Methods for inhibiting fascin

Abstract

The present invention relates to methods for inhibiting fascin. The present invention provides compositions and methods for treating a condition or disorder mediated by the activity of fascin in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of at least one compound of any one of Formulae I-a to I-n, Formula II, Formula II-a, Formula II-b, or Formula III, or a pharmaceutically acceptable salt thereof.

Description

[0001] This application is a divisional application of Chinese patent application filed on August 21, 2013, with application number 201380055065.X and invention title "Method for Inhibiting Myofascitis".

[0002] Cross-references to related applications

[0003] This application claims the benefit of U.S. Provisional Patent Application No. 61 / 692177, filed August 22, 2012, and U.S. Provisional Patent Application No. 61 / 778015, filed March 12, 2013, the entire disclosure of which is incorporated herein by reference.

[0004] Government Funds

[0005] The technology described in this article was developed using grants from the National Institutes of Health (NIH) grant number R01 CA136837. The U.S. government holds certain rights to this technology. Technical Field

[0006] This technology generally relates to methods for treating or preventing cancer. Background Technology

[0007] In recent years, progress has been made in cancer treatment, particularly in the development of targeted therapies. However, very little progress has been made in the treatment of tumor metastasis, which remains a leading cause of death in cancer patients. Tumor metastasis accounts for 90% of all cancer deaths (1, 2). Metastasis is a multi-stage process in which the primary tumor spreads from its primary site to secondary tissues and organs (3-5). This metastatic process is selective for cells that successfully complete cell migration, invasion, embolization, survival in circulation, retention in distant capillary beds, extravasation, and proliferation in solid organs. Failure at any of these stages can halt the entire metastatic process. Because tumor spread is the cause of death in most cancer patients, there is a need to develop therapeutics that inhibit tumor metastasis.

[0008] Most current treatments for metastatic cancer aim to kill or stop the growth of the primary cancer cells (6-8). While tumor cell migration and invasion are key steps in the metastatic process (9-12), inhibitors of tumor cell migration are currently unavailable for treating metastatic cancer. Therefore, it is ideal to develop small-molecule inhibitors that target tumor cell migration. Summary of the Invention

[0009] This technology provides a method for treating a condition or disorder mediated by the activity of myofascitis in a subject in need, the method comprising administering to the subject a therapeutically effective amount of at least one compound of formula Ia, formula Ib, formula II or formula III, or their tautomers, and / or their pharmaceutically acceptable salts as described herein.

[0010] In one aspect, this technology provides a method for treating a condition or disorder mediated by the activity of myofascitis in a subject in need, the method comprising administering to the subject a therapeutically effective amount of at least one compound or composition, the composition comprising an effective amount of at least one compound of formula Ia or Ib.

[0011]

[0012] or their tautomers, and / or their pharmaceutically acceptable salts, wherein

[0013] Q 1 and Q 2 Independently, it is phenyl, 5-membered heteroaryl, or 6-membered heteroaryl, and in formula Ia, Q 1 and Q 2 They are thickened together;

[0014] Q 3 It is a 6-member unsaturated ring, where (1) in Y 1 and Y 2 The bond between them is a double bond, and in Y 3 and Y 2 The bond between them is a single bond, or (2) in Y 1 and Y 2 The bond between them is a single bond, and in Y 3 and Y 2 The bond between them is a double bond, where Q in equation Ib 3 and Q 2 Condensation;

[0015] S is 0 or 1; t is 1 or 2;

[0016] Y 1 Y 3 and Y 5 Independently C or N; Y 2 Y 4 and Y 6 Independently CH, CR 3 Or N; the condition is Y 1 Y 2 Y 3 Y 4 Y 5 and Y 6 At most four of them are N;

[0017] R 1 It is a phenyl, 5-membered heteroaryl, or 6-membered heteroaryl group, wherein the phenyl, 5-membered heteroaryl, or 6-membered heteroaryl group is optionally surrounded by 1 to 3 R groups. 6 replace;

[0018] R and R 4 One of them is absent or is hydrogen, a halogenated group or a lower alkyl group (preferably methyl or ethyl), R and R 4 The other one is L 2 -R 5 or L 3 -R 5 ; or R does not exist and R 4 -(CH2) j -R 11 j is 1, 2, or 3; R 11 Selected from -OH, -OR 7 -SH, -SR 7 -NR 10 R 10 , cyano, nitro, -COH, -COR 7 -CO2H, -CO2R 7 -CONR 10 R 10 -OCOR 7 -OCO2R 7 -OCONR 10 R 10 -NR 10 COR 10 -NR 10 CO2R 10 -SOR 7 -SO2R 7 -SO2NR 10 R 10 and -NR 10 SO2R 7 ;

[0019] X 1 Selected from OR 8 NHR 8 and SR 8 ;

[0020] X 2 Selected from O, NR 8 and S;

[0021] L 1 Selected from -(C(R) 8 )2) j -、-(C(R 8 )2) q -C(O)-(C(R8 )2) r -、-(C(R 8 )2) q -C(O)N(R 8 )-(C(R 8 )2) r -、-(C(R 8 )2) q -N(R 8 )C(O)-(C(R 8 )2) r -、-(C(R 8 )2) q -N(R 8 )S(O)2-(C(R 8 )2) r -、-(CH2) q -S(O)2N(R 8 )-(CH2) r -、-S-、-O- and -NR 8 -;

[0022] q is 0 or 1;

[0023] r is 0 or 1;

[0024] L 2 Selected from covalent bonds, -C(O)N(R) 8 )-、-N(R 8 )C(O)-、-N(R 8 S(O)2- and -S(O)2N(R) 8 )-;

[0025] L 3 =NC(O)- or =NS(O)2-;

[0026] Each R 3 Independently selected from lower alkyl groups (preferably methyl or ethyl) and halogen groups;

[0027] R 5 It is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocycloalkyl, or 6-membered heterocycloalkyl; wherein the phenyl, 5-membered heteroaryl, or 6-membered heteroaryl group is optionally surrounded by 1 to 4 R groups. 2 Replace, where each R 2 Independently selected from lower alkyl groups, lower haloalkyl groups, -OH, -OR 7 -SH, -SR 7 -NR 10 R 10 , halogen, cyano, nitro, -COH, -COR 7 -CO2H, -CO2R 7-CONR 10 R 10 -OCOR 7 -OCO2R 7 -OCONR 10 R 10 -NR 10 COR 10 -NR 10 CO2R 10 -SOR 7 -SO2R 7 -SO2NR 10 R 10 and -NR 10 SO2R 7 ;

[0028] Each R 6 Independently selected from halogen groups and lower alkyl groups (preferably methyl or ethyl) optionally substituted with 1-3 halogen groups; or two adjacent R groups on the benzene ring. 6 It fuses with the benzene ring to form a 5-membered cycloalkyl, a 6-membered cycloalkyl, a 5-membered heterocycloalkyl, or a 6-membered heterocycloalkyl;

[0029] R 7 It is a lower alkyl group (preferably methyl or ethyl);

[0030] R 8 It is hydrogen or a lower alkyl group (preferably methyl or ethyl); and

[0031] Each R 10 Independently hydrogen or a lower alkyl group (preferably methyl or ethyl), or two R groups. 10 Together with the atoms attached to it, they form 4- to 6-membered rings.

[0032] In some embodiments of compounds having formula Ia and formula Ib

[0033] Q 1 and Q 2 Independently, it is phenyl, 5-membered heteroaryl, or 6-membered heteroaryl, and in formula Ia, Q 1 and Q 2 They are thickened together;

[0034] Q 3 It is a 6-member unsaturated ring, where (1) in Y 1 and Y 2 The bond between them is a double bond, and in Y 3 and Y 2 The bond between them is a single bond, or (2) in Y 1 and Y 2 The bond between them is a single bond, and in Y 3 and Y 2The bond between them is a double bond, where Q in equation Ib 3 and Q 2 Condensation;

[0035] s is 0 or 1; t is 1 or 2;

[0036] Y 1 Y 3 and Y 5 Independently C or N; Y 2 Y 4 and Y 6 Independently CH, CR 3 Or N; the condition is Y 1 Y 2 Y 3 Y 4 Y 5 and Y 6 At most four of them are N;

[0037] R 1 It is a phenyl, 5-membered heteroaryl, or 6-membered heteroaryl group, wherein the phenyl, 5-membered heteroaryl, or 6-membered heteroaryl group is optionally surrounded by 1 to 3 R groups. 6 replace;

[0038] R and R 4 One of them is absent or is hydrogen, a halogenated group or a lower alkyl group (preferably methyl or ethyl), R and R 4 The other one is L 2 -R 5 or L 3 -R 5 ;

[0039] X 1 Selected from OR 8 NHR 8 and SR 8 ;

[0040] X 2 Selected from O, NR 8 and S;

[0041] L 1 Selected from -C(R) 8 -2, -S, -O, and -NR 8 -;

[0042] L 2 Selected from covalent bonds, -C(O)N(R) 8 )-、-N(R 8 )C(O)-、-N(R 8 S(O)2- and -S(O)2N(R) 8 )-;

[0043] L3 =NC(O)- or =NS(O)2-;

[0044] Each R 3 Independently selected from lower alkyl groups (preferably methyl or ethyl) and halogen groups;

[0045] R 5 It is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocycloalkyl, or 6-membered heterocycloalkyl; wherein the phenyl, 5-membered heteroaryl, or 6-membered heteroaryl group is optionally surrounded by 1 to 4 R groups. 2 Replace, where each R 2 Independently selected from lower alkyl groups, lower haloalkyl groups, -OH, -OR 7 -SH, -SR 7 -NR 10 R 10 , halogen, cyano, nitro, -COH, -COR 7 -CO2H, -CO2R 7 -CONR 10 R 10 -OCOR 7 -OCO2R 7 -OCONR 10 R 10 -NR 10 COR 10 -NR 10 CO2R 10 -SOR 7 -SO2R 7 -SO2NR 10 R 10 and -NR 10 SO2R 7 ;

[0046] Each R 6 The components are independently selected from halogen groups and lower alkyl groups (preferably methyl or ethyl) that are optionally substituted with 1-3 halogen groups;

[0047] R 7 It is a lower alkyl group (preferably methyl or ethyl);

[0048] R 8 It is hydrogen or a lower alkyl group (preferably methyl or ethyl); and

[0049] Each R 10 Independently hydrogen or a lower alkyl group (preferably methyl or ethyl), or two R groups. 10 Together with the atoms attached to it, they form 4- to 6-membered rings.

[0050] In one aspect, this technology provides a method for treating a condition or disorder mediated by the activity of myofascitis proteins in a subject in need, the method comprising administering to the subject a therapeutically effective amount of at least one compound or composition, the composition comprising an effective amount of at least one compound of formula Ic or formula Id.

[0051]

[0052] or their tautomers, and / or their pharmaceutically acceptable salts, wherein

[0053] R 1 It is a phenyl, 5-membered heteroaryl, or 6-membered heteroaryl group; wherein the phenyl, 5-membered heteroaryl, or 6-membered heteroaryl group is optionally surrounded by 1 to 3 R groups. 6 replace;

[0054] R 2 Selected from lower alkyl groups, lower haloalkyl groups, -OH, -OR 7 -SH, -SR 7 -NR 10 R 10 , halogen, cyano, nitro, -COH, -COR 7 -CO2H, -CO2R 7 -CONR 10 R 10 -OCOR 7 -OCO2R 7 -OCONR 10 R 10 -NR 10 COR 10 -NR 10 CO2R 10 -SOR 7 -SO2R 7 -SO2NR 10 R 10 and -NR 10 SO2R 7 ;

[0055] Each R 3 Independently selected from lower alkyl and halogen groups;

[0056] m can be 0, 1, 2, or 3;

[0057] n can be 0, 1, 2, 3, or 4;

[0058] X 1 Selected from OR 8 NHR 8 and SR 8 ;

[0059] X2 Selected from O, NR 8 and S;

[0060] L 1 -S-, -O-, or -NR 8 -;

[0061] L 2 Selected from -C(O)N(R) 8 )-、-N(R 8 )C(O)-、-N(R 8 S(O)2- and -S(O)2N(R) 8 )-;

[0062] L 3 =NC(O)- or =NS(O)2-;

[0063] Each R 6 Independently selected from halogens and lower alkyl groups optionally substituted with 1-3 halogens;

[0064] R 7 It is a lower alkyl group;

[0065] R 8 It is hydrogen or a lower alkyl group; and

[0066] Each R 10 Independently hydrogen or a lower alkyl group, or two R groups 10 Together with the atoms attached to it, they form 4- to 6-membered rings.

[0067] In one embodiment, the present technology provides a method for treating a condition or disorder mediated by the activity of myofascitis in a subject in need, the method comprising administering to the subject a therapeutically effective amount of at least one compound or composition, the composition comprising an effective amount of at least one compound of formula II.

[0068]

[0069] or its tautomers, and / or their pharmaceutically acceptable salts, wherein

[0070] Ring A is a 5-membered heteroaryl or a 5-membered heterocyclic alkyl group;

[0071] W 1 and W 4 Independently selected from C and CR 8 , N, NR 8 O and S, W 2 and W 3 Independently C or N, provided W 1 W 2 W 3 or W4 At least one of them is C, and W 1 W 2 W 3 or W 4 At least one of them is N; wherein one of N may have a positive charge;

[0072] R 21 and R 22 It is independently a phenyl, 5-membered heteroaryl, or 6-membered heteroaryl group; wherein the phenyl, 5-membered heteroaryl, or 6-membered heteroaryl group is optionally surrounded by 1 to 3 R groups. 6 replace;

[0073] R 23 Selected from hydrogen, lower alkyl, phenyl, lower alkylphenyl, 5-membered heteroaryl, or 6-membered heteroaryl; wherein the phenyl, lower alkylphenyl, 5-membered heteroaryl, or 6-membered heteroaryl group is optionally surrounded by 1 to 3 R groups. 6 replace;

[0074] Each R 6 Independently selected from halogens and lower alkyl groups optionally substituted with 1-3 halogens;

[0075] Each R 8 Independently hydrogen or a lower alkyl group; and

[0076] For single or double bonds, when When it is a single bond, then R 24 It is hydrogen or a lower alkyl group; when When it is a double bond, then R 24 It does not exist.

[0077] In another embodiment, the present technology provides a method for treating a condition or disorder mediated by the activity of myofascitis in a subject in need, the method comprising administering to the subject a therapeutically effective amount of at least one compound or composition, the composition comprising an effective amount of at least one compound of formula III.

[0078]

[0079] or tautomers, and / or their pharmaceutically acceptable salts, wherein

[0080] R 30 The phenyl group is selected from lower alkyl groups, lower alkenyl groups optionally substituted with phenyl groups, and phenyl groups optionally substituted with one or two substituents independently selected from nitro and halogen groups.

[0081] R 31 Selected from lower haloalkyl groups, -OH, -OR 9 -SH, -SR 7 -NR 10 R10 , halogen, cyano, nitro, -COH, -COR 7 -CO2H, -CO2R 7 -CONR 10 R 10 -OCOR 7 -OCO2R 7 -OCONR 10 R 10 -SO2NR 10 R 10 and -NR 10 SO2R 7 ;

[0082] p is 0, 1, or 2;

[0083] X 30 It is C(=O) or S(O)2;

[0084] R 7 It is a lower alkyl group;

[0085] R 9 It is phenyl; and

[0086] Each R 10 Independently hydrogen or a lower alkyl group, or two R groups 10 Together with the atoms attached to it, they form a ring.

[0087] In one embodiment, the present technology provides a method for inhibiting the activity of myofascitis, the method comprising administering an effective amount of a compound or a composition comprising an effective amount of the compound to cells in need, thereby inhibiting the activity of myofascitis in the cells, wherein the compound is a compound of formula Ia, Ib, II or III, or a tautomer, and / or a pharmaceutically acceptable salt thereof.

[0088] In another embodiment, the present technology provides a compound or composition comprising a compound for treating, in a subject of need, a condition or disorder mediated by the activity of myotrigin, or for inhibiting the activity of myotrigin, wherein the compound is a compound of formula Ia, Ib, II or III, or a tautomer, and / or a pharmaceutically acceptable salt thereof.

[0089] In another embodiment, the present technology provides the use of a compound or a composition comprising a compound in the preparation of a pharmaceutical agent for treating, in a subject of need, a condition or disorder mediated by the activity of myofascitis, or for inhibiting the activity of myofascitis, wherein the compound is a compound of formula Ia, Ib, II or III, or a tautomer, and / or a pharmaceutically acceptable salt thereof.

[0090] In some embodiments, the cells are cells within an animal. In some embodiments, the cells have been removed from the animal. In some embodiments, the animal is a human. In some embodiments, the human suffers from a disease or ailment.

[0091] In some embodiments, the condition or obstacle is metastatic cancer, neuronal disorder, neuronal degeneration, inflammatory disease, viral infection, bacterial infection, lymphoproliferation, Hodgkin's disease, or tissue damage related to local ischemia. In some embodiments, the condition or obstacle is metastatic cancer.

[0092] In some implementations, the cancer is carcinoma, lymphoma, sarcoma, melanoma, astrocytoma, mesothelioma, ovarian cancer, colon cancer, pancreatic cancer, esophageal cancer, stomach cancer, lung cancer, urinary tract cancer, bladder cancer, breast cancer, stomach cancer, leukemia, lung cancer, colon cancer, central nervous system cancer, melanoma, ovarian cancer, kidney cancer, or prostate cancer. Attached Figure Description

[0093] The invention will be more fully understood with reference to the following accompanying drawings, which are for illustrative purposes only:

[0094] Figure 1 The inhibitory effects of 2-chloro-N-(6-chlorobenzo[d]thiazol-2-yl)-5-nitrobenzenesulfonamide (compound 3, NP-3) and N-(3-(1H-1,2,4-triazol-3-ylthio)-4-hydroxynaphthyl-1-yl)-4-methoxybenzenesulfonamide (compound 10, NP-10) on breast tumor metastasis in a mouse model are shown. Lung metastasis was determined by a clonogenic assay of 6-thioguanine. Compound 3 (8 mg / kg) and compound 10 (30 mg / kg) were used. Results are presented as mean ± standard deviation (SD) (n = 5). *, P < 0.01. Detailed Implementation

[0095] In the following detailed description, reference is made to the accompanying drawings, which form a part of this document. In the drawings, similar symbols generally identify similar parts unless the context otherwise indicates. The illustrative embodiments described in the detailed description, the drawings, and the claims are not intended to be limiting. Other embodiments may be adopted, and other changes may be made, without departing from the spirit or scope set forth herein.

[0096] Myofascitises are actin bundlers. For cell migration to occur, the actin cytoskeleton must be reorganized through the formation of polymers and bundles to influence the dynamic changes in cell shape (13–15). Individual actin filaments are flexible, and the elongation of individual filaments is insufficient for membrane protrusions, which are essential for cell migration. Bundling of actin filaments provides rigidity to form protrusions in the form of plate-like pseudopodia and filamentous pseudopodia to counteract compressive forces from the plasma membrane (16)(17). As noted, one of the key actin bundlers is myofascitis (18–22). Myofascitises are the major actin crosslinkers in filamentous pseudopodia and show no sequence homology with other actin bundlers (23). Maximal crosslinking of actin filaments into linear, dense, and rigid bundles is required (24).

[0097] Elevated levels of myofascitisin have been found in many types of metastatic tumors, including breast, prostate, ovary, lung, stomach, esophagus, etc., and are associated with clinically aggressive phenotypes, poor prognosis, and shorter survival (25-29)(30, 31)(32-34). Inhibitors of myofascitisin can target tumor cell migration and invasion, and provide therapeutic options for metastatic cancers.

[0098] definition

[0099] This document uses several definitions to describe the technology, as previously stated throughout the specification.

[0100] The terms “a,” “an,” and “the,” as well as similar references, used in the description of elements (especially in the content of the claims below) are to be interpreted as including both singular and plural forms, unless otherwise indicated herein or clearly contradicted by the context.

[0101] As used herein, “about” will be understood by one of ordinary skill in the art and will vary to some extent depending on the context in which it is used. If the use of this term is unclear to one of ordinary skill in the art given the context in which it is used, “about” will mean adding or subtracting up to 10% from that specific term.

[0102] A hyphen ("-") not between two letters or symbols is used to indicate the connection point of a substituent. For example, -CONH2 is connected by a carbon atom.

[0103] "Optional" or "optionally" means that the event or condition described below may or may not occur, and the description includes examples in which the event or condition occurs, as well as examples in which the event or condition does not occur. For example, "optionally substituted alkyl" includes both "alkyl" and "substituted alkyl" as defined herein. Those skilled in the art will understand that for any group containing one or more substituents, these groups are not intended to introduce any substitution or substitution pattern that is stereoimpractical, synthetically infeasible, and / or inherently unstable.

[0104] "Alkyl" includes straight-chain and branched alkyl groups with a specified number of carbon atoms, typically from 1 to 20 carbon atoms, such as from 1 to 8 carbon atoms, or from 1 to 6 carbon atoms. For example, C1-C6 alkyl groups include straight-chain and branched alkyl groups with 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, etc. Alkylenes are another subset of alkyl groups, referring to the same residues as alkyl groups but with two bonding sites. Alkylenes typically have 2 to 20 carbon atoms, such as from 2 to 8 carbon atoms, or from 2 to 6 carbon atoms. For example, C0 alkylene represents a covalent bond, and C1 alkylene is methylene. When naming alkyl residues with a specific number of carbon atoms, all geometric isomers having that number of carbon atoms are intended to be included; thus, for example, "butyl" is intended to include n-butyl, sec-butyl, isobutyl, and tert-butyl; "propyl" includes n-propyl and isopropyl. "Lower alkyl" refers to alkyl groups having 1 to 4 carbon atoms.

[0105] "Alkenyl" refers to a straight-chain or branched hydrocarbon group having a specified number of carbon atoms, typically 1 to 8 carbon atoms, for example 2 to 4 carbon atoms, and at least one vinyl (>C=C<) unsaturated site, preferably 1 to 2 vinyl unsaturated sites. Such groups can be listed, for example, by vinyl, allyl, and but-3-en-1-yl. Cis and trans isomers, or mixtures of these isomers, are included within this term. "Lower alkenyl" refers to an alkenyl group having 1 to 4 carbon atoms, which can be represented by an alkenyl group of C2-C4.

[0106] “Cycloalkyl” means a non-aromatic, partially or fully saturated carbon ring having a specified number of carbon atoms, such as 3 to 10, 3 to 8, or 3 to 6 carbon atoms. A cycloalkyl group can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, and cyclohexyl, as well as bridged and cage-like cycloalkyl groups (e.g., norcamphene, bicyclo[2.2.2]octane). Furthermore, one ring of a polycyclic cycloalkyl group can be aromatic, and the provided polycyclic cycloalkyl group is bonded to the parent structure via a non-aromatic carbon atom. For example, 1,2,3,4-tetrahydronaphth-1-yl (wherein this moiety is bonded to the parent structure via a non-aromatic carbon atom) is a cycloalkyl group, while 1,2,3,4-tetrahydronaphth-5-yl (wherein this moiety is bonded to the parent structure via an aromatic carbon atom) is not considered a cycloalkyl group. The following describes examples of polycyclic cycloalkyl groups, including cycloalkyl groups fused to an aromatic ring.

[0107] "Aryl" indicates an aromatic carbon ring with a specified number of carbon atoms, for example, 6 to 12 or 6 to 10 carbon atoms. An aryl group can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). In some examples, both rings of a polycyclic aryl group are aromatic rings (e.g., naphthyl). In other examples, a polycyclic aryl group can comprise an aromatic ring fused with non-aromatic rings (e.g., cycloalkyl, cycloalkenyl, heterocyclic alkyl, heterocyclic alkenyl), the provided polycyclic aryl group being bonded to the parent structure via atoms in the aromatic ring. Therefore, 1,2,3,4-tetrahydronaphth-5-yl (where this portion is bonded to the parent structure via aromatic carbon atoms) is considered an aryl group, while 1,2,3,4-tetrahydronaphth-1-yl (where this portion is bonded to the parent structure via non-aromatic carbon atoms) is not considered an aryl group. Similarly, 1,2,3,4-tetrahydroquinoline-8-yl (where the moiety is bonded to the parent structure via an aromatic carbon atom) is considered an aryl group, while 1,2,3,4-tetrahydroquinoline-1-yl (where the moiety is bonded to the parent structure via a non-aromatic nitrogen atom) is not considered an aryl group. However, as defined herein, the term "aryl" does not include "heteroaryl" or overlaps with "heteroaryl," regardless of the bonding point (e.g., quinoline-5-yl and quinoline-2-yl are heteroaryl groups). In some examples, the aryl group is phenyl or naphthyl. In some examples, the aryl group is phenyl. Examples of aryl groups are described below, which include an aromatic carbon ring fused to a non-aromatic ring.

[0108] "Carboxy" or "carboxyl" refers to -COOH or its salt.

[0109] "Heteroaryl" refers to an aromatic ring containing a specified number of atoms (e.g., 5- to 12-membered or 5- to 10-membered heteroaryls), consisting of one or more heteroatoms selected from N, O, and S (e.g., 1, 2, 3, or 4 heteroatoms), with the remaining ring atoms being carbon. A 5-membered heteroaryl is a heteroaryl having 5 ring atoms. A 6-membered heteroaryl is a heteroaryl having 6 ring atoms. Heteroaryls do not contain adjacent S and O atoms. In some embodiments, the total number of S and O atoms in a heteroaryl is not greater than 2. In some embodiments, the total number of S and O atoms in a heteroaryl is not greater than 1. Unless otherwise specified, heteroaryls can be bonded to the parent structure via carbon or nitrogen atoms when valence permits. For example, "pyridyl" includes 2-pyridyl, 3-pyridyl, and 4-pyridyl, while "pyrrole" includes 1-pyrrole, 2-pyrrole, and 3-pyrrole. When nitrogen is present within the heteroaryl ring, it can be in an oxidized state (i.e., N). + -O - The presence of sulfur within a heteroaryl ring allows for nitrogen to exist in this state. Furthermore, when sulfur is present within the heteroaryl ring, it can exist in an oxidized state (i.e., S). + -O - (Or SO2) may be present, where the properties of adjacent atoms and groups allow sulfur to be present. Heteroaryl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic).

[0110] In some cases, the heteroaryl group is a monocyclic compound. Examples include pyrrole, pyrazole, imidazole, triazole (e.g., 1,2,3-triazole, 1,2,4-triazole, 1,2,4-triazole), tetrazolium, furan, isoxazole, oxazole, oxadiazole (e.g., 1,2,3-diazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole), thiophene, isothiazole, thiazole, thiadiazole (e.g., 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole), pyridine, pyridazine, pyrimidine, pyrazine, triazine (e.g., 1,2,4-triazine, 1,3,5-triazine), and tetrazine.

[0111] In some cases, both rings of the polycyclic heteroaryl group are aromatic. Examples include indole, isoindole, indazole, benzimidazole, benzotriazole, benzofuran, benzoxazole, benzoisoxazole, benzoxadiazole, benzothiophene, benzothiazole, benzoisothiazole, benzothiadiazole, 1H-pyrrolo[2,3-b]pyridine, 1H-pyrazolo[3,4-b]pyridine, 3H-imidazo[4,5-b]pyridine, 3H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrrolo[3,2-b]pyridine, 1H-pyrazolo[4,3-b]pyridine, 1H-imidazo[4,5-b]pyridine, 1H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrrolo[2,3-c]pyridine, 1H-pyrazolo[3,4-c]pyridine 3H-Imidazolo[4,5-c]pyridine, 3H-[1,2,3]triazolo[4,5-c]pyridine, 1H-pyrrolo[3,2-c]pyridine, 1H-pyrazolo[4,3-c]pyridine, 1H-imidazo[4,5-c]pyridine, 1H-[1,2,3]triazolo[4,5-c]pyridine, furano[2,3-b]pyridine, oxazolo[5,4-b]pyridine, isoxazolo[5,4-b]pyridine, [1,2,3]oxadiazolo[5,4-b]pyridine, furano[3,2-b]pyridine, oxazolo[4,5-b]pyridine, isoxazolo[4,5-b]pyridine, [1,2,3]oxadiazolo[4,5-b]pyridine, furano[2,3-c]pyridine Pyridine, oxazolo[5,4-c]pyridine, isoxazolo[5,4-c]pyridine, [1,2,3]oxadiazolo[5,4-c]pyridine, furano[3,2-c]pyridine, oxazolo[4,5-c]pyridine, isoxazolo[4,5-c]pyridine, [1,2,3]oxadiazolo[4,5-c]pyridine, thieno[2,3-b]pyridine, thiazo[5,4-b]pyridine, isothiazolo[5,4-b]pyridine, [1,2,3]thiadiazolo[5,4-b]pyridine, thieno[3,2-b]pyridine, thiazo[4,5-b]pyridine, isothiazolo[4,5-b]pyridine, [1,2,3]thiadiazolo[4,5-b]pyridine, thieno[2,3]pyridine [-c]pyridine, thiazo[5,4-c]pyridine, isothiazolo[5,4-c]pyridine, [1,2,3]thiadiazolo[5,4-c]pyridine, thieno[3,2-c]pyridine, thiazo[4,5-c]pyridine, isothiazolo[4,5-c]pyridine, [1,2,3]thiadiazolo[4,5-c]pyridine, quinoline, isoquinoline, cinnamoline, quinazoline, quinoxaline, phthalazine, naphthidine (e.g., 1,8-naphthidine, 1,7-naphthidine, 1,6-naphthidine, 1,5-naphthidine, 2,7-naphthidine, 2,6-naphthidine), imidazo[1,2-a]pyridine, 1H-pyrazolo[3,4-d]thiazole, 1H-pyrazolo[4,3-d]thiazole and imidazo[2,1-b]thiazole.

[0112] In other examples, polycyclic heteroaryl groups may include non-aromatic rings (e.g., cycloalkyl, cycloalkenyl, heterocyclic alkyl, heterocyclic alkenyl) fused to a heteroaryl ring, the provided polycyclic heteroaryl group being bonded to the parent structure via atoms in the aromatic ring. For example, 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl (wherein this moiety is bonded to the parent structure via aromatic carbon atoms) is considered a heteroaryl group, while 4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl (wherein this moiety is bonded to the parent structure via non-aromatic carbon atoms) is not considered a heteroaryl group. Examples of polycyclic heteroaryl groups are described below, which include heteroaryl rings fused to non-aromatic rings.

[0113] "Heterocyclic alkyl" refers to a non-aromatic, partially or fully saturated ring having a specified number of atoms (e.g., 3- to 10-membered heterocyclic alkyl, or 3- to 7-membered heterocyclic alkyl), consisting of one or more heteroatoms selected from N, O, and S (e.g., 1, 2, 3, or 4 heteroatoms), with the remaining ring atoms being carbon. A 5-membered heterocyclic alkyl is a heterocyclic alkyl having 5 ring atoms. A 6-membered heterocyclic alkyl is a heterocyclic alkyl having 6 ring atoms. Heterocyclic alkyl can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of heterocyclic alkyl include ethylene oxide, acridine, aziridine, pyrrolidinyl, imidazoalkyl, pyrazolyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl. When nitrogen is present within the heterocyclic alkyl ring, it can be in an oxidized state (i.e., N). + -O - The presence of nitrogen in this state is permitted by the properties of adjacent atoms and groups. Examples include piperidinyl N-oxide and morpholinyl N-oxide. Furthermore, when sulfur is present within a heterocyclic alkyl ring, it can exist in an oxidized state (i.e., S). + -O - (or -SO2-) may be present, where the nature of adjacent atoms and groups allows sulfur to be present. Examples include thiomorpholine S-oxide and thiomorpholine S,S-dioxide. Furthermore, one ring of the polycyclic heterocyclic alkyl group may be an aromatic ring (e.g., aryl or heteroaryl), provided that the polycyclic heterocyclic alkyl group is bonded to the parent structure via a non-aromatic carbon or nitrogen atom. For example, 1,2,3,4-tetrahydroquinoline-1-yl (wherein the moiety is bonded to the parent structure via a non-aromatic nitrogen atom) is considered a heterocyclic alkyl group, while 1,2,3,4-tetrahydroquinoline-8-yl (wherein the moiety is bonded to the parent structure via an aromatic carbon atom) is not considered a heterocyclic alkyl group. The following description includes examples of polycyclic heterocyclic alkyl groups comprising heterocyclic alkyl groups fused to an aromatic ring.

[0114] "Alkoxy" refers to an alkyl group with a specified number of carbon atoms connected by an oxygen bridge, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentylooxy, 2-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, etc. Alkoxy is also intended to include cycloalkyl groups, as defined above, that are also connected by an oxygen bridge. Alkoxy groups typically have 1 to 6 carbon atoms connected by an oxygen bridge. "Lower alkoxy" refers to an alkoxy group having 1 to 4 carbon atoms.

[0115] The term "halogen" includes fluorine, chlorine, bromine, and iodine groups, while the term "halogen" includes fluorine, chlorine, bromine, and iodine.

[0116] As used herein, the term "substituted" means that any one or more hydrogen atoms on a specified atom or group are replaced by a group selected from the specified groups, provided that the replacement does not exceed the normal valence of the specified atom. When the substituent is oxo (i.e., =O), then two hydrogen atoms on the atom are replaced. Combinations of substituents and / or variables are permitted, provided that such combinations produce a stable compound or a useful synthetic intermediate. A stable compound or a stable structure means that the compound is robust enough to be isolated from the reaction mixture and subsequently formulated as a reagent with at least practical utility. Unless otherwise specified, substituents are named to the core structure. For example, it can be understood that when (cycloalkyl)alkyl is listed as a possible substituent, the attachment point of the substituent to the core structure is on the alkyl moiety.

[0117] "Halogenated alkyl" means an alkyl group substituted with one to five, one to three, or one to two halogen groups, wherein the alkyl and halogen groups are as defined herein.

[0118] "Lower alkylphenyl" refers to C1-C4 alkylphenyl.

[0119] "Isomers" are different compounds with the same molecular formula. "Stereoisomers" are isomers that differ only in the spatial arrangement of their atoms. "Enantiomers" are stereoisomers that are non-overlapping mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The symbol "(±)" can be used to specify a suitable racemic mixture. "Diarrhetinic isomers" are stereoisomers having at least two asymmetric atoms, but they are not mirror images of each other. A "meta-compound" or "meta-isomer" is a group of stereoisomers with non-optically active components. Meta-isomers contain two or more stereocenters, but not chiral centers (i.e., a plane of symmetry exists within the molecule). Absolute stereochemistry is defined according to the Cahn-Ingold-Prelog RS system. When the compound is a pure enantiomer, the stereochemistry on each chiral carbon can be defined as R or S. The absolute configuration of the decomposed compounds is unknown and can be designated (+) or (-) according to the direction of rotation (right-handed or left-handed) of their plane-polarized light at the wavelength of the sodium D line. Some of the compounds disclosed and / or described herein contain one or more asymmetric centers, thus giving rise to enantiomers, diastereomers, mesoisomeres, and other stereoisomers. Unless otherwise specified, the compounds disclosed and / or described herein include all such possible enantiomers, diastereomers, mesoisomeres, and other stereoisomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Enantiomers, diastereomers, mesoisomeres, and other stereoisomers can be prepared using chiral synthons or chiral reagents, or by resolution using conventional techniques. Unless otherwise specified, when the compounds disclosed and / or described herein contain alkene double bonds or other geometrically asymmetric centers, it is intended that these compounds include E and Z isomers.

[0120] "Tautomers" are structurally different isomers obtained through tautomerism. Tautomerism is a form of isomerization that includes proton transfer tautomerism or proton shift tautomerism, which is considered a subset of acid-base chemistry. Proton transfer tautomerism or proton shift tautomerism involves the migration of protons accompanied by a change in bond order, typically the exchange of a single bond with an adjacent double bond. Where tautomerism occurs (e.g., in solution), chemical equilibrium of the tautomer can be achieved. An example of tautomerism is keto-enol tautomerism. A specific example of keto-enol tautomerism is the exchange of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the exchange of pyridine-4-ol and pyridine-4(1H)-keto tautomers. When a compound described herein contains a tautomerizable moiety, unless otherwise specified, it is intended that the compound include all possible tautomers.

[0121] The pharmaceutically acceptable forms of the compounds described herein include pharmaceutically acceptable salts, as well as mixtures thereof.

[0122] "Pharmaceutically acceptable salts" include, but are not limited to, inorganic acid salts, such as hydrochlorides, phosphates, diphosphates, hydrobroms, sulfates, sulfinates, nitrates, and similar salts; and organic acid salts, such as malates, maleates, fumarates, tartrates, succinates, citrates, acetates, lactates, methanesulfonates, p-toluenesulfonates, 2-hydroxyethylsulfonates, benzoates, salicylates, stearates, and alkanes, such as acetates, HOOC-(CH2) salts. n -COOH (where n is 0-4) and similar salts. Similarly, pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium.

[0123] Furthermore, if the compound described herein is obtained as an acid addition salt, the free base can be obtained by alkalizing a solution of the acid salt. Conversely, if the product is a free base, the addition salt (especially a pharmaceutically acceptable addition salt) can be produced by dissolving the free base in a suitable organic solvent and treating the solution with acid, following conventional methods for preparing acid addition salts from base compounds. Those skilled in the art will recognize that various synthetic methods are available for preparing non-toxic, pharmaceutically acceptable addition salts.

[0124] The compounds disclosed and / or described herein may be in enriched isotopic form, for example, enriched isotopes. 2 H, 3 H, 11 C 13 C and / or 14C. In one embodiment, the compound contains at least one deuterium atom. This deuterated form can be prepared, for example, by the methods described in U.S. Patents Nos. 5,846,514 and 6,334,997. Such deuterated compounds can enhance therapeutic efficacy and increase the duration of action of the compounds disclosed and / or described herein. Deuterated compounds can be synthesized using a variety of methods, such as those described below: Dean, D., Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development, Curr. Pharm. Des., 2000; 6(10); Kabalka, G. et al., The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), pp. 6601-21; and Evans, E., Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), pp. 9-32.

[0125] As used herein, the terms “group,” “base,” or “segment” are synonymous and are intended to indicate that a functional group or molecular segment is attached to a bond or segment of another molecule.

[0126] The term "active agent" is used to refer to a substance that has biological activity. In some embodiments, an "active agent" is a substance that has pharmaceutical efficacy. For example, an active agent can be an anti-metastatic therapeutic agent.

[0127] The term "therapeutic effective amount" refers to an effective amount that provides therapeutic benefit when applied to a human or non-human subject, such as improvement of symptoms, delay of disease progression, or prevention of disease. For example, a therapeutic effective amount may be an amount sufficient to reduce the symptoms of disease in response to inhibition of myofascitis activity.

[0128] "Inhibition of myotrigin activity" refers to a reduction in myotrigin activity in the presence of at least one compound described herein or a pharmaceutically acceptable salt thereof, as a direct or indirect reaction, relative to the activity of myotrigin in the absence of at least one compound described herein or a pharmaceutically acceptable salt thereof. The reduction in activity may be due to a direct interaction between at least one compound described herein or a pharmaceutically acceptable salt thereof and myotrigin, or with one or more other factors that, in turn, affect myotrigin activity.

[0129] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof have an IC50 value. 50 (Concentration that inhibits 50% of myofascitis activity) values ​​are approximately 500 micromolars, approximately 100 micromolars, approximately 10 micromolars, approximately 1 micromolar, approximately 500 nanomolars, approximately 400 nanomolars, approximately 300 nanomolars, approximately 200 nanomolars, approximately 100 nanomolars, approximately 50 nanomolars, approximately 10 nanomolars, less than approximately 10 nanomolars, or within the range of any two of these values.

[0130] "Diseases that respond to inhibition of myofascitis activity" are diseases that inhibit myofascitis and provide therapeutic benefits such as improvement of symptoms, slowing disease progression, prevention or delay of disease onset, prevention or improvement of inflammatory responses, or inhibition of abnormal activity and / or death of certain cell types (such as cancer cells).

[0131] "Treatment" or "therapeutic" refers to any treatment of a disease in a patient, including:

[0132] a) Disease prevention, that is, preventing disease from developing into clinical symptoms;

[0133] b) Inhibit the progression of the disease;

[0134] c) Delaying or halting the development of clinical symptoms; and / or

[0135] d) Alleviate the disease, that is, reduce clinical symptoms.

[0136] "Object" or "patient" refers to an animal, such as a mammal, that has been or will be the subject of treatment, observation, or experimentation. The methods described herein are useful in both human therapy and veterinary administration. In some embodiments, the object is a mammal; in others, the object is a human.

[0137] As used herein, the term "cancer" includes tumors of solid mammals as well as hematologic malignancies. The terms "tumor cells" and "cancer cells" are used interchangeably in this document.

[0138] "Solid mammalian tumors" include head and neck cancer, lung cancer, mesothelioma cancer, mediastinal cancer, esophageal cancer, stomach cancer, pancreatic cancer, hepatobiliary system cancer, small intestine cancer, colon cancer, colorectal cancer, rectal cancer, anal cancer, kidney cancer, urethral cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, gynecological organ cancer, ovarian cancer, breast cancer, endocrine system cancer, skin cancer, central nervous system cancer; soft tissue sarcoma and osteosarcoma; as well as melanoma of the skin and melanoma of intraocular origin.

[0139] The term "blood malignancies" includes childhood leukemia and lymphoma, Hodgkin's disease, lymphomas of lymphocyte and skin origin, acute and chronic leukemia, plasma cell tumors, and cancers associated with AIDS.

[0140] In addition, in these embodiments and elsewhere, the abbreviations have the following meanings:

[0141] ℃ = degrees Celsius

[0142] μL = microliter

[0143] μM = micromolar

[0144] DDT = Dithiothreitol

[0145] DMSO = dimethyl sulfoxide

[0146] g = grams

[0147] kg = kilogram

[0148] hr or h = hours

[0149] L = Liter

[0150] M = mole

[0151] nM = nanomolar

[0152] mg = milligram

[0153] MHz = Megahertz

[0154] min = minutes

[0155] mL = milliliters

[0156] mM = millimole

[0157] mmol = millimole

[0158] mol = mole

[0159] PMSF = Benzylsulfonyl fluoride

[0160] N = Normal

[0161] EDTA = ethylenediaminetetraacetic acid

[0162] μm = micrometer

[0163] rpm = revolutions per minute

[0164] SD = Standard Deviation

[0165] v / v = volume / volume

[0166] wt = weight

[0167] Treatment

[0168] In one aspect, this technology provides a method for treating a condition or disorder mediated by the activity of myofascitis in a subject in need, the method comprising administering to the subject a therapeutically effective amount of at least one compound of formula Ia or Ib.

[0169]

[0170] or their tautomers, and / or their pharmaceutically acceptable salts, wherein

[0171] Q 1 and Q 2 Independently, it is phenyl, 5-membered heteroaryl, or 6-membered heteroaryl, and in formula Ia, Q 1 and Q 2 They are thickened together;

[0172] Q 3 It is a 5-membered unsaturated ring or a 6-membered unsaturated ring, where (1) in Y 1 and Y 2 The bond between them is a double bond, and in Y 3 and Y 2 The bond between them is a single bond, or (2) in Y 1 and Y 2 The bond between them is a single bond, and in Y 3 and Y 2 The bond between them is a double bond, where Q in equation Ib 3 and Q 2 Condensation;

[0173] s is 0 or 1; t is 1 or 2;

[0174] Y 1 Y 3 and Y 5 Independently C or N; Y 2 Y 4 and Y 6 Independently CH, CR 3 Or N; the condition is Y 1 Y 2 Y 3 Y 4 Y 5 and Y 6 At most four of them are N;

[0175] R 1 It is a phenyl, 5-membered heteroaryl, or 6-membered heteroaryl group, wherein the phenyl, 5-membered heteroaryl, or 6-membered heteroaryl group is optionally surrounded by 1 to 3 R groups. 6replace;

[0176] R and R 4 One of them is absent or is hydrogen, a halogenated group or a lower alkyl group (preferably methyl or ethyl), R and R 4 The other one is L 2 -R 5 or L 3 -R 5 ; or R does not exist and R 4 -(CH2) j -R 11 j is 1, 2, or 3; R 11 Selected from -OH, -OR 7 -SH, -SR 7 -NR 10 R 10 , cyano, nitro, -COH, -COR 7 -CO2H, -CO2R 7 -CONR 10 R 10 -OCOR 7 -OCO2R 7 -OCONR 10 R 10 -NR 10 COR 10 -NR 10 CO2R 10 -SOR 7 -SO2R 7 -SO2NR 10 R 10 and -NR 10 SO2R 7 ;

[0177] X 1 Selected from OR 8 NHR 8 and SR 8 ;

[0178] X 2 Selected from O, NR 8 and S;

[0179] L 1 Selected from -(C(R) 8 )2) j -、-(C(R 8 )2) q -C(O)-(C(R 8 )2) r -、-(C(R 8 )2) q -C(O)N(R 8)-(C(R 8 )2) r -、-(C(R 8 )2) q -N(R 8 )C(O)-(C(R 8 )2) r -、-(C(R 8 )2) q -N(R 8 )S(O)2-(C(R 8 )2) r -、-(CH2) q -S(O)2N(R 8 )-(CH2) r -、-S-、-O- and -NR 8 -;

[0180] q is 0 or 1;

[0181] r is 0 or 1;

[0182] L 2 Selected from covalent bonds, -C(O)N(R) 8 )-、-N(R 8 )C(O)-、-N(R 8 S(O)2- and -S(O)2N(R) 8 )-;

[0183] L 3 =NC(O)- or =NS(O)2-;

[0184] Each R 3 Independently selected from lower alkyl groups (preferably methyl or ethyl) and halogen groups;

[0185] R 5 It is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocycloalkyl, or 6-membered heterocycloalkyl; wherein the phenyl, 5-membered heteroaryl, or 6-membered heteroaryl group is optionally surrounded by 1 to 4 R groups. 2 Replace, where each R 2 Independently selected from lower alkyl groups, lower haloalkyl groups, -OH, -OR 7 -SH, -SR 7 -NR 10 R 10 , halogen, cyano, nitro, -COH, -COR 7 -CO2H, -CO2R 7 -CONR 10 R 10 -OCOR 7 -OCO2R 7 -OCONR10 R 10 -NR 10 COR 10 -NR 10 CO2R 10 -SOR 7 -SO2R 7 -SO2NR 10 R 10 and -NR 10 SO2R 7 ;

[0186] Each R 6 Independently selected from halogen groups and lower alkyl groups (preferably methyl or ethyl) optionally substituted with 1-3 halogen groups; or two adjacent R groups on the benzene ring. 6 It fuses with the benzene ring to form a 5-membered cycloalkyl, a 6-membered cycloalkyl, a 5-membered heterocycloalkyl, or a 6-membered heterocycloalkyl;

[0187] R 7 It is a lower alkyl group (preferably methyl or ethyl);

[0188] R 8 It is hydrogen or a lower alkyl group (preferably methyl or ethyl); and

[0189] Each R 10 Independently hydrogen or a lower alkyl group (preferably methyl or ethyl), or two R groups. 10 Together with the atoms attached thereto, they form 4-membered heterocyclic alkyl rings to 6-membered heterocyclic alkyl rings.

[0190] In some embodiments, a method is provided for treating a condition or disorder mediated by the activity of myofascitis in a subject in need, the method comprising administering to the subject a therapeutically effective amount of at least one compound of formula Ic or formula Id.

[0191]

[0192] or their tautomers, and / or their pharmaceutically acceptable salts, wherein

[0193] R 1 It is a phenyl, 5-membered heteroaryl, or 6-membered heteroaryl group; wherein the phenyl, 5-membered heteroaryl, or 6-membered heteroaryl group is optionally surrounded by 1 to 3 R groups. 6 replace;

[0194] R 2 Selected from lower alkyl groups, lower haloalkyl groups, -OH, -OR 7 -SH, -SR 7 -NR 10 R 10 , halogen, cyano, nitro, -COH, -COR7 -CO2H, -CO2R 7 -CONR 10 R 10 -OCOR 7 -OCO2R 7 -OCONR 10 R 10 -NR 10 COR 10 -NR 10 CO2R 10 -SOR 7 -SO2R 7 -SO2NR 10 R 10 and -NR 10 SO2R 7 ;

[0195] Each R 3 Independently selected from lower alkyl and halogen groups;

[0196] m can be 0, 1, 2, or 3;

[0197] n can be 0, 1, 2, 3, or 4;

[0198] X 1 Selected from OR 8 NHR 8 and SR 8 ;

[0199] X 2 Selected from O, NR 8 and S;

[0200] L 1 -S-, -O-, or -NR 8 -;

[0201] L 2 Selected from -C(O)N(R) 8 )-、-N(R 8 )C(O)-、-N(R 8 S(O)2- and -S(O)2N(R) 8 )-;

[0202] L 3 =NC(O)- or =NS(O)2-;

[0203] Each R 6 Independently selected from halogens and lower alkyl groups optionally substituted with 1-3 halogens;

[0204] R 7 It is a lower alkyl group;

[0205] R 8 It is hydrogen or a lower alkyl group; and

[0206] Each R 10 Independently hydrogen or a lower alkyl group, or two R groups 10 Together with the atoms attached to it, they form 4- to 6-membered rings.

[0207] In some implementations of Equation Ib, Q is a 6-member unsaturated ring and s is 1.

[0208] In some implementations, L 1 For O. In some implementations, L 1 S is used. In some implementations, L is used. 1 For -NH-. In some implementations, L 1 It is -NCH3-.

[0209] In some implementations, L 2 -N(R) 8 )S(O)2-. In some implementations, L 2 For -NHS(O)2-. In some embodiments, L 3 =NS(O)2-.

[0210] In some embodiments, the compound is a compound of formula Ie or formula If.

[0211]

[0212] Or their tautomers, and / or their pharmaceutically acceptable salts.

[0213] In some embodiments, the compound is a compound of formula Ig or formula Ih.

[0214]

[0215] Or their tautomers, and / or their pharmaceutically acceptable salts.

[0216] In some embodiments, the compound is a compound of formula Ii or Ij.

[0217]

[0218] Or tautomers, and / or their pharmaceutically acceptable salts,

[0219] Wherein, Y is N or CR, R is hydrogen or a lower alkyl group, and R 1 L 1 L 2 and R 5 As defined in formula Ia or formula Ib.

[0220] In some embodiments, the compound is a compound of formula Ik.

[0221]

[0222] Or tautomers, and / or their pharmaceutically acceptable salts,

[0223] Among them, R 1 L 1 and R 5 As defined in equation Ib.

[0224] In some embodiments, the compound is a compound of formula Il or formula Im.

[0225]

[0226] Among them, L 1 R 2 and R 6 As specified in equation Ib, n is 0, 1, 2, 3 or 4 and u is 1, 2 or 3.

[0227] In some embodiments, the compound is a compound of the formula In.

[0228]

[0229] Or tautomers, and / or their pharmaceutically acceptable salts,

[0230] Among them, R 1 L 1 j and R 11 As defined in Equation Ib. In some embodiments, R 11 It is OH.

[0231] In some implementations, R 1 It is a phenyl group. In some embodiments, R... 1 For 1 to 3 R 6 Substituted phenyl groups. In some embodiments, R 1 The phenyl group is substituted with a group selected from a lower alkyl group, or optionally substituted with one to three halogen groups. In some embodiments, R 1 The phenyl group is substituted with two groups selected from lower alkyl groups, or optionally substituted with one to three halogen groups. In some embodiments, R 1 The phenyl group is substituted with three groups selected from lower alkyl groups, or optionally substituted with one to three halogen groups. In some embodiments, R 1 It is trifluoromethylphenyl. In some embodiments, R 1It is a dichlorophenyl. In some embodiments, R 1 For two adjacent R 6 Substituted phenyl groups, and the two adjacent R groups 6 It fuses with the benzene ring to form a 5-membered or 6-membered cycloalkyl group. In some embodiments, R 1 For two adjacent R 6 Substituted phenyl groups, and the two adjacent R groups 6 It fuses with the benzene ring to form a 5-membered or 6-membered heterocyclic alkyl group (e.g., a heterocyclic alkyl group including one or two epoxy atoms).

[0232] In some implementations, R 1 It is an unsubstituted 5-membered heteroaryl group. In some embodiments, R 1 It is a 5-membered heteroaryl group substituted with a group selected from halogens or lower alkyl groups. In some embodiments, R 1 It is a 5-membered heteroaryl group substituted with two groups selected from halogens or lower alkyl groups. In some embodiments, R 1 It is a 5-membered heteroaryl group substituted with three groups selected from halogens or lower alkyl groups. In some embodiments, R 1 It is an unsubstituted 6-membered heteroaryl group. In some embodiments, R 1 It is a 6-membered heteroaryl group substituted with a group selected from halogens or lower alkyl groups. In some embodiments, R 1 It is a 6-membered heteroaryl group substituted with two groups selected from halogens or lower alkyl groups. In some embodiments, R 1 It is a 6-membered heteroaryl group substituted with three groups selected from halogens or lower alkyl groups.

[0233] In some implementations, R 1 It is an unsubstituted triazole. In some embodiments, R 1 It is a triazole substituted with a group selected from halogen or lower alkyl groups.

[0234] In some implementations, X 1 It is OH. In some embodiments, X 2 It is O.

[0235] In some implementations, m is 0. In some implementations, m is 1.

[0236] In some implementations, R 3 It is a halogen group. In some embodiments, R 3 It is a lower alkyl group.

[0237] In some implementations, n is 1. In some implementations, n is 2. In some implementations, n is 3.

[0238] In some implementations, R 2 Independently selected from OH, halogen, lower alkyl and -OR 7 In some implementations, R 2 Selected from bromo, methyl, ethyl, methoxy, and ethoxy groups. In some embodiments, R 2 It is a halogen group. In some embodiments, R 2 For -OR 7 In some implementations, R 2 It is methyl. In some embodiments, R 2 It is ethyl. In some embodiments, n is 2 or 3, and each R 2 It is a methyl group.

[0239] In some implementations, L 1 -(C(R) 8 )2) j -、-(C(R 8 )2) q -C(O)-(C(R 8 )2) r -、-(C(R 8 )2) q -C(O)N(R 8 )-(C(R 8 )2) r -、-(C(R 8 )2) q -N(R 8 )C(O)-(C(R 8 )2) r -、-(C(R 8 )2) q -N(R 8 )S(O)2-(C(R 8 )2) r -or-(CH2) q -S(O)2N(R 8 )-(CH2) r -. In some implementations, R 8 For hydrogen. In some embodiments, j is 1. In some embodiments, L 1 -(CH2) j -. In some implementations, L 1 It is a methylene group. In some embodiments, L 1 It is -CH2C(O)-. In some embodiments, L 1 It is -C(O)(CH2)-. In some embodiments, L 1 It is -CH2-C(O)NH-CH2-. In some embodiments, L1 It is -CH2-NHC(O)-CH2-. In some embodiments, L 1 It is -NHC(O)-CH2-. In some embodiments, L 1 It is -CH2-NHC(O)-. In some embodiments, L 1 It is -C(O)NH-CH2-. In some embodiments, L 1 It is -CH2-C(O)NH-. In some embodiments, L 1 Selected from -S-, -O- and -NR 8 -. In some implementations, L 1 For -S-. In some implementations, L 1 For -O-. In some implementations, L 1 For -NR 8 -

[0240] In some implementations, Y is N.

[0241] In some implementations, L 2 It is a covalent bond and R 5 It is a 5-membered or 6-membered heterocyclic alkyl group. In some embodiments, the 5-membered or 6-membered heterocyclic alkyl group includes a sulfide ring atom, which is oxidized to SO2. In some embodiments, L 2 For -NHC(O)- and R 5 It is a 5-membered heteroaryl or a 6-membered heteroaryl.

[0242] In some implementations, L 1 It is a methylene group. In some embodiments, R 1 It is a phenyl group.

[0243] In some embodiments, the compound is selected from...

[0244] N-(3-(1H-1,2,4-triazol-3-ylthio)-4-hydroxynaphth-1-yl)-2,5-dimethylbenzenesulfonamide;

[0245] N-(3-(1H-1,2,4-triazol-3-ylthio)-4-hydroxynaphth-1-yl)-4-ethoxybenzenesulfonamide;

[0246] N-(3-(1H-1,2,4-triazol-3-ylthio)-4-hydroxynaphth-1-yl)-4-methoxybenzenesulfonamide;

[0247] N-(3-(1H-1,2,4-triazol-3-ylthio)-4-hydroxynaphth-1-yl)-4-ethylbenzenesulfonamide;

[0248] N-(3-(1H-1,2,4-triazol-3-ylthio)-4-hydroxynaphthyl-1-yl)-2,4,5-trimethylbenzenesulfonamide;

[0249] (Z)-N-(3-(1H-1,2,4-triazol-3-ylthio)-4-oxonaphth-1(4H)-ylidene)benzenesulfonamide;

[0250] N-(3-(1H-1,2,4-triazol-3-ylthio)-4-hydroxynaphthyl-1-yl)-4-bromobenzenesulfonamide; and

[0251] N-(3-(1H-1,2,4-triazol-3-ylthio)-4-hydroxynaphth-1-yl)-2,4-dimethylbenzenesulfonamide;

[0252] Or tautomers, and / or their pharmaceutically acceptable salts.

[0253] In some embodiments, the compound is

[0254] 5-(3,4-dichlorobenzyl)-1-(S,S,-dioxo-tetrahydrothiophene-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one or

[0255] N-(1-(4-(trifluoromethyl)benzyl)-1H-indazol-3-yl)furan-2-carboxamide,

[0256] Or tautomers, and / or their pharmaceutically acceptable salts.

[0257] In some embodiments, the compound is selected from...

[0258] 5-(3-chlorobenzyl)-1-(2-hydroxyethyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one;

[0259] 2-(4-oxo-1-(S,S,-dioxo-tetrahydrothiophene-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)-N-(3-(trifluoromethyl)phenyl)acetamide;

[0260] N-(4-fluorobenzyl)-2-(4-oxo-1-(S,S-dioxo-tetrahydrothiophene-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)acetamide;

[0261] N-(benzo[d][1,3]dioxacyclopenten-5-ylmethyl)-2-(4-oxo-1-(S,S-dioxo-tetrahydrothiophen-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)acetamide;

[0262] N-(4-chlorophenyl)-2-(4-oxo-1-(S,S-dioxo-tetrahydrothiophene-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)acetamide;

[0263] 5-(2-(2,3-dihydrobenzo[b][1,4]dioxane-6-yl)-2-oxoethyl)-1-(S,S-dioxo-tetrahydrothiophene-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one;

[0264] 5-(2-(2,4-dimethylphenyl)-2-oxoethyl)-1-(S,S-dioxo-tetrahydrothiophene-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one;

[0265] 5-(2-(benzo[d][1,3]dioxacyclopenten-5-yl)-2-oxoethyl)-1-(S,S-dioxo-tetrahydrothiophene-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one;

[0266] 5-(3,4-dichlorobenzyl)-1-o-tolyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one;

[0267] 5-(3,4-dichlorobenzyl)-1-(2,3-dimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one; and

[0268] 5-(3,4-dichlorobenzyl)-1-(2,4-dimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one;

[0269] Or tautomers, and / or their pharmaceutically acceptable salts.

[0270] A method for treating a condition or disorder mediated by the activity of myofascitis in a subject of need is also provided, the method comprising administering to the subject a therapeutically effective amount of at least one compound of formula II.

[0271]

[0272] or its tautomers, and / or their pharmaceutically acceptable salts, wherein

[0273] Ring A is a 5-membered heteroaryl or a 5-membered heterocyclic alkyl group;

[0274] W 1 and W 4 Independently selected from C and CR 8 , N, NR 8 O and S, W 2 and W3 Independently C or N, provided W 1 W 2 W 3 or W 4 At least one of them is C, and W 1 W 2 W 3 or W 4 At least one of them is N; wherein one of N may have a positive charge;

[0275] R 21 and R 22 It is independently a phenyl, 5-membered heteroaryl, or 6-membered heteroaryl group; wherein the phenyl, 5-membered heteroaryl, or 6-membered heteroaryl group is optionally surrounded by 1 to 3 R groups. 6 replace;

[0276] R 23 Selected from hydrogen, lower alkyl, phenyl, lower alkylphenyl, 5-membered heteroaryl, or 6-membered heteroaryl; wherein the phenyl, lower alkylphenyl, 5-membered heteroaryl, or 6-membered heteroaryl group is optionally surrounded by 1 to 3 R groups. 6 replace;

[0277] Each R 6 Independently selected from halogens and lower alkyl groups optionally substituted with 1-3 halogens;

[0278] Each R 8 Independently hydrogen or a lower alkyl group; and

[0279] For single or double bonds, when When it is a single bond, then R 24 It is hydrogen or a lower alkyl group; when When it is a double bond, then R 24 It does not exist.

[0280] In some embodiments, ring A is a thiadiazole.

[0281] In some embodiments, the compound is a compound of formula II-a or II-b.

[0282]

[0283] Or their tautomers, and / or their pharmaceutically acceptable salts.

[0284] In some implementations, W 4 For S. In some implementations, W 4 It is O. In some implementations, W 4 It is NH.

[0285] In some implementations, R 21and R 22 Independently, it is a phenyl group optionally substituted with a halogen or alkyl group. In some embodiments, R 21 and R 22 It is a phenyl group. In some embodiments, R... 21 and R 22 Independently, it is a phenyl group substituted with one, two, or three groups selected from halogenated or lower alkyl groups. In some embodiments, R 21 and R 22 Independently, it is a phenyl group substituted with a group selected from halogens or lower alkyl groups. In some embodiments, R 21 and R 22 Independently, it is a phenyl group substituted with two groups selected from halogens or lower alkyl groups. In some embodiments, R 21 and R 22 Independently, it is a phenyl group substituted with three groups selected from halogens or lower alkyl groups.

[0286] In some implementations, R 23 It is methyl, phenyl, or benzyl. In some embodiments, R 23 It is methyl. In some embodiments, R 23 It is a phenyl group. In some embodiments, R... 23 It is benzyl. In some embodiments, R 23 It is a lower alkylphenyl group. In some embodiments, R 23 It is a 5-membered heteroaryl or a 6-membered heteroaryl.

[0287] In some implementations, R 24 It is hydrogen.

[0288] In some embodiments, the compound is selected from...

[0289] (Z)-N-(2,3-diphenyl-1,2,4-thiadiazole-5(2H)-ylidene)methylamine;

[0290] N-Methyl-2,3-diphenyl-1,2,4-thiadiazolium-5-amine;

[0291] N-Benzyl-2,3-diphenyl-1,2,4-thiadiazolium-5-amine; and

[0292] N-Phenylacetyl-2,3-diphenyl-1,2,4-thiadiazolium-5-amine;

[0293] Or tautomers, and / or their pharmaceutically acceptable salts.

[0294] In another embodiment, the present technology provides a method for treating a condition or disorder mediated by the activity of myofascitis in a subject in need, the method comprising administering to the subject a therapeutically effective amount of at least one compound of formula III.

[0295]

[0296] or tautomers, and / or their pharmaceutically acceptable salts, wherein

[0297] R 30 The phenyl group is selected from lower alkyl groups, lower alkenyl groups optionally substituted with phenyl groups, and phenyl groups optionally substituted with one or two substituents independently selected from nitro and halogen groups.

[0298] R 31 Selected from lower haloalkyl groups, -OH, -OR 9 -SH, -SR 7 -NR 10 R 10 , halogen, cyano, nitro, -COH, -COR 7 -CO2H, -CO2R 7 -CONR 10 R 10 -OCOR 7 -OCO2R 7 -OCONR 10 R 10 -SO2NR 10 R 10 and -NR 10 SO2R 7 ;

[0299] p is 0, 1, or 2;

[0300] X 30 It is C(=O) or S(O)2;

[0301] R 7 It is a lower alkyl group;

[0302] R 9 It is phenyl; and

[0303] Each R 10 Independently hydrogen or a lower alkyl group, or two R groups 10 Together with the atoms attached to it, they form a ring.

[0304] In some implementations, R 30 It is a lower alkyl group.

[0305] In some implementations, R 30 It is a lower alkenyl group. In some embodiments, R30 It is a lower alkenyl group substituted with phenyl.

[0306] In some implementations, R 30 A phenyl group that is optionally substituted with one or two substituents selected from nitro and halogen groups (e.g., chloro, bromo, or fluorine).

[0307] In some implementations, X 30 C (=O) and R 30 It is a lower alkyl group. In some embodiments, X 30 C (=O) and R 30 The lower alkenyl group can be optionally substituted with phenyl.

[0308] In some implementations, X 30 S(O)2 and R 30 It is a phenyl group. In some embodiments, X... 30 S(O)2 and R 30 A phenyl group that is substituted by one or two substituents that are independently nitro or halogen (e.g., chloro).

[0309] In some implementations, R 31 Selected from halogenated and phenoxy groups. In some embodiments, R 31 It is selected from fluorine, chlorine or phenoxy groups.

[0310] In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2.

[0311] In some embodiments, the compound is selected from...

[0312] 2-Chloro-N-(6-chlorobenzo[d]thiazo-2-yl)-5-nitrobenzenesulfonamide,

[0313] 3-Chloro-N-(6-phenoxybenzo[d]thiazolyl-2-yl)benzenesulfonamide,

[0314] N-(6-fluorobenzo[d]thiazo-2-yl)-3-nitrobenzenesulfonamide,

[0315] 2,3-Dichloro-N-(6-fluorobenzo[d]thiazo-2-yl)benzenesulfonamide,

[0316] N-(6-chlorobenzo[d]thiazolyl)acetamide, and

[0317] N-(benzo[d]thiazo-2-yl)cinnamamide,

[0318] Or tautomers, and / or their pharmaceutically acceptable salts.

[0319] In one embodiment, the present technology provides a method for inhibiting the activity of myofascitis proteins, the method comprising administering an effective amount of a myofascitis protein inhibitor to cells, thereby inhibiting the activity of myofascitis proteins in the cells, wherein the myofascitis protein inhibitor is a compound of formula Ia, Ib, II, or III. In some embodiments, the myofascitis protein inhibitor has an IC50 value. 50 The inhibitory effect is up to 100 μM of myofascitis protein. In some embodiments, the myofascitis protein inhibitor has an IC50 value. 50 The inhibitory effect is up to 50 μM of myofascitis protein. In some embodiments, the myofascitis protein inhibitor has an IC50 value. 50 The inhibitory effect is up to 20 μM of myofascitis protein. In some embodiments, the myofascitis protein inhibitor has an IC50 value. 50 It has an inhibitory effect on myofascitis up to 8 μM.

[0320] In some implementations, the condition or disorder is metastatic cancer, neuronal disorder, neuronal degeneration, inflammatory disease, viral infection, bacterial infection, lymphoid hyperplasia, Hodgkin's disease, or tissue damage related to local ischemia.

[0321] In some implementations, the condition or obstacle is metastatic cancer.

[0322] In some embodiments, the cancer is carcinoma, lymphoma, sarcoma, melanoma, astrocytoma, mesothelioma, ovarian cancer, colon cancer, pancreatic cancer, esophageal cancer, stomach cancer, lung cancer, urinary tract cancer, bladder cancer, breast cancer, stomach cancer, leukemia, lung cancer, colon cancer, central nervous system cancer, melanoma, ovarian cancer, kidney cancer, or prostate cancer. In some embodiments, the cancer is lung cancer, breast cancer, or prostate cancer.

[0323] In another aspect, this technology provides a method for inhibiting the activity of myofascitis proteins, the method comprising administering an effective amount of a myofascitis protein inhibitor to cells, thereby inhibiting the activity of myofascitis proteins in the cells, wherein the myofascitis protein inhibitor is a compound of formula Ia or Ib.

[0324]

[0325] or their tautomers, and / or their pharmaceutically acceptable salts, wherein

[0326] Q 1 and Q 2 Independently, it is phenyl, 5-membered heteroaryl, or 6-membered heteroaryl, and in formula Ia, Q 1 and Q 2 They are thickened together;

[0327] Q 3It is a 5-membered unsaturated ring or a 6-membered unsaturated ring, where (1) in Y 1 and Y 2 The bond between them is a double bond, and in Y 3 and Y 2 The bond between them is a single bond, or (2) in Y 1 and Y 2 The bond between them is a single bond, and in Y 3 and Y 2 The bond between them is a double bond, where Q in equation Ib 3 and Q 2 Condensation;

[0328] s is 0 or 1; t is 1 or 2;

[0329] Y 1 Y 3 and Y 5 Independently C or N; Y 2 Y 4 and Y 6 Independently CH, CR 3 Or N; the condition is Y 1 Y 2 Y 3 Y 4 Y 5 and Y 6 At most four of them are N;

[0330] R 1 It is a phenyl, 5-membered heteroaryl, or 6-membered heteroaryl group, wherein the phenyl, 5-membered heteroaryl, or 6-membered heteroaryl group is optionally surrounded by 1 to 3 R groups. 6 replace;

[0331] R and R 4 One of them is absent or is hydrogen, a halogenated group or a lower alkyl group (preferably methyl or ethyl), R and R 4 The other one is L 2 -R 5 or L 3 -R 5 ; or R does not exist and R 4 -(CH2) j -R 11 j is 1, 2, or 3; R 11 Selected from -OH, -OR 7 -SH, -SR 7 -NR 10 R 10 , cyano, nitro, -COH, -COR 7 -CO2H, -CO2R 7 -CONR 10 R 10 -OCOR7 -OCO2R 7 -OCONR 10 R 10 -NR 10 COR 10 -NR 10 CO2R 10 -SOR 7 -SO2R 7 -SO2NR 10 R 10 and -NR 10 SO2R 7 ;

[0332] X 1 Selected from OR 8 NHR 8 and SR 8 ;

[0333] X 2 Selected from O, NR 8 and S;

[0334] L 1 Selected from -(C(R) 8 )2) j -、-(C(R 8 )2) q -C(O)-(C(R 8 )2) r -、-(C(R 8 )2) q -C(O)N(R 8 )-(C(R 8 )2) r -、-(C(R 8 )2) q -N(R 8 )C(O)-(C(R 8 )2) r -、-(C(R 8 )2) q -N(R 8 )S(O)2-(C(R 8 )2) r -、-(CH2) q -S(O)2N(R 8 )-(CH2) r -、-S-、-O- and -NR 8 -;

[0335] q is 0 or 1;

[0336] r is 0 or 1;

[0337] L2 Selected from covalent bonds, -C(O)N(R) 8 )-、-N(R 8 )C(O)-、-N(R 8 S(O)2- and -S(O)2N(R) 8 )-;

[0338] L 3 =NC(O)- or =NS(O)2-;

[0339] Each R 3 Independently selected from lower alkyl groups (preferably methyl or ethyl) and halogen groups;

[0340] R 5 It is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocycloalkyl, or 6-membered heterocycloalkyl; wherein the phenyl, 5-membered heteroaryl, or 6-membered heteroaryl group is optionally surrounded by 1 to 4 R groups. 2 Replace, where each R 2 Independently selected from lower alkyl groups, lower haloalkyl groups, -OH, -OR 7 -SH, -SR 7 -NR 10 R 10 , halogen, cyano, nitro, -COH, -COR 7 -CO2H, -CO2R 7 -CONR 10 R 10 -OCOR 7 -OCO2R 7 -OCONR 10 R 10 -NR 10 COR 10 -NR 10 CO2R 10 -SOR 7 -SO2R 7 -SO2NR 10 R 10 and -NR 10 SO2R 7 ;

[0341] Each R 6 Independently selected from halogen groups and lower alkyl groups (preferably methyl or ethyl) optionally substituted with 1-3 halogen groups; or two adjacent R groups on the benzene ring. 6 It fuses with the benzene ring to form a 5-membered cycloalkyl, a 6-membered cycloalkyl, a 5-membered heterocycloalkyl, or a 6-membered heterocycloalkyl;

[0342] R 7 It is a lower alkyl group (preferably methyl or ethyl);

[0343] R 8 It is hydrogen or a lower alkyl group (preferably methyl or ethyl); and

[0344] Each R 10 Independently hydrogen or a lower alkyl group (preferably methyl or ethyl), or two R groups. 10 Together with the atoms attached thereto, they form 4-membered heterocyclic alkyl rings to 6-membered heterocyclic alkyl rings.

[0345] In some implementations of Equation Ib, Q is a 6-member unsaturated ring and s is 1.

[0346] In some implementations, L 1 For O. In some implementations, L 1 S is used. In some implementations, L is used. 1 For -NH-. In some implementations, L 1 It is -NCH3-. In some implementations, L 1 It is -CH2-.

[0347] In some implementations, L 2 -N(R) 8 )S(O)2-. In some implementations, L 2 For -NHC(O)-. In some embodiments, L 2 For -NHS(O)2-. In some embodiments, L 2 It is a covalent bond. In some implementations, L 2 It is -C(O)NH-. In some embodiments, L 3 =NS(O)2-.

[0348] In some embodiments, a method for inhibiting the activity of myofascitis proteins is provided, the method comprising administering an effective amount of a myofascitis protein inhibitor to cells, thereby inhibiting the activity of myofascitis proteins in the cells, wherein the myofascitis protein inhibitor is a compound of formula Ic or formula Id.

[0349]

[0350] or their tautomers, and / or their pharmaceutically acceptable salts, wherein

[0351] R 1 It is a phenyl, 5-membered heteroaryl, or 6-membered heteroaryl group; wherein the phenyl, 5-membered heteroaryl, or 6-membered heteroaryl group is optionally surrounded by 1 to 3 R groups. 6 replace;

[0352] R 2 Selected from lower alkyl groups, lower haloalkyl groups, -OH, -OR 7 -SH, -SR7 -NR 10 R 10 , halogen, cyano, nitro, -COH, -COR 7 -CO2H, -CO2R 7 -CONR 10 R 10 -OCOR 7 -OCO2R 7 -OCONR 10 R 10 -NR 10 COR 10 -NR 10 CO2R 10 -SOR 7 -SO2R 7 -SO2NR 10 R 10 and -NR 10 SO2R 7 ;

[0353] Each R 3 Independently selected from lower alkyl and halogen groups;

[0354] m can be 0, 1, 2, or 3;

[0355] n can be 0, 1, 2, 3, or 4;

[0356] X 1 Selected from OR 8 NHR 8 and SR 8 ;

[0357] X 2 Selected from O, NR 8 and S;

[0358] L 1 -S-, -O-, or -NR 8 -;

[0359] L 2 Selected from -C(O)N(R) 8 )-、-N(R 8 )C(O)-、-N(R 8 S(O)2- and -S(O)2N(R) 8 )-;

[0360] L 3 =NC(O)- or =NS(O)2-;

[0361] Each R 6 Independently selected from halogens and lower alkyl groups optionally substituted with 1-3 halogens;

[0362] R 7 It is a lower alkyl group;

[0363] R 8 It is hydrogen or a lower alkyl group; and

[0364] Each R 10 Independently hydrogen or a lower alkyl group, or two R groups 10 Together with the atoms attached to it, they form 4- to 6-membered rings.

[0365] In some implementations, L 1 For O. In some implementations, L 1 S is used. In some implementations, L is used. 1 For -NH-. In some implementations, L 1 It is -NCH3-.

[0366] In some implementations, L 2 -N(R) 8 )S(O)2-. In some implementations, L 2 For -NHS(O)2-. In some embodiments, L 3 =NS(O)2-.

[0367] In some embodiments, the compound is a compound of formula Ie or formula If.

[0368]

[0369] Or their tautomers, and / or their pharmaceutically acceptable salts.

[0370] In some embodiments, the compound is a compound of formula Ig or formula Ih.

[0371]

[0372] or their tautomers, and / or their pharmaceutically acceptable salts, wherein, This indicates a single key that can be on the same side as a double key.

[0373] In some embodiments, the compound is a compound of formula Ii or Ij.

[0374]

[0375] Or tautomers, and / or their pharmaceutically acceptable salts,

[0376] Wherein, Y is N or CR, R is hydrogen or a lower alkyl group, and R 1 L 1 L2 and R 5 As defined in formula Ia or formula Ib.

[0377] In some embodiments, the compound is a compound of formula Ik.

[0378]

[0379] Or tautomers, and / or their pharmaceutically acceptable salts,

[0380] Among them, R 1 L 1 and R 5 As defined in equation Ib.

[0381] In some embodiments, the compound is a compound of formula Il or formula Im.

[0382]

[0383] Among them, L 1 R 2 R 6 And n is as defined in equation Ib, and u is 1, 2 or 3.

[0384] In some embodiments, the compound is a compound of the formula In.

[0385]

[0386] Or tautomers, and / or their pharmaceutically acceptable salts,

[0387] Among them, R 1 L 1 j and R 11 As defined in Equation Ib. In some embodiments, R 11 It is OH.

[0388] In some implementations, R 1 It is a phenyl group. In some embodiments, R... 1 For 1 to 3 R 6 Substituted phenyl groups. In some embodiments, R 1 For two adjacent R 6 Substituted phenyl groups, and the two adjacent R groups 6 It fuses with the benzene ring to form a 5-membered or 6-membered cycloalkyl group. In some embodiments, R 1 For two adjacent R 6 Substituted phenyl groups, and the two adjacent R groups 6Fusing with the benzene ring to form a 5-membered or 6-membered heterocyclic alkyl group (e.g., a heterocyclic alkyl group comprising one or two epoxy atoms). In some embodiments, R 1 The phenyl group is substituted with a group selected from a lower alkyl group, or optionally substituted with one to three halogen groups. In some embodiments, R 1 The phenyl group is substituted with two groups selected from lower alkyl groups, or optionally substituted with one to three halogen groups. In some embodiments, R 1 The phenyl group is substituted with three groups selected from lower alkyl groups, or optionally substituted with one to three halogen groups. In some embodiments, R 1 It is trifluoromethylphenyl. In some embodiments, R 1 It is dichlorophenyl.

[0389] In some implementations, R 1 It is an unsubstituted 5-membered heteroaryl group. In some embodiments, R 1 It is a 5-membered heteroaryl group substituted with a group selected from a halogroup or a lower alkyl group. In some embodiments, R 1 It is a 5-membered heteroaryl group substituted with two groups selected from halogens or lower alkyl groups. In some embodiments, R 1 It is a 5-membered heteroaryl group substituted with three groups selected from halogens or lower alkyl groups. In some embodiments, R 1 It is an unsubstituted 6-membered heteroaryl group. In some embodiments, R 1 It is a 6-membered heteroaryl group substituted with a group selected from halogens or lower alkyl groups. In some embodiments, R 1 It is a 6-membered heteroaryl group substituted with two groups selected from halogens or lower alkyl groups. In some embodiments, R 1 It is a 6-membered heteroaryl group substituted with three groups selected from halogens or lower alkyl groups.

[0390] In some implementations, R 1 It is an unsubstituted triazole. In some embodiments, R 1 It is a triazole substituted with a group selected from halogen or lower alkyl groups.

[0391] In some implementations, X 1 It is OH. In some embodiments, X 2 It is O.

[0392] In some implementations, m is 0. In some implementations, m is 1.

[0393] In some implementations, R 3 It is a halogen group. In some embodiments, R 3 It is a lower alkyl group.

[0394] In some implementations, n is 1. In some implementations, n is 2. In some implementations, n is 3.

[0395] In some implementations, R 2 Independently selected from OH, halogen, lower alkyl and -OR 7 In some implementations, R 2 Selected from bromo, methyl, ethyl, methoxy, and ethoxy groups. In some embodiments, R 2 It is a halogen group. In some embodiments, R 2 For -OR 7 In some implementations, R 2 It is methyl. In some embodiments, R 2 It is ethyl. In some embodiments, n is 2 or 3, and each R 2 It is a methyl group.

[0396] In some implementations, L 1 -(C(R) 8 )2) j -、-(C(R 8 )2) q -C(O)-(C(R 8 )2) r -、-(C(R 8 )2) q -C(O)N(R 8 )-(C(R 8 )2) r -、-(C(R 8 )2) q -N(R 8 )C(O)-(C(R 8 )2) r -、-(C(R 8 )2) q -N(R 8 )S(O)2-(C(R 8 )2) r -or-(CH2) q -S(O)2N(R 8 )-(CH2) r -. In some implementations, R 8 For hydrogen. In some embodiments, j is 1. In some embodiments, L 1 -(CH2) j -. In some implementations, L 1 It is a methylene group. In some embodiments, L 1 It is -CH2C(O)-. In some embodiments, L 1It is -C(O)(CH2)-. In some embodiments, L 1 It is -CH2-C(O)NH-CH2-. In some embodiments, L 1 It is -CH2-NHC(O)-CH2-. In some embodiments, L 1 It is -NHC(O)-CH2-. In some embodiments, L 1 It is -CH2-NHC(O)-. In some embodiments, L 1 It is -C(O)NH-CH2-. In some embodiments, L 1 It is -CH2-C(O)NH-. In some embodiments, L 1 Selected from -S-, -O- and -NR 8 -. In some implementations, L 1 For -S-. In some implementations, L 1 For -O-. In some implementations, L 1 For -NR 8 -

[0397] In some implementations, Y is N.

[0398] In some implementations, L 2 It is a covalent bond and R 5 It is a 5-membered or 6-membered heterocyclic alkyl group. In some embodiments, the 5-membered or 6-membered heterocyclic alkyl group includes a sulfide ring atom, which is oxidized to SO2. In some embodiments, L 2 For -NHC(O)- and R 5 It is a 5-membered heteroaryl or a 6-membered heteroaryl. In some embodiments, L 1 It is a methylene group. In some embodiments, R 1 It is a phenyl group.

[0399] In some embodiments, the compound is selected from...

[0400] N-(3-(1H-1,2,4-triazol-3-ylthio)-4-hydroxynaphth-1-yl)-2,5-dimethylbenzenesulfonamide;

[0401] N-(3-(1H-1,2,4-triazol-3-ylthio)-4-hydroxynaphth-1-yl)-4-ethoxybenzenesulfonamide;

[0402] N-(3-(1H-1,2,4-triazol-3-ylthio)-4-hydroxynaphth-1-yl)-4-methoxybenzenesulfonamide;

[0403] N-(3-(1H-1,2,4-triazol-3-ylthio)-4-hydroxynaphth-1-yl)-4-ethylbenzenesulfonamide;

[0404] N-(3-(1H-1,2,4-triazol-3-ylthio)-4-hydroxynaphthyl-1-yl)-2,4,5-trimethylbenzenesulfonamide;

[0405] (Z)-N-(3-(1H-1,2,4-triazol-3-ylthio)-4-oxonaphth-1(4H)-ylidene)benzenesulfonamide;

[0406] N-(3-(1H-1,2,4-triazol-3-ylthio)-4-hydroxynaphthyl-1-yl)-4-bromobenzenesulfonamide; and

[0407] N-(3-(1H-1,2,4-triazol-3-ylthio)-4-hydroxynaphth-1-yl)-2,4-dimethylbenzenesulfonamide;

[0408] Or tautomers, and / or their pharmaceutically acceptable salts.

[0409] In some embodiments, the compound is

[0410] 5-(3,4-dichlorobenzyl)-1-(S,S,-dioxo-tetrahydrothiophene-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one or

[0411] N-(1-(4-(trifluoromethyl)benzyl)-1H-indazol-3-yl)furan-2-carboxamide,

[0412] Or tautomers, and / or their pharmaceutically acceptable salts.

[0413] In some embodiments, the compound is selected from...

[0414] 5-(3-chlorobenzyl)-1-(2-hydroxyethyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one;

[0415] 2-(4-oxo-1-(S,S,-dioxo-tetrahydrothiophene-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)-N-(3-(trifluoromethyl)phenyl)acetamide;

[0416] N-(4-fluorobenzyl)-2-(4-oxo-1-(S,S-dioxo-tetrahydrothiophene-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)acetamide;

[0417] N-(benzo[d][1,3]dioxacyclopenten-5-ylmethyl)-2-(4-oxo-1-(S,S-dioxo-tetrahydrothiophen-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)acetamide;

[0418] N-(4-chlorophenyl)-2-(4-oxo-1-(S,S-dioxo-tetrahydrothiophene-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)acetamide;

[0419] 5-(2-(2,3-dihydrobenzo[b][1,4]dioxane-6-yl)-2-oxoethyl)-1-(S,S-dioxo-tetrahydrothiophene-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one;

[0420] 5-(2-(2,4-dimethylphenyl)-2-oxoethyl)-1-(S,S-dioxo-tetrahydrothiophene-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one;

[0421] 5-(2-(benzo[d][1,3]dioxacyclopenten-5-yl)-2-oxoethyl)-1-(S,S-dioxo-tetrahydrothiophene-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one;

[0422] 5-(3,4-dichlorobenzyl)-1-o-tolyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one;

[0423] 5-(3,4-dichlorobenzyl)-1-(2,3-dimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one; and

[0424] 5-(3,4-dichlorobenzyl)-1-(2,4-dimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one;

[0425] Or tautomers, and / or their pharmaceutically acceptable salts.

[0426] A method for inhibiting the activity of myofascitis is also provided, comprising administering an effective amount of a myofascitis inhibitor to cells, thereby inhibiting the activity of myofascitis in the cells, wherein the myofascitis inhibitor is a compound of formula II.

[0427]

[0428] or its tautomers, and / or their pharmaceutically acceptable salts, wherein

[0429] Ring A is a 5-membered heteroaryl or a 5-membered heterocyclic alkyl group;

[0430] W 1 and W 4 Independently selected from C and CR 8 , N, NR 8 O and S, W 2 and W 3 Independently C or N, provided W 1 W 2 W 3 or W 4 At least one of them is C, and W 1 W 2 W 3 or W 4 At least one of them is N; wherein one of N may have a positive charge;

[0431] R 21 and R 22 It is independently a phenyl, 5-membered heteroaryl, or 6-membered heteroaryl group; wherein the phenyl, 5-membered heteroaryl, or 6-membered heteroaryl group is optionally surrounded by 1 to 3 R groups. 6 replace;

[0432] R 23 Selected from hydrogen, lower alkyl, phenyl, lower alkylphenyl, 5-membered heteroaryl, and 6-membered heteroaryl; wherein the phenyl, lower alkylphenyl, 5-membered heteroaryl, or 6-membered heteroaryl group is optionally surrounded by 1 to 3 R groups. 6 replace;

[0433] Each R 6 Independently selected from halogens and lower alkyl groups optionally substituted with 1-3 halogens;

[0434] Each R 8 Independently hydrogen or a lower alkyl group; and

[0435] For single or double bonds, when When it is a single bond, then R 24 It is hydrogen or a lower alkyl group; when When it is a double bond, then R 24 It does not exist.

[0436] In some embodiments, ring A is a thiadiazole.

[0437] In some embodiments, the method includes a compound of formula II-a or II-b.

[0438]

[0439] Or their tautomers, and / or their pharmaceutically acceptable salts.

[0440] In some implementations, W4 S. In some implementations, W 4 It is O. In some implementations, W 4 It is NH.

[0441] In some implementations, R 21 and R 22 Independently, it is a phenyl group optionally substituted with a halogen or alkyl group. In some embodiments, R 21 and R 22 It is a phenyl group. In some embodiments, R... 21 and R 22 Independently, it is a phenyl group substituted with one, two, or three groups selected from halogenated or lower alkyl groups. In some embodiments, R 21 and R 22 Independently, it is a phenyl group substituted with a group selected from halogens or lower alkyl groups. In some embodiments, R 21 and R 22 Independently, it is a phenyl group substituted with two groups selected from halogens or lower alkyl groups. In some embodiments, R 21 and R 22 Independently, it is a phenyl group substituted with three groups selected from halogens or lower alkyl groups.

[0442] In some implementations, R 23 It is methyl, phenyl, or benzyl. In some embodiments, R 23 It is methyl. In some embodiments, R 23 It is a phenyl group. In some embodiments, R... 23 It is benzyl. In some embodiments, R 23 R is an alkyl group substituted with a phenyl group. In some embodiments, R 23 It is an alkyl group substituted with a 5-membered heteroaryl group or a 6-membered heteroaryl group.

[0443] In some implementations, R 24 It is hydrogen.

[0444] In some embodiments, the compound is selected from...

[0445] (Z)-N-(2,3-diphenyl-1,2,4-thiadiazole-5(2H)-ylidene)methylamine;

[0446] N-Methyl-2,3-diphenyl-1,2,4-thiadiazolium-5-amine;

[0447] N-Benzyl-2,3-diphenyl-1,2,4-thiadiazolium-5-amine; and

[0448] N-Phenylacetyl-2,3-diphenyl-1,2,4-thiadiazolium-5-amine;

[0449] Or tautomers, and / or their pharmaceutically acceptable salts.

[0450] A method for inhibiting the activity of myofascitis is also provided, comprising administering an effective amount of a myofascitis inhibitor to cells, thereby inhibiting the activity of myofascitis in the cells, wherein the myofascitis inhibitor is a compound of formula III.

[0451]

[0452] or tautomers, and / or their pharmaceutically acceptable salts, wherein

[0453] R 30 The phenyl group is selected from lower alkyl groups, lower alkenyl groups optionally substituted with phenyl groups, and phenyl groups optionally substituted with one or two substituents independently selected from nitro and halogen groups.

[0454] R 31 Selected from lower haloalkyl groups, -OH, -OR 9 -SH, -SR 7 -NR 10 R 10 , halogen, cyano, nitro, -COH, -COR 7 -CO2H, -CO2R 7 -CONR 10 R 10 -OCOR 7 -OCO2R 7 -OCONR 10 R 10 -SO2NR 10 R 10 and -NR 10 SO2R 7 ;

[0455] p is 0, 1, or 2;

[0456] X 30 It is C(=O) or S(O)2;

[0457] R 7 It is a lower alkyl group;

[0458] R 9 It is phenyl; and

[0459] Each R 10 Independently hydrogen or a lower alkyl group, or two R groups 10 Together with the atoms attached to it, they form a ring.

[0460] In some implementations, R 30 It is a lower alkyl group.

[0461] In some implementations, R 30 It is a lower alkenyl group. In some embodiments, R 30 It is a lower alkenyl group substituted with phenyl.

[0462] In some implementations, R 30 A phenyl group that is optionally substituted with one or two substituents selected from nitro and halogen groups (e.g., chloro, bromo, or fluorine).

[0463] In some implementations, X 30 C (=O) and R 30 It is a lower alkyl group. In some embodiments, X 30 C (=O) and R 30 The lower alkenyl group can be optionally substituted with phenyl.

[0464] In some implementations, X 30 S(O)2 and R 30 It is a phenyl group. In some embodiments, X... 30 S(O)2 and R 30 A phenyl group that is substituted by one or two substituents that are independently nitro or halogen (e.g., chloro).

[0465] In some implementations, R 31 Selected from halogenated and phenoxy groups. In some embodiments, R 31 It is selected from fluorine, chlorine or phenoxy groups.

[0466] In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2.

[0467] In some embodiments, the compound is selected from...

[0468] 2-Chloro-N-(6-chlorobenzo[d]thiazo-2-yl)-5-nitrobenzenesulfonamide,

[0469] 3-Chloro-N-(6-phenoxybenzo[d]thiazolyl-2-yl)benzenesulfonamide,

[0470] N-(6-fluorobenzo[d]thiazo-2-yl)-3-nitrobenzenesulfonamide,

[0471] 2,3-Dichloro-N-(6-fluorobenzo[d]thiazo-2-yl)benzenesulfonamide,

[0472] N-(6-fluorobenzo[d]thiazo-2-yl)acetamide,

[0473] N-(6-chlorobenzo[d]thiazolyl)acetamide, and

[0474] N-(benzo[d]thiazo-2-yl)cinnamamide,

[0475] Or tautomers, and / or their pharmaceutically acceptable salts.

[0476] In some embodiments, the cells are in an animal. In some embodiments, the cells have been removed from the animal. In some embodiments, the animal is a human. In some embodiments, the human suffers from a disease or ailment.

[0477] In some embodiments, the condition or obstacle is metastatic cancer, neuronal disorder, neuronal degeneration, inflammatory disease, viral infection, bacterial infection, lymphoproliferation, Hodgkin's disease, or tissue damage related to local ischemia. In some embodiments, the condition or obstacle is metastatic cancer.

[0478] In some embodiments, the cancer is carcinoma, lymphoma, sarcoma, melanoma, astrocytoma, mesothelioma, ovarian cancer, colon cancer, pancreatic cancer, esophageal cancer, stomach cancer, lung cancer, urinary tract cancer, bladder cancer, breast cancer, stomach cancer, leukemia, lung cancer, colon cancer, central nervous system cancer, melanoma, ovarian cancer, kidney cancer, or prostate cancer. In some embodiments, the cancer is lung cancer, breast cancer, or prostate cancer.

[0479] Agents that modulate the activity of myofascitis can be used to treat a variety of diseases and conditions. For example, as shown in this article, myofascitis promotes actin tufting and plays a key role in cell migration and cancer cell metastasis. Therefore, regulators and inhibitors of myofascitis can be used to treat and inhibit metastatic cancer.

[0480] However, myofascitis also plays a role in other diseases and conditions. For example, it regulates the shape and trajectory of neurites (Kraft et al., Phenotypes of Drosophila brain neurons in primary culture reveal a role for fascin in neurite shape and trajectory, J. Neurosci, 26(34): 8734-47 (2006)). Myofascitis is also involved in neuronal degeneration (Fulga et al., Abnormal bundling and accumulation of F-actin mediates tau-induced neuronal degeneration in vivo Nat Cell Biol. 9(2): 139-48 (2007)). In addition, myofascitis plays a role in Hodgkin's disease (Pinkus et al., Fascin, a sensitive new marker for Reed-Sternberg cells of Hodgkin's disease, Am J Pathol. 150(2): 543-562 (1997)). Myofascitis also plays a role in the processing and presentation of antigens, for example, in antigen-presenting cells (Mosialos et al., Circulating human dendritic cells differentially express high levels of a 55-kd actin-bundling protein. Am. J. Pathol. 148(2): 593-600 (1996); Said et al., The role of follicular and inter digitating dendritic cells in HIV-related lymphoid hyperplasia: localization of fascin. Mod Pathol. 10(5): 421-27 (1997)). In addition, myofascitis also plays a role in ischemic injury (Meller et al., Ubiquitin proteasome-mediated synaptic reorganization: a novel mechanism underlying rapid ischemic tolerance, J Neurosci. 28(l): 50-9 (2008)).

[0481] This article provides reagents for regulating the activity of myofascitis proteins, as well as methods for treating and inhibiting tissue damage associated with metastatic cancer, neuronal disorders, neuronal degeneration, inflammatory conditions, viral infections, bacterial infections, lymphoproliferation, Hodgkin's disease, and ischemia.

[0482] Tumor metastasis is a leading cause of death in cancer patients (Weiss 2000, Fidler 2003). Therefore, inhibiting or preventing tumor metastasis will significantly improve the survival rate of cancer patients, allow for milder radiation or chemotherapy with fewer side effects, and control the progression of solid tumors.

[0483] Tumor cell migration and invasion are key steps in the process of tumor metastasis (Partin et al. 1989, Aznavoorian et al. 1993, Condeelis et al. 2005). For cell migration to occur, the actin cytoskeleton must be reorganized by forming polymers and bundles to influence the dynamic changes in cell shape (Jaffe et al. 2005, Matsudaira 1994, Otto 1994). Individual actin filaments are flexible, and the elongation of a single filament is insufficient for membrane protrusion, which is essential for cell migration. Bundles of actin filaments provide the rigidity for protrusion against compressive forces from the plasma membrane (Mogilner et al. 2005).

[0484] One of the key actin bundlers is myofascitis. Myofascitis is a major actin cross-linker in filamentous pseudopodia, acting as a membrane protrusion and crucial for cancer cell migration and metastasis. Myofascitis requires maximally cross-linking actin filaments into straight, dense, and rigid bundles. High expression of myofascitis mRNA and protein in cancer cells has been associated with invasive clinical features, poor prognosis, and shorter survival. Therefore, administration of myofascitis inhibitors, as described in this article, can treat, prevent, and / or inhibit metastatic cancer.

[0485] Furthermore, any stage of cancer progression (e.g., primary cancer, metastatic cancer, and recurrent cancer) can be treated using the methods of this technology. In some embodiments, cancer is treated before metastasis is detected to inhibit its development into metastatic cancer. In other embodiments, cancer is treated when metastasis is detected to inhibit further metastasis and progression of cancer.

[0486] The compounds described herein, or pharmaceutically acceptable salts thereof, may also be used to treat Kaposi's sarcoma associated with autoimmune deficiency syndromes, cancers of the adrenal cortex, cervical cancer, endometrial cancer, esophageal cancer, head and neck cancer, liver cancer, pancreatic cancer, prostate cancer, thymic cancer, carcinoid tumors, chronic lymphocytic leukemia, Ewing's sarcoma, gestational trophoblastic tumors, hepatoblastoma, multiple myeloma, non-small cell lung cancer, retinoblastoma, or tumors in the ovaries. Treatment or detection may be possible at any stage of cancer progression (e.g., primary cancer, metastatic cancer, and recurrent cancer). Information on numerous types of cancer can be found, for example, from the American Cancer Society (www.cancer.org), or from, for example, Wilson et al. (1991), Harrison's Principles of Internal Medicine, 12th edition, McGraw-Hill.

[0487] In some embodiments, a method for treating or inhibiting the metastasis of cancer in animals is provided, for example, for human or veterinary use, comprising administering to a test animal (e.g., a human) a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the cells have been removed from the animal.

[0488] Treatment of a disease or condition (e.g., cancer) or the treatment of a disease or condition (e.g., cancer) refers to the relief or reduction of at least one symptom commonly associated with the disease or condition. The treatment also includes the relief or reduction of more than one symptom of the disease or condition. Treatment can cure a disease or condition by, for example, eliminating the symptoms and / or the root cause of the disease or condition. For example, treatment can cure cancer by substantially inhibiting the metastasis of cancer cells, thereby substantially eliminating cancer by removing or killing the primary tumor cells or cancer cells. Treatment can also prevent or inhibit the metastasis of cancer cells and / or tumor cells without directly killing or promoting the apoptosis of cancer cells.

[0489] Myofascitises play a role in a variety of cellular functions, including regulating cell growth, cell motility, and cell interactions. However, the actin bundles of myofascitises are directly involved in tumor metastasis and invasive growth.

[0490] Those skilled in the art can evaluate the anti-metastatic activity of myotrigin against various cancers using the methods described herein (e.g., various assays or therapeutics as described herein exist). Anti-cancer activity, for example, can be demonstrated by inhibiting 50% of cancer cell metastasis (IC50) by recognizing compounds or compositions as described herein. 50 The dosage is determined by the amount of the drug.

[0491] Methods for evaluating effective doses of the compounds described herein or their pharmaceutically acceptable salts for treating cancer (e.g., inhibiting metastasis) are also provided, the method comprising: determining the IC50 of the reagent in vitro. 50 This method allows for the calculation of an approximate amount per volume required to inhibit cancer cell migration. This amount can be determined, for example, by standard microdilution methods. In some embodiments, compounds or compositions as described herein can be administered in multiple doses over a duration of time, or intermittently.

[0492] Composition

[0493] Compounds described herein (e.g., myofascitis inhibitors) can be formulated into pharmaceutical compositions and administered to mammalian hosts (e.g., human patients) in various forms suitable for a chosen route of administration, such as oral or parenteral route, intravenous route, intramuscular route, local route, percutaneous route, intrathecal route, ocular route, intranasal route, intraperitoneal route, or subcutaneous route.

[0494] The compounds described herein (e.g., myofascitis inhibitors) can be administered systemically, for example, by oral administration in combination with a pharmaceutically acceptable medium (e.g., an inert diluent or an absorbable, edible carrier). They can be encapsulated in hard or soft gelatin capsules, compressed into tablets, or directly incorporated into the patient's diet. For oral therapeutic administration, the active compound can be combined with one or more excipients and used in the form of ingestible tablets, sublingual tablets, lozenges, capsules, elixirs, suspensions, syrups, dry sheets, etc. Such compositions and formulations should contain at least 0.1% of the active compound. Of course, the percentage of the composition and formulation can vary and is conveniently between about 2% to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions results in an effective dose level.

[0495] Tablets, lozenges, pills, capsules, etc., may also contain the following: binders, such as gum arabic, gum arabic, corn starch, or gelatin; excipients, such as dicalcium phosphate; disintegrants, such as corn starch, potato starch, alginic acid, etc.; lubricants, such as magnesium stearate; and may include sweeteners such as sucrose, fructose, lactose, or aspartame, or flavorings such as peppermint, wintergreen oil, or cherry flavoring. When the unit dosage form is a capsule, in addition to the materials of the above types, it may contain a liquid carrier, such as vegetable oil or polyethylene glycol. Various other materials may be present as coatings or in other altered forms of appearance for solid unit dosage forms. For example, tablets, pills, or capsules may be coated with gelatin, wax, shellac, or sugar, etc. Syrups or elixirs may contain active compounds, sucrose or fructose as sweeteners, methylparaben and propylparaben as preservatives, dyes, and flavorings (such as cherry flavoring or orange flavoring). The materials used to prepare any unit dosage form should be pharmaceutically acceptable and in substantially non-toxic amounts. Furthermore, the active compound may be incorporated into sustained-release formulations and devices.

[0496] The active compounds described herein can also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compounds or their salts can be prepared in water and optionally mixed with a non-toxic surfactant. Dispersants can also be prepared in glycerol, liquid polyethylene glycol, triacetin, and mixtures thereof, and in oils. Under normal storage and use conditions, these formulations contain preservatives to prevent microbial growth.

[0497] Suitable drug dosage forms for injection or infusion may include sterile aqueous solutions or dispersions or sterile powders containing the active ingredient. These dosage forms are suitable for the ad hoc preparation of sterile injectable or infusion solutions or dispersions, optionally encapsulated in liposomes. In all cases, the final dosage form should be sterile, liquid, and stable under the conditions of manufacture and storage. The liquid carrier or medium can be a solvent or liquid dispersion medium, including, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glycerides, and suitable mixtures thereof. Appropriate fluidity can be maintained, for example, by the formation of liposomes, by maintaining the particle size required in the dispersed case, or by using surfactants. The antimicrobial effect can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. In many cases, isotonic agents, such as sugars, buffers, or sodium chloride, will be preferred. Extended absorption of injectable compositions can be achieved by using compositions with delayed absorption agents (e.g., aluminum monostearate and gelatin).

[0498] Sterile injectable solutions are prepared by incorporating the desired amount of the active compound into a suitable solvent, and, if necessary, incorporating some of the other components listed above into the solvent, followed by filtration and sterilization. For sterile powders used to prepare sterile injectable solutions, preferred methods of preparation include vacuum drying and freeze-drying techniques, which produce powders containing the active ingredient plus any additional desired components present in the previously sterile filtered solution.

[0499] For topical application, these compounds can be applied in their pure form (i.e., when they are liquid). However, it is generally desirable for them to be combined with a dermatologically acceptable carrier as a composition or formulation for skin application, which can be solid or liquid.

[0500] Useful solid carriers include very finely dispersed solids such as talc, clay, microcrystalline cellulose, silica, alumina, etc. Useful liquid carriers include water, alcohol, or ethylene glycol or water-alcohol / ethylene glycol blends, wherein the compound can optionally be dissolved or dispersed in an effective amount using a non-toxic surfactant. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given application. The resulting liquid compositions can be applied to absorbent pads, used for impregnating bandages and other dressings, or sprayed onto the affected area using a pump-type sprayer or aerosol sprayer.

[0501] For example, synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified cellulose or modified mineral materials thickeners can also be used with liquid carriers to form spreadable pastes, gels, ointments, soaps, etc., for direct application to the user's skin.

[0502] Examples of useful dermatological compositions known in the art that can be used to deliver the compounds described herein or their pharmaceutically acceptable salts onto the skin; see, for example, Jacquet et al. (US Patent No. 4,608,392), Geria (US Patent No. 4,992,478), Smith et al. (US Patent No. 4,559,157), and Wortzman (US Patent No. 4,820,508).

[0503] Useful doses of the compounds described herein or their pharmaceutically acceptable salts can be determined by comparing their in vitro and in vivo activities in animal models. Extrapolation methods from effective doses in mice and other animals to humans are known in the art; see, for example, U.S. Patent No. 4,938,949.

[0504] Typically, the concentrations of the compounds described herein or their pharmaceutically acceptable salts in liquid compositions (e.g., lotions) will be about 0.01 wt%, about 0.1 wt%, about 1.0 wt%, about 2.0 wt%, about 3.0 wt%, about 4.0 wt%, about 5.0 wt%, about 10.0 wt%, about 25.0 wt%, or in the range of any two of these values. The concentrations in semi-solid or solid compositions (e.g., gels or powders) will be about 0.01 wt%, about 0.1 wt%, about 1.0 wt%, about 2.0 wt%, about 3.0 wt%, about 4.0 wt%, about 5.0 wt%, about 10.0 wt%, about 25.0 wt%, or in the range of any two of these values.

[0505] The amount of the compound or active salt or derivative to be used in treatment will vary not only with the specific salt chosen, but also with the route of administration, the nature of the condition being treated, and the patient's age and condition. This amount will ultimately be determined by the attending physician or clinician. However, a generally appropriate dose will be in the range of about 1.0 mg / kg to about 200 mg / kg, for example, about 1 mg / kg body weight to about 100 mg / kg body weight daily, for example, about 2.0 mg / kg body weight to about 100 mg / kg body weight daily, for example, about 3.0 mg to about 50 mg per kilogram of the recipient's body weight daily, or in the range of about 5 mg / kg / day to 20 mg / kg / day. Alternatively, the composition may be administered five times a week for five consecutive days and two days off, or four times a week for four consecutive days and three days off, or four times every other day.

[0506] Methods for extrapolating effective doses in mice and other animals to humans are known in the art (e.g., see U.S. Patent No. 4,938,949). For example, in some embodiments, the dosage levels at which the compounds described herein or pharmaceutically acceptable salts thereof (e.g., those used to treat colon cancer and / or ovarian cancer) can be administered are approximately 0.01 mg / kg body weight to approximately 300 mg / kg body weight daily, approximately 0.1 mg / kg body weight to approximately 250 mg / kg body weight, approximately 1 mg / kg body weight to approximately 200 mg / kg body weight, approximately 1 mg / kg body weight to approximately 150 mg / kg body weight, approximately 1 mg / kg body weight to approximately 100 mg / kg body weight, approximately 1 mg / kg body weight to approximately 90 mg / kg body weight, and approximately 1 mg / kg body weight per day. Approximately 80 mg / kg of body weight, approximately 1 mg / kg of body weight to approximately 70 mg / kg of body weight, approximately 1 mg / kg of body weight to approximately 60 mg / kg of body weight, approximately 1 mg / kg of body weight to approximately 50 mg / kg of body weight, approximately 1 mg / kg of body weight to approximately 40 mg / kg of body weight, approximately 1 mg / kg of body weight to approximately 30 mg / kg of body weight, approximately 1 mg / kg of body weight to approximately 20 mg / kg of body weight, approximately 5 mg / kg of body weight to approximately 100 mg / kg of body weight, approximately 5 mg / kg of body weight to approximately 90 mg / kg of body weight, approximately 5 mg / kg of body weight to approximately 80 mg / kg of body weight. g of subject body weight, approximately 5 mg / kg of subject body weight to approximately 70 mg / kg of subject body weight, approximately 5 mg / kg of subject body weight to approximately 60 mg / kg of subject body weight, approximately 5 mg / kg of subject body weight to approximately 50 mg / kg of subject body weight, approximately 5 mg / kg of subject body weight to approximately 40 mg / kg of subject body weight, approximately 5 mg / kg of subject body weight to approximately 30 mg / kg of subject body weight, approximately 5 mg / kg of subject body weight to approximately 20 mg / kg of subject body weight, approximately 10 mg / kg of subject body weight to approximately 100 mg / kg of subject body weight, approximately 10 mg / kg of subject body weight to approximately 90 mg / kg of subject body weight, approximately 10 mg / kg of subject body weight to approximately 80 mg / kg of subject body weight, Approximately 10 mg / kg of body weight to approximately 70 mg / kg of body weight, approximately 10 mg / kg of body weight to approximately 60 mg / kg of body weight, approximately 10 mg / kg of body weight to approximately 50 mg / kg of body weight, approximately 10 mg / kg of body weight to approximately 40 mg / kg of body weight, approximately 10 mg / kg of body weight to approximately 30 mg / kg of body weight, approximately 10 mg / kg of body weight to approximately 20 mg / kg of body weight, approximately 20 mg / kg of body weight to approximately 100 mg / kg of body weight, approximately 20 mg / kg of body weight to approximately 90 mg / kg of body weight, approximately 20 mg / kg of body weight to approximately 80 mg / kg of body weight,The compound may be administered at doses of approximately 20 mg / kg body weight to approximately 70 mg / kg body weight, approximately 20 mg / kg body weight to approximately 60 mg / kg body weight, approximately 20 mg / kg body weight to approximately 50 mg / kg body weight, approximately 20 mg / kg body weight to approximately 40 mg / kg body weight, and approximately 20 mg / kg body weight to approximately 30 mg / kg body weight, once or more daily, to achieve the desired therapeutic effect. In some embodiments, the compound may be administered at doses of approximately 1 mg / kg body weight or more, 5 mg / kg body weight or more, 10 mg / kg body weight or more, 15 mg / kg body weight or more, 20 mg / kg body weight or more, 25 mg / kg body weight or more, 30 mg / kg body weight or more, 35 mg / kg body weight or more, 40 mg / kg body weight or more, 45 mg / kg body weight or more, 50 mg / kg body weight or more, 60 mg / kg body weight or more, and 70 mg / kg body weight or more. It will also be understood that doses less than 0.01 mg / kg or greater than 70 mg / kg (e.g., 70-200 mg / kg) may be administered to the subject. ,

[0507] In some embodiments, the compounds described herein may be used in chemotherapy (i.e., to inhibit metastasis) and may be administered at higher doses. For example, compounds used in chemotherapy may be administered daily at approximately 100 mg / kg body weight to approximately 300 mg / kg body weight, approximately 120 mg / kg body weight to approximately 280 mg / kg body weight, approximately 140 mg / kg body weight to approximately 260 mg / kg body weight, approximately 150 mg / kg body weight to approximately 250 mg / kg body weight, approximately 160 mg / kg body weight to approximately 240 mg / kg body weight, once or more daily to achieve the desired therapeutic effect.

[0508] In some other embodiments, the compounds described herein may be used in supportive therapy (e.g., as adjuvants to surgery or radiation in the range of common types of tumors) and may be administered at lower doses. For example, compounds used in supportive therapy may be administered once or more daily at a dose of about 1 mg / kg body weight to about 30 mg / kg body weight, about 1 mg / kg body weight to about 25 mg / kg body weight, or about 5 mg / kg body weight to about 20 mg / kg body weight to achieve the desired therapeutic effect.

[0509] In some other embodiments, the compounds described herein can be used to treat metastatic cancers (e.g., ovarian cancer and / or colon cancer) and can be administered at intermediate doses. For example, compounds used in supportive therapy can be administered daily at about 1 mg / kg body weight to about 100 mg / kg body weight, about 1 mg / kg body weight to about 80 mg / kg body weight, about 5 mg / kg body weight to about 70 mg / kg body weight, about 10 mg / kg body weight to about 70 mg / kg body weight, about 10 mg / kg body weight to about 60 mg / kg body weight, about 20 mg / kg body weight to about 70 mg / kg body weight, about 20 mg / kg body weight to about 60 mg / kg body weight, once or more daily to achieve the desired therapeutic effect.

[0510] The compound can be conveniently administered in unit dosage forms; for example, each unit dosage form contains 45 mg to 3000 mg of active ingredient, conveniently 90 mg to 2250 mg of active ingredient, and most conveniently 450 mg to 1500 mg of active ingredient. In some embodiments, the compound is administered at a dose of about 1 mg / kg to about 100 mg / kg.

[0511] Ideally, the active ingredient should be administered to achieve peak plasma concentrations of the active compound at a concentration of about 0.5 nM to about 10 μM, or about 1 nM to 1 μM, or about 10 nM to about 0.5 μM. This can be achieved, for example, by intravenous injection of a solution of 0.05% to 5% of the active ingredient (optionally in saline), or by oral administration of a pill containing about 20-2000 mg of the active ingredient. The desired blood level can be maintained by continuous infusion of about 0.2 mg / kg / hr to 1.0 mg / kg / hr, or by intermittent infusion of about 0.4 mg / kg to 20 mg / kg of the active ingredient. The desired dose can be conveniently provided as a single dose or as fractions administered at appropriate intervals, such as two, three, four, or more sub-dose per day. The sub-dose itself can be further divided into, for example, multiple discrete, loosely spaced administrations; for example, by multiple inhalations from an inhaler or by multiple drops into the eye.

[0512] The compounds described herein, or their pharmaceutically acceptable salts, are administered as therapeutic agents to inhibit cell migration and treat metastatic cancers. Such cancers include, but are not limited to, cancers involving, for example, the head, neck, lungs, mesothelioma, mediastinum, esophagus, stomach, pancreas, hepatobiliary system, small intestine, colon, colorectal, rectum, anus, kidneys, ureters, bladder, prostate, urethra, penis, testes, gynecological organs, ovaries, breasts, endocrine system, skin, or central nervous system in animals. Thus, for example, cancers could be breast cancer, leukemia, lung cancer, colon cancer, central nervous system cancer, melanoma, ovarian cancer, kidney cancer, or prostate cancer.

[0513] Furthermore, the compounds described herein or their pharmaceutically acceptable salts, such as the exemplary salts described herein, can be used as pharmacological tools for further investigation of cell migration inhibition.

[0514] The compounds described herein, or their pharmaceutically acceptable salts, may also be used in combination with other therapeutic agents, which is effective in treating or controlling the spread of cancer cells or tumor cells.

[0515] Furthermore, the compounds described herein, or pharmaceutically acceptable salts thereof, can be tested in appropriate animal models. For example, the compounds described herein, or pharmaceutically acceptable salts thereof, can be tested in animals with known tumors, or in animals that have been injected with tumor cells into a localized area. The extent or number of secondary tumors that form over time is a measure of metastasis, and the ability of the compounds to inhibit such metastasis can be evaluated relative to control animals with primary tumors but not receiving the tested compounds.

[0516] The compounds described herein, or their pharmaceutically acceptable salts, will also be found to treat brain disorders (Kraft et al., J. Neurosci. 23 Aug 2006; 26(34): 8734-47); Hodgkin's disease (Pinkus et al., Am J Pathol. 2007 Feb; 150(2): 543-62); viral infections (Mosialos et al., Am J Pathol. 2006 Feb; 148(2): 593-600); neuronal degeneration (Fulga et al., Nat Cell Biol. 2007 Feb; 9(2): 139-48); lymphoproliferation (Said et al., Mod Pathol. 2007 May; 10(5): 421-7); and local ischemia (Meller et al., J. Neurosci. January 2, 2008; 28(1): pp. 50-9.

[0517] Typical synthesis methods

[0518] The compounds described herein are commercially available or can be prepared from readily available starting materials using the following conventional methods and processes. It should be understood that typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given herein, and other process conditions may be used unless otherwise stated. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art through conventional optimization processes.

[0519] Furthermore, it will be apparent to those skilled in the art that conventional protecting groups are necessary to prevent certain functional groups from undergoing undesirable reactions. Suitable protecting groups for various functional groups and suitable conditions for protecting and deprotecting specific functional groups are well known in the art. For example, many protecting groups are described in, for example, TW Greene and GMWuts, *Protecting Groups in Organic Synthesis*, 3rd edition, Wiley, New York, 1999, and their cited references.

[0520] Furthermore, the compounds described herein may contain one or more chiral centers. Therefore, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as mixtures enriched with stereoisomers. Unless otherwise stated, all such stereoisomers (and enriched mixtures) are included within the scope of this invention. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active starting materials or stereoselective reagents known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, etc.

[0521] The starting materials used in the following reactions are typically known compounds, or can be prepared by known processes or their obvious modifications. For example, many starting materials are available from commercial suppliers such as Aldrich Chemical Company (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce, or Sigma (St. Louis, Missouri, USA). Others can be prepared by means of the procedures in standard references or their obvious modifications, such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1–15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1–5 and Supplements (Elsevier Science, 1989), Organic Reactions, Volumes 1–40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry (John Wiley and Sons, 4th Edition), and Larock's Comprehensive Organic Transformations (VCH Publishing, 1989).

[0522] Various starting materials, intermediates, and compounds described herein can be separated and purified using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography. These compounds can be characterized using conventional methods such as melting point analysis, mass spectrometry, nuclear magnetic resonance, and various other spectroscopic analyses.

[0523] Schemes 1-7 illustrate exemplary methods for preparing the compounds described herein.

[0524] In Scheme 1, compound 1-1 (where Lg is a leaving group, such as OH, fluorine, chloro, bromine, iodo, toluenesulfonate, trifluoromethanesulfonate, etc.) and R 1 -OH,R 1 -SH or R 1 -HNR 8 The reaction forms compounds 1-2, in which L 1 They are -O-, -S-, or -NR respectively. 8 - For example, under Mitsunobu reaction conditions, compound 1-1 (where Lg is OH) reacts in the presence of diethyl azodicarbonate (DEAD) and triphenylphosphine to form compound 1-2. Alternatively, in compound 1-1, Lg is hydrogen and Y... 3 It is nitrogen, and this compound 1-1 is related to R.1 -L 1 -Lg 2 (where Lg) 2 (As a leaving group, such as halogen) reacts to form compounds 1-2, wherein L 1 As defined in equation Ia, for example, L 1 -C(R) 8 )2-.

[0525] Option 1

[0526]

[0527] In the presence of a catalyst (e.g., Pd), compounds 1-2 are reduced to compounds 1-3 using a reducing agent (e.g., H2). In some embodiments, compounds 1-3 are coupled with carboxylic acid compound R under coupling conditions (e.g., using an amide coupling agent). 5 The reaction of CO2H forms a compound of formula Ia, where R is L. 2 -R 5 And L 2 The form is -NHC(O)-. In some embodiments, compounds 1-3 can be reacted with sulfonyl chloride compound R. 5 SO 2 The C1 reaction forms a compound of formula Ia, where R is L. 2 -R 5 And L 2 The form is -NHS(O)2-. In some embodiments, compounds 1-3 and sodium nitrite, along with the nucleophile Z, are used. - M + (where Z) - It is a nucleophile, such as iodide, bromide, chloride, fluoride, cyanide, carboxyl group, and M + To counteract ions (such as copper, sodium, etc.), various intermediates represented by compounds 1-4 are formed. Compounds 1-4 can undergo various transformations to provide embodiments of compounds of formula Ia. For example, when Z is iodo, bromo, or chloro, compounds 1-4 can undergo various cross-coupling reactions with another iodo, bromo, or chloro compound or a compound with boric acid functionality to form compounds of formula Ia, where R is L. 2 -R 5 And L 2 The bonds are covalent. Preferably, this reaction is carried out under catalytic conditions using a catalyst (e.g., CuI or palladium catalyst). Alternatively, when Z is a carboxyl group, compounds 1-4 can react with amine R. 5 -NHR 8 The reaction forms a compound of formula Ia, where R is L. 2 -R 5 And L 2-C(O)N(R) 8 Alternatively, compounds 1-3 react with sodium nitrite, sulfur dioxide, and copper chloride (I) to form sulfonyl chloride compounds (Z is SO2Cl), which can react with amine R. 5 -NHR 8 The reaction forms a compound of formula Ia, where R is L. 2 -R 5 And L 2 -S(O)2N(R) 8 In scheme 1, Q 1 Q 2 R 1 R 4 R 5 X 1 Y 1 Y 2 Y 3 Y 5 Y 6 , s and t are as defined in equation Ia.

[0528] Amide coupling reagents are known in the art and may include, but are not limited to, reagents based on ammonium and phosphonium. Ammonium salts include N-[(dimethylamino)-1H-1,2,3-triazol[4,5-b]pyridin-1-ylmethylene]-N-methylmethylammonium hexafluorophosphate N-oxide (HATU), N-[(1H-benzotriazol-1-yl)(dimethylamino)methylene]-N-methylmethylammonium hexafluorophosphate N-oxide (HBTU), N-[(1H-6-chlorobenzotriazol-1-yl)(dimethylamino)methylene]-N-methylmethylammonium hexafluorophosphate N-oxide (HCTU), N-[(1H-benzotriazol-1-yl)(dimethylamino)methylene]-N-methylmethylammonium tetrafluoroboronic acid N-oxide (TBTU) and N-[(1H-6-chlorobenzotriazol-1-yl)(dimethylamino)methylene]-N-methylmethylammonium tetrafluoroboronic acid N-oxide (TCTU). Phosphorus salts include 7-azabenzotriazol-1-yl-N-oxo-tris(pyrrolidinyl)phosphorus hexafluorophosphate (PyAOP) and benzotriazol-1-yl-N-oxo-tris(pyrrolidinyl)phosphorus hexafluorophosphate (PyBOP). The amide formation step can be carried out in a polar solvent (e.g., dimethylformamide (DMF)) and may also include an organic base (e.g., diisopropylethylamine (DIEA) or dimethylaminopyridine (DMAP)).

[0529] Cross-coupling reactions are well known in the art, for example in Anna Roglans et al., Diazonium Salts as Substrates in Palladium-Catalyzed Cross-Coupling Reactions, Chem. Rev., 2006, 106(11): 4622-4643; Brad M. Rosen et al., Nickel-Catalyzed Cross-Couplings Involving Carbon-Oxygen Bonds, Percec Chem. Rev., 2011, 111(3): 1346-1416; Jean-Pierre Corbet et al., Selected Patented Cross-Coupling Reaction Technologies, Chem. Rev., 2006, 106(7): 2651-2710; Gwilherm Evano et al., Copper-Mediated Coupling Reactions and Their Applications in Natural Products and Designed Biomolecules. Synthesis, Chem. Rev., 2008, 108(8): 3054-3131; Benny Bogoslavsky et al., Formation of a Carbon-Carbon Triple Bond by Coupling Reactions In Aqueous Solution, Science 308(5719): 234-235 (2005); and M. Lafrance et al., Catalytic Intermolecular Direct Arylation of Perfluorobenzenes, J. Am. Chem. Soc. 128(27): 8754-8756 (2006); Norio Miyaura et al., “A newstereospecific cross-coupling by the palladium-catalyzed reaction of 1-alkenylboranes with 1-alkenyl or 1-alkynyl halides,” Tetrahedron Letters, 1979, 20(36): pp. 3437-3440; PEFanta, “The Ullmann Synthesis of Biaryls”, Synthesis, 1974, pp. 9-21; M. Gomberg and WEBachmann, J. Am. Chem. Soc, 1924, 42(10): pp. 2339-2343; R. J. Corriu and Masse, JP, “Activation of Grignard reagents by transition-metal complexes. A new and simple synthesis of trans-stilbenes and polyphenyls”, Journal of the Chemical Society, Chemical Communications, 1972, (3): 144a.

[0530] Option 2

[0531]

[0532] In scheme 2, compound 2-1 (where Lg is a leaving group, such as OH, fluorine, chlorine, bromine, iodo, toluenesulfonate, trifluoromethanesulfonate, etc., R) p (Protected by hydrogen or carboxyl groups, such as lower alkyl or benzyl groups) and R 1 -OH,R 1 -SH or R 1 -HNR 8 The reaction forms compound 2-2. For example, under Mitsunobu reaction conditions, compound 2-1 (where Lg is OH) reacts in the presence of diethyl azodicarbonate (DEAD) and triphenylphosphine to form compound 2-2. When R... P When the protecting group is a carboxyl group, compound 2-2 can be deprotected to form compound 2-3. Under coupling conditions (e.g., using an amide coupling agent), compound 2-2 or compound 2-3 can react with optionally substituted aniline to form a compound of formula Ic, wherein L 2 -C(O)NR 8 - In scheme 2, R 1 R 2 R 3 L 1 X 1 m and n are as defined in equation Ic.

[0533] Option 3

[0534]

[0535] In scheme 3, compound 3-1 (where Lg is a leaving group, such as OH, fluorine, chlorine, bromine, iodo, toluenesulfonate, trifluoromethanesulfonate, etc.) and R 1 -OH,R 1 -SH or R 1 -HNR 8 The reaction forms compound 3-2, which is then reduced to compound 3-3 by a reducing agent (e.g., H2) in the presence of a catalyst (e.g., Pd). For example, under Mitsunobu reaction conditions, compound 3-1 (where Lg is OH) reacts in the presence of diethyl azodicarbonate (DEAD) and triphenylphosphine to form compound 3-2. Then, under coupling conditions (e.g., using an amide coupling agent), compound 3-3 reacts with optionally substituted benzoic acid to form a compound of formula Ic, where Lg... 2 The form is -NHC(O)-. Alternatively, compound 3-3 can react with optionally substituted benzenesulfonyl chloride to form a compound of formula Ic, wherein L 2 It is -NHS(O)2-. In scheme 3, R 1 R 2 R 3 L 1 X 1 m and n are as defined in equation Ic.

[0536] Compounds of formula Ic can have tautomers of the structure of formula Id, wherein L 3 =NC(O)- or =NSO2- and X 2 For O, S or NR 8 .

[0537] Option 4

[0538]

[0539] In scheme 4, compound 4-1, Pr is an amino protecting group, such as tert-butoxycarbonyl, benzyloxycarbonyl, or carboxybenzyl, Z 1 and Z 2 These are groups suitable for cross-coupling reactions, such as iodo, bromo, chloro, toluenesulfonate, and boric acid. Other variables are as defined in Formula II. Z 1 and Z 2 They can be the same or different. When Z 1 and Z 2 At the same time, compound 4-2 (where R) 21 and R 22 (The same) can be achieved through a one-step cross-coupling reaction and at least two equivalents of formula R. 21 Z 3 The compound is prepared by reaction, wherein Z3 It can react with Z in cross-coupling reactions. 1 and Z 2 The reactive group. Alternatively, Z 1 and Z 2 They are different, compound 4-2 (where R) 21 and R 22 Different) can use selective coupling of R 21 and R 22 The first condition in the process is achieved through the first cross-coupling reaction, and then through coupling R. 21 and R 22 The second one in the formula is prepared by a second cross-coupling reaction. The amino protecting group of compound 4-2 can be deprotected under conditions known in the art to provide a compound of formula II, in which... It is a single bond and R 24 Hydrogen can exist in its tautomers, among which It is a double bond and R 24 It does not exist, or can be alkylated with lower haloalkyl groups to form compounds of formula II, wherein It is a single bond and R 24 It is a lower alkyl group.

[0540] Option 5

[0541]

[0542] In scheme 5, under coupling conditions (e.g., using an amide coupling agent), compound 5-1 and R... 30 The -CO2H reaction forms a compound of formula III, wherein X 30 The form is C (=O). Alternatively, under Mitsunobu reaction conditions, compound 5-1 reacts in the presence of diethyl azodicarbonate (DEAD) and triphenylphosphine to form compound III. Alternatively, compound 5-1 reacts with R... 30 -COC1 or R 30 -SO₂Cl reacts under alkaline conditions (e.g., using an organic base, such as triethylamine, diisopropylethylamine, or pyridine) to form a compound of formula III, wherein X 30 It is C (=O) or SO2. The variables in Scheme 5 are defined as in Equation III.

[0543] Option 6

[0544]

[0545] In scheme 6, compound 6-1 (where Lg is a leaving group, such as toluenesulfonate, trifluoromethanesulfonate, etc.) and R 1 -OH,R 1 -SH or R1 -HNR 8 The reaction forms compound 6-2, in which L 1 They are -O-, -S-, or -NR respectively. 8 - Alternatively, under the Mitsunobu reaction conditions, compound 6-1 reacts in the presence of diethyl azodicarbonate (DEAD) and triphenylphosphine to form compound 6-2. Alternatively, Lg is hydrogen and compound 6-1 reacts with R... 1 -L 1 -Lg 2 (where Lg) 2 (As a leaving group, such as a halogen group) reacts to form compound 6-2, wherein L 1 As defined in equation Ia, for example, L 1 -C(R) 8 )2-.

[0546] In the presence of a catalyst (e.g., Pd), compound 6-2 is reduced to compound 6-3 by a reducing agent (e.g., H2). In some embodiments, compound 6-3 reacts with carboxylic acid compound R under coupling conditions (e.g., using an amide coupling agent). 5 The reaction of CO2H forms a compound of formula Ij, where R is L. 2 -R 5 And L 2 The form is -NHC(O)-. In some embodiments, compound 6-3 can be reacted with sulfonyl chloride compound R. 5 SO 2 The C1 reaction forms a compound of formula Ij, where R is L. 2 -R 5 And L 2 The form is -NHS(O)2-. In some embodiments, compound 6-3 and sodium nitrite, along with the nucleophile Z, are used. - M + (where Z) - It is a nucleophile, such as iodide, bromide, chloride, fluoride, cyanide, carboxyl group, and M + To counteract ions (such as copper, sodium, etc.), various intermediates represented by compound 6-4 are formed. Compound 6-4 can undergo various transformations to provide embodiments of compounds of formula Ij. For example, when Z is iodo, bromo, or chloro, compound 6-4 can undergo various cross-coupling reactions with another iodo, bromo, or chloro compound or a compound with boric acid functionality to form compounds of formula Ij, where R is L. 2 -R 5 And L 2The bond is covalent. Preferably, this reaction is carried out under catalytic conditions using a catalyst (e.g., CuI or palladium catalyst). Alternatively, when Z is a carboxyl group, compound 6-4 can react with amine R. 5 -NHR 8 The reaction forms a compound of formula Ij, where R is L. 2 -R 5 And L 2 -C(O)N(R) 8 Alternatively, compound 6-3 reacts with sodium nitrite, sulfur dioxide, and copper chloride (I) to form a sulfonyl chloride compound (Z is SO2Cl), which can react with amine R. 5 -NHR 8 The reaction forms a compound of formula Ij, where R is L. 2 -R 5 And L 2 -S(O)2N(R) 8 In scheme 6, R 1 L 1 R 5 and L 2 As defined in equation Ia.

[0547] Option 7

[0548]

[0549] In scheme 7, compound 7-1 (Pr is an amino protecting group, such as tert-butoxycarbonyl, benzyloxycarbonyl, or carboxybenzyl, and Lg is a leaving group, such as toluenesulfonate, trifluoromethanesulfonate, etc.) and R 1 -OH,R 1 -SH or R 1 -HNR 8 The reaction forms compound 7-2, in which L 1 They are -O-, -S-, or -NR respectively. 8 - Alternatively, compound 7-1 can be reacted with diethyl azodicarbonate (DEAD) and triphenylphosphine under Mitsunobu reaction conditions to form compound 7-2. Alternatively, Lg is hydrogen and compound 7-1 reacts with R... 1 -L 1 -Lg 2 (where Lg) 2 (As a leaving group, such as a halogen group) reacts to form compound 7-2, wherein L 1 As defined in equation Ia, for example, L 1 -C(R) 8 )2-.

[0550] Compound 7-2 can be alkylated with a substituted lower haloalkyl group to form compounds of formula Ii, such as formula In, where L 2 and R 5 As defined in equation Ia.

[0551] All publications, patent applications, granted patents, and other documents mentioned in this specification are incorporated herein by reference, and where each individual publication, patent application, granted patent, or other document is specifically and individually identified, it is incorporated herein by reference in its entirety. Definitions contained herein by reference are excluded in the sense that they contradict any definition in this disclosure.

[0552] Therefore, the present technology, as generally described, will be more readily understood by referring to the following embodiments, which are provided by way of illustration and are not intended to limit the present technology.

[0553] Example

[0554] Example 1: High-throughput myofascitis inhibition assay

[0555] A high-throughput assay was developed to screen for specific inhibitors of myotrigin. Purified polymerized F-actin with or without myotrigin was mixed and cultured to allow actin bundle formation. The F-actin polymer was then bound to a poly-D-lysine-coated plate. After extensive washing, the F-actin polymers were visualized using Alexa Fluor 488 phalloidin labeling. Four images were acquired from each well, and the average fiber length was analyzed for each compound tested. As shown below, actin fibers were longer and thicker in the presence of myotrigin. 30 μM of 2-chloro-N-(6-chlorobenzo[d]thiazo-2-yl)-5-nitrobenzenesulfonamide (compound 3) inhibited fiber growth.

[0556]

[0557] Based on a preliminary screening of ~150,000 small molecule compounds, ~700 compounds were identified that resulted in shorter and thinner actin bundles when compared with those that did not contain small molecule compounds.

[0558] Images from these ~700 compounds were individually examined to ensure they resembled those from the control group of actin only. Following second and third deterministic screenings, in which both muscle and non-muscle actin were tested, 145 small molecule compounds were confirmed to inhibit actin bundle function of myotonic fasciculators. Dose-response curves were established for these 145 compounds.

[0559] Example 2: Expression and purification of human myofascitisin-1

[0560] Recombinant human myofascitis 1 was expressed as a GST fusion protein in BL21 *E. coli*. One liter of 2YT medium containing ampicillin was inoculated with 3 mL of BL21 / DE3 culture transformed with the pGEX4T-myofascitis 1 plasmid and incubated overnight at 37°C until growth was achieved at 600 nm (D). 600 The attenuation rate reached approximately 0.8. The culture was then transferred to 18°C ​​and induced for 12 hours with the addition of 0.1 mM isopropyl β-d-thiogalactoside (IPTG). Bacteria were collected by centrifugation at 5000 rpm for 10 minutes. The pellets were resuspended in 30 mL of PBS supplemented with 0.2 mM PMSF, 1 mM DTT, 1% (v / v) Triton X-100, and 1 mM EDTA. After sonication, the suspension was centrifuged at 15000 rpm for 30 minutes to remove cell debris. The supernatant was then incubated with 4 mL of glutathione beads (Sigma) at 4°C for 2 hours. After thorough washing with PBS, the beads were resuspended in 10 mL of thrombin lysis buffer (20 mM Tris-HCl pH 8.0, 150 mM NaCl, 2 mM CaCl2, 1 mM DTT). Myofascitis was released from the beads by incubating overnight at 4°C with 40-100 U of thrombin. After centrifugation, 0.2 mM PMSF was added to the supernatant to inactivate residual thrombin activity. Myofascitis was then... (Boca Raton, Florida) The filter further concentrates the concentration to approximately 50 mg / mL.

[0561] Example 3: Quantitative analysis of myofascitis protein expression levels

[0562] Myofascitis mRNA and protein levels were determined by real-time PCR and Western blotting, respectively. For quantitative real-time PCR, samples from cancer patients were used for RNA isolation. Myofascitis mRNA-specific oligonucleotide primers were used in the PCR reaction. For Western blotting, samples from cancer patients were evaluated using antibodies against myofascitis. The intensity of the bands representing myofascitis was quantified using image documentation and quantification software.

[0563] Example 4: Chemical Library Screening and Analysis

[0564] Approximately 150,000 compounds were screened. These chemical compounds were collected from LOPAC 1280, Prestwick Chemical Library, Pharmakon, MicroSource Spectroscopic Library, Life Chemistry Library, Greenpharma Natural Compound Library, Enamine Library, ChemBridge Library, Chem-X-Infinity Library, and BioFocus DPI Library. Purified myofascitis (15 μL, 0.5 μM) in buffer (100 mM KCl, 20 mM Tris / HCl, pH 7.5, 2 mM MgCl2) was added to each well of a clear 384-well plate (Corning) using a ThermoMultidrop Combi (Fisher). Compound solutions (180 nmL) (5 mM stock solution) from various chemical libraries were transferred from the stock solution 384-well plate to the 384-well assay plate using a needle and incubated for 30 minutes. Then, 15 μL of 0.5 μM polymerized actin (in 100 mM KCl, 20 mM Tris / HCl, pH 7.5, 2 mM MgCl2, 1 mM DTT, and 1 mM ATP) (Cytoskeleton) was added to obtain a final concentration of 30 μM of the chemical compound. After another 30 minutes, 10 μL of Alexa Fluro 488 phalloidin (diluted 25 times with 100% methanol, Invitrogen) was added to stain F-actin, and the mixture was incubated in the dark for one hour. The mixed solution (25 μL) was then transferred to one well of a black 384-well plate coated with poly-D-lysine and stained. Actin bundles or F-actin adhered to the poly-D-lysine plate. After washing the plate thoroughly three times with 1×PBS, the plate was imaged using the ImageXpress micro high-throughput sieving system (molecular device). The images were processed and analyzed using MetaMorph software. Background correction was performed on the raw image data for each well by subtracting the average intensity of all wells on the plate. The background-corrected data was used to calculate the bundle length for each well. Negative control wells were used for quality control: multiple DMSO-only control wells (16 wells / plate) were present on each assay plate. The top ten compounds with the shortest bundle lengths on each plate were selected for subsequent validation screening. In the validation screening, ~700 compounds were tested in duplicate. One hundred and forty-five compounds with confirmatory reactions were selected and continued with IC50 testing. 50 Research.

[0565] In the validation screening of the selected compounds, another actin bundle protein (filament protein) was used as a control to eliminate compounds that were not specific to myofascitis. Furthermore, in the validation screening, each compound was tested in duplicate on the same plate.

[0566] The concentration of the test compound varies in some assays.

[0567] Table 1 below shows some compounds of formula Ia, Ib, II or III and their IC50 values. 50 .

[0568] Table 1. Inhibition of myofascitis activity

[0569]

[0570]

[0571]

[0572]

[0573]

[0574]

[0575] Based on their in vitro myofascitis-inhibiting activity, the above compounds are expected to be used to treat conditions or disorders mediated by myofascitis activity.

[0576] Example 5: Boyden-Large Chamber Cell Migration Assay

[0577] Since myotrigin is crucial for tumor cell migration, its inhibitors should prevent tumor cell migration. Representative compounds were selected from the identified myotrigin inhibitors to test their ability to inhibit tumor cell migration (see Table 2). Boyden chamber assays of cell migration have shown that these compounds inhibit the migration of breast tumor cells, prostate tumor cells, and lung tumor cells. Therefore, tumor cells expressing myotrigin are sensitive to these myotrigin inhibitors. The cell lines used are listed below.

[0578] 4T1 breast tumor cells MDA-MB-231 breast tumor cells DU145 prostate tumor cells PC-3 prostate tumor cells LLC lung tumor cells

[0579] Exemplary procedure: MDA-MB-231 cells (5 × 10⁶) suspended in 100 μl of starvation medium 4 ) or 4T1 cells (1×10 5Add the inhibitor to the upper chamber of the insert (6.5 mm diameter, 8 μm well size; Becton Dickson), and place the insert in a 24-well plate containing 700 μL of starvation medium (with or without 10% FBS). When in use, add the inhibitor to the lower chamber. Perform a 6-hour migration assay and fix the cells with 3.7% formaldehyde. Stain the cells with crystal violet staining solution and remove cells from the upper side of the insert with a swab. Photograph three randomly selected fields of view (×10 objectives) on the lower side of the insert and count the migrated cells. Migration in the field of view is expressed as the mean number of migrated cells.

[0580] Table 2. Inhibition of myofascitis activity and tumor cell migration

[0581]

[0582]

[0583]

[0584] Statistical analysis: Data are expressed as mean ± standard deviation and analyzed by Student's t test, which is limited to significance of p < 0.05.

[0585] The compounds shown above represent those that inhibit tumor cell migration. The correlation between in vitro data obtained in this assay and results obtained from in vivo models is known. See, for example, Shan, D, et al., Synthetic analogues of migrastatin that inhibit mammary tumor metastasis in mice, Proc. Nat. Acad. Sci. 102: pp. 3772-3776 (2005). Based on their in vitro cell migration-inhibiting activity and the known correlation with in vivo activity, these compounds are expected to be used to treat conditions or disorders mediated by myofascitis activity and / or tumor metastasis.

[0586] Example 6: Tumor metastasis in a mouse model

[0587] Tumor cell migration is essential for tumor metastasis. Two representative compounds shown in Table 1, 2-chloro-N-(6-chlorobenzo[d]thiazo-2-yl)-5-nitrobenzenesulfonamide (compound 3) and N-(3-(1H-1,2,4-triazol-3-ylthio)-4-hydroxynaphthyl-1-yl)-4-methoxybenzenesulfonamide (compound 10), were selected to investigate their effects on tumor metastasis in an animal model. Tumor cells (4T1 mammary tumor cells) were injected into the mammary fat pads of mice. Metastasis of these mammary tumor cells from the mammary gland to the lung was monitored by clonal assays. Figure 1 As shown, these two representative myofascitis inhibitors (compound 3 and compound 10) reduced tumor metastasis in a mouse model.

[0588] Balb / c rats were purchased from Charles River. All animal procedures were approved by the Animal Care and Use Committees of the Weill Cornell Medical College and performed in accordance with policy. The study of xenograft tumor metastasis will involve 5 × 10⁻⁶ rats. 5 4T1 cells were suspended in 100 μL of PBS and subcutaneously injected into the mammary glands of 6–8 week old female Balb / c mice. Tumor incidence was monitored for 21 days post-injection. Tumor size was measured three times weekly and calculated using the formula length × width. 2 ×0.5 Calculated volume. Compound therapy began 7 days after tumor implantation; animals were administered the specified dose daily for 2 weeks. Mice were sacrificed on day 28. The number of metastatic 4T1 cells in the lungs was determined by clonal assay. Briefly, on day 28, the lungs of each mouse were removed, finely minced, and digested on a shaker in 5 mL of a complex enzyme cocktail containing 1 mg / mL type IV collagenase at 37°C for 2 hours. After culture, the samples were filtered through a 70-μm nylon cell filter and washed twice with PBS. The resulting cells were suspended in 10 cm tissue culture dishes in a series of dilutions of RPMI-1640 medium containing 60 μM thioguanine. After 14 days, metastatic tumor cells formed lesions, at which point they were fixed with methanol and counted by staining with 0.03% methylene blue. Data are expressed as mean ± standard deviation and analyzed by Student's t-test for significance limited to p < 0.05.

[0589] The two compounds shown above represent those that inhibit tumor metastasis, and therefore the compounds described herein are intended for use in treating conditions mediated by myofascitis and / or treating tumor metastasis.

[0590] Example 7: In vivo mouse model of prostate tumor metastasis

[0591] Male severe combined immunodeficiency (SCI) mice (n=20) aged 5-6 weeks, purchased from Charles River (Wilmington, MA), were randomly divided into two groups (n=10 animals per group). In both groups, human prostate tumor cells PC-3Luc cells (stable transfected with luciferase gene) (2×10⁻⁶ cells) were injected under 1.75% isoflurane / air anesthesia. 5 One cell in 100 μl of calcium-deficient... 2+ and Mg 2+ The test compound was introduced into the animals via intracardiac injection in Dulbecco phosphate-buffered saline (PBS). Throughout the experiment, animals in Group 1 received daily intraperitoneal (ip) administration of the test compound in 0.2 mL of sterile saline, starting one week prior to tumor cell inoculation. In Group 2 (blank control), animals received daily ip injection of the test compound in sterile saline. Mice were continuously imaged weekly for 5 weeks using an IVIS system (Xenogen, Alameda, CA), and the results were analyzed using in vivo imaging software (Xenogen). For imaging, mice were ip injected with fluorescein (40 mg / mL) under 1.75% isoflurane / air anesthesia, and ventral images were acquired 15 minutes after injection. At the end of the experiment, the animals were euthanized, and tissues were collected for histopathological confirmation of bone metastases. It was expected that fewer bone metastases were found in the animals in Group 1 treated with the myofascitis inhibitory compound disclosed herein, compared to those found in Group 2 animals. This test compound could be used to treat cancer, particularly metastatic prostate cancer.

[0592] Example 8: In vivo mouse model of lung tumor metastasis

[0593] Divide the 20 mice into two groups, and place 2×10 6 A549 human lung tumor cells were injected into mice via tail vein. One group was treated with the compound disclosed herein, and the other served as a control. After 8 weeks, lungs were harvested, fixed, and embedded in paraffin. The number of metastatic lung nodules was counted in serial tissue sections stained with H&E. The area of ​​metastatic lung nodules in scanned images of H&E-stained tumor sections was measured using Paint.NET software. It can be expected that the number and area of ​​metastatic lung nodules in the treated animals were smaller than those in the untreated control animals. This test compound could be used to treat cancer, particularly metastatic lung tumors.

[0594] Example 9: Treatment of tumor metastasis in the human body

[0595] In a randomized, open-label trial, human patients with metastatic breast cancer were administered intravenously with either the myotrigin inhibitory compound disclosed herein or placebo. Patients were randomly assigned to five groups. During a 3-week cycle, patients in each group were administered a daily dose of the compound at 0 mg (placebo), 100 mg, 200 mg, 500 mg, or 1000 mg, respectively. At the end of each cycle, time to disease progression, overall response rate (ORR), duration of response, and overall survival (OS) were determined using known techniques. It can be expected that patients administered the myotrigin inhibitory compound will have a longer median or mean time to disease progression and / or duration of response, a higher median or mean overall response rate, and / or overall survival than patients administered placebo. Patients administered the myotrigin inhibitory compound will form fewer new tumors distant from the original tumor site than patients administered placebo. In a preferred embodiment, one or more results are dose-responsive. Side effects are monitored and recorded. This test compound can be used to treat tumor metastases in humans.

[0596] References

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[0599] 3. Weiss, L. (2000) Metastasis of cancer: a conceptual history from antiquity to the 1990s, Cancer Metastasis Rev 19, 1-XI, pp. 193-383.

[0600] 4. Fidler, IJ (2003) The pathogenesis of cancer metastasis: the'seedand soil'hypothesis revisited, Nat Rev Cancer 3, pp. 453-458.

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[0604] 8.Sondak, VK, Han, D., Deneve, J. and Kudchadkar, R. (2011) Current and planned multicenter trials for patients with primary or metastatic melanoma, JSurg Oncol 104, pp. 430-437.

[0605] 9. Partin, AW, Schoeniger, JS, Mohler, JL and Coffey, DS (1989) Fourier analysis of cell motility: correlation of motility with metastatic potential, Proc Natl Acad Sci USA 86, pp. 1254-1258.

[0606] 10. Aznavoorian, S., Murphy, AN, Stetler-Stevenson, WG and Liotta, LA (1993) Molecular aspects of tumor cell invasion and metastasis, Cancer 71, pp. 1368-1383.

[0607] 11. Condeelis, J., Singer, R. FL and Segall, JE (2005) The great escape: when cancer cells hijack the genes for chemotaxis and motility, Annu Rev Cell DevBiol 21, pp. 695-718.

[0608] 12. Roussos, ET, Condeelis, JS, and Patsialou, A. (2011) Chemotaxis in cancer, Nat Rev Cancer 11, pp. 573-587.

[0609] 13. Jaffe, AB and Hall, A. (2005) Rho GTPases: biochemistry and biology, Annu Rev Cell Dev Biol 21, pp. 247-269.

[0610] 14. Matsudaira, P. (1994) Actin crosslinking proteins at the leading edge, Semin Cell Biol 5, pp. 165-174.

[0611] 15. Otto, JJ (1994) Actin-bundling proteins, Curr Opin Cell Biol 6, pp. 105-109.

[0612] 16. Mogilner, A. and Rubinstein, B. (2005) The physics of filopodial protrusion, Biophys J 89, pp. 782-795.

[0613] 17. Mattila, PK and Lappalainen, P. (2008) Filopodia: molecular architecture and cellular functions, Nat Rev Mol Cell Biol 9, pp. 446-454.

[0614] 18. Otto, JJ, Kane, RE and Bryan, J. (1979) Formation of filopodia incoelomocytes: localization of fascin, a 58,000dalton actin cross-linking protein, Cell 17, pp. 285-293.

[0615] 19. Bryan, J. and Kane, RE (1978) Separation and interaction of the major components of sea urchin actin gel, J Mol Biol 125, pp. 207-224.

[0616] 20. Yamashiro-Matsumura, S. and Matsumura, F. (1985) Purification and characterization of an F-actin-bundling 55-kilodalton protein from HeLacells, J Biol Chem 260, pp. 5087-5097.

[0617] 21. Vignjevic, D., Yaar, D., Welch, MD, Peloquin, J., Svitkina, T., and Borisy, GG (2003) Formation of filopodia-like bundles in vitro from a dendritic network, J Cell Biol 160, pp. 951-962.

[0618] 22. Vignjevic, D., Kojima, S., Aratyn, Y., Danciu, O., Svitkina, T. and Borisy, GG (2006) Role of fascin in filopodial protrusion, J Cell Biol 174, pp. 863-875.

[0619] 23. Adams, JC (2004) Roles of fascin in cell adhesion and motility, Curr Opin Cell Biol 16, pp. 590-596.

[0620] 24. Tilney, L.G., Connelly, P.S., Vranich, K.A., Shaw, M.K., and Guild, G.M. (1998) Why are two different cross-linkers necessary for actin bundle formation in vivo and what does each cross-link contribute?, J Cell Biol 143, pp. 121 - 133.

[0621] 25. Darnel, A.D., Behmoaram, E., Vollmer, R.T., Corcos, J., Bijian, K., Sircar, K., Su, J., Jiao, J., Alaoui-Jamali, M.A., and Bismar, T.A. (2009) Fascin regulates prostate cancer cell invasion and is associated with metastasis and biochemical failure in prostate cancer, Clin Cancer Res 15, pp. 1376 - 1383.

[0622] 26. Pelosi, G., Pasini, F., Fraggetta, F., Pastorino, U., Iannucci, A., Maisonneuve, P., Arrigoni, G., De Manzoni, G., Bresaola, E., and Viale, G. (2003) Independent value of fascin immunoreactivity for predicting lymph node metastases in typical and atypical pulmonary carcinoids, Lung Cancer 42, pp. 203 - 213.

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[0627] 31.Hashimoto, Y., Skacel, M. and Adams, J.C. (2005) Roles of fascin in human carcinoma motility and signaling: prospects for a novel biomarker?, Int J Biochem Cell Biol 37, pp. 1787 - 1804.

[0628] 32.Maitra, A., Iacobuzio - Donahue, C, Rahman, A., Sohn, T.A., Argani, P., Meyer, R., Yeo, C.J., Cameron, J.L., Goggins, M., Kern, S.E., Ashfaq, R., Hruban, R.H. and Wilentz, R.E. (2002) Immunohistochemical validation of a novel epithelial and a novel stromal marker of pancreatic ductal adenocarcinoma identified by global expression microarrays: sea urchin fascin homolog and heat shock protein 47, Am J Clin Pathol 118, pp. 52 - 59.

[0629] 33.Yoder, B.J., Tso, E., Skacel, M., Pettay, J., Tarr, S., Budd, T., Tubbs, R.R., Adams, J.C. and Hicks, D.G. (2005) The expression of fascin, an actin - bundling motility protein, correlates with hormone receptor - negative breast cancer and a more aggressive clinical course, Clin Cancer Res 11, pp. 186 - 192.

[0630] 34. Zigeuner, R., Droschl, N., Tauber, V., Rehak, P. and Langner, C. (2006) Biologic significance of fascin expression in clear cell renal cell carcinoma: systematic analysis of primary and metastatic tumor tissues using atissue microarray technique, Urology 68, pp. 518-522.

[0631] Equivalent example

[0632] The embodiments described illustratively herein can be suitably implemented without any elements or limitations, and are not specifically disclosed herein. Therefore, terms such as “comprising,” “including,” and “containing” should be interpreted broadly without limitation. Furthermore, the terms and expressions used herein are used as descriptive rather than limiting terms, and there is no intention to use terms and expressions that exclude any equivalents or parts thereof of the features shown and described, but it is appreciated that various modifications can be made within the scope of the claimed technology. Moreover, the phrase “substantially comprises” will be understood to include those specifically stated elements, as well as those additional elements that do not substantially affect the essential nature and novelty of the claimed technology. The phrase “comprising” excludes any unspecified elements.

[0633] This disclosure is not limited to the specific embodiments described herein, which are intended to be illustrative of various aspects. Many modifications and variations may be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent compositions, apparatuses, and methods within the scope of this disclosure, in addition to those listed herein, will be apparent to those skilled in the art from the foregoing description. These modifications and variations will fall within the scope of the appended claims. The invention is limited only by the terms of the appended claims together with the full scope of their equivalents. However, it should be understood that this disclosure is not limited to specific methods, reagents, compound compositions, or biological systems, which are of course subject to variation. It should also be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting.

[0634] Furthermore, those skilled in the art will recognize that, regarding the features or aspects of this disclosure described by the Markush group, this disclosure is also described by any single member or a subset of the members of the Markush group.

[0635] As will be understood by those skilled in the art, for any and all purposes, particularly with respect to the provided written description, all scopes disclosed herein also include any and all possible subscopes and combinations of subscopes. Any listed scope is readily identifiable due to its sufficient description, and the same scope can be divided into at least two, three, four, five, ten, etc., equal parts. As a non-limiting example, each scope discussed herein can be readily divided into a lower third, a middle third, and a higher third, etc. Also, as will be understood by those skilled in the art, all language such as “up to,” “at least,” “greater than,” “less than,” etc., including the number of statements and the scope involved, can subsequently be divided into subscopes as discussed above. Finally, as will be understood by those skilled in the art, a scope includes each individual member.

[0636] While certain implementations have been described and illustrated, it should be understood that variations and modifications can be made herein by those skilled in the art without departing from the broader aspects of the technology as defined in the following claims.

Claims

1. Use of compounds of formula III, or tautomers, and / or pharmaceutically acceptable salts thereof, in the preparation of medicaments for treating conditions or disorders mediated by the activity of myofascitis proteins. in, In Equation III: R 30 The vinyl group selected from methyl, optionally substituted with phenyl, or optionally substituted with one or two substituents independently selected from nitro and halogen groups; R 31 Selected from -OR 9 and halogens; p is 0, 1, or 2; X 30 For C (=O) or S (O)2; and R 9 It is a phenyl group. Among them, the conditions or disorders mediated by the activity of myofascitis are breast cancer, prostate cancer, or lung cancer.

2. The use according to claim 1, wherein, R 30 It is a methyl group.

3. The use according to claim 1, wherein, R 30 Vinyl groups optionally substituted with phenyl groups.

4. The use according to claim 1, wherein, R 30 A phenyl group that is optionally substituted with one or two substituents selected from nitro and halogen groups.

5. The use according to claim 1, wherein, X 30 Let C be O, and R be... 30 It is a vinyl group that is methyl or optionally substituted with a phenyl group.

6. The use according to claim 1, wherein, X 30 It is S(O)2, and R 30 A phenyl group that is optionally substituted with one or two substituents that are independently nitro or halogen.

7. The use according to claim 1, wherein, The compound is selected from 2-Chloro-N-(6-chlorobenzo[d]thiazo-2-yl)-5-nitrobenzenesulfonamide, 3-Chloro-N-(6-phenoxybenzo[d]thiazolyl-2-yl)benzenesulfonamide, N-(6-fluorobenzo[d]thiazo-2-yl)-3-nitrobenzenesulfonamide, 2,3-Dichloro-N-(6-fluorobenzo[d]thiazo-2-yl)benzenesulfonamide, N-(6-chlorobenzo[d]thiazolyl)acetamide, and N-(benzo[d]thiazo-2-yl)cinnamamide.

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