz, 1H), 4.89 (s, 1H), 4.81 (s, 1H), 4.71 (d, J= 5.8 Hz, 2H), 3.96 (d, J= 1.1 Hz, 4H), 3.85 (dd, J= 7.6, 4.7 Hz, 4H), 3.73 (t, J= 6.5 Hz, 1H), 3.62 (t, J= 6.2 Hz, 1H), 3.58 - 3.51 (m, 1H), 2.12 - 1.97 (m, 2H).EXAMPLE 13 SYNTHESIS OF MZ0229-2 te / 7- Butyl 2-(3-amino-4-carbamoyl-5-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-177- pyrazol-l-yl)acetate (MZ0229-2)

[0152] General Procedure B. Purification via column chromatography (DCM / MeOH = 30 / 1 to 20 / 1) afforded MZ0229-2 (107.4 mg, 11% yield) as a white solid. 'H NMR (300 MHz, CDCfi) 6 8.43 (t, .7= 6.1 Hz, 1H), 7.93 (dd, J= 9.4, 3.3 Hz, 1H), 7.51 (d,J= 8.2 Hz, 2H), 7.40 (d,J= 8.2 Hz, 2H), 7.17 (ddd, J= 9.1, 7.2, 3.3 Hz, 1H), 6.98 (dd, J= 9.1, 4.1 Hz, 1H), 5.69 (s, 2H), 5.08 (s, 2H), 4.76 (d, J= 6.1 Hz, 2H), 4.33 (s, 2H), 3.97 (s, 3H), 1.40 (s, 9H).13C NMR (75 MHz, CDCI3) 5166.9, 166.5, 164.5 (d, J= 1.9 Hz), 157.2 (d, J= 240.2 Hz), 156.9, 153.7 (d, J= 2.1 Hz), 143.2, 141.6, 130.1, 128.3, 127.6, 122.5 (d, J = 6.8 Hz), 119.4 (d, J = 23.4 Hz), 118.7 (d, J = 25.1 Hz), 112.9 (d, J= 7.6 Hz), 100.4, 82.8, 56.7, 51.2, 43.2, 27.9.EXAMPLE 14SYNTHESIS OF MZ02322-(3-Amino-4-carbamoyl-5-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)- I / / -pyrazol- 1 - yl)acetic acid (MZ0232)

[0153] General Procedure C. 0.30 mmol scale, afforded MZ0232 (163.1 mg, 97% yield) as a white solid.EXAMPLE 15SYNTHESIS OF MZ02383-Amino-5-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-l-(2-oxo-2-(4-(4-(l-(l-oxo-l,2- dihydroisoquinolin-5-yl)-5 -(trifluoromethyl)- l / / -pyrazolc-4-carboxamido)-6-(trifluoromethyl)pyridin-2-yl)piperazin- 1 -y I )cthy I )- 1 / / -pyrazol c-4-carboxam ide (MZ0238)

[0154] General Procedure D. Purification via column chromatography (DCM / NHs’MeOH = 10 / 1) afforded MZ0238 (29.3 mg, 60% yield) as a white solid. HPLC purity 99.4% ( / R = 16.98 min).1HNMR (300 MHz, CDCh / MeOD) 5 8.68 (t, .7= 6.1 Hz, 1H), 8.59 (dt, J= 8.0 Hz, 1H), 8.22 (s, 1H), 7.79 (dd, J = 9.3, 3.3 Hz, 1H), 7.75 (dd,J= 7.7, 1.4 Hz, 1H), 7.64 (t, J= 7.9 Hz, 1H), 7.54 (d, .7= 8.0Hz, 2H), 7.46 (d, J= 8.1 Hz, 2H), 7.33 (d, J= 1.4 Hz, 1H), 7.25 - 7.10 (m, 2H), 7.01 (dd, J= 9.1, 4.1 Hz, 1H), 5.93 (d, J= 7.4 Hz, 1H), 4.73 (d, J= 6.0 Hz, 2H), 4.63 (s, 2H), 3.99 (s, 3H), 3.68 (s, 2H), 3.62 (q, J= 3.3 Hz, 4H), 3.51 (d, J = 4.6 Hz, 2H).13C NMR (201 MHz, CDCh / MeOD) 5 167.1, 165.8, 165.6, 165.5, 162.8, 160.7, 159.9, 157.3 (d, J= 240.1 Hz), 156.9, 154.2, 148.1, 147.4 (q, J = 34.2 Hz), 144.6, 141.9, 141.9, 140.2, 136.0, 134.2, 133.7 (q, J= 39.8 Hz), 131.8, 130.4, 128.6, 127.5, 127.3, 126.4, 122.3, 122.3, 122.3, 121.7 (q, J= 273.9 Hz), 120.3, 119.9 (d, .7= 23.4 Hz) , 119.3 (q, J = 271.3 Hz), 118.3 (d, J= 25.1 Hz), 113.3 (d, .7= 7.8 Hz), 102.1 (q, .7= 2.9 Hz), 100.4, 100.3, 99.0, 56.8, 50.1, 44.8, 44.7, 43.5, 43.4, 42.1EXAMPLE 16SYNTHESIS OF MZ0240-1 te / 7- Butyl 4-(5-amino-4-carbamoyl-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-177- pyrazol-l-yl)butanoate (MZ0240-1)

[0155] General Procedure B. Purification via column chromatography (DCM / MeOH = 30 / 1 to 25 / 1) afforded MZ0240-1 (395.7 mg, 38% yield) as a yellow solid. 'H NMR (300 MHz, CDCh) 6 8.29 (t, J= 5.8 Hz, 1H), 7.94 (ddt, J= 9.5, 3.1, 1.4 Hz, 1H), 7.59 - 7.50 (m, 2H), 7.43 (d, J= 7.8 Hz, 2H), 7.21 - 7.08 (m, 1H), 6.94 (dd, J= 9.1, 4.1 Hz, 1H), 5.87 (s, 2H), 5.43 (s, 2H), 4.71 (d, J= 5.7 Hz, 2H), 4.00 (t, J= 6.9 Hz, 2H), 3.92 (s, 3H), 2.28 (t, J= 6.5 Hz, 2H), 2.08 (p, J= 6.8 Hz, 2H), 1.46 (s, 9H).13C NMR (75 MHz, CDCh) 5 173.1, 167.0, 164.3 (d, J= 1.9 Hz), 157.3 (d, J= 240.1 Hz), 153.8 (d, .7= 2.2 Hz), 149.2, 139.6, 129.7, 128.1, 123.0 (d, .7= 6.8 Hz), 119.3 (d, J= 23.4 Hz), 118.8 (d, J= 25.2 Hz), 113.0 (d, J= 7.7 Hz), 95.1, 81.3, 56.8, 45.8, 43.7, 31.6, 28.2, 24.5.EXAMPLE 17SYNTHESIS OF MZ02794-(5-Amino-4-carbamoyl-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)- 177-pyrazol- 1 - yl)butanoic acid (MZ0279)

[0156] General Procedure C. 0.75 mmol scale, afforded MZ0279 (456.6 mg, quant, yield) as a yellow solid.EXAMPLE 18SYNTHESIS OF MZ02815-Amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-l-(4-oxo-4-(4-(4-(l-(l-oxo-l,2- dihydroisoquinolin-5-yl)-5-(trifLuoromethyl)-177-pyrazole-4-carboxamido)-6-(trifluoromethyl)pyridin-2-yl)piperazin-l-yl)butyl)-177-pyrazole-4-carboxamide (MZ0281)

[0157] General Procedure D. Purification via column chromatography (DCM / MeOH = 10 / 1) afforded MZ0281 (13.2 mg, 26% yield) as a white solid. HPLC purity 99.2% (fe = 19.97 min). 'HNMR QOO MHz, CDCh / MeOD) 5 8.60 (dt, J= 8.0, 1.2 Hz, 1H), 8.55 (t, .7= 6.0 Hz, 1H), 8.22 (s, 1H), 7.83 (dd, J= 9.3, 3.3 Hz, 1H), 7.74 (dd, J= 7.7, 1.4 Hz, 1H), 7.64 (t, J= 7.9 Hz, 1H), 7.59 - 7.51 (m, 3H), 7.47 (s, 2H), 7.23 (d, J= 1.5 Hz, 1H), 7.21 - 7.16 (m, 1H), 7.13 (d, J= 7.4 Hz, 1H), 7.02 (dd, J= 9.1, 4.1 Hz, 1H), 5.91 (d, J= 7.3 Hz, 1H), 4.71 (d, J= 5.8 Hz, 2H), 4.03 (t, J= 6.9 Hz, 2H), 3.96 (s, 3H), 3.81 - 3.74 (m, 2H), 3.71 (d, J = 5.5 Hz, 2H), 3.64 (t, J= 3.6 Hz, 4H), 2.48 (t, J= 6.6 Hz, 2H), 2.15 (p, J= 6.8 Hz, 2H).13C NMR (201 MHz, CDCh / MeOD) 5 171.9, 167.7, 165.3, 162.8, 160.7, 160.1, 157.4 (d, J = 239.9 Hz), 154.2, 151.6, 149.6, 148.1, 147.5 (q,J = 34.3 Hz), 140.2, 139.8, 136.1, 134.2, 133.8 (q, J= 39.9 Hz), 132.4, 131.9, 130.4, 130.4, 129.7, 128.2, 127.6, 126.5, 122.6 (d, J = 6.9 Hz), 121.8 (d, .7= 273.9 Hz), 120.4, 119.8 (d, J= 23.3 Hz), 119.3 (d, J = 271.3 Hz), 118.4 (d, .7= 25.0 Hz), 113.3 (d,J= 7.4 Hz), 102.0 (d, .7= 2.9 Hz), 100.4, 99.1, 94.8, 56.8, 46.2, 45.4, 45.0, 45.0, 43.7, 41.6, 29.5, 24.4.EXAMPLE 19SYNTHESIS OF MZ0240-2 te / 7- Butyl 4-(3-amino-4-carbamoyl-5-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-177- pyrazol- 1 -yl)butanoate (MZ0240-2)

[0158] General Procedure B. Purification via column chromatography (DCM / MeOH = 30 / 1 to 25 / 1) afforded MZ0240-2 (293.8 mg, 28% yield) as a yellow solid. 'H NMR (300 MHz, CDCfi) 6 8.43 (t, J= 6.1 Hz, 1H), 7.94 (dd, J= 9.4, 3.3 Hz, 1H), 7.53 (d, J= 7.9 Hz, 2H), 7.37 (d, J= 8.1 Hz, 2H), 7.17 (ddd, J= 9.0, 7.2, 3.3 Hz, 1H), 6.98 (dd, J= 9.1, 4.1 Hz, 1H), 5.62 (s, 2H), 5.08 (s, 2H), 4.76 (d, J= 6.1 Hz, 2H), 3.98 (s, 3H), 3.70 (t, J= 6.9 Hz, 2H), 2.13 (t, J = 7.6 Hz, 2H), 1.96 (p, J= 7.2 Hz, 2H), 1.36 (s, 9H).13C NMR (75 MHz, CDCI3) 5 171.9, 166.7, 164.5 (d, J= 1.9 Hz), 157.3 (d, J= 240.2 Hz), 156.7, 153.8 (d, J= 2.2 Hz), 142.2, 141.5, 130.3, 128.5, 128.1, 122.7 (d, J= 6.7 Hz), 119.5 (d, J= 23.5 Hz), 118.8 (d, J = 25.2 Hz), 113.0 (d, J= 7.6 Hz), 99.7, 80.6, 56.8, 43.3, 32.5, 28.1, 25.3.EXAMPLE 20SYNTHESIS OF MZ02804-(3-Amino-4-carbamoyl-5-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)- 1 / / -pyrazol- 1 - yl)butanoic acid (MZ0280)

[0159] General Procedure C. 0.56 mmol scale, afforded MZ0280 (311.5 mg, 98% yield) as a yellow solid.EXAMPLE 21SYNTHESIS OF MZ02823-Amino-5-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-l-(4-oxo-4-(4-(4-(l-(l-oxo-l,2- dihydroisoquinolin-5-yl)-5-(trifLuoromethyl)-177-pyrazole-4-carboxamido)-6-(trifluoromethy l)pyridin-2-yl)piperazin- 1 -yl)butyl)- I / / -py razo I c-4-carboxam ide (MZ0282)

[0160] General Procedure D. Purification via column chromatography (DCM / MeOH = 10 / 1) afforded MZ0282 (5.1 mg, 10% yield) as a white solid. HPLC purity 92.0% (fe = 21.06 min). 'H NMR (300 MHz, CDCh / MeOD) 5 8.72 (t, J= 6.1 Hz, 1H), 8.60 (d, J= 8.3 Hz, 1H), 8.22 (s, 1H), 7.82 (dd, J= 9.3, 3.3 Hz, 1H), 7.75 (d, J= 7.5 Hz, 1H), 7.63 (dd, J= 15.2, 7.8 Hz, 3H), 7.50 (d, J = 7.0 Hz, 2H), 7.43 (s, 1H), 7.27 (d, J= 1.3 Hz, 1H), 7.22 (ddd, J= 9.2, 7.3, 3.3 Hz, 1H), 7.14 (d, J= 7.4 Hz, 1H), 7.05 (dd, J= 9.1, 4.1 Hz, 1H), 5.92 (d, J= 7.5 Hz, 1H), 4.78 (d, J= 5.9 Hz, 2H), 4.02 (m, 5H), 3.73 - 3.55 (m, 8H), 2.44 (t, J= 7.1 Hz, 2H), 2.13 - 2.05 (m, 2H).13C NMR (201 MHz, CDCh / MeOD) 5 171.2, 166.3, 165.6, 162.7, 160.6, 160.1, 157.4 (d, J= 240.2 Hz), 154.1, 148.0, 147.4 (q, J= 34.1 Hz), 146.5, 142.9, 142.4, 140.2, 136.0, 134.2, 133.8 (q, .7 = 40.1 Hz), 131.8, 130.4, 130.3, 130.2, 128.9, 127.5, 126.4, 126.3, 122.4 (d, .7= 6.9 Hz), 121.7 (q, J= 273.5 Hz), 120.4, 120.0 (d, .7= 22.7 Hz), 119.3 (q, .7= 270.7 Hz), 118.4 (d, J= 24.8 Hz), 113.3 (d, J = 7.8 Hz), 102.5, 102.0, 100.4, 99.0, 56.8, 45.2, 45.0, 44.9, 43.5, 41.5, 32.1, 25.6, 22.9.EXAMPLE 22SYNTHESIS OF MZ0241-1 te / 7- Butyl 6-(5-amino-4-carbamoyl-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-177- pyrazol- 1 -y l)hexano ate (MZ0241 - 1 )

[0161] General Procedure B. Purification via column chromatography (DCM / MeOH = 30 / 1 to 25 / 1) afforded MZ0241-1 (510.3 mg, 46% yield) as a yellow solid. ' H NMR (300 MHz, CDCh) 5 8.28 (t, J= 5.7 Hz, 1H), 7.95 (dd, J= 9.4, 3.3 Hz, 1H), 7.53 (d, J= 8.1 Hz, 2H), 7.43 (d, J= 8.2 Hz, 2H), 7.15 (ddd, J= 9.0, 7.1, 3.3 Hz, 1H), 6.94 (dd, J= 9.1, 4.1 Hz, 1H), 5.55 (s, 2H), 5.40 (s, 2H), 4.71 (d, J= 5.7 Hz, 2H), 3.92 (m, 5H), 2.22 (t, J= 7.3 Hz, 2H), 1.85 (p, J= 7.4 Hz, 2H), 1.63 (p, J = 1.3 Hz, 2H), 1.42 (m, 11H).13C NMR (75 MHz, CDCh) 5 173.0, 166.8, 164.2 (d, J= 1.9 Hz), 157.2 (d, .7= 240.2 Hz), 153.7 (d, .7= 2.1 Hz), 150.3, 148.8, 139.4, 132.6, 129.6, 128.0, 122.8 (d, .7= 6.8 Hz), 119.2 (d, .7= 23.5 Hz), 118.7 (d, .7= 25.1 Hz), 112.8 (d, .7 = 7.7 Hz), 95.3, 80.2, 56.7, 46.9, 43.5, 35.2, 28.6, 28.1, 26.2, 24.5.EXAMPLE 23SYNTHESIS OF MZ02606-(5-Amino-4-carbamoyl-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)- 1 / / -pyrazol- 1 - yl)hexanoic acid (MZ0260)

[0162] General Procedure C. 0.44 mmol scale, afforded MZ0260 (250 mg, 96% yield) as a yellow solid.EXAMPLE 24SYNTHESIS OF MZ0268-1 terZ-Butyl 2-(2-(5-amino-4-carbamoyl-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)- 177-pyrazol- 1 -yl)ethoxy)acetate (MZ0268-1)

[0163] General Procedure B. Purification via column chromatography (DCM / MeOH = 30 / 1 to 25 / 1) afforded MZ0268-1 (576.2 mg, 53% yield) as a yellow solid. 'H NMR (300 MHz, CDCh) 5 8.35 (t, J= 5.8 Hz, 1H), 7.91 (dd, J= 9.4, 3.3 Hz, 1H), 7.53 (d, J= 8.1 Hz, 2H), 7.43 (d,J= 7.9 Hz, 2H), 7.13 (ddd, J= 9.1, 7.2, 3.3 Hz, 1H), 6.94 (dd, J= 9.1, 4.1 Hz, 1H), 6.06 (s, 2H), 5.25 (d, J= 198.1 Hz, 2H), 4.70 (d, J= 5.8 Hz, 2H), 4.23 (t, J= 4.6 Hz, 2H), 3.99 (s, 2H), 3.91 (s, 3H), 3.87 (t, .7= 4.8 Hz, 1H), 1.46 (s, 9H).13C NMR (75 MHz, CDCh) 5 168.7, 166.9, 164.1 (d, J = 1.9 Hz), 156.9 (d, J= 239.7 Hz), 153.6 (d, J= 2.1 Hz), 152.4, 148.8, 139.3, 132.5, 129.3, 127.8, 122.7 (d, J = 6.7 Hz), 119.0 (d, J= 23.5 Hz), 118.3 (d, .7= 25.1 Hz), 112.8 (d, .7= 7.5 Hz), 95.5, 82.0, 70.9, 69.0, 56.5, 48.5, 43.3, 27.9.EXAMPLE 25SYNTHESIS OF MZ02692-(2-(5-Amino-4-carbamoyl-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-177-pyrazol- l-yl)ethoxy)acetic acid (MZ0269)

[0164] General Procedure C. 0.89 mmol scale, afforded MZ0269 (490.0 mg, 95% yield) as a yellow solid.EXAMPLE 26SYNTHESIS OF MZ02725-Amino-3-(4-((5-fhioro-2-methoxybenzamido)methyl)phenyl)-l-(2-(2-oxo-2-(4-(4-(l -(1-oxo- l,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-177-pyrazole-4-carboxamido)-6-(trifluoromethyl)pyridin-2-yl)piperazin- 1 -yl)ethoxy)ethyl)- I / / -pyrazo lc-4-carboxam ide(MZ0272)

[0165] General Procedure D. Purification via column chromatography (DCM / MeOH = 10 / 1) afforded MZ0272 (11.2 mg, 22% yield) as a white solid. HPLC purity 99.4% (fe = 19.61 min). 'H NMR (300 MHz, CDCh / MeOD) 5 8.65 - 8.50 (m, 2H), 8.25 (s, 1H), 7.83 (dd, J= 9.3, 3.3 Hz, 1H), 7.75 (d, J= 7.5 Hz, 1H), 7.64 (t, J= 7.9 Hz, 1H), 7.57 - 7.47 (m, 3H), 7.41 (d, J= 7.9 Hz, 2H), 7.24 (d, J= 1.4 Hz, 1H), 7.20 (td, J= 6.6, 3.5 Hz, 1H), 7.13 (d, J= 7.4 Hz, 1H), 7.02 (dd, J = 9.1, 4.1 Hz, 1H), 5.91 (d, J= 7.4 Hz, 1H), 4.70 (d, J= 5.7 Hz, 2H), 4.29 (s, 2H), 4.26 (s, 2H), 3.96 (s, 3H), 3.92 (t, J= 4.9 Hz, 2H), 3.73 (s, 2H), 3.69 - 3.58 (m, 4H), 3.49 (d, J= 5.5 Hz, 2H).13C NMR (201 MHz, CDCh / MeOD) 5 168.3, 167.6, 165.3, 162.8, 160.7, 160.1, 157.4 (d, J = 239.9 Hz), 154.2, 152.7, 149.8, 148.2, 147.4 (q, J= 33.8 Hz), 140.3, 139.8, 139.8, 136.1, 134.3, 133.8 (d, J= 40.1 Hz), 132.2, 131.8, 130.4, 130.4, 129.7, 128.1, 127.6, 126.5, 122.5 (d, J= 6.8 Hz), 121.8 (q, J= 273.9 Hz), 120.4, 119.9 (d, J= 23.5 Hz), 119.3 (q, .7= 271.3 Hz), 118.4 (d, J= 25.2 Hz), 102.2 (q, J= 2.9 Hz), 100.4, 99.1, 95.3, 70.5, 70.0, 56.8, 47.9, 45.0, 44.9, 44.5, 43.6, 41.8.EXAMPLE 27SYNTHESIS OF MZ0268-2 terZ-Butyl 2-(2-(3-amino-4-carbamoyl-5-(4-((5-fLuoro-2-methoxybenzamido)methyl)phenyl)-177-pyrazol- 1 -yl)ethoxy)acetate (MZ0268-2)

[0166] General Procedure B. Purification via column chromatography (DCM / MeOH = 30 / 1 to 25 / 1) afforded MZ0268-2 (200.0 mg, 18% yield) as a yellow solid. 'H NMR (300 MHz, CDCfi) 6 8.42 (t, J= 6.0 Hz, 1H), 7.95 (dd, J= 9.4, 3.3 Hz, 1H), 7.52 (d, J= 8.3 Hz, 2H), 7.47 (d, J= 8.3 Hz, 2H), 7.17 (ddd, J= 9.1, 7.2, 3.3 Hz, 1H), 6.97 (dd, J= 9.1, 4.1 Hz, 1H), 5.58 (s, 2H), 5.10 (s, 2H), 4.76 (d, J= 6.0 Hz, 2H), 3.98 (s, 3H), 3.87 (s, 2H), 3.86 - 3.79 (m, 3H), 1.44 (s, 9H).13C NMR (75 MHz, CDCh) 5 169.2, 166.7, 164.5 (d, J= 1.9 Hz), 157.3 (d, J= 240.1 Hz), 156.9, 153.8 (d, J =2.2 Hz), 143.3, 141.3, 130.8, 128.3, 127.9, 122.7 (d, J = 6.7 Hz), 119.5 (d, .7= 23.4 Hz), 118.8 (d, J= 25.0 Hz), 113.0 (d, J= 7.6 Hz), 99.7, 69.4, 69.2, 56.8, 48.6, 43.4, 28.2.EXAMPLE 28 SYNTHESIS OF MZ0270 2-(2-(3-Amino-4-carbamoyl-5-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-177-pyrazol- l-yl)ethoxy)acetic acid (MZ0270)

[0167] General Procedure C. 0.18 mmol scale, afforded MZ0270 (108.4 mg, quant, yield) as a yellow solid.EXAMPLE 29SYNTHESIS OF MZ02733-Amino-5-(4-((5-fhioro-2-methoxybenzamido)methyl)phenyl)-l-(2-(2-oxo-2-(4-(4-(l -(1-oxo- l,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-177-pyrazole-4-carboxamido)-6- (trifluoromethyl)pyridin-2-yl)piperazin- 1 -yl)ethoxy)ethyl)- 177-pyrazole-4-carboxamide(MZ0273)

[0168] General Procedure D. Purification via column chromatography (DCM / NHs’MeOH = 10 / 1) afforded MZ0273 (13.4 mg, 26% yield) as a white solid. HPLC purity 99.1% (fe = 19.60 min). 'H NMR (300 MHz, CDCh / MeOD) 5 8.66 (t, J= 6.1 Hz, 1H), 8.59 (d, J= 8.0 Hz, 1H), 8.33 (s, 1H), 7.82 (dd, J= 9.3, 3.3 Hz, 1H), 7.74 (d, J= 7.5 Hz, 1H), 7.64 (t, J= 7.8 Hz, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.45 (d, J= 7.9 Hz, 2H), 7.27 (s, 1H), 7.20 (ddd, J= 9.0, 7.2, 3.3 Hz, 1H), 7.13 (d, J = 7.4 Hz, 1H), 7.02 (dd, J= 9.1, 4.1 Hz, 1H), 5.92 (d, J= 7.3 Hz, 1H), 4.74 (d, J= 6.1 Hz, 2H), 4.13 (s, 2H), 3.99 (s, 3H), 3.90 (d, J= 5.0 Hz, 2H), 3.84 (d, J= 4.9 Hz, 2H), 3.74 - 3.61 (m, 4H), 3.47 (s, 2H), 3.41 (s, 2H).13C NMR (201 MHz, CDCh / MeOD) 5 168.0, 167.2, 165.4, 162.8, 160.5, 160.1, 157.4 (d, J= 240.4 Hz), 157.1, 154.2, 148.2, 147.5 (q, J= 34.0 Hz), 144.0, 141.7, 140.4, 136.0, 134.3, 133.9 (q,J= 40.1 Hz), 131.8, 130.7, 130.4, 130.3, 128.6, 127.5, 127.4, 126.5, 122.3 (d, .7= 6.7 Hz), 121.8 (q, J= 274.2 Hz), 120.3, 119.9 (d, J= 23.1 Hz), 119.3 (q, .7= 271.5 Hz), 118.4 (d, .7= 25.1 Hz), 113.3 (d, J= 7.4 Hz), 102.4 (q, J= 3.2 Hz), 100.4, 99.5, 98.9, 70.9, 68.9, 56.8, 48.5, 45.3, 44.8, 44.8, 43.4, 41.9.EXAMPLE 30SYNTHESIS OF MZ02445-Amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-l-(8-oxo-8-(4-(4-(l-(l-oxo-l,2- dihydroisoquinolin-5-yl)-5 -(trifluoromethyl)- l / / -pyrazolc-4-carboxamiclo)-6- (trifluoromethyl)pyridin-2-yl)piperazin- 1 -yl)octanoyl)- 1 / / -pyrazolc-4-carboxam ide (MZ0244)

[0169] General Procedure D. Purification via column chromatography (DCM / NHa’MeOH = 10 / 1) afforded MZ0244 (2.2 mg, 4% yield) as a white solid. HPLC purity 98.8% (fe = 22.16 min). 'H NMR (300 MHz, CDCh / MelD) 5 8.60 (d, J= 8.2 Hz, 2H), 8.22 (s, 1H), 7.84 (dd, J= 9.3, 3.3 Hz, 1H), 7.75 (d,J= 7.2 Hz, 1H), 7.66 (d, J= 8.0 Hz, 1H), 7.59 (dd, J= 9.0, 7.3 Hz, 3H), 7.51 (t, J= 6.4 Hz, 3H), 7.26 - 7.16 (m, 2H), 7.13 (d, J= 7.4 Hz, 1H), 7.03 (dd, J= 9.1, 4.1 Hz, 1H), 5.91 (d, J= 7.4 Hz, 1H), 4.73 (d, J= 5.9 Hz, 2H), 3.98 (s, 3H), 3.74 (s, 4H), 3.63 (s, 4H), 3.07 (t, J = 7.4 Hz, 2H), 2.41 (t, J= 7.6 Hz, 2H), 1.79 (t, J= 7.2 Hz, 2H), 1.72 - 1.62 (m, 2H), 1.52 - 1.36 (m, 4H).13C NMR (201 MHz, CDCh / MeOD) 5 176.8, 172.9, 166.9, 165.2, 162.7, 160.6, 160.1,157.4 (d, J = 240.0 Hz), 154.8, 154.1, 153.0, 148.0, 140.7, 140.2, 136.0, 134.2, 133.8 (q, J= 39.2 Hz), 131.8, 131.3, 130.4, 130.3, 129.6, 128.3, 127.5, 126.4, 122.4 (d, J= 6.5 Hz), 121.7 (q, J = 215A }iz), 120.4, 119.8 (d, J = 24.2 Hz), 119.2 (q, J = 268.5 Hz), 118.4 (d, J = 25.6 Hz), 113.2 (d, J= 7.1 Hz), 101.9, 100.3, 99.0, 94.1, 56.8, 45.6, 45.1, 43.6, 41.5, 35.3, 33.4, 29.3, 28.9, 25.3, 23.9.EXAMPLE 31SYNTHESIS OF MZ0286-1 terZ-Butyl (2-(5 -ami no-4-carbamoy 1-3 -(4-((5- fl uoro-2-methoxybenzami do )m ethyl )pheny 1 )-] / / - pyrazol- 1 -yl)ethyl)carbamate (MZ0286- 1)

[0170] General Procedure B. Purification via column chromatography (DCM / MeOH = 30 / 1 to 25 / 1) afforded MZ0286-1 (275.3 mg, 52% yield) as a white solid. 'H NMR (300 MHz, CDCh / MeOD) 5 8.55 (t, J= 5.9 Hz, 1H), 7.84 (dd, J= 9.4, 3.3 Hz, 1H), 7.53 (d, J= 8.2 Hz, 2H), 7.46 (d, J= 8.2 Hz, 2H), 7.20 (ddd, J= 9.1, 7.2, 3.3 Hz, 1H), 7.02 (dd, J= 9.1, 4.1 Hz, 1H), 4.72 (d, J= 5.9 Hz, 2H), 4.03 (t, J= 6.6 Hz, 2H), 3.97 (s, 3H), 3.44 (t, J= 6.6 Hz, 2H), 1.44 (s, 9H).13C NMR (75 MHz, CDCh / MeOD) 5 167.5, 165.3 (d, J = 1.8 Hz), 157.4 (d, J = 240.0 Hz), 157.3, 154.1 (d, J= 22 Hz), 151.8, 149.8, 139.9, 132.3, 129.7, 128.1, 122.7 (d, J= 6.7 Hz), 119.7 (d, J= 23.4 Hz), 118.4 (d, J= 25.2 Hz), 113.3 (d, J= 7.6 Hz), 94.8, 80.2, 56.8, 46.3, 43.7, 39.5, 28.4.EXAMPLE 32 SYNTHESIS OF MZ02875- Amino- l-(2-aminoethyl)-3-(4-((5-fhioro-2-methoxybenzamido)methyl)phenyl)-l / / -pyr azole- 4-carboxamide (MZ0287)

[0171] General Procedure C. 0.28 mmol scale, afforded MZ0287 (138.4 mg, 97% yield) as a yellow solid.EXAMPLE 33SYNTHESIS OF MZ02895-Amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-l-(2-(l-(l-oxo-l,2- dihydroisoquinolin-5-yl)-5-(trifhioromethyl)-177-pyrazole-4-carboxamido)ethyl)-177-pyrazole-4- carboxamide (MZ0289)

[0172] General Procedure E. Purification via column chromatography (DCM / MeOH = 10 / 1) afforded MZ0289 (18.7 mg, 51% yield) as a white solid. HPLC purity 95.3% (fe = 16.37 min). 'H NMR QOO MHz, CDCh / MeOD) 5 8.69 (t, J= 6.1 Hz, 1H), 8.57 (dt, J= 8.0, 1.2 Hz, 1H), 8.06 (d, J= 0.8 Hz, 1H), 7.81 (dd, J= 9.3, 3.3 Hz, 1H), 7.72 (dd, J= 7.7, 1.4 Hz, 1H), 7.62 (t, J= 7.8 Hz, 1H), 7.54 (d, J= 8.1 Hz, 2H), 7.41 (d, J= 8.2 Hz, 2H), 7.21 (ddd, J= 9.1, 7.3, 3.3 Hz, 1H), 7.12 (d, .7= 7.4 Hz, 1H), 7.03 (dd, J= 9.1, 4.1 Hz, 1H), 5.87 (dd, J= 7.4, 0.8 Hz, 1H), 4.75 (d, J = 6.1 Hz, 2H), 3.98 (s, 3H), 3.93 (t, J= 6.2 Hz, 2H), 3.68 (t, J= 5.9 Hz, 2H).13C NMR (201 MHz, DMSO-tTs) 8 166.6, 164.5, 161.3, 160.7, 156.4 (d, .7= 236.9 Hz), 153.8, 151.3, 148.5, 140.6, 140.2, 135.7, 134.3, 132.8, 132.1, 131.9, 131.8 (q, J= 39.1 Hz), 129.8, 129.2, 127.6, 127.4, 126.5, 124.9 (d, .7 = 6.6 Hz), 121.1, 119.6 (q, J = 270.8 Hz), 118.8 (d, J = 22.8 Hz), 116.9 (d, J = 24.7 Hz), 114.3 (d, J= 7.5 Hz), 98.4, 95.2, 56.9, 45.9, 42.9, 38.7.EXAMPLE 34SYNTHESIS OF MZ0286-2 terZ-Butyl (2-(3 -ami no-4-carbamoy 1-5 -(4-((5-fL uoro-2-methoxybenzami do )m ethyl )pheny 1 )-] / / - pyrazol- 1 -yl)ethyl)carbamate (MZ0286-2)

[0173] General Procedure B. Purification via column chromatography (DCM / MeOH = 30 / 1 to 25 / l)afforded MZ0286-2 (119.0 mg, 23% yield) as a yellow solid. 'H NMR (300 MHz, CDCh / MeOD) 5 8.56 (t, J= 6.0 Hz, 1H), 7.88 (dd, J= 9.4, 3.3 Hz, 1H), 7.53 (d, J= 8.2 Hz, 2H), 7.37 (d, J= 8.0 Hz, 2H), 7.20 (ddd, J= 9.1, 7.2, 3.3 Hz, 1H), 7.01 (dd, J= 9.1, 4.1 Hz, 1H), 5.98 - 4.95 (m, 2H), 4.74 (d, J= 6.0 Hz, 2H), 3.99 (s, 3H), 3.79 - 3.71 (m, 2H), 3.67 (s, 3H), 3.40 (q, J= 6.6 Hz, 2H), 1.40 (s, 9H).13C NMR (75 MHz, CDCh / MeOD) 5 166.8 (d, J= 3.5 Hz), 165.0 (d, J= 2.0 Hz), 157.1 (d, J= 240.1 Hz), 156.8, 156.1, 153.8 (d, J= 2.2 Hz), 143.3, 141.4, 130.2, 128.4, 127.5, 122.3 (d, J = 6.8 Hz), 119.6 (d, J = 23.5 Hz), 118.3 (d, J = 25.1 Hz), 113.0 (d, J = 7.7 Hz), 99.5, 79.6, 56.6, 48.3, 43.3, 40.0, 28.3.EXAMPLE 35SYNTHESIS OF MZ02883- Amino- l-(2-aminoethyl)-5-(4-((5-fhioro-2-methoxybenzamido)methyl)phenyl)-177-pyr azole- 4-carboxamide (MZ0288)

[0174] General Procedure C. 0.19 mmol scale, afforded MZ0288 (93.9 mg, 98% yield) as a yellow solid.EXAMPLE 36 SYNTHESIS OF MZ0290 3-Amino-5-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-l-(2-(l-(l-oxo-l,2- dihydroisoquinofin-5-yl)-5-(trifhioromethyl)-177-pyrazole-4-carboxamido)ethyl)-177-pyrazole-4- carboxamide (MZ0290)

[0175] General Procedure E. Purification via column chromatography (DCM / MeOH = 10 / 1) afforded MZ0290 (11.3 mg, 31% yield) as a white solid. HPLC purity 99.1% (fe = 15.98 min).'H NMR (300 MHz, CDCh / MeOD) 5 8.69 (t, J= 6.1 Hz, 1H), 8.57 (dt, J= 8.0, 1.2 Hz, 1H), 8.06 (d, J= 0.8 Hz, 1H), 7.81 (dd, J= 9.3, 3.3 Hz, 1H), 7.72 (dd, J= 7.7, 1.4 Hz, 1H), 7.62 (t, J= 7.8 Hz, 1H), 7.54 (d, J= 8.1 Hz, 2H), 7.41 (d, J= 8.2 Hz, 2H), 7.21 (ddd, J= 9.1, 7.3, 3.3 Hz, 1H), 7.12 (d, .7= 7.4 Hz, 1H), 7.03 (dd, J= 9.1, 4.1 Hz, 1H), 5.87 (dd, J= 7.4, 0.8 Hz, 1H), 4.75 (d, J = 6.1 Hz, 2H), 3.98 (s, 3H), 3.93 (t, J= 6.2 Hz, 2H), 3.68 (t, J= 5.9 Hz, 2H).13C NMR (201 MHz, CDCh / MeOD) 5 167.2, 165.6, 162.8, 161.8, 157.4 (d, J = 239.9 Hz), 157.1, 154.2, 143.7, 141.8, 140.4, 136.1, 134.4, 133.0 (q, J= 39.6 Hz), 131.8, 130.4, 130.3, 130.3, 128.7, 127.5, 127.4, 126.5, 122.4 (d, .7= 6.6 Hz), 120.3, 119.4 (q, J = 271.3 Hz), 119.0 (d, J = 23.4 Hz), 118.4 (d, J = 25.0 Hz), 113.3 (d, J= 7.4 Hz), 100.5, 99.9, 56.8, 47.8, 43.5, 39.8.EXAMPLE 37SYNTHESIS OF MZ0202Methyl 6-chloro-4-(l-(l -oxo- l,2-dihydroisoquinolin-5-yl)-5 -(trifluoromethyl)- l / / -pyrazolc-4- carboxamido)picolinate (MZ0202)

[0176] To a solution of 1-(1 -oxo- l,2-dihydroisoquinolin-5-yl)-5 -(trifluoromethyl)- l / / -pyrazolc-4- carboxylic acid (compound 1) (323.2 mg, 1 mmol, 1 equiv.) and methyl 4-amino-6-chloropicolinate (205.3 mg, 1.1 mmol, 1.1 equiv.) in DCM (7 mL) and pyridine (3 mL) was added POCI3 (0.19 mL, 2 mmol, 2 equiv.) at 0 °C, then stirred at rt overnight. The reaction mixture was concentrated and diluted with DCM. The organic layer was washed with a saturated NaHCO, solution. The aqueous solution was extracted with DCM, and the organic layer was separated, washed by brine, dried with Na2SC>4, and concentrated. The residue was purified via column chromatography (DCM / MeOH = 30 / 1 to 20 / 1) to afford MZ0202 (310.2 mg, 63% yield) as a white solid. HPLC purity 99.9% (fa = 15.43 min). 'H NMR (300 MHz, CDCh / MeOD) 5 8.60 (ddd, J= 8.0, 1.4, 0.7 Hz, 1H), 8.31 (d, J= 1.8 Hz, 1H), 8.26 (d, .7= 0.7 Hz, 1H), 8.20 (d, J= 1.8 Hz, 1H), 7.76 (dd, .7= 7.6, 1.4 Hz, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.15 (d, J= 7.4 Hz, 1H), 5.91 (dd, J= 7.3, 0.8 Hz, 1H), 4.02 (s, 3H).13C NMR (75 MHz, CDCh / MeOD) 5 165.0, 163.0, 160.8, 153.0, 149.3, 148.8, 140.4, 136.2, 134.4, 134.3 (q, J= 39.9 Hz), 132.0, 130.6, 130.5, 127.7, 126.6, 120.0 (q, J= 1.3 Hz), 119.4 (q, .7= 271.3Hz), 117.4, 115.1, 100.4, 53.4. HRMS (ESI) calcd for C21H14CIF3N5O4492.0681 [M + H]+; found, 492.0681.EXAMPLE 38SYNTHESIS OF MZ03186-Chloro-4-(l-(l -oxo- l,2-dihydroisoquinolin-5-yl)-5 -(trifluoromethyl)- 177-pyrazole-4- carboxamidojpicolinic acid (MZ0318)

[0177] To a solution of MZ0202 (245.9 mg, 0.5 mmol, 1 equiv.) in THF / MeOH / H2O (15 / 5 / 5 mL) was added LiOH (104.9 mg, 2.5 mmol, 5 equiv.) then stirred at rt overnight. Then the reaction mixture was concentrated and add IN HC1 to adjust pH until 3. The precipitate was filtered to afford MZ0318 (181.7 mg, 78% yield) as a white solid without further purification.EXAMPLE 39SYNTHESIS OF MZ0326A-(2-(5-Amino-4-carbamoyl-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-l / / -pyrazol- l-yl)ethyl)-6-chloro-4-(l-(l -oxo- 1 ,2-dihydroisoquinolin-5-yl)-5-(trifluoromcthyl)-l / / -pyr azole-4-carboxamido)picolinamide (MZ0326)

[0178] General Procedure E. Purification via column chromatography (DCM / MeOH = 10 / 1) afforded MZ0326 (18.0 mg, 41% yield) as a white solid. 'H NMR (300 MHz, CDCh / MeOD) 5 8.86 (t, J= 6.1 Hz, 1H), 8.60 (dt, J= 8.0, 1.1 Hz, 2H), 8.36 (d, J= 1.8 Hz, 1H), 8.28 (d, J= 0.7 Hz, 1H), 8.03 (d, J= 1.8 Hz, 1H), 7.84 (dd, J= 9.3, 3.3 Hz, 1H), 7.76 (dd, J= 7.7, 1.4 Hz, 1H),7.65 (t, J= 7.9 Hz, 1H), 7.61 - 7.56 (m, 2H), 7.51 - 7.47 (m, 2H), 7.21 (ddd, J= 9.1, 7.2, 3.3 Hz, 1H), 7.15 (d, .7= 7.4 Hz, 1H), 7.04 (dd, J= 9.1, 4.1 Hz, 1H), 5.92 (dd, J= 7.4, 0.8 Hz, 1H), 4.73 (d, J= 5.9 Hz, 2H), 4.20 (t, J= 6.3 Hz, 2H), 3.98 (s, 3H), 3.84 (q, J = 6.1 Hz, 2H).EXAMPLE 40 SYNTHESIS OF MZ0327A-(2-(3-Amino-4-carbamoyl-5-(4-((5-fhioro-2-methoxybenzamido)methyl)phenyl)-177-pyrazol- l-yl)ethyl)-6-chloro-4-(l-(l -oxo- l,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-17 / -pyr azole- 4-carboxamido)picolinamide (MZ0327)

[0179] General Procedure E. Purification via column chromatography (CHCh / MeOH = 10 / 1) afforded MZ0327 (11.8 mg, 26% yield) as a white solid. 'H NMR (300 MHz, CDCh / MeOD) 5 8.70 (t, J= 6.1 Hz, 1H), 8.59 (dt, J= 8.0, 1.2 Hz, 1H), 8.38 (d, J= 1.8 Hz, 1H), 8.31 (d, J= 0.7 Hz, 1H), 7.89 (d, J= 1.8 Hz, 1H), 7.81 - 7.72 (m, 2H), 7.65 (t, J= 7.9 Hz, 1H), 7.42 (d, J= 8.2 Hz, 2H), 7.35 - 7.29 (m, 2H), 7.22 (ddd, J= 9.1, 7.3, 3.3 Hz, 1H), 7.13 (d, J= 7.4 Hz, 1H), 7.05 (dd, J= 9.1, 4.1 Hz, 1H), 5.91 (dd, J= 7.4, 0.8 Hz, 1H), 4.70 (d, J= 6.1 Hz, 2H), 4.01 (s, 5H), 3.76 - 3.68 (m, 2H).EXAMPLE 41SYNTHESIS OF MZ0150-15-Amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-l-(l-(l-oxo-l,2- dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-17Z-pyrazole-4-carbonyl)-177-pyrazole-4- carboxamide (MZ0150-1)

[0180] General Procedure E. Purification via column chromatography (DCM / MeOH = 15 / 1) afforded MZ0150-1 (31.5 mg, 46% yield) as a yellow solid. HPLC purity 96.7 % (YR = 16.61 min). 'H NMR (300 MHz, CDCh / MeOD) 5 8.58 (d, J= 8.0 Hz, 2H), 8.48 (s, 1H), 7.85 (dd, J= 9.3, 3.3 Hz, 1H), 7.76 (dd, J= 7.7, 1.3 Hz, 1H), 7.69 (d, J= 5.0 Hz, 1H), 7.62 (dt, J= 7.8, 3.8 Hz, 3H), 7.52 (d, J= 8.1 Hz, 2H), 7.26 - 7.16 (m, 1H), 7.09 (d, J= 7.4 Hz, 1H), 7.02 (dd, J= 9.1, 4.1 Hz, 1H), 5.98 (d, J = 7.4 Hz, 1H), 4.75 (d, J = 6.0 Hz, 2H), 3.98 (s, 3H).13C NMR (75 MHz, CDCh / MeOD) 5 166.8, 165.3 (d, J= 2.0 Hz), 162.8, 162.8, 157.4 (d, J= 239.9 Hz), 155.7, 154.1 (d, J = 2.2 Hz), 154.1, 143.3, 141.0, 135.9, 135.8 (q, J = 39.8 Hz), 134.1, 131.8, 130.9, 130.4, 130.3, 129.6, 128.2, 127.6, 126.4, 122.6 (d,J= 6.9 Hz), 119.8 (d, J= 23.5 Hz), 119.1 (q, .7= 271.4 Hz), 118.4 (d, J = 25.2 Hz), 117.2 (q, J = 1.0 Hz), 113.3 (d, J = 7.7 Hz), 100.6, 94.4, 56.9, 43.6. HRMS (ESI) calcd for C33H25F4N8O5 711.1698 [M + Na]+; found, 711.1695.EXAMPLE 42SYNTHESIS OF MZ0150-23-Amino-5-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-l-(l-(l-oxo-l,2- dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-177-pyrazole-4-carbonyl)-177-pyrazole-4- carboxamide (MZO 150-2)

[0181] General Procedure E. Purification via column chromatography (DCM / MeOH = 15 / 1) afforded MZ0150-2 (32.9 mg, 48% yield) as a white solid. HPLC purity 90.2% (fe = 15.38 min). 'H NMR (300 MHz, CDCh / MeOD) 5 8.59 (d, J= 8.1 Hz, 2H) , 8.30 (s, 1H), 7.85 (dd, J= 9.3, 3.3 Hz, 1H), 7.76 (dd, J= 7.7, 1.4 Hz, 1H), 7.63 (dd, J= 16.3, 8.1 Hz, 3H), 7.52 (d, J= 8.2 Hz, 2H), 7.21 (ddd, J= 9.1, 7.2, 3.3 Hz, 1H), 7.15 (d, J= 7.4 Hz, 1H), 7.03 (dd, J= 9.1, 4.1 Hz, 1H), 5.93 (d, J= 7.3 Hz, 1H), 4.75 (d, J= 5.9 Hz, 2H), 3.99 (s, 3H).13C NMR (75 MHz, CDCh / MeOD) 5 167.4, 167.3, 165.7 (d, J= 1.9 Hz), 162.9, 158.8, 157.5 (d, J= 239.9 Hz), 154.4 (d, J = 22 Hz), 140.8, 136.1, 134.4, 134.1 (q, .7= 40.2 Hz), 131.9, 130.6, 130.5, 129.9, 129.8, 128.5, 128.3, 127.7, 126.6, 122.8 (d, J = 6.7 Hz), 119.9 (d, J= 23.5 Hz), 119.4 (q, .7= 271.4 Hz), 119.3 (q), 118.4 (d, J= 252 Hz), 113.6 (d, J= 7.7 Hz), 100.5, 99.1, 56.9, 43.7. HRMS (ESI) calcd for C33H25F4N8O5 689.1879 [M + H]+; found, 689.1873.EXAMPLE 43SYNTHESIS OF MZ02575-Fluoro-2-methoxy-7V-(4-nitrobenzyl)benzamide (MZ0257)

[0182] To a solution of 5-fluoro-2-methoxybenzoic acid (425.4 mg, 2.5 mmol, 1 equiv.) and 4- nitrobenzylamine (518.7 mg, 2.75 mmol, 1.1 equiv.) in pyridine / DCM (3:7) (25 mL) was added EDCI (958.5 mg, 5 mmol, 2 equiv.). The reaction mixture was stirred at rt overnight. Then the reaction mixture was concentrated and purified via column chromatography (DCM / MeOH = 30 / 1) afforded MZ0257 (489.0 mg, 64% yield) as a yellow solid. 'H NMR (300 MHz, CDCh) 6 8.54 - 8.35 (m, 1H), 8.21 - 8.10 (m, 2H), 7.91 (dd, J= 9.4, 3.3 Hz, 1H), 7.54 - 7.44 (m, 2H), 7.21 - 7.10 (m, 1H), 6.97 (dd, J= 9.1, 4.1 Hz, 1H), 4.76 (d, J= 6.0 Hz, 2H), 3.96 (s, 3H).13C NMR (75 MHz, CDCh) 5 164.5 (d, J= 2.1 Hz), 157.2 (d, J= 240.3 Hz), 153.8 (d, J= 2.2 Hz), 147.2, 146.4, 128.0, 123.8, 122.3 (d, J= 6.8 Hz), 119.5 (d, J = 23.5 Hz), 118.7 (d, .7= 25.1 Hz), 112.9 (d, J= 7.7 Hz), 56.7, 43.2.EXAMPLE 44 SYNTHESIS OF MZ0258 7V-(4-aminobenzyl)-5-fluoro-2-methoxybenzamide (MZ0258)

[0183] General Procedure A. 1.60 mmol scale, purification via column chromatography (DCM / MeOH = 25 / 1) afforded MZ0258 (400.8 mg, 91% yield) as a yellow solid. 'H NMR (300 MHz, CDCh) 5 8.14 (t, J= 5.8 Hz, 1H), 7.91 (dd, J= 9.5, 3.4 Hz, 1H), 7.18 - 7.00 (m, 3H), 6.85 (dd, J= 9.1, 4.1 Hz, 1H), 6.67 - 6.57 (m, 2H), 4.51 (d, .7= 5.5 Hz, 2H), 3.81 (s, 3H), 3.74 (s, 2H).13C NMR (75 MHZ, CDCh) 6 163.8 (d,J= 1.9 Hz), 156.9 (d, .7= 239.4 Hz), 153.5 (d,J= 2.1 Hz), 145.9, 128.7, 127.8, 122.9 (d, .7= 6.6 Hz), 118.8 (d, J= 23.5 Hz), 118.2 (d, .7= 25.0 Hz), 115.1, 112.7 (d, .7 = 7.7 Hz), 56.4, 43.4.EXAMPLE 45SYNTHESIS OF MZ0259? / -(4-((5-Fluoro-2-methoxybenzamido)methyl)phenyl)-l-(l-oxo-l,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)- lZ7-pyrazole-4-carboxamide (MZ0259)

[0184] General Procedure E. Purification via column chromatography (DCM / MeOH = 15 / 1) afforded MZ0259 (55.7 mg, 96% yield) as a white solid. HPLC purity % (fe = 18.995 min). 'H NMR (300 MHz, CDCh / MeOD) 5 8.58 (dt, J= 8.0, 1.1 Hz, 1H), 8.49 (t, J= 5.7 Hz, 1H), 8.19 (s, 1H), 7.83 (dd, J= 9.4, 3.3 Hz, 1H), 7.78 - 7.66 (m, 3H), 7.62 (t, J= 7.9 Hz, 1H), 7.41 - 7.32 (m, 2H), 7.19 (ddd, J= 9.1, 7.2, 3.3 Hz, 1H), 7.12 (d, J= 7.4 Hz, 1H), 7.00 (dd, J= 9.1, 4.1 Hz, 1H), 5.93 (d, J= 7.4 Hz, 1H), 4.64 (d, J= 5.7 Hz, 2H), 3.94 (s, 3H).13C NMR (75 MHz, CDCh / MeOD) 5 165.2, 165.2, 165.1 (d, J = 1.9 Hz), 162.9, 160.1, 157.4 (d, J=239.9 Hz), 154.2 (d, J = 2.2 Hz), 140.2, 137.6, 136.2, 134.9, 134.3, 133.2 (z, J = 39.7 Hz), 131.9, 130.3, 128.4, 127.5, 126.4, 122.7 (d, J = 6.8 Hz), 121.2, 119.7 (d, J =23.4 Hz), 119.4 (q, J = 271.1 Hz), 118.3 (d, J = 25.2 Hz), 113.4 (d, J =7.7 Hz), 100.6, 56.8, 43.6.EXAMPLE 46SYNTHESIS OF MZ02625-Fluoro-2-methoxy-A-(4-nitrophenyl)benzamide (MZ0262)

[0185] To a solution of 5-fluoro-2-methoxybenzoic acid (425.4 mg, 2.5 mmol, 1 equiv.) and 4- nitroaniline (518.7 mg, 2.75 mmol, 1.1 equiv.) in pyridine / DCM (3:7) (25 mL) were added POCI3 (0.467 mL, 5 mmol, 2 equiv.) at 0 °C in a round bottom flask, then stirred at rt for overnight. The reaction mixture was concentrated and diluted with DCM. The organic layer was washed with a saturated NaHCO3 solution. The aqueous solution was extracted with DCM, and the organic layer was separated, washed by brine, dried with Na2SO4, and concentrated. The residue was purified bycolumn chromatography (DCM / MeOH = 50 / 1) to afford MZ0262 (187.0 mg, 26% yield) as a white solid. 1H NMR (300 MHz, DMSO-rh) 6 10.77 (s, 1H), 8.32 - 8.21 (m, 2H), 8.04 - 7.92 (m, 2H), 7.46 (dd, J= 8.6, 3.2 Hz, 1H), 7.39 (ddd, J= 9.1, 8.1, 3.2 Hz, 1H), 7.22 (dd, J= 9.1, 4.3 Hz, 1H), 3.88 (s, 3H).13C NMR (75 MHz, DMSO-rh) 6 164.2 (d, J= 1.9 Hz), 155.9 (d, J= 237.6 Hz), 152.9 (d, J= 1.9 Hz), 144.9, 142.5, 125.7 (d, J= 6.9 Hz), 124.9, 119.4, 118.5 (d, J= 22.9 Hz), 115.9 (d, J = 24.7 Hz), 113.8 (d,J= 8.0 Hz), 56.5.EXAMPLE 47 SYNTHESIS OF MZ0263 A-(4-Aminobenzyl)-5-fluoro-2-methoxybenzamide (MZ0263)

[0186] General Procedure A. 0.50 mmol scale, purification via column chromatography (DCM / MeOH = 25 / 1) afforded MZ0263 (113.4 mg, 87% yield) as a yellow solid. 'H NMR (300 MHz, CDCh / MeOD) 5 7.95 (dd, J= 9.5, 3.3 Hz, 1H), 7.50 - 7.36 (m, 2H), 7.17 (ddd, J= 9.0, 7.2, 3.3 Hz, 1H), 6.98 (dd, J= 9.1, 4.1 Hz, 1H), 6.75 - 6.65 (m, 2H), 4.02 (s, 3H), 2.33 (s, 2H).13C NMR (75 MHz, CDCh / MeOD) 5 162.2 (d, J= 1.9 Hz), 157.1 (d, J = 239.9 Hz), 153.4 (d, J= 2.1 Hz), 143.7, 128.9, 123.0 (d, J = 6.8 Hz), 122.4, 119.3 (d, J = 23.5 Hz), 117.9 (d, J = 25.3 Hz), 115.6, 113.1 (d, J= 7.7 Hz), 56.6.EXAMPLE 48SYNTHESIS OF MZ0264A-(4-(5-Fluoro-2-methoxybenzamido)phenyl)-l -(1-oxo- l,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)- 177-pyrazole-4-carboxamide (MZ0264)

[0187] General Procedure E. Purification via column chromatography (DCM / MeOH = 15 / 1) afforded MZ0264 (6.7 mg, 12% yield) as a white solid. 'H NMR (300 MHz, CDCh / MeOD) 510.02 (s, 1H), 8.59 (d, J= 8.1 Hz, 1H), 8.21 (s, 1H), 7.88 (dd, J= 9.3, 3.3 Hz, 1H), 7.80 - 7.59 (m, 6H), 7.25 (ddd, J= 9.1, 7.2, 3.3 Hz, 1H), 7.14 (d, J= 7.4 Hz, 1H), 7.09 (dd, J= 9.1, 4.1 Hz, 1H), 5.95 (d, J= 7.4 Hz, 1H), 4.09 (s, 3H).13C NMR (201 MHz, CDCh / MeOD) 5 163.2, 163.0, 160.2, 157.8 (d, J = 240.3 Hz), 154.1, 140.4, 136.4, 135.2, 135.0, 134.6, 133.3 (q, .7 = 39.7 Hz), 132.1, 130.4, 130.4, 127.8, 126.5, 123.7 (d, J = 6.7 Hz), 121.7, 121.4, 120.1 (d, J = 23.6 Hz), 119.7 (d, J= 270.7 Hz), 118.5 (d, J= 25.4 Hz), 113.9 (d, J= 7.7 Hz), 100.6, 57.3.EXAMPLE 49SYNTHESIS OF MZ03024-Fluoro- 1 -metho xy-2-(4-nitrophenoxy)benzene (MZ0302)

[0188] To a solution of l-fluoro-4-nitrobenzene (388.0 mg, 2.75 mmol, 1.1 equiv.) and 5-fluoro- 2-methoxyphenol (355.3 mg, 2.5 mmol, 1 equiv.) in MeCN (25 mL) were added potassium carbonate (391.0 mg, 5 mmol, 2 equiv.). After addition, the reaction mixture was stirred at 80 °C overnight. Then the reaction mixture was filtered, concentrated, and purified by column chromatography chromatography (hexane / EtOAc = 15 / 1) to afford MZ0302 (394.8 mg, 60% yield) as a yellow solid. 'H NMR (300 MHz, CDC13) 6 8.19 (d, J= 2.2 Hz, 1H), 8.17 (d, J= 2.2 Hz, 1H), 7.04 - 6.92 (m, 4H), 6.88 (ddd, J= 8.5, 2.6, 0.9 Hz, 1H), 3.76 (s, 3H).13C NMR (75 MHz, CDCI3) 5 163.0, 156.8 (d, J= 241.8 Hz), 148.2 (d, .7= 3.1 Hz), 143.0 (d, J= 10.6 Hz), 142.8, 125.9, 116.1, 113.8 (d, .7= 9.2 Hz), 112.8 (d, .7= 22.4 Hz), 110.5 (d, .7= 25.3 Hz), 56.5.EXAMPLE 50SYNTHESIS OF MZ03034-(5-Fluoro-2-methoxyphenoxy)aniline (MZ0303)

[0189] General Procedure A. 1.40 mmol scale, purification via column chromatography (DCM / MeOH = 30 / 1) afforded MZ0303 (303.9 mg, 93% yield) as a brown solid. 'H NMR (300 MHz, CDCI3) 5 6.85 (dd, J= 8.9, 5.1 Hz, 3H), 6.72 - 6.60 (m, 3H), 6.51 (dd, J= 9.8, 3.0 Hz, 1H), 3.84 (s, 3H), 3.60 (s, 2H).13C NMR (75 MHz, CDCI3) 5 156.9 (d, J= 239.4 Hz), 148.3 (d, J= 9.9Hz), 148.1, 146.5 (d, J = 3.9 Hz), 143.1, 120.6, 116.2, 113.0 (d, .7 = 9.8 Hz), 108.2 (d, J = 22.2 Hz), 105.5 (d, J= 26.9 Hz), 56.6.EXAMPLE 51SYNTHESIS OF MZ03047V-(4-(5-Fluoro-2 -methoxyphenoxy )phenyl)-l-(l -oxo-1, 2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)- 177-pyrazole-4-carboxamide (MZ0304)

[0190] General Procedure E. Purification via column chromatography (DCM / MeOH = 10 / 1) afforded MZ0304 (50.2 mg, 93% yield) as a white solid. HPLC purity 97.9% (IR = 20.65 min). 'H NMR (300 MHz, DMSO-< / 6) 6 11.61 (s, 1H), 10.54 (s, 1H), 8.44 (d, J= 9.2 Hz, 2H), 7.92 (d, J= 7.6 Hz, 1H), 7.69 (dd, J= 8.5, 3.2 Hz, 3H), 7.29 (t, J= 6.1 Hz, 1H), 7.18 (dd, J= 9.1, 5.4 Hz, 1H), 7.02 (td, J= 8.7, 3.2 Hz, 1H), 6.95 (d, J= 9.0 Hz, 2H), 6.90 (dd, J= 9.4, 3.1 Hz, 1H), 5.67 (d, J= 7.3 Hz, 1H), 3.76 (s, 3H).13C NMR (75 MHz, DMSO-t / 6) 6 160.8, 158.5, 156.0 (d, J = 237.9 Hz), 153.1, 147.6 (d, J= 2.9 Hz), 145.0 (d, J= 10.5 Hz), 140.2, 135.3, 133.9, 133.7, 131.7, 131.5, 131.3 (q, J = 39.2 Hz), 129.4, 127.0, 126.0, 121.6, 121.0, 119.2 (q, J = 270.8 Hz), 117.2, 114.1 (d, J= 9.6 Hz), 110.7 (d, J= 22.3 Hz), 108.3 (d, J= 25.6 Hz), 98.0, 56.2.EXAMPLE 52 SYNTHESIS OF MZ03081 -(1 -Oxo- 1 ,2-dihydroisoquinolin-5-yl)-A-(4-phenoxyphenyl)-5-(trifluoromethyl)- 1 / / -pyrazolc- 4-carboxamide (MZ0308)

[0191] General Procedure E. Purification via column chromatography (DCM / MeOH = 10 / 1) afforded MZ0308 (46.0 mg, 94% yield) as a white solid. HPLC purity 97.9% (fe = 20.65 min). 'H NMR (300 MHz, DMSO-< / 6) 6 11.61 (d, J= 5.5 Hz, 1H), 10.58 (s, 1H), 8.49 - 8.39 (m, 2H), 7.92 (dd, .7= 7.7, 1.3 Hz, 1H), 7.75 (dd, J= 8.8, 1.5 Hz, 2H), 7.67 (t, J= 7.9 Hz, 1H), 7.44 - 7.35 (m, 2H), 7.33 - 7.25 (m, 1H), 7.12 (td, J= 7.2, 1.1 Hz, 1H), 7.09 - 7.03 (m, 2H), 7.03 - 6.97 (m, 2H), 5.67 (d, J= 7.3 Hz, 1H).13C NMR (75 MHz, DMSO-< / 6) 6 160.8, 158.6, 157.2, 152.4, 140.2, 135.3, 134.4, 133.6, 131.7, 131.5, 131.3 (q, J= 38.9 Hz), 130.0, 129.4, 127.0, 126.0, 123.1, 121.6, 120.9, 119.4, 119.2 (q, J= 270.7 Hz), 118.0, 98.0.EXAMPLE 53SYNTHESIS OF MZ0309 l-(l-Oxo-l,2-dihydroisoquinofin-5-yl)-A-(4-(phenylamino)phenyl)-5-(trifLuoromethyl)-177- pyrazole-4-carboxamide (MZ0309)

[0192] General Procedure E. Purification via column chromatography (DCM / MeOH = 10 / 1) afforded MZ0309 (43.8 mg, 90% yield) as a pink solid. 'H NMR (300 MHz, DMSO-t / e) 5 11.60 (d, .7= 5.8 Hz, 1H), 10.38 (s, 1H), 8.44 (d, .7= 8.1 Hz, 1H), 8.40 (s, 1H), 8.11 (s, 1H), 7.91 (dd, J = 7.7, 1.3 Hz, 1H), 7.67 (t, J= 7.9 Hz, 1H), 7.59 (dd, J= 8.8, 1.7 Hz, 2H), 7.34 - 7.26 (m, 1H), 7.22 (t, J= 7.9 Hz, 2H), 7.09 (d, J= 8.7 Hz, 2H), 7.04 (d, J= 8.1 Hz, 2H), 6.79 (tt, J= 7.3, 1.2 Hz, 1H), 5.68 (d, J= 7.3 Hz, 1H).13C NMR (75 MHz, DMSO-< / 6) 6 160.8, 158.2, 143.8, 140.1, 139.6, 135.3, 133.7, 131.6, 131.5, 131.2 (q, J= 39.7 Hz), 129.3, 129.1, 127.0, 126.0, 121.3, 119.2, 119.2 (q, J = 270.6 Hz), 117.5, 116.1, 98.0.EXAMPLE 54SYNTHESIS OF MZ0310;V-(4-Bcnzoylphcnyl)-l -( l -oxo- l ,2-di hydro isoquinol in-5 -y I )-5 -(tri fl uorom ethyl )- 1 / / -pyrazo I c-4- carboxamide (MZ0310)

[0193] General Procedure E. Purification via column chromatography (DCM / MeOH = 10 / 1) afforded MZ0310 (47.1 mg, 94% yield) as a white solid.1H NMR (300 MHz, DMSO-A) 6 11.62 (d, J= 5.6 Hz, 1H), 10.92 (s, 1H), 8.54 - 8.39 (m, 2H), 7.94 (d, J= 9.0 Hz, 3H), 7.82 (d, J= 8.4 Hz, 2H), 7.78 - 7.71 (m, 2H), 7.67 (t, J= 7.7 Hz, 2H), 7.57 (t, J= 7.5 Hz, 2H), 7.30 (t, J= 6.5 Hz, 1H), 5.69 (d, J= 7.3 Hz, 1H).13CNMR (75 MHz, DMSO-r / 6) 6 194.6, 160.8, 159.2, 142.7, 140.4, 137.4, 135.3, 133.6, 132.3, 132.1, 131.7, 131.6 (q, J = 39.0 Hz), 131.5, 131.1, 129.4, 129.4, 128.4, 127.0, 126.0, 120.6 (q, J= 1.5 Hz), 119.1, 119.1 (q, J = 270.8 Hz), 97.9, 79.1.EXAMPLE 55SYNTHESIS OF MZ0311(5-Fluoro-2-methoxyphenyl)(4-nitrophenyl)methanone (MZ0311)

[0194] To a solution of l-fluoro-4-nitrobenzene (388.0 mg, 2.75 mmol, 1.1 equiv.), 5-fluoro-2- methoxybenzaldehyde (385.4 mg, 2.5 mmol, 1 equiv.) and 1,3-dimethylimidazolium iodide (56.3 mg, 0.25 mmol, 0.1 equiv.) in DMF (25 mL) was added sodium hydride (400.0 mg, 10 mmol, 4 equiv.) at -15 °C. After addition, the reaction mixture was stirred at 0 °C for 2 h. Then the reaction mixture was concentrated and purified by column chromatography (hexane / EtOAc = 4 / 1 to 2 / 1) to afford MZ0311 (262.1.0 mg, 38% yield) as a yellow solid. 'H NMR (300 MHz, CDCh) 6 8.33 - 8.24 (m, 2H), 7.97 - 7.87 (m, 2H), 7.31 - 7.15 (m, 2H), 6.99 (dd, J= 9.0, 4.0 Hz, 1H), 3.68 (s, 3H).13C NMR (75 MHz, CDCh) 5 193.4 (d, J= 1.5 Hz), 156.8 (d, J = 241.6 Hz), 153.8 (d, J =2.1 Hz), 150.2, 142.5, 130.3, 128.2 (d, J = 6.2 Hz), 123.5, 119.5 (d, J = 23.2 Hz), 116.7 (d, J = 24.5 Hz), 113.0 (d, J = 7.7 Hz), 56.1.EXAMPLE 56SYNTHESIS OF MZ0311(4-Aminophenyl)(5-fluoro-2-methoxyphenyl)methanone (MZ0312)

[0195] General Procedure A. 0.90 mmol scale, purification via column chromatography (hexane / EtOAc = 4 / 1 to 2 / 1) to afford MZ0312 (66.2 mg, 30% yield) as a yellow solid. 'H NMR (300 MHz, CDC13) 5 7.69 - 7.59 (m, 2H), 7.14 - 7.04 (m, 1H), 7.00 (dd, J= 8.0, 3.1 Hz, 1H), 6.90 (dd, J= 9.0, 4.1 Hz, 1H), 6.65 - 6.55 (m, 2H), 4.20 (s, 2H), 3.70 (s, 3H).13C NMR (75 MHz, CDCI3) 6 193.0 (d, J= 1.4 Hz), 156.8 (d, J= 240.7 Hz), 153.2 (d, J= 2.2 Hz), 151.8, 132.8, 131.2 (d, .7= 6.1 Hz), 127.5, 117.0 (d, .7= 23.0 Hz), 115.9 (d, J= 24.3 Hz), 113.8, 113.0 (d, J = 7.9 Hz), 56.6.EXAMPLE 57SYNTHESIS OF MZ0157 tert- Butyl 4-(3-amino-5 -methoxyphenoxy )butanoate (MZ0157)

[0196] General Procedure F. 0.7 mmol scale, purification via column chromatography (hexane / EtOAc = 2 / 1) afforded MZ0157 (174.2 mg, 88% yield) as a red solid. 'H NMR (300 MHz, CDCI3) 5 5.91 (s, 1H), 5.86 (s, 2H), 3.92 (t, J= 6.1 Hz, 2H), 3.73 (s, 3H), 3.65 (s, 2H), 2.40 (t, J= 7.4 Hz, 2H), 2.02 (p, J= 6.6 Hz, 2H), 1.45 (s, 9H).13C NMR (75 MHz, CDCI3) 6 172.6, 161.7, 161.1, 148.4, 94.4, 93.9, 91.6, 66.8, 55.2, 32.1, 28.1, 24.8.EXAMPLE 58SYNTHESIS OF MZ0160 terZ-Butyl 4-(3-methoxy-5-(l-(l-oxo-l,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-177- pyrazole-4-carboxamido)phenoxy)butanoate (MZ0160)

[0197] General Procedure E. 1 mmol scale, purification via column chromatography (DCM / MeOH = 15 / 1) afforded MZ0160 (554.3 mg, 94% yield) as a yellow solid. HPLC purity 98.3% (fe = 17.93 min). 'HNMR QOO MHz, CDCi / MeOD) 5 8.59 (d, .7= 8.1 Hz, lH), 8.17 (s, 1H), 7.74 (d, J= 7.6 Hz, 1H), 7.63 (t, J= 7.8 Hz, 1H), 7.13 (d, J= 7.2 Hz, 1H), 6.96 (s, 2H), 6.31 (s, 1H), 5.93 (d, J= 7.4 Hz, 1H), 4.01 (t, J= 5.5 Hz, 2H), 3.81 (s, 3H), 2.45 (t, J= 7.1 Hz, 2H), 2.06 (p, J= 6.4 Hz, 2H), 1.47 (s, 9H).13C NMR (75 MHz, CDCh / MeOD) 5 173.5, 162.9, 161.3, 160.6, 160.1, 140.2, 140.0, 136.2, 134.3, 133.1 (q, .7= 39.7 Hz), 131.9, 130.3, 127.5, 126.4, 121.2, 119.6 (q, J = 270.8 Hz), 100.6, 99.7, 99.3, 98.0, 81.1, 67.3, 55.6, 32.4, 28.2, 25.0. HRMS (ESI) calcd for C29H30F3N4O6 587.2112 [M + H]+; found, 587.2113.EXAMPLE 59 SYNTHESIS OF MZ01664-(3 -Metho xy-5-(l-(l -oxo-1, 2-dihydroisoquinolin-5-yl)-5 -(trifluoromethyl)- 177-pyrazole-4- carboxamido)phenoxy)butanoic acid (MZ0166)

[0198] General Procedure C. 0.40 mmol scale, purification via column chromatography (DCM / MeOH = 15 / 1 to 10 / 1) afforded MZ0166 (230.0 mg, quant, yield) as a white solid. HPLC purity 98.2% (fe = 15.15 min). 'H NMR (300 MHz, CDCh / MeOD) 5 8.59 (d, J= 7.8 Hz, 1H), 8.16(s, 1H), 7.75 (d, J= 7.4 Hz, 1H), 7.64 (t, J= 7.7 Hz, 1H), 7.13 (d, J= 7.2 Hz, 1H), 6.95 (d, J= 9.8 Hz, 2H), 6.31 (t, J= 2.2 Hz, 1H), 5.94 (d, J= 7.1 Hz, 1H), 4.04 (t, J= 6.1 Hz, 2H), 3.82 (s, 3H), 2.52 (t, J = 7.3 Hz, 2H), 2.11 (p, J = 6.7 Hz, 2H).13C NMR (75 MHz, CDCh / MeOD) 5 176.1, 162.9, 161.3, 106.6, 160.1, 140.2, 140.0, 136.2, 133.9, 133.2 (q, J= 39.9 Hz), 132.0, 130.3, 130.2, 127.6, 126.5, 121.3, 119.5 (q, J= 271.3 Hz), 100.6, 99.7, 99.3, 98.0, 67.3, 55.6, 30.8, 24.9. HRMS (ESI) calcd for C25H22F3N4O6 531.4786 [M + H]+; found, 531.4785.EXAMPLE 60SYNTHESIS OF MZ0170-15-Amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)- 1-(4-(3 -metho xy-5-(l -(1-oxo-1 ,2-dihydroisoquinolin-5-yl)-5-(trifluoromcthyl)-l / / -pyrazolc-4- carboxamido)phcnoxy)butanoyl)- l / / -pyrazolc-4-carboxamidc (MZ0170-1)

[0199] General Procedure E. Purification via column chromatography (DCM / NHa-MeOH = 15 / 1) afforded MZ0170-1 (46.6 mg, 52% yield) as a white solid. HPLC purity 97.1% (fe = 17.37 min). 1H NMR (300 MHz, CDCh / MeOD) 5 8.58 (dt, J= 8.0, 1.2 Hz, 2H), 8.16 (s, 1H), 7.83 (dd, J = 9.4, 3.3 Hz, 1H), 7.74 (dd, J= 7.7, 1.4 Hz, 1H), 7.63 (t, J= 7.9 Hz, 1H), 7.57 - 7.45 (m, 4H), 7.20 (ddd, J = 9.1, 7.2, 3.3 Hz, 1H), 7.12 (d, J= 7.4 Hz, 1H), 7.01 (dd, J= 9.1, 4.1 Hz, 1H), 6.92 (d, J= 2.2 Hz, 2H), 6.26 (t, J = 2.2 Hz, 1H), 5.93 (d, J= 7.4 Hz, 1H), 4.72 (d, J= 5.9 Hz, 2H), 4.10 (t, J= 5.9 Hz, 2H), 3.97 (s, 3H), 3.79 (s, 3H), 3.27 (t, J= 7.1 Hz, 2H), 2.26 (p, J= 6.7 Hz, 2H).13C NMR (75 MHz, CDCh / MeOD) 5 176.4, 167.0, 165.3 (d, J = 1.9 Hz), 162.8, 161.2, 160.4, 160.0, 157.4 (d, J= 239.9 Hz), 154.9, 154.2 (d, J = 2.2 Hz), 153.2, 140.7, 140.2, 140.0, 136.2, 134.3, 133.1 (q, J = 39.6 Hz), 131.9, 131.3, 130.3, 130.2, 129.6, 128.3, 127.6, 126.4, 124.8, 122.6 (d,J= 7.0 Hz), 121.2, 119.8 (d, J = 23.5 Hz), 119.4 (q, J = 271.2 Hz), 118.4 (d, J= 25.2 Hz), 117.6, 113.4 (d, J= 7.7 Hz), 100.6, 99.6, 99.3, 97.8, 94.2, 67.1, 56.9, 55.6, 43.6, 32.4, 24.3. HRMS (ESI) calcd for C44H38F4N9O10 918.2593 [M + Na]+; found, 918.2584.EXAMPLE 61SYNTHESIS OF MZ0170-23-Amino-5-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)- 1-(4-(3 -metho xy-5-(l -(1-oxo- l,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-177-pyrazole-4- carboxamido)phcnoxy)butanoyl)- l / / -pyrazolc-4-carboxamidc (MZ0170-2)

[0200] General Procedure E. Purification via column chromatography (DCM / NHa-MeOH = 15 / 1) afforded MZ0170-2 (19.6 mg, 22% yield) as a white solid. HPLC purity 98.5% (fe = 16.25 min). 'HNMR QOO MHz, CDCh / MeOD) 5 8.58 (d, J= 8.5 Hz, 2H), 8.15 (s, 1H), 7.83 (dd, J= 9.3, 3.3 Hz, 1H), 7.75 (dd, J= 7.7, 1.4 Hz, 1H), 7.63 (t, J= 7.9 Hz, 1H), 7.59 - 7.47 (m, 4H), 7.21 (ddd, J= 9.1, 7.3, 3.3 Hz, 1H), 7.12 (d, J= 7.4 Hz, 1H), 7.03 (dd, J= 9.1, 4.1 Hz, 1H), 6.99 (s, 1H), 6.92 (s, 1H), 6.30 (t, J= 2.2 Hz, 1H), 5.93 (d, J= 7.3 Hz, 1H), 4.73 (d, J= 6.1 Hz, 2H), 4.10 (t, J= 6.0 Hz, 2H), 3.98 (s, 3H), 3.81 (s, 3H), 2.74 (t, J= 7.2 Hz, 2H), 2.24 (p, J= 6.7 Hz, 2H).13C NMR (75 MHz, CDCh / MeOD) 5 172.3, 167.0, 165.4 (d, J= 1.8 Hz), 162.9, 161.3, 160.4, 160.1, 157.4 (d, J = 239.9 Hz), 154.2 (d, .7= 2.1 Hz), 140.4, 140.2, 140.0, 136.2, 134.3, 133.1 (q, J = 39.9 Hz), 132.0, 131.2, 130.3, 130.3, 129.8, 129.7, 128.3, 127.6, 126.5, 122.6 (d, .7= 6.6 Hz), 121.3, 119.9 (d, J = 23.5 Hz), 119.5 (q, .7= 271.0 Hz), 118.4 (d, J= 25.1 Hz), 117.7, 113.4 (d, J = 1.1 Hz), 100.6, 99.5, 99.5, 98.0, 67.0, 56.8, 55.6, 43.7, 33.5, 25.0. HRMS (ESI) calcd for C44H38F4N9O10 896.2774 [M + H]+; found, 896.2785.EXAMPLE 62SYNTHESIS OF MZ03325-Amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-l-(2-(4-(3-methoxy-5-(l-(l- oxo- l,2-dihydroisoquinolin-5-yl)-5 -(trifluoromethyl)- 177-pyrazole-4- carboxamido)phenoxy)butanamido)ethyl)-177-pyrazole-4-carboxamide (MZ0332)

[0201] General Procedure E. Purification via column chromatography (DCM / MeOH = 10 / 1) afforded MZ0332 (14.3 mg, 30% yield) as a yellow solid. 'H NMR (300 MHz, CDCh / MeOD) 5 8.65 - 8.53 (m, 2H), 8.17 (s, 1H), 7.81 (dd, J= 9.3, 3.3 Hz, 1H), 7.75 (dd, J= 7.6, 1.4 Hz, 1H), 7.64 (t, J= 7.9 Hz, 1H), 7.52 (d, J= 8.4 Hz, 2H), 7.46 (d, J= 8.3 Hz, 2H), 7.21 (ddd, J= 9.1, 7.3, 3.3 Hz, 1H), 7.13 (d, J= 7.4 Hz, 1H), 7.03 (dd, J= 9.1, 4.1 Hz, 1H), 6.97 (t, J= 2.0 Hz, 1H), 6.92 (t, J= 2.0 Hz, 1H), 6.28 (t, J= 2.2 Hz, 1H), 5.93 (d, J= 7.4 Hz, 1H), 4.75 - 4.67 (m, 2H), 4.06 (t, J= 6.6 Hz, 2H), 4.00 (t, J= 6.1 Hz, 2H), 3.96 (s, 3H), 3.80 (s, 3H), 3.56 (t, J= 6.6 Hz, 2H), 2.41 (t, J= 7.3 Hz, 2H), 2.09 (p, J= 6.5 Hz, 2H).EXAMPLE 63SYNTHESIS OF MZ0317 tert- Butyl 2-(3-amino-5-methoxyphenoxy)acetate (MZ0317)

[0202] General Procedure A. Purification via column chromatography (DCM / MeOH = 25 / 1) afforded MZ0317 (1.20 g, 95% yield) as a brown solid. 'H NMR (300 MHz, CDC13) 5 5.91 (t, J = 2.2 Hz, 1H), 5.89 (t, J= 2.1 Hz, 1H), 5.86 (t, J= 2.0 Hz, 1H), 4.44 (s, 2H), 3.73 (s, 3H), 3.66 (s, 2H), 1.49 (s, 9H).13C NMR (75 MHz, CDCI3) 5 168.2, 161.8, 160.1, 148.5, 94.7, 94.6, 91.6, 82.3, 65.8, 55.3, 28.2.EXAMPLE 64SYNTHESIS OF MZ0320 terZ-Butyl 2-(3-methoxy-5-(l-(l -oxo-1 , 2-dihydroisoquinol in-5-yl )-5-(tri 11 uoromcthyl )-! / / - pyrazole-4-carboxamido)phenoxy)acetate (MZ0320)

[0203] General Procedure E. 3 mmol scale. Purification via column chromatography (DCM / MeOH = 25 / 1 to 20 / 1) afforded MZ0320 (441.8 mg, 32% yield) as a white solid. 'H NMR (300 MHz, CDC13) 6 11.75 (s, 1H), 9.12 (s, 1H), 8.61 (d, .7= 7.8 Hz, 1H), 8.16 (s, 1H), 7.62 (d, J = 7.4 Hz, 1H), 7.55 (t, J = 1.8 Hz, 1H), 7.16 (t, J= 6.0 Hz, 1H), 7.02 (d, J= 11.5 Hz, 2H), 6.29 (t, J= 2.1 Hz, 1H), 5.70 (d, J= 7.2 Hz, 1H), 4.52 (s, 2H), 3.73 (s, 3H), 1.49 (s, 9H).13C NMR (75 MHz, CDCh) 5 168.2, 163.4, 161.1, 159.2, 159.1, 140.2, 139.8, 135.6, 134.0, 132.7 (q, J= 39.5 Hz), 131.8, 130.2, 129.9, 126.9, 126.5, 120.9, 119.1 (d, J= 271.1 Hz), 100.6, 99.4, 98.9, 97.7, 82.7, 65.6, 55.4, 28.0.EXAMPLE 65SYNTHESIS OF MZ03212-(3 -Metho xy-5-(l-(l -oxo-1, 2-dihydroisoquinolin-5-yl)-5 -(trifluoromethyl)- l / / -pyrazolc-4- carboxamido)phenoxy)acetic acid (MZ0321)

[0204] General Procedure C. 0.90 mmol scale, afforded MZ0321 (542.4 mg, quant, yield) as a white solid without further purification.EXAMPLE 66SYNTHESIS OF MZ03245-Amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)- 1-(2-(3 -metho xy-5-(l -(1-oxo- l,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-l / 7-pyrazole-4-carboxamido)phenoxy)acetyl)- l / 7-pyrazole-4-carboxamide (MZ0324)

[0205] General Procedure E. Purification via column chromatography (CHCh / MeOH = 10 / 1) afforded MZ0324 (11.6 mg, 27% yield) as a white solid. 'H NMR (300 MHz, CDCh / MeOD) 5 8.64 (t,J= 6.0 Hz, 1H), 8.59 (dt,J= 8.0, 1.2 Hz, 1H), 8.20 (s, 1H), 7.83 (dd, J= 9.3, 3.3 Hz, 1H), 7.76 (dd, J= 7.7, 1.4 Hz, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.57 (d, J= 8.3 Hz, 2H), 7.51 (d, J= 8.3 Hz, 2H), 7.28 (s, 1H), 7.22 (ddd, J= 9.1, 7.2, 3.3 Hz, 1H), 7.13 (d, J= 7.4 Hz, 1H), 7.04 (dd, J= 9.1, 4.1 Hz, 1H), 6.93 (t, J= 2.1 Hz, 1H), 6.48 (t, J= 2.2 Hz, 1H), 5.94 (d, J= 7.4 Hz, 1H), 4.81 - 4.68 (m, 4H), 3.99 (s, 3H), 3.86 (s, 3H).EXAMPLE 67SYNTHESIS OF MZ03295-Amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-l-(2-(2-(3-methoxy-5-(l-(l- oxo- l,2-dihydroisoquinolin-5-yl)-5 -(trifluoromethyl)- l / / -pyrazolc-4- carboxamido)phenoxy)acetamido)ethyl)-l / / -pyrazole-4-carboxamide (MZ0329)

[0206] General Procedure E. Purification via column chromatography (CHCfi / MeOH = 10 / 1) afforded MZ0329 (18.9 mg, 42% yield) as a white solid. 'H NMR (300 MHz, CDCh / MeOD) 5 8.63 - 8.51 (m, 2H), 8.18 (s, 1H), 7.97 (t, J= 5.9 Hz, 1H), 7.83 (dd, J= 9.3, 3.3 Hz, 1H), 7.74 (dd, J= 7.7, 1.4 Hz, 1H), 7.63 (t, J= 7.8 Hz, 1H), 7.56 - 7.48 (m, 2H), 7.44 (d, J= 8.3 Hz, 2H), 7.20 (ddd, J= 9.1, 7.2, 3.3 Hz, 1H), 7.12 (d, J= 7.4 Hz, 1H), 7.08 - 6.98 (m, 2H), 6.94 (t, J= 2.0 Hz, 1H), 6.30 (t, J= 2.2 Hz, 1H), 5.93 (dd, J= 7.4, 0.7 Hz, 1H), 4.70 (d, J= 5.9 Hz, 2H), 4.51 (s, 2H), 4.12 (t, J= 6.4 Hz, 2H), 3.96 (s, 3H), 3.78 (s, 3H), 3.71 (q, J= 6.3 Hz, 2H).EXAMPLE 68SYNTHESIS OF MZ03443-Amino-5-(4-((5-fhioro-2-methoxybenzamido)methyl)phenyl)-l-(2-(2-(3-methoxy-5-(l-(l- oxo- l,2-dihydroisoquinolin-5-yl)-5 -(trifluoromethyl)- l / / -pyrazolc-4- carboxamido)phcnoxy)acctamido)cthyl)-l / / -pyrazolc-4-carboxamidc (MZ0344)

[0207] General Procedure E. Purification via column chromatography (DCM / MeOH = 10 / 1) afforded MZ0344 (10.2 mg, 22% yield) as a white solid. 'H NMR (300 MHz, CDCh / MeOD) 5 8.66 (t, J= 6.1 Hz, 1H), 8.58 (dt, J= 8.0, 1.1 Hz, 1H), 8.20 (s, 1H), 7.81 (dd, J= 9.3, 3.3 Hz, 1H), 7.77 - 7.66 (m, 2H), 7.63 (t, J= 7.8 Hz, 1H), 7.52 (d, J= 8.0 Hz, 2H), 7.40 - 7.32 (m, 2H), 7.21(ddd, J= 9.0, 7.2, 3.3 Hz, 1H), 7.14 - 7.08 (m, 2H), 7.03 (dd, J= 9.1, 4.2 Hz, 1H), 6.98 (q, J = 2.4 Hz, 1H), 6.33 (t, J= 2.3 Hz, 1H), 5.93 (d, J= 7.4 Hz, 1H), 4.74 (d, J= 6.1 Hz, 2H), 4.39 (s, 2H), 3.99 (s, 3H), 3.89 (dd, J= 6.6, 4.5 Hz, 2H), 3.83 (s, 3H), 3.60 (q, J= 5.7 Hz, 2H).EXAMPLE 69SYNTHESIS OF MZ0333 terZ-Butyl 2-(2-(3-amino-5-methoxyphenoxy)ethoxy)acetate (MZ0333)

[0208] General Procedure A. Purification via column chromatography (hexane / EtO Ac = 1 / 1) to afford MZ0333 (1.38 g, 93% yield) as a red solid. 'H NMR (300 MHz, CDC13) 5 5.93 (t, J = 2.2 Hz, 1H), 5.87 (dt, J= 4.2, 2.0 Hz, 2H), 4.13 - 4.05 (m, 4H), 3.92 - 3.84 (m, 2H), 3.72 (s, 3H), 3.66 (s, 2H), 1.48 (s, 9H).13C NMR (75 MHz, CDCI3) 5 169.7, 161.7, 160.8, 148.5, 94.5, 94.2, 91.7, 81.7, 69.9, 69.2, 67.4, 55.2, 28.2.EXAMPLE 70SYNTHESIS OF MZ0335 terZ-Butyl 2-(2-(3 -metho xy-5-(l-(l -oxo- l,2-dihydroisoquinolin-5-yl)-5 -(trifluoromethyl)- 1H- pyrazole-4-carboxamido)phenoxy)ethoxy)acetate (MZ0335)

[0209] General Procedure E. 3mmol scale. Purification via column chromatography (DCM / MeOH = 20 / 1 to 10 / 1) afforded MZ0335 (1.63 g, 90% yield) as a white solid. 'H NMR (300 MHz, DMSO-< / 6) 6 11.61 (d, J= 5.7 Hz, 1H), 10.47 (s, 1H), 8.44 (dt, J= 8.0, 1.1 Hz, 1H),8.41 (d, .7 = 0.9 Hz, 1H), 7.91 (dd,J= 7.7, 1.3 Hz, 1H), 7.67 (t, J= 7.9 Hz, 1H), 7.29 (dd,J= 7.3, 5.9 Hz, 1H), 6.99 (dt,J= 12.5, 1.9 Hz, 2H), 6.32 (t,J= 2.2 Hz, 1H), 5.66 (d, .7 = 7.3 Hz, 1H), 4.14 - 4.08 (m, 2H), 4.07 (s, 2H), 3.85 - 3.78 (m, 2H), 3.75 (s, 3H), 1.43 (s, 9H).13C NMR (75 MHz, DMSO-t / e) 6 169.3, 160.8, 160.5, 159.6, 158.8, 140.3, 140.2, 135.3, 133.6, 131.7, 131.5, 131.3 (q, J= 38.8 Hz), 129.4, 127.0, 126.0, 121.0 (q,J= 1.7 Hz), 119.1 (q, J= 270.8 Hz), 98.7, 98.3, 98.0, 96.5, 80.7, 69.0, 68.2, 67.1, 55.2, 27.7.EXAMPLE 71SYNTHESIS OF MZ03382-(2-(3 -Metho xy-5-(l-(l -oxo- l,2-dihydroisoquinolin-5-yl)-5 -(trifluoromethyl)- 1H -pyrazole-4- carboxamido)phenoxy)ethoxy)acetic acid (MZ0338)

[0210] General Procedure C. 2.40 mmol scale, afforded MZ0338 (1.50 g, quant, yield) as a white solid without further purification.EXAMPLE 72SYNTHESIS OF MZ03425-Amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-l-(2-(2-(3-methoxy-5-(l-(l- oxo- l,2-dihydroisoquinolin-5-yl)-5 -(trifluoromethyl)- l / / -pyrazolc-4- carboxamido)phcnoxy)cthoxy)acctyl)-l / / -pyrazolc-4-carboxamidc (MZ0342)

[0211] General Procedure E. Purification via column chromatography (DCM / MeOH = 10 / 1) afforded MZ0342 (13.2 mg, 30% yield) as a white solid. 'H NMR (300 MHz, CDCh / MeOD) 5 8.63 - 8.53 (m, 2H), 8.16 (s, 1H), 7.84 (dd, J= 9.3, 3.3 Hz, 1H), 7.73 (dd, J= 7.7, 1.4 Hz, 1H), 7.62 (t, J= 7.8 Hz, 1H), 7.57 - 7.52 (m, 2H), 7.48 (d, J= 8.3 Hz, 2H), 7.20 (ddd, J= 9.1, 7.2, 3.3 Hz, 1H), 7.11 (d, J = 7 A Hz, 1H), 7.07 - 6.97 (m, 2H), 6.91 (s, 1H), 6.31 (t,J= 2.2 Hz, 1H), 5.91 (d, J= 7.4 Hz, 1H), 4.71 (s, 2H), 4.28 (dd, J= 5.7, 3.3 Hz, 2H), 4.04 (dd, J= 5.4, 3.6 Hz, 2H), 3.97 (s, 3H), 3.79 (s, 3H).EXAMPLE 73SYNTHESIS OF MZ03455-Amino-3-(4-((5-fhioro-2-methoxybenzamido)methyl)phenyl)-l-(2-(2-(2-(3-methoxy-5-(l-(l- oxo- l,2-dihydroisoquinolin-5-yl)-5 -(trifluoromethyl)- l / / -pyrazolc-4- carboxamido)phcnoxy)cthoxy)acctamido)cthyl)-l / / -pyrazolc-4-carboxamidc (MZ0345)

[0212] General Procedure E. Purification via column chromatography (CHC3 / MeOH = 10 / 1) afforded MZ0329 (18.9 mg, 42% yield) as a white solid. 'H NMR (300 MHz, CDCh / MeOD) 5 8.63 - 8.51 (m, 2H), 8.18 (s, 1H), 7.97 (t, J= 5.9 Hz, 1H), 7.83 (dd, J= 9.3, 3.3 Hz, 1H), 7.74 (dd,J= 7.7, 1.4 Hz, 1H), 7.63 (t, J= 7.8 Hz, 1H), 7.56 - 7.48 (m, 2H), 7.44 (d, J= 8.3 Hz, 2H), 7.20 (ddd, J= 9.1, 7.2, 3.3 Hz, 1H), 7.12 (d, J= 7.4 Hz, 1H), 7.08 - 6.98 (m, 2H), 6.94 (t, J= 2.0 Hz, 1H), 6.30 (t, J= 2.2 Hz, 1H), 5.93 (dd, J= 7.4, 0.7 Hz, 1H), 4.70 (d, J= 5.9 Hz, 2H), 4.51 (s, 2H), 4.12 (t, J= 6.4 Hz, 2H), 3.96 (s, 3H), 3.78 (s, 3H), 3.71 (q, J= 6.3 Hz, 2H).EXAMPLE 74SYNTHESIS OF MZ03463-Amino-5-(4-((5-fhioro-2-methoxybenzamido)methyl)phenyl)-l-(2-(2-(2-(3-methoxy-5-(l-(l- oxo- l,2-dihydroisoquinolin-5-yl)-5 -(trifluoromethyl)- l / / -pyrazolc-4- carboxamiclo)phcnoxy)cthoxy)acctamiclo)cthyl)-l / / -pyrazolc-4-carboxamiclc (MZ0346)

[0213] General Procedure E. Purification via column chromatography (DCM / MeOH = 10 / 1) afforded MZ0346 (15.4 mg, 32% yield) as a white solid. 'H NMR (300 MHz, CDCi / MeOD) 5 8.66 - 8.54 (m, 2H), 8.23 (s, 1H), 7.84 (dd, J= 9.3, 3.3 Hz, 1H), 7.73 (dd, J= 7.7, 1.4 Hz, 1H), 7.62 (t, J= 7.9 Hz, 1H), 7.55 - 7.47 (m, 2H), 7.44 (t, J= 6.1 Hz, 1H), 7.37 - 7.32 (m, 2H), 7.20 (ddd, J= 9.1, 7.2, 3.3 Hz, 1H), 7.14 - 7.06 (m, 2H), 7.01 (dd, J= 9.1, 4.1 Hz, 1H), 6.85 (t, J= 2.0 Hz, 1H), 6.29 (t, J= 2.2 Hz, 1H), 5.92 (d, J= 7.5 Hz, 1H), 4.72 (d, J= 6.0 Hz, 2H), 4.22 - 4.14 (m, 2H), 3.99 (s, 3H), 3.95 (s, 2H), 3.86 (ddd, J= 11.5, 5.6, 2.2 Hz, 4H), 3.81 (s, 3H), 3.55 (q, J = 6.0 Hz, 2H).EXAMPLE 75SYNTHESIS OF MZ02845-Amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)- 1 -(1 -oxo- 1 ,2- dihydroisoquinolinc-5-carbonyl)-l / / -pyrazolc-4-carboxamidc (MZ0284)

[0214] General Procedure E. Purification via column chromatography (DCM / MeOH = 15 / 1) afforded MZ0284 (8.8 mg, 16% yield) as a white solid. HPLC purity 98.4% (fe = 17.09 min). 'H NMR (300 MHz, CDCh / MeOD) 5 8.54 (d, J= 8.2 Hz, 2H), 8.02 (dd, J= 7.5, 1.4 Hz, 1H), 7.82 (dd, J= 9.3, 3.3 Hz, 1H), 7.75 (s, 2H), 7.56 (t, J= 7.8 Hz, 1H), 7.48 (d, J= 8.3 Hz, 2H), 7.41 (s, 2H), 7.25 - 7.17 (m, 1H), 7.15 (d, J= 7.3 Hz, 1H), 7.00 (dd, J= 9.1, 4.1 Hz, 1H), 6.72 (d, J= 7.5 Hz, 1H), 4.68 (d, J= 5.9 Hz, 2H), 3.94 (s, 3H).13C NMR (201 MHz, CDCh / MeOD) 5 170.7, 166.9, 165.3, 163.3, 157.4 (d, J = 239.9 Hz), 155.9, 154.1, 153.9, 140.8, 136.8, 136.8, 134.8, 131.2, 130.8, 129.6, 129.6, 129.2, 128.2, 127.0, 125.8, 122.4 (d, J= 6.6 Hz), 119.9 (d, .7= 23.4 Hz), 118.4 (d, .7= 25.1 Hz), 113.3 (d, .7= 7.4 Hz), 104.0, 94.3, 56.8, 43.6.EXAMPLE 76 SYNTHESIS OF MZ02911 -( 1 -Oxo- 1 ,2-dihydroisoquinolin-5 -yl)-7V-(prop-2-yn- 1 -yl)-5 -(trifluoromethyl)- 177-pyrazole-4- carboxamide (MZ0291)

[0215] General Procedure E. 5 mmol scale, purification via column chromatography (DCM / MeOH = 25 / 1 to 20 / 1) afforded MZ0291 (1.25 g, 70% yield) as a yellow solid. 'H NMR (300 MHz, DMSO-tTs) 8 11.57 (s, 1H), 9.07 (t, J= 5.5 Hz, 1H), 8.42 (dt,J= 8.1, 1.1 Hz, 1H), 8.34 - 8.23 (m, 1H), 7.89 (dd, J= 7.6, 1.3 Hz, 1H), 7.64 (t, J= 7.9 Hz, 1H), 7.25 (dd, J= 7.7, 4.2 Hz, 1H), 5.62 (d, J= 7.3 Hz, 1H), 4.07 (dd, J= 5.7, 2.6 Hz, 2H), 3.18 (t, J = 2.5 Hz, 1H).13C NMR(75 MHz, DMSO-rh) 6 160.8, 159.7, 140.0, 135.3, 133.8, 131.6, 131.4 (q, J= 39.1 Hz), 131.4, 129.3, 126.9, 126.0, 120.1 (q, J= 1.3 Hz), 119.1 (q, J= 270.8 Hz), 98.0, 80.6, 73.2, 28.3.EXAMPLE 77SYNTHESIS OF MZ02925-Amino-l-(4-azidobutanoyl)-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-17 / - pyrazole-4-carboxamide (MZ0292)

[0216] General Procedure D. 1 mmol scale. Purification via column chromatography (DCM / MeOH = 25 / 1 to 20 / 1) afforded MZ0292 (287.4 mg, 58% yield) as a white solid. 'H NMR (300 MHz, CDC13) 5 8.32 (s, 1H), 7.96 (dd, J= 9.4, 3.3 Hz, 1H), 7.61 - 7.43 (m, 6H), 7.17 (ddd, J= 9.1, 7.1, 3.3 Hz, 1H), 6.95 (dd, J= 9.1, 4.1 Hz, 1H), 5.20 (s, 2H), 4.74 (d, J= 5.9 Hz, 2H), 3.95 (s, 3H), 3.42 (t, J= 6.7 Hz, 2H), 3.17 (t, J = 7.2 Hz, 2H), 2.04 (p, J= 7.0 Hz, 2H).13C NMR (75 MHz, CDCh) 5 175.4, 166.1, 164.3 (d, J= 1.9 Hz), 164.3, 157.3 (d, J = 240.3 Hz) , 154.7, 153.7 (d, J = 2.3 Hz), 152.9, 140.8, 131.1, 129.4, 128.2, 122.7 (d, J= 6.8 Hz), 119.3 (d, .7= 23.5 Hz), 118.8 (d, J= 25.1 Hz), 112.8 (d, J= 7.7 Hz), 94.2, 56.7, 50.5, 43.4, 32.3, 23.3.EXAMPLE 78SYNTHESIS OF MZ02945-(6-Azidohexanamido)-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-177-pyrazole-4- carboxamide (MZ0294)

[0217] General Procedure D. 1 mmol scale. Purification via column chromatography (DCM / MeOH = 25 / 1 to 20 / 1) afforded MZ0294 (221.5 mg, 42% yield) as a white solid. 'H NMR (300 MHz, CDCh) 5 12.02 (s, 1H), 10.60 (s, 1H), 8.34 (d, J= 5.5 Hz, 1H), 7.96 (dd, J= 9.4, 3.3 Hz, 1H), 7.61 - 7.52 (m, 2H), 7.47 (d, J= 8.2 Hz, 2H), 7.16 (ddd, J= 9.1, 7.2, 3.3 Hz, 1H), 6.95 (dd, J= 9.1, 4.1 Hz, 1H), 5.54 (s, 2H), 4.74 (d, J= 5.9 Hz, 2H), 3.94 (s, 3H), 3.29 (t, J= 6.8 Hz, 2H), 2.52 (t,J= 7.4 Hz, 2H), 1.78 (p, J= 7.4 Hz, 2H), 1.71 - 1.60 (m, 2H), 1.56 - 1.39 (m, 2H).13CNMR (75 MHz, CDCh) 5172.5, 166.3, 164.3 (d, J= 1.9 Hz), 157.3 (d, .7 = 240.3 Hz), 153.7 (d, J= 2.1 Hz), 149.2, 144.2, 140.2, 131.6, 129.6, 128.1, 122.7 (d, 7= 6.7 Hz), 119.1 (d, 7= 23.5 Hz), 118.8 (d, J= 25.1 Hz), 112.8 (d, J= 7.6 Hz), 112.9, 112.8, 97.0, 56.7, 51.2, 43.4, 36.6, 28.6, 26.2, 24.6.EXAMPLE 79SYNTHESIS OF MZ0295A-((l-(6-((4-Carbamoyl-3-(4-((5-fhioro-2-methoxybenzamido)methyl)phenyl)-177-pyrazol-5- yl)amino)-6-oxohexyl)-177-l,2,3-triazol-4-yl)methyl)-l-(l-oxo-l,2-dihydroisoquinolin-5-yl)-5- (trifluoromethyl)- l / 7-pyrazole-4-carboxamide (MZ0295)

[0218] To a solution of MZ0291 (21.6 mg, 0.06 mmol, 1.2 equiv.) and MZ0294 (26.1 mg, 0.05 mmol, 1.5 equiv.) in DMF (1 mL) were added copper iodide (1.9 mg, 0.01 mmol, 0.2 equiv.) and sodium ascorbate (2.0 mg, 0.01 mmol, 0.2 equiv.). After addition, the reaction mixture was stirred at rt overnight. Then the reaction mixture was filtered, concentrated, and purified by column chromatography (DCM / MeOH = 5 / 1) afforded MZ0295 (221.5 mg, 42% yield) as a white solid. . HPLC purity 98.4% (fa = 17.09 min). 'H NMR (300 MHz, CDCh / MeOD) 5 8.68 - 8.59 (m, 1H), 8.56 (d, J= 8.1 Hz, 1H), 8.09 (s, 1H), 7.82 (d, J= 7.8 Hz, 2H), 7.71 (d, J= 7.4 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.55 (d, J= 7.7 Hz, 2H), 7.49 (d, J= 7.8 Hz, 2H), 7.21 (td, J= 8.2, 3.3 Hz, 1H), 7.10 (d, 7= 7.6 Hz, 1H), 7.04 (dd, J = 9.2, 4.1 Hz, 1H), 5.87 (d, 7= 7.6 Hz, 1H), 4.73 (d, 7= 6.1 Hz, 2H), 4.63 (s, 2H), 4.41 (t, J= 7.1 Hz, 2H), 3.98 (s, 3H), 2.52 (t, J= 7.4 Hz, 2H), 2.00 (p, J = 7.4 Hz, 2H), 1.81 (p, 7= 7.4 Hz, 2H), 1.46 (p, J= 8.8 Hz, 2H).13C NMR (75 MHz, CDCh / MeOD) 5 188.5, 165.3, 163.5, 162.8, 160.7, 160.1, 148.2, 147.6 (q, J = 34.3 Hz), 140.3, 136.1, 135.5, 134.3, 133.8 (q, 7= 39.9 Hz), 132.0, 131.9, 131.3, 130.4, 130.4, 129.0, 127.6, 126.5, 121.8 (q, J = 273.9 Hz), 120.4 (q, J= 1.4 Hz), 119.3 (d, 7= 271.2 Hz), 116.1, 102.2 (1, 7= 3.1 Hz), 100.4, 99.2, 46.0, 45.4, 45.0, 42.3.EXAMPLE 80 MALT1 EXPRESSION IN IBN-R MCL CELLS

[0219] BTKi like ibrutinib and BCL2 inhibitors like venetoclax are highly efficacious in treating patients with MCL. However, the development of single or dual resistance to targeted therapy is common. To investigate the potential mechanism underlying this resistance, whole transcrip tomeprofiling was performed on nine MCL cell lines that had varying degrees of targeted agent sensitivity (FIG. 1A). MALT1 was among the top differentially expressed genes (DEGs) across the genome-wide transcriptome and among all NF-KB signaling genes, and it was more highly expressed in IBN-R than IBN-S cells (p < 0.001) (FIG. 1B-F). MALT1 expression was also significantly higher in cells resistant to both IBN and venetoclax (Dual-R cells) than in cells sensitive to both drugs (Dual-S cells) (p < 0.001) (FIG. ID). Interestingly, expression of CARD11, which encodes the upstream binding partner of MALT 1, was lower in IBN-R MCL cells (data not shown).

[0220] Elevated MALT1 expression was also observed in IBN-R MCL cells (p < 2.22e-16) compared to IBN-S MCL cells in primary patient samples, based on our scRNA sequencing analysis (FIG. 2A). Furthermore, quantitative PCR revealed that MALT1 expression was also higher in primary MCL cells compared to healthy PBMCs (p < 0.05) (FIG. 2B). Consistent with the whole transcriptomic analysis, IBN-R and Dual-R MCL patient samples expressed significantly higher levels otMALTl compared with IBN-S MCL patient samples (p < 0.001 and p < 0.01, respectively) (FIG. 2C). High MALT1 expression was associated with poor clinical outcomes (p < 0.05) (FIG. 2D) as it also was for two similarly-defined patient cohorts described by others (p < 0.05) (FIG. 2E-F).

[0221] MALT1 is crucial in mediating NF-KB and other signaling pathways. Gene set enrichment analysis (GSEA) revealed that multiple cancer signaling hallmarks, including MYC targets, NF- KB signaling, and G2M checkpoint, were associated with IBN-R and Dual-R MCL cells (FIG. 2G). Importantly, deeper analysis showed that both canonical and non-canonical NF-KB signaling were upregulated in IBN-R and Dual-R cells at the transcriptional level (FIG. 2H). This was further confirmed by the activation of NF-KB family members in IBN-R cells compared to IBN-S cells (FIG. 21), suggesting upregulated NF-KB signaling associated with poor MCL patient survival.EXAMPLE 81MALT1 ACTS AS AN ONCOGENIC DRIVER OF IBN RESISTANCE IN MCL CELLS

[0222] To investigate how MALT1 overexpression may confer IBN resistance, MALT1 protein levels were assessed in JeKo BTK KD_1 and _2 cells with intrinsic IBN resistance and in JeKo-R cells with acquired IBN resistance. These IBN-R cells expressed much higher levels of MALT 1 protein, even as CARD11 protein was expressed at notably reduced levels (FIG. 3 A). The cleavage of MALT 1 substrates was also investigated to determine whether MALT1 overexpression was correlated with increased paracaspase activity. Higher MALT1 expression indeed correlated positively with the increased cleavage of its substrates (FIG. 3 A). MALT1 endogenous cleavageactivity in JeKo BTK KD_2 cells was further confirmed to be significantly higher than that observed in JeKo-1 cells (p < 0.0001) (FIG. 3B).

[0223] MALT1 overexpression and its heightened paracaspase activity were further validated in MCL cell lines having primary IBN resistance (FIG. 3C) and in primary patient MCL cells (FIG. 3D). Transient knockdown (KD) of MALT1 expression by MALT1 shRNA (as outlined in Pan et al. Oncogene, 2016; 35(7)919-28) resulted in significant cell proliferation perturbation in vitro in all MCL cell lines tested at 24 (p < 0.05), 48 (p < 0.05) and 72 (p < 0.001) hours (FIG. 3E-F). Further, ectopic expression otMALTl induced by doxycycline in JeKo-MALTl cells promoted cell proliferation at days 3-5 (p < 0.01) compared to parental JeKo-1 cells (FIG. 3G-H). This suggested that MALT1, as a key BTK downstream signaling molecule, was critical for MCL cell proliferation.

[0224] CRISPR-Cas9 technology was used to generate stable cell lines from JeKo-1 and JeKo BTK KD_2 cells with KO of MALT1 or CARD11. No MALT1 or CARD11 protein was detected in the resulting cell lines (FIG. 4A). Consistent with the transient KD assessment, stable KO of MALT1 led to significant suppression of cell proliferation in both JeKo-1 and JeKo BTK KD_2 cells (p < 0.0001) (FIG. 4B-C). In contrast, stable KO of CARD11 resulted in notable inhibition of cell proliferation in IBN-S JeKo-1 cells but not IBN-R JeKo BTK KD_2 cells (FIG. 4B-C).

[0225] Subcutaneous CDX models were next established in immunodeficient NOD.Cg-Prkdc scid I12rg tml Wjl / SzJ (NSG) mice. Consistent with the in vitro cell proliferation assays (FIG. 4B- C), MALT1 KO greatly suppressed tumor growth and serum levels of B2M, a systematic indicator of tumor load, in both JeKo-1 (p < 0.0001 and p < 0.05, respectively) and JeKo BTK KD_2 CDX (p < 0.001 and p < 0.0001, respectively) models, while CARD11 KO suppressed tumor growth and serum levels of B2M in only the JeKo-1 CDX model 1 (p < 0.0001 and p < 0.05, respectively) (FIG. 4D-H). These data demonstrate that MALT1 is crucial in driving MCL tumorigenesis and IBN resistance via a compensatory mechanism that appears to bypass upstream BTK-CARD11 signaling.EXAMPLE 82MI-2 BLOCKS MALTl’S PARACASPASE ACTIVITY AND MCL CELL PROLIFERATION BY SUPPRESSING NF-KB SIGNALING

[0226] To assess the potential role of MALTl ’s paracaspase activity, MCL cells were treated with MI-2 (31). A 6-h MI-2 treatment suppressed endogenous MALT1 cleavage activity in a dosedependent manner in JeKo-1 (p < 0.0001), JeKo BTK KD_2 (p < 0.0001), and Z138 (p < 0.0001) cells (Figure 5 A). A 72-h treatment with MI-2 produced a potent loss of viability in JeKo-1 and JeKo-derived resistant cells as well as other cell lines with half-maximal inhibitory concentrations(ICso) in the nanomolar range (FIG. 5B-D). After 24 h of treatment, MI-2 also effectively inhibited cell viability of primary MCL patient cells resistant to IBN (FIG. 5E). This activity was lost when MALT1 expression was depleted by shRNA in JeKo-1 and JeKo BTK KD_2 cells (FIG. 5F). MI-2 also induced robust apoptosis in MCL cells regardless of their IBN sensitivity (p < 0.001) (FIG. 5G), which was accompanied by cleavage of poly(ADP-ribose) polymerase (PARP) and caspase3 in JeKo BTK KD_2 and primary MCL patient cells (FIG. 5H). To further assess the potency of MI-2 against MCL in vivo, we engineered JeKo BTK KD_2 cells to stably express the luciferase reporter gene and then established JeKo BTK KD_2 CDX models. MI-2 treatment (25 mg / kg, daily) significantly inhibited tumor growth in these IBN-R CDX models (p < 0.001) (FIG. 51- J).

[0227] Both canonical and non-canonical NF-KB signaling pathways were upregulated in IBN- R cells (FIG. 2H) suggesting that MALT1 overexpression may be the key factor conferring their constitutive activation. To address this, unbiased whole transcriptome GSEA profiling was performed on JeKo- 1 and JeKo BTK KD_2 cells treated with MI-2 or vehicle (dimethyl sulfoxide, DMSO) for 6 h. NF-KB signaling and related inflammatory responses as the top downregulated pathways upon MALT1 inhibition (FIG. 6A). These analyses also revealed that MALT inhibition suppressed both canonical and non-canonical NF-KB signaling in these cells (FIG. 6B). This was further validated by assays assessing p65, p50, c-Rel, RelB, and p52 activity in JeKo-1 (p < 0.05) and JeKo BTK KD_2 (p < 0.0001) cells (FIG. 6C-D). In the IBN-S cells, canonical NF-KB family members were suppressed to a greater extent upon MALT1 inhibition compared to the non- canonical family members. Conversely, in the JeKo BTK KD_2 cells both the canonical and non- canonical NF-KB family members were markedly inhibited.

[0228] Excess ROS production can trigger apoptosis, and NF-KB activation attenuates ROS production to promote cell survival. MALT1 inhibition triggered upregulation of the ROS pathway (p < 0.05) and ROS production (p < 0.05) and loss of mitochondrial membrane potential (ATm) (p < 0.0001) (FIG. 6E-F), suggesting a role of mitochondrial dysfunction in the observed MI-2-induced ROS production. Together, these data suggest that targeting MALT1 paracaspase activity with MI-2 is effective in overcoming IBN resistance in MCL via modulating NF-KB activity and the ROS pathway.EXAMPLE 83MALT1 AND BTK ARE REQUIRED FOR MCL CELL DISSEMINATION IN VIVO

[0229] Once disseminated, MCL can involve one or more lymph nodes, peripheral blood (PB), bone marrow (BM), spleen, liver, gastrointestinal tract, and even the central nervous system, as can be recapitulated using CDX or PDX xenografts. Further, MALT 1 -dependent cleavage of BCL10 reportedly controls integrin-dependent adhesion of T cells and MALT lymphomas.Therefore, it was speculated that MALT1 may mediate cell adhesion, and potentially MCL dissemination, via interaction between MCL cells and the TME.

[0230] Disseminated CDX models were established by intravenous injection using JeKo-1 and JeKo BTK KD_2 cells with or without MALT1 or CARD11 KO (FIG. 7A). In CDX models using JeKo-1 cells, the tumor cells accumulated markedly in the spleen, liver, BM, and even in PB (FIG. 7B-I), demonstrating MCL dissemination to these tissues. In JeKo-1 cells with MALT1 KO, a significant decrease in the frequency of tumor cells was observed in the spleen (p < 0.0001), liver (p < 0.0001), BM (p < 0.0001), and PB (p < 0.01) (FIG. 7B-I). BTK KD in the JeKo-1 cells showed comparably decreased tumor cell presence in the spleen (p < 0.001) and BM (p < 0.001), which was also seen with MALT1 KO cells (FIG. 7C-F). However, BTK KD did not result in dramatic suppression in tumor cell presence in PB or liver (FIG. 7B and FIG. 5G-I).

[0231] CARD 11 KO in JeKo-1 cells showed modest effects on tumor cell presence in PB (p < 0.05), and it had no obvious impact on tumor cell incidence in the spleen, liver, or BM (FIG. 7B- G). MALT1 KO in JeKo BTK KD_2 cells did not appear to have an effect on the tumor burden in the spleen or liver, since these cells were already very limited in their quantity at these sites. However, MALT1 KO, but not CARD11 KO, showed an additional significant decrease in the tumor cell incidence in BM (p < 0.0001) and PB (p < 0.01).

[0232] An in vivo short-term homing assay was performed on a patient apheresis sample that contained > 95% MCL cells. The cells were pretreated with MI-2 or DM SO for 30 min, then washed before injecting intravenously into NSG mice. The percentage of MCL cells in PB was determined to be similar for both groups at 1 h post-injection (FIG. 8 A), but at 4 d post-drug pretreatment it was significantly reduced in the MI-2 group compared to control in PB (p < 0.05), spleen (p < 0.05), and BM (p < 0.0001) (FIG. 8B-D). To assess the long-term effect of MALT 1 inhibition on MCL tumor dissemination, we established PDX models by intravenous injection of IBN-R PDX cells. Treatment with MI-2, but not IBN, significantly decreased tumor burden in the spleen (p < 0.05), BM (p < 0.05), and PB (p < 0.05) (FIG. 8E-F). These data indicate that MALT1 inhibition is potentially useful in suppressing dissemination in IBN-R MCL tumors.EXAMPLE 84MALT1 INHIBITION POTENTIALLY SUPPRESSES CELL PI3K-AKT-mTOR SIGNALING, ADHESION, AND MIGRATION IN VITRO

[0233] Unbiased reverse-phase protein array (RPPA) analyses were performed on cultured MCL cells to further understand the possible mechanisms of MALT 1 -driven dissemination. IBN- sensitive and -resistant cells were treated with MI-2 for 6 h and subjected to RPPA profiling. Many molecules involved in PI3K-AKT-mTOR signaling, including phosphorylated mTOR, rictor,AKT, P70-S6K, and S6, were dramatically downregulated in all of these cells following MI-2 treatment (FIG. 9A).

[0234] Activation of PI3K-AKT-mTOR and intcgrin-[31 signaling is reportedly important for TME-driven IBN resistance and was confirmed in IBN-R cells. Therefore, it was hypothesized that MALT1 modulates MCL dissemination via regulating PI3K-AKT-mTOR and intcgrin-[31 signaling. Phosphorylation of AKT, S6, and p90RSK was upregulated in JeKo-1 -derived ibrutinib- resistant cell lines (FIG. 9B). A 1-h MI-2 pretreatment effectively blocked phosphorylation and activation of PLCy2, BTK, and AKT when JeKo-1 cells were stimulated with anti-IgM for 5 min to induce BCR-triggered PI3K-AKT-mTOR signaling (FIG. 9C). Consequently, MI-2 treatment also led to a dose-dependent reduction in intracellular ATP levels in all MCL cell lines tested (FIG. 9D).

[0235] Whole transcriptome profiling revealed that apical junction regulation was one of the top cancer hallmarks notably downregulated following MALT1 inhibition (FIG. 6A). In addition to apical junction regulation, further analysis revealed that MALT1 inhibition suppressed multiple pathways involved in MCL dissemination, including cell adhesion molecules, focal adhesion complexes, and adherents junction proteins (FIG. 10A). DEG analysis showed that multiple integrin signaling molecules and cell adhesion molecules were downregulated upon MALT1 inhibition in both JeKo-1 and JeKo BTK KD_2 cells (FIG. 10B-C). Most of these proteins can directly or indirectly regulate integrin-mediated signaling and cell adhesion.

[0236] Extracellular matrix (ECM) components were screened to further address this finding. Among 8 ECM components, fibronectin and laminin were identified as the dominant ECM factors involved in cell adhesion using MCL cell lines; interestingly, IBN-R cells (JeKo-R, JeKo BTK KD_1 and JeKo BTK KD_2) showed significantly higher cell adhesion to fibronectin (p < 0.0001), laminin (p < 0.0001), and bovine serum albumin (p < 0.0001) compared to IBN-S JeKo-1 cells (FIG. 10D). MI-2 treatment diminished MCL cell adhesion to fibronectin (p < 0.001), laminin (p < 0.01), and FBS (p < 0.0001), especially for IBN-R MCL cells (FIG. 10E-G). Furthermore, MI- 2 treatment diminished the capacity of MCL cells to migrate through Transwell inserts to a preseeded HS-5 stromal cell monolayer (p < 0.0001) (FIG. 10H). MCL cells showed greater capacity in cell migration through Transwell inserts to stromal cells than to the culture supernatants harvested from HS-5 stromal cell cultures (p < 0.0001) (FIG. 101), suggesting that this HS-5- induced cell migration requires MCL-stromal cell contact. Together, these data suggest that MALT1 plays important roles in mediating cell adhesion, migration, and dissemination.EXAMPLE 85CO-TARGETING OF MALT1 AND BTK OVERCOMES IBN RESISTANCE IN VITRO AND IN VIVO

[0237] To screen for combinational therapies that have the potential to overcome IBN resistance, MCL cells were treated with MI-2 in combination with more than ten drugs either FDA approved or under investigation. Among these, MI-2 in combination with IBN (MI-2+IBN combination) showed the greatest anti-MCL efficacy against two IBN-R patient samples and one IBN-R PDX sample (FIG. 11A-B). This was further validated using MCL cell lines and additional patient and PDX samples (FIG. 11C-D). Consistent with this, the MI-2 and IBN combination significantly induced apoptosis that was higher than with either single agent in JeKo-1 and JeKo BTK KD_1 and 2 cells (Fig. HE).

[0238] Unbiased RPPA profiling showed that the MI-2 and IBN combination induced a synergistic effect on protein profiles of both JeKo-1 and JeKo BTK KD_2 cells (FIG. HF). The top cancer hallmarks that were suppressed by the combination were PI3K-AKT-mTOR signaling, apical junction proteins, G2M checkpoint proteins, and E2F target proteins (FIG. 11G), while apoptosis and hypoxia were among the top cancer hallmarks that were upregulated (FIG. 11G). PI3K-AKT-mTOR and NF-KB signaling were further confirmed to be dramatically downregulated via western blotting in JeKo-1 and JeKo BTK KD_2 cells treated with the MI-2 and IBN combination, compared to either single agent or vehicle (FIG. 11H). MI-2 in combination with PBN also showed stronger anti-tumor activity than either single agent in IBN- R cells (p < 0.0001) (FIG. 12A). Of note, JeKo-R and JeKo BTK KD_2 were demonstrated to be resistant to PBN (FIG. 12B).

[0239] MI -2 is commonly used as a chemical tool to inhibit MALT1 paracaspase in mechanistic and functional studies. For rational therapeutic development, another MALT1 inhibitor named safimaltib was tested. Safimaltib was recently developed as a specific MALT1 paracaspase inhibitor (e.g., see Philippar et al. Cancer Res., 2020; 80( 16)), and it is currently under early clinical investigation in patients with non-Hodgkin lymphoma and chronic lymphocytic leukemia (NCT03900598). Safimaltib showed effective anti-MCL activity not only in IBN-sensitive cells, but also in both IBN- and PBN-resistant cells (FIG. 12B). Additionally, safimaltib in combination with IBN or PBN was highly synergistic against JeKo-R cells in vitro (FIG. 12C). Furthermore, safimaltib at 50 mg / kg daily in combination with PBN at 30 mg / kg twice daily dramatically inhibited tumor growth of an IBN-R PDX model (p < 0.01), and prolonged mouse survival (p < 0.05) beyond that observed by either single agent treatment (FIG. 12D-E). No effects on body weight were observed for either single agent or the combination treatment during this experiment(FIG. 12F). Together, these data indicate that co-targeting of MALT 1 and BTK is promising to overcome resistance to BTK inhibitors in MCL.EXAMPLE 86BIOLOGICAL METHODSCell Samples

[0240] MCL specimens and healthy peripheral blood mononuclear cell (PBMC) samples were acquired from patients and healthy donors, respectively, after obtaining written informed consent following the University of Texas MD Anderson Cancer Center Institutional Review Board- approved protocols and in accordance with the Declaration of Helsinki. The MCL patient characteristics are presented in TABLE 3.TABLE 3Reagents and Antibodies

[0241] IBN, PBN, MI-2, and venetoclax were purchased from Selleck Chemicals (Houston, TX). Safimaltib was generated by custom synthesis through a contract research organization service. TABLE 4 lists antibodies used and their sources. DMSO was purchased from Sigma- Aldrich (St Louis, MO).TABLE 4Cell Culture

[0242] The MCL cell lines JeKo-1 , JeKo-R, JeKo BTK KD_1 , JeKo BTK KD_2, Mino, Mino- VR, Rec-1, Rec-VR, Grant-519, Grant-519-VR, Maver-1, Z138, and SP-49 were maintained in RPMI 1640 medium supplemented with 1% penicillin / streptomycin, 25 mM 4-(2-hydroxyethyl)- 1 -piperazineethanesulfonic acid (HEPES), and 10% fetal bovine serum (FBS; all from Sigma- Aldrich, St Louis, MO), and cultured in a CO2incubator at 37° C as described previously (Zhang et al. Nat Commun, 2021; 72(1):2877). JeKo-1 cells are sensitive to IBN but resistant to venetoclax (Fig. 1A). JeKo BTK KD_1 and 2 cells derived from JeKo-1 cells have intrinsic IBN resistance due to BTK depletion, and JeKo-R cells have acquired resistance to IBN. Mino-VR, Rec-VR, and Granta-519-VR cells have acquired resistance to venetoclax (VEN). These cells were grouped into three pairings based on their drug sensitivity: (1) IBN-R versus IBN-S cells, (2) VEN-R versus VEN-S cells, and (3) Dual-R versus Dual-S cells (Fig. 1 A). In addition, Maver- 1 and Z138 are primarily resistant to IBN while SP-49 is sensitive to IBN. Cell lines were authenticated by single-nucleotide polymorphism profile fingerprinting.Generation of MCL Cells with Stable Gene KD Via shRNA or With Inducible Expression of MALT1

[0243] The method for generating MCL cells with stable MALT1 KD has been described elsewhere (Pan et al. Oncogene, 2016; 35(7):919-28). Quantitative real-time PCR was used to quantify the KD efficiency; > 70% of mRNA expression was knocked down in all cells with stable MALT1 KD.Generation of JeKo-MALTl Cells with Inducible Expression ofMALTl

[0244] MALT 1 -with C-terminal Flag tag (MALT 1 -F) was cloned into the pINDUCER lentiviral vector. Lentivirus carrying MALT1-F was prepared and used to transduce JeKo-1 cells asdescribed previously (Meerbrey et al. Proc Natl Acad Sci U S A, 2011; 70S(9):3665-70). Doxycycline (Sigma- Aldrich, St Louis, MO), at 1 pg / mL was used to induce MALT1-F expression in JeKo-1 cells.Genetic Knockout of MALT1 or CARD11 in JeKo-1 and JeKo BTK KD 2 Cells

[0245] MALT1 and CARD11 KO cell lines were generated using the CRISPR / Cas9 genome editing system as described previously (Li et al. Mol Cancer Ther, 2019; 7S(2):267-77).Establishment of JeKo BTK KD_GFP-Luc Cells

[0246] JeKo BTK KD_2 cells were infected with pseudo-lentiviruses packaged with pGFl- CMV-GFP-Luc and then sorted for GFP-positive cells. These cells were further expanded for a second sorting for GFP-positive cells and maintained in the same conditions as the other MCL cell lines.Bulk RNA Sequencing And Analysis

[0247] Bulk RNA sequencing and analysis were performed as described previously (Zhang et al. Sci Transl Med, 2019; 77(491)). The sequencing dataset has been deposited in the European Genome-Phenome Archive (EGA) database. An accession number is currently awaited. cDNA Synthesis and Quantitative Real-Time PCR

[0248] The method for cDNA synthesis and quantitative real-time PCR has been described elsewhere (Pan et al. Oncogene, 2016; 35(7):919-28). Briefly, first-strand cDNA was synthesized via the iScript cDNA Synthesis Kit (1725037, Bio-Rad, Hercules, CA) according to the manufacturer’s manual. Quantitative real-time PCR was conducted using SsoAdvanced Universal SYBR Green Supermix (1725271, Bio-Rad) according to the manufacturer’s manual. KiCqStart SYBR Green Primers Predesigned primers for ALTl and GAPDH (Sigma) were used in real-timer PCR experiments. MALT1 mRNA expression was normalized to GAPDH and further normalized to one of the PBMCs samples from the healthy donors.Cell Viability and Apoptosis Assays

[0249] Cell viability and apoptosis assays were performed as described previously (Zhang et al. Nat Commun, 2021; 72(1):2877). Briefly, cells from MCL cell lines were seeded at 10,000 cells per well, and PDX tumor cells or primary patient tumor cells were seeded at 125,000 cells per well in a 96-well white flat-bottomed plate (cat. 3558; Coming, Tewksbury, MA). Cells were treated in triplicate with various doses of compounds. The compounds were prepared in DMSO to make a stock solution, from which two-fold serial dilutions were prepared. Cell viability was determined at 72 h (cell lines) or 24 h (primary tumor cells) after seeding. For viability testing, cells were subjected to lysis with Cell Titer-Gio Luminescent Cell Viability Assay Reagent (Promega). Further, luminescence was measured via a BioTek synergy HTX Multi-mode micro plate reader(BioTek, Winooski, VT). For cell apoptosis assay, cells treated with or without MI-2 for 24 h were stained with annexin-V and propidium iodide (Abeam, Cambridge, UK), followed by flow cytometry in a NovoCyte Flow Cytometer (ACEA Biosciences, San Diego, CA) to quantify apoptosis. The experiments were repeated at least three times.Immunoblotting

[0250] The immunoblotting assay was performed as described previously (Zhang et al. Nat Commun, 2021; 12(1):2877). Briefly, 5-10 x 106cells were seeded and treated as indicated. The cells were lysed in lysis buffer containing 50 mM HEPES (pH 7.4), 250 mM NaCl, 1 mM EDTA, 1% Nonidet P-40, 1 mM NasVCU, 1 mM PMSF, 1 mM NaF, and a protease inhibitor mixture (all purchased from Roche Diagnostics, Mannheim, Germany). Protein concentration in cell lysates was measured using a Quick Start Bradford Protein Assay Kit (Bio-Rad) and the lysates were subject to SDS-polyacrylamide gel electrophoresis (SDS-PAGE) and western blotting. Primary antibodies used to detect total proteins, phosphorylated proteins, and their sources are presented in TABLE 4MALT1 ELASA ASSA Y

[0251] The method for MALT1 ELASA assay measuring MALT1 endogenous cleavage activity has been described elsewhere (Hachmann et al, Biochem J, 2012; 443(l):287-95). Briefly, 0.2-1 x 106cells / ml of MCL cells were seeded on a 6-well plate and treated with MI-2 for 6 h. The cells were harvested and subjected to MALT1 ELASA assay to measure MALT1 endogenous cleavage activity. The experiments were repeated at least three times.NF-KB DNA-Binding Assay

[0252] Nuclear fractions were extracted via the Nuclear Extract Kit (40410; ActiveMotif, Carlsbad, CA) and the DNA-b inding activity of NF-KB family members was measured using TransAM NF-KB Family Kit (43296; ActiveMotif) according to the manufacturer’s manual.RPPA Analysis

[0253] RPPA analysis was conducted as described previously (Huang et al. Am J Cancer Res, 2022; 12(3): 1102- 15). Briefly, RPPA analysis was conducted by the MD Anderson RPPA Core Facility. A total of 54 samples, representing six cell lines (JeKo-1, JeKo-R, JeKo BTK KD_2, Maver-1, Mino, and Z-138) and three doses of MI -2 (0, 1, 2 pM), tested in triplicate, were subjected to RPPA analysis. The slide images were quantified using MicroVigene 4.0 (Vigene- Tech, Carlisle, MA). Spot-level raw data were processed using the R package, SuperCurve, developed in-house. This package returns the estimated protein concentration (raw concentration), as well as a quality control score. Raw concentration data were normalized via median-centering each sample across all of the proteins to correct loading bias. In total, 307 antibodies andsecondary antibody negative controls were analyzed. NormLog2_MedianCentered values were selected for heatmap generation. The differences of values of proteins in MI-2-treated samples were normalized to untreated samples, and differences < -0.3 and > 0.3 in three or more cell lines were selected for the heatmap. The heatmap was generated using Cluster 3.0 software and visualized in Treeview. The results were presented in a high-resolution bitmap format. Each treatment was set up triplicate.Measurement of Cellular ROS, Δ 'Ψm, ATP, Lactate, and Glutamine

[0254] The DCFDA / H2DCFDA-cellular Reactive Oxygen Species Detection Assay Kit (ab 113851; Abeam), the AΨm assay kit (Ab 113852; Abeam), the ATP Colorimetric / Fluorometric Assay Kit (K354; Biovision, Milipitas, CA), the Lactate Colorimetric Assay Kit II (K627-100; Biovision), and the Glutamine Colorimetric Assay Kit II (K556-100; Biovision) were used to detect cellular ROS levels, LILIm, ATP levels, and extracellular lactate and glutamine, respectively, according to the corresponding manufacturers’ manuals. The experiments were repeated at least three times.Screen for Extracellular Matrix, Cell Adhesion and Migration Assay

[0255] These assays were performed as described previously (Blonska et al. Blood, 2015; 125(6):981-91). Briefly, the ECM Cell Adhesion Array Kit (Millipore, #ECM540) was used to screen for MCL cell adhesion to extracellular matrix according to the manufacturer’s manual. For specific cell adhesion assay, the plates were first coated with 10% FBS, fibronectin, or laminin, seeded with MCL cells pretreated with MI-2 at 0.5 pM for 30 min, and incubated for an additional 4 h. The cells in suspension were thoroughly washed with PBS, and the resulting cells were subjected to lysis with Cell Titer-Gio Luminescent Cell Viability Assay Reagent (Promega). A BioTek synergy HTX multi-mode micro plate reader was used to quantify luminescence.Animal Studies

[0256] The Institutional Animal Care and Use Committee of The University of Texas MD Anderson Cancer Center approved the experimental protocols involving animals, which are described further below.Subcutaneous Cell Line-Derived Xenograft (CDX) or PDX Models

[0257] The in vivo experiments using subcutaneous CDX or PDX models were performed as described previously (Huang et al. Am J Cancer Res, 2022; 12(5): 1102- 15 and Jiang et al. JHematol Oncol, 2021; 74(1):132). JeKo-1, JeKo-derived cells with BTK KD_2, MALT1 KO and / or CARD 11 KO, JeKo BTK KD_GFP-Luc cells, or PDX cells were injected subcutaneously (5 x 106cells per mouse) into 6- to 8-week-old NSG female mice (Jackson Laboratory, Bar Harbor, ME). Drug treatment began once the tumor size became palpable. MI-2 was dissolved in 2% DMSO +30% PEG 300. The same vehicle without the drug served as the control. Pirtobrutinib was dissolved in 0.6% methylcellulose and 0.5% Tween-80. Safimaltib was dissolved in 5% DMSO + 30% PEG 300 and 5% Tween-20. The mice were treated with vehicle, MI-2 (25 mg / kg, i.p., daily), safimaltib (50 mg / kg, orally, daily), pirtobrutinib (30 mg / kg, orally, twice daily), alone or in combination. Mice were monitored daily for health condition and imaged weekly for tumor burden using the IVIS system for the luciferase-expressing JeKo-BTK-KD GFP-luc cells, or alternatively, the tumor size was weekly measured using calipers for non-luciferase-expressing models.In Vivo Short-Term MCL Cell Homing Experiment

[0258] One MI-2-sensitive primary sample was stained with CellTracker Green CMFDA dye (Thermo Fisher Scientific) for 1 h. The cells were washed and treated with DMSO or 1 pM MI-2 for 30 min. Cells were washed again and re-suspended with complete medium, then 2 x 107were intravenously injected into each NSG mouse (five mice per group). After 4 d, the mice were euthanized and dissected to remove blood, spleen, and bone marrow. CMFDA-positive cells representing MCL cells homing to each organ were detected by flow cytometry.In Vivo Disseminated CDX or PDX Models

[0259] The in vivo experiments using disseminated CDX or PDX models were performed as described previously (Zhang et al. Nat Commun, 2021; 72(1):2877). CDX or PDX models were established via the intravenous method. MCL cell lines or freshly isolated primary PDX cells (2 x 106) were injected into NSG mice intravenously via the tail vein. The mice (n = 5 per group) were treated with vehicle, ibrutinib (50 mg / kg, orally, daily), or MI-2 (25 mg / kg, i.p., daily) for 4 weeks at 6 weeks post injection. The mice were monitored daily for health condition and survival. At the end of the experiment, mice were euthanized and dissected for spleen, liver, blood, and bone marrow. The spleen weight was measured, and the cells from blood, spleen, liver, and bone marrow were isolated and stained for fluorescence-conjugated CD5 and CD20 antibodies. CD5 and CD20 double-positive cells representing MCL cells present in each organ or tissue were detected by flow cytometry.Statistical Analyses

[0260] All analyses were performed using statistical software R v3.4.3 with packages betareg v3.1-0, nlme v3.1131, and survival v2.41-3, or GraphPad Prism v9. To control for multiple hypothesis testing, we applied the Benjamini-Hochberg method to correct p values and calculated the false discovery rates (q-values). Log rank test was used to generate the statistical significance of progress-free survival. Wilcoxon rank sum test was used to generate statistical significance for MALT1 expression using single cell RNA sequencing dataset. Where appropriate, the data are presented as mean ± SD of triplicate samples. The IC50 values were calculated from at least threeindependent experiments. Comparison of differences between groups were conducted by two- sided, two-sample / -test. Data represent mean ± SD. For endogenous MALT1 cleavage assays, statistical significance was calculated based on the differences in slopes using mixed-effects regression. Results were considered statistically significant as indicated: p < 0.05 (*); p < 0.01 (**); p < 0.001 (***); p < 0.0001 (****).Study Approval

[0261] Cell samples were acquired from patients and healthy donors after obtaining written informed consent following the University of Texas MD Anderson Cancer Center Institutional Review Board-approved protocols and in accordance with the Declaration of Helsinki. The Institutional Animal Care and Use Committee of The University of Texas MD Anderson Cancer Center approved the experimental protocols involving animals.

[0262] Although the invention has been described with reference to the presently preferred embodiment, it should be understood that various modifications can be made without departing from the spirit of the invention. Accordingly, the invention is limited only by the following claims.

Claims

What Is Claimed Is:

1. A compound according to Formula I:or an enantiomer, diastereomer, stereoisomer, or a pharmaceutically acceptable salt or solvate thereof, wherein:Z1is N or CR1, Z2is N or CR2, and at most one of Z1and Z2is N;R1and R2are independently hydrogen, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, halogen, cyano, NH2, or hydroxyl;R3is hydrogen, halogen, NH2, or aminocarbonyl;X1and X2are each independently selected from a bond,Z3is N or CR5, Z4is N or CR6, and at most one of Z3and Z4is N;R4, R5, and R6are independently hydrogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, halogen, cyano, NH2, hydroxyl, C1-6 alkoxyalkyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, C1-6 aminoalkyl, or C1-6 hydroxyalkyl;Z5is N or CR9, Z6is N or CR10, and Z7is N or CR11, wherein at most one ofZ5, Z6, and Z7is N;R7, R8, R9, R10, and R11are each independently hydrogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, halogen, cyano, NH2, hydroxyl, C1-6alkoxyalkyl, Ci-6 alkoxycarbonyl, Ci-6 alkylcarbonyl, Ci-6 aminocarbonyl, Ci-6 alkylaminocarbonyl, Ci-6 aminoalkyl, or Ci-6 hydroxyalkyl;X3is a bondR12and R13are each independently hydrogen, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, halogen, cyano, NH2, or hydroxyl; andR14is hydrogen or C1-3 alkyl.

2. The compound of claim 1, wherein Z1is N.

3. The compound of claim 1, wherein Z2is CR2.

4. The compound of claim 1, wherein Z1is N and Z2is CR2.

5. The compound of claim 2, wherein Z1is N and Z2is CCF3.

6. The compound of claim 1, wherein Z1is CR1and Z2is N.

7. The compound of claim 6, wherein Z1is CNH2 and Z2is N.

8. The compound of claim 1, wherein R1and R2are independently selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, halogen, or cyano.

9. The compound of claim 8, wherein R1and R2are independently selected from hydrogen or C1-C3 haloalkyl.

10. The compound of claim 8, wherein R1and R2are independently selected from hydrogen, Ci haloalkyl, or methyl.

11. The compound of claim 8, wherein R1and R2are independently selected from hydrogen or CF3.

12. The compound of claim 1 , wherein R3is selected from hydrogen or NH2.

13. The compound of claim 12, wherein R3is hydrogen.

14. The compound of claim 1 , wherein X1is a bond or15. The compound of claim 1 , wherein X1isoV'sA AA16. The compound of claim 1, wherein X2is selected from ’ , ,17. The compound of claim 1, wherein X2is selected from18. The compound of claim 1, wherein Z3CR5.

19. The compound of claim 18, wherein Z3CH.

20. The compound of claim 1, wherein Z4CR6.

21. The compound of claim 20, wherein Z4CH.

22. The compound of claim 1, wherein R4, R5, and R6are independently selected from hydrogen, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, halogen, cyano, NH2, or hydroxyl.

23. The compound of claim 22, wherein two of R4, R5, and R6are hydrogen and the remaining instance of R4, R5, and R6is selected from C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, halogen, cyano, NH2, or hydroxyl.

24. The compound of claim 22, wherein R4, R5, and R6are independently selected from hydrogen, methyl, OCH3, CF3, halogen, or hydroxyl.

25. The compound of claim 22, wherein R4, R5, and R6are each hydrogen.

26. The compound of claim 1, wherein Z5is CR9, Z6is CR10, and Z7is CR11.

27. The compound of claim 26, wherein two of R9, R10, and R11are hydrogen.

28. The compound of claim 26, wherein Z5is CH, Z6is CR10, and Z7is CH.

29. The compound of claim 28, wherein R10is halogen.

30. The compound of claim 1, wherein Z5, Z6, and Z7are each CH.

31. The compound of claim 1, wherein R7, R8, R9, R10, and R11are independently selected from hydrogen, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, halogen, cyano, NH2, or hydroxyl.

32. The compound of claim 31, wherein R7, R8, R9, R10, and R11are independently selected from hydrogen, methyl, OCH3, CF3, halogen, or hydroxyl.

33. The compound of claim 1, wherein R7is H and R8is C1-C3 alkoxy.

34. The compound of claim 33, wherein R7is H and R8is OCH3.

36. The compound of claim 1, wherein X3is a bond.

37. The compound of claim 1, wherein R12and R13are independently selected from hydrogen, methyl, OCH3, CF3, halogen, or hydroxyl.

38. The compound of claim 1, wherein R12and R13are each hydrogen.

39. The compound of claim 1, wherein R14is hydrogen.

40. The compound of claim 1, wherein the compound is selected from41 . A compound according to Formula II:or an enantiomer, diastereomer, stereoisomer, or a pharmaceutically acceptable salt or solvate thereof, wherein:is a divalent group or a bond;X4isZ21is N or CR21, Z22is N or CR22, Z23is N or CR23, Z24is N or CR24, Z25is N or CR25, at most one of Z21and Z22is N, and at most one of Z23, Z24, and Z25is N; each instance of R21, R22, R23, R24, R25, R28, R29, and R30is independently hydrogen, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy, halogen, cyano, NH2, hydroxyl, C1-6 alkoxyalkyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyl, C1-6 aminocarbonyl, C1-6 alkylaminocarbonyl, C1-6 aminoalkyl, or C1-6 hydroxyalkyl;R31and R32are each independently C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, halogen, cyano, NH2, or hydroxyl;R33is H or C1-3 alkyl;Z26is CR26or N, Z27is CR27or N, and at most one of Z26and Z27is N;R26and R27are independently hydrogen, C1-6 alkyl, C1-6 alkoxyl, C1-6 haloalkyl, C1-6 haloalkoxy, halogen, cyano, or hydroxyl;Ring A is selected fromR34and R35are independently selected from hydrogen, Ci-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, halo, NH2, C1-6 alkoxyalkyl, C1-6 aminoalkyl, hydroxyl, C1-6 aminocarbonyl, or C1-6 hydroxyalkyl.Ring C is a C2-8N-heterocycle, C4-12N-heterobicycle, or C3-8cycloalkyl, wherein Ring C is optionally substituted with one or more groups independently selected from amine, C2-8N- heterocycle, C3-C8cycloalkyl, or C1-6aminoalkyl;is selected from- is selected fromeach instance of n is independently an integer from 1 to 10; and each instance of m is independently an integer from 1 to 10.

43. The compound of claim 42, whereinis selected fromFA44. The compound of claim 42, wherein Ring B is selected from45. The compound of claim 42, wherein46. The compound of claim 42, wherein is selected from47. The compound of claim 42, whereinis selected from or48. The compound of claim 42, wherein each instance of n is independently an integer from 1 to5.

49. The compound of claim 42, wherein each instance of m is independently an integer from 1 to5.

50. The compound of claim 42, wherein Ring C is selected from51. The compound of claim 50, wherein Ring C is selected from52. The compound of claim 51, wherein Ring C is53. The compound of claim 41, wherein X4is selected from54. The compound of claim 53, wherein X4is55. The compound of claim 41, wherein Z21and Z22are each independently selected from N, CH, CF, CC1, CBr, CI, CCH3, CCF3, COH, COCH3, or CCN, wherein at most one of Z21and Z22is N.

56. The compound of claim 41, wherein Z21and Z22are each independently selected from N or CH, wherein at most one of Z21and Z22is N.

57. The compound of claim 41, wherein Z21and Z22are each CH.

58. The compound of claim 41, wherein Z23, Z24, and Z25are each independently selected from N, CH, CF, CC1, CBr, CI, CCH3, CCF3, COH, COCH3, or CCN, wherein at most one of Z23, Z24, and Z25is N.

59. The compound of claim 58, wherein Z23, Z24, and Z25are each independently selected from CH, CF, CC1, CBr, CI, CCH3, CCF3, COH, COCH3, or CCN.

60. The compound of claim 41, wherein Z23is CH.

61. The compound of claim 41, wherein Z24is COCH3.

62. The compound of claim 41, wherein Z25is CH.

63. The compound of claim 41, wherein each instance of R28, R29, and R30is independently hydrogen, Ci-3alkyl, Ci-3alkoxy, Ci-3haloalkyl, halogen, cyano, NH2, or hydroxyl.

64. The compound of claim 41, wherein R28is H.

65. The compound of claim 41, wherein R29is OCH3.

66. The compound of claim 41, wherein R30is H.

67. The compound of claim 41, wherein68. The compound of claim 41, wherein R31and R32are each independently selected from hydrogen, methyl, OCH3, CF3, halogen, or hydroxyl.

69. The compound of claim 41, wherein R31and R32are each hydrogen.

70. The compound of claim 41, wherein R33is hydrogen.

71. The compound of claim 41 , wherein Z26is N.

72. The compound of claim 41, wherein Z27is CR27.

73. The compound of claim 41, wherein R26and R27are each independently selected from hydrogen, C1-3 alkyl, C1-3 haloalkyl, halogen, or cyano.

74. The compound of claim 41, wherein Z26is N and Z27is CCF3.

75. The compound of claim 41, wherein R34and R35are each independently selected from hydrogen, NH2, C1-3 alkyl, and C1-3 aminocarbonyl. herein Ring A is selected from77. The compound of claim 41, wherein the compound is selected from78. A pharmaceutical composition comprising a compound of any one of claims 1-77.

79. The pharmaceutical composition of claim 78, further comprising a pharmaceutically acceptable excipient.

80. The pharmaceutical composition of claim 79, wherein the pharmaceutically acceptable excipient is selected from a buffer, an antioxidant, a preservative, a peptide, a protein, ahydrophilic polymer, an amino acid, a sugar, a polysaccharide, a chelating agent, a salt-forming counter-ion, a non-ionic surfactant, an anti-adherent, a binder, a synthetic polymer, a lubricant, a vitamin, selenium, or a paraben.

81. The pharmaceutical composition of claim 78, further comprising a pharmaceutically acceptable carrier.

82. The pharmaceutical composition of claim 81, wherein the pharmaceutically acceptable carrier comprises a liposome, a nanoparticle, a microparticle, a polysaccharide, a protein, a hydrogel, an ointment, a micelle, a microsphere, a cream, an emulsion, or a gel.

83. The pharmaceutical composition of claim 81, wherein the compound is coupled to the carrier.

84. A method of treating a disease or disorder in a subject comprising administering a compound of any one of claims 1-77 or a pharmaceutical composition of any one of claims 78-83 to the subject, thereby treating the disease or disorder in the subject.

85. The method of claim 83, wherein the disease is cancer.

86. The method of claim 84, wherein the cancer is selected from activated B-cell type diffuse large B-cell lymphoma (ABC-DLBCL), acute myeloid leukemia (AML), bile duct cancer, bladder cancer, brain cancer, breast cancer, carcinoma, cervical cancer, chronic lymphocytic leukemia (CLL), colorectal cancer, endometrial cancer, epitheloid carcinoma of the bone, esophageal cancer, follicular lymphoma (FL), gallbladder cancer, gastric cancer, glioblastoma, head and neck cancer, hepatocellular cancer, large B-cell lymphoma (LBCL), large cell lung carcinoma, leukemia, lung cancer, lymphoma, mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), medulloblastoma, melanoma, mucosa assisted lymphoid tissue (MALT), myelodysplastic syndrome (MDS), non-Hodgkin’s lymphoma (NHL), ovarian cancer, non-small cell lung cancer, pancreatic cancer, prostate cancer, renal cell cancer, small lymphocytic lymphoma (SLL), thyroid cancer, or Waldenstrom macroglobulinemia (WM).

87. The method of claim 85, wherein the cancer is selected from activated B-cell type diffuse large B-cell lymphoma (ABC-DLBCL), chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), non-Hodgkin’s lymphoma (NHL), or breast cancer.

88. The method of claim 83, wherein the disorder is an inflammatory disorder.

89. The method of claim 87, wherein the inflammatory disorder is selected from rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, ankylosing spondylitis, graft-versus-host disease, stroke, spinal cord injury, chronic renal disease; allergies, type 1 diabetes, inflammatory bowel disorder, Crohn's disease, ulcerative colitis; myasthenia gravis, fibromyalgia; psoriasis, vitiligo, dermatitis, or systemic lupus.

90. The method of claim 83, wherein the disease is an autoimmune disease.

91. The method of claim 90, wherein the autoimmune disease is selected from type I diabetes, Crohn's disease, ulcerative colitis, myasthenia gravis, vitiligo, Graves' disease, Hashimoto's disease, Addison's disease, autoimmune gastritis, autoimmune hepatitis, rheumatoid disease, systemic lupus erythematosus, progressive systemic sclerosis, polymyositis, dermatomyositis, pernicious anemia, autoimmune gastritis, primary biliary cirrhosis, autoimmune thrombocytopenia, Sjogren's syndrome, multiple sclerosis, or psoriasis.

92. A compound selected from93. A compound selected from:; g ;2k) ; wherein n is an integer from 1 to 10;; wherein n is an integer from 1 to 5;q) ; wherein n is an integer from 1 to 10;F "; wherein n is an integer from 1 to 5;; wherein n is an integer from 1 to 10; or; wherein n is an integer from 1 to 10.

94. A method of treating a disease or condition in a subject in need thereof comprising administering to the subject a compound comprising: i) a first moiety that inhibits BTK and ii) a second moiety that inhibits MALT 1 ; thereby treating the disease or condition in the subject.

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