Compositions and methods for treating inflammatory bowel disease

Abstract

The present invention relates to the unexpected discovery that the oral administration of charged sodium channel blockers (also known as "Nocions") alleviates inflammation in intestinal inflammatory diseases, such as inflammatory bowel disease (IBD), ulcerative colitis and / or Crohn's disease, without substantial systemic exposure, as proved by low plasma concentrations. The formulations are designed as enteric-coated tablets to release the composition at selected locations of the intestinal tract.

Description

[0001] Related Applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 337,833, filed May 3, 2022. The entire teachings of the above application are incorporated herein by reference.

[0003] Field of the application

[0004] The present invention relates to compositions and methods for treating inflammatory bowel disease.

[0005] background

[0006] Inflammatory bowel disease (IBD) includes two specific forms of chronic inflammation in the intestine, ulcerative colitis (UC) and Crohn's disease (CD). Although the clinical presentation is different, these two conditions share common features, including obvious symptoms of abdominal pain, diarrhea, and intestinal dysfunction, accompanied by weakness, fatigue, and weight loss, all of which can seriously affect quality of life. In addition to these symptoms, IBD is characterized by clinical signs such as endoscopic mucosal ulcers and swelling, tissue friability, intestinal strictures, fistulas, obstructions, and abdominal masses.

[0007] Treatments for UC and CD focus on the role of inflammation in their etiology. For example, tofacitinib and other similar agents act as immunomodulators by affecting pathways such as the intracellular JAK-STAT signaling pathway. However, these agents, even when administered orally, have systemic distribution and affect any cell with their intended immunoactive target, and can have diffuse systemic effects, including risk of serious infection, venous thrombosis, and thromboembolism, as well as a range of less serious adverse reactions. Therefore, there is a need to provide improved therapies with lower risks.

[0008] summary

[0009] The present invention relates to the unexpected discovery that orally administered charged sodium channel blockers (also referred to as "Nocions") reduce inflammation in intestinal inflammatory diseases such as IBD, ulcerative colitis and / or Crohn's disease without substantial systemic exposure (as evidenced by low plasma concentrations).

[0010] Detailed Description

[0011] Compounds that can be used in the compositions, formulations and methods of the present invention include charged sodium channel blockers, also known as Nocions. One or more Nocions can be formulated into a pharmaceutically acceptable composition or formulation, preferably formulated for oral delivery, such as enteral delivery. Preferred compositions include sustained release compositions. Preferred Nocions are described in the following documents: PCT / US2020 / 22076 filed by Cole et al. on March 11, 2020 (attorney docket number 4270.3001WO); PCT / US2020 / 21985 filed by Cole et al. on March 11, 2020 (attorney docket number 4270.3002WO); PCT / US2020 / 59076 filed by Cole et al. on November 5, 2020 (attorney docket number 4270.3003WO); PCT / US2020 / 59097 filed by Cole et al. on November 5, 2020 (attorney docket number 4270.3004WO); PCT / U filed by Cole et al. on March 11, 2020 S2020 / 22097 (Attorney Docket No. 4270.3005WO); PCT / US2020 / 21978 filed by Cole et al. on March 11, 2020 (Attorney Docket No. 4270.3006WO); PCT / US2020 / 22127 filed by Cole et al. on March 11, 2020 (Attorney Docket No. 4270.3007WO); PCT / US2020 / 22142 filed by Cole et al. on March 11, 2020 (Attorney Docket No. 4270.3008WO); and PCT / US2021 / 21697 filed by Cole et al. on March 10, 2021 (Attorney Docket No. 4270.3014WO), each of which is incorporated herein in its entirety.

[0012] The present invention provides a compound represented by formula (I):

[0013]

[0014] in:

[0015] Y - is a pharmaceutically acceptable anion;

[0016] R F and R G With N + together form an optionally substituted heteroaromatic ring having one or more heteroatoms or having one or

[0017] an optionally substituted bicyclic heteroaryl ring having multiple heteroatoms;

[0018] R A , R Band R C are each independently selected from H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, nitrile, OR I NR J R K NR L C(O)R M 、S(O)R N 、SO2R O ,

[0019] S02R O R P 、SO2NR Q R R 、SO3R S 、CO2R T 、C(O)R U and C(O)NR V R W ; or R B and adjacent

[0020] R C Together with the carbon atom to which they are attached, they form a substituted or unsubstituted 3-7 membered cycloalkyl group (C3-C7 cycloalkyl) or

[0021] substituted or unsubstituted aryl (e.g. phenyl);

[0022] R I , R J , R K , R L , R M , R N , R O , R P , R Q , R R , R S , R T , R U , R V and R W are each independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl

[0023] and substituted or unsubstituted heteroalkyl;

[0024] X 1 Selected from—CR X R Y —、—NR Z C(O)—, —OC(O)—, —SC(O)—, —NR Z S(O)—、—

[0025] S(O)NRZ —、—NR X C(O)NR Y —, —C(O)NR 1A —, —C(O)O—, —C(O)—, —

[0026] S(O)—, —S(O)2— and —(O)CS—; 1 Can also be -NR Z C(O)CR X R Y —;

[0027] R X , R Y , R Z and R 1A are each independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted heteroalkyl; and R D and R E R is each independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, optionally substituted with halogen, cyclic alkyl, aryl or heteroaryl, and cycloalkyl; or D and R E Together with the carbon to which they are attached, they form a substituted or unsubstituted 3-7 membered cycloalkyl (C3-

[0028] C7 cycloalkyl) or a substituted or unsubstituted heterocyclic or heteroalkyl ring; or R D and R Z Together with the carbon to which they are attached and -NC(O)-, they form an optionally substituted 5-8 membered lactam.

[0029] In a preferred embodiment, X 1 In another preferred embodiment, X 1 It is —NHC(O)—.

[0030] In some embodiments, R A and R B are each independently selected from H, D, halogen, substituted or unsubstituted C 1-4 (C1-C4) alkyl and NR J R K ; and R J and R K are each independently selected from H and substituted or unsubstituted C 1-4 Alkyl; and / or wherein R C Not H, such as halogen, C 1-4 Alkyl and NR J RK .

[0031] In a preferred embodiment, R A and R B Each is –CH3.

[0032] In certain other embodiments, R D C 1-4 Alkyl, which is optionally substituted by a substituent selected from the group consisting of halogen, oxygen (oxo), C 3-8 (C3-C8) cycloalkyl, aryl and heteroaryl, and / or R E H or C 1-4 Alkyl, the C 1-4 The alkyl group is optionally substituted with a substituent selected from the group consisting of halogen, oxygen, C 3-8 Cycloalkyl, aryl and heteroaryl.

[0033] In a preferred embodiment, R D and R E Each is independently selected from -H, -CH3, -CH2CH3 and -(CH2)2CH3. In a more preferred embodiment, R E is hydrogen, and R D It is –H, –CH3, –CH2CH3 or –(CH2)2CH3.

[0034] In certain preferred embodiments, R D and R E Both are hydrogen. In yet another preferred embodiment, R D is hydrogen and R E is an alkyl group, for example, a C1-C6 alkyl group or a C1-C4 alkyl group, including but not limited to methyl, ethyl, propyl and butyl. In certain other preferred embodiments, R D and R E Together with the carbon to which they are attached they form a C3-C6 cycloalkyl group including but not limited to cyclopropyl or cyclobutyl.

[0035] The present invention provides a compound represented by formula (II):

[0036]

[0037] in:

[0038] Y - is a pharmaceutically acceptable anion;

[0039] R A , R B and R Care each independently selected from H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, OR I 、CN、NR J R K ,

[0040] NR L C(O)R M 、S(O)R N 、S(O)2R N 、SO2R O R P 、SO2NR Q R R 、SO3R S 、CO2R T ,

[0041] C(O)R U and C(O)NR V R W ; (preferably H, F, Cl or CN, and more preferably H);

[0042] R I , R J , R K , R L , R M , R N , R O , R P , R Q , R R , R S , R T , R U , R V and R W R is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; J and R K or R V and R W or R Q and R R They can also form with their attached nitrogen

[0043] a substituted or unsubstituted 5-, 6-, 7- or 8-membered ring;

[0044] R A , R B and / or R CTogether with the benzene ring to which they are attached, they can form a fused bicyclic or tricyclic ring system, such as naphthalene.

[0045] yl, dihydroindanyl, tetrahydronaphthyl, quinolyl, indolyl, etc.;

[0046] X 1 Selected from—CR X R Y —、—NR Z C(O)—, —OC(O)—, —SC(O)—, —C(O)NR 1A —、—

[0047] C(O)O—, -C(O)-, —(O)CS—, —NR 1A S(O)—,—S(O)NR 1A —、—

[0048] NR 1A C(O)NR 1A —, —S(O)— and —S(O)2—; X 1 Can also be -NR Z C(O)CR X R Y —;

[0049] R X , R Y , R Z and R 1A are each independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted heteroalkyl;

[0050] R D and R E are each independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted cycloalkyl; or R D and R E Together with the carbon to which they are attached, they form a substituted or unsubstituted 3-6 membered cycloalkyl (C3-C6 cycloalkyl), a substituted or unsubstituted heterocyclic ring, or a substituted or unsubstituted heteroalkyl ring; or R D and R Z The carbon and-

[0051] NC(O)-together form an optionally substituted 5-8 membered lactam;

[0052] R F and R G With N + together form an optionally substituted heterocyclic ring having one or more nitrogen atoms; or R F and RG are each independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyne

[0053] alkyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted C 3-6 Cycloalkyl; and

[0054] R H is a substituted or unsubstituted aromatic ring or a substituted or unsubstituted heteroaromatic ring.

[0055] In another embodiment, R H It may be a substituted alkyl. The substituent is preferably an ester group, such as -OC(O)R 1B , where R 1B R is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 1B Preferably, it is a substituted or unsubstituted phenyl group. H Preferred is -CH2OC(O)-phenyl.

[0056] The present invention provides a compound represented by formula (III):

[0057]

[0058] in:

[0059] Y - is a pharmaceutically acceptable anion;

[0060] R A , R B and R C are each independently selected from H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, OR I NR J R K NR L C(O)R M 、CN、S(O)R N 、S(O)2R N 、SO2R O R P 、SO2NR Q R R 、SO3R S 、CO2R T 、C(O)R U and C(O)NR V R W ;

[0061] R I , RJ , R K , R L , R M , R N , R O , R P , R Q , R R , R S , R T , R U , R V and R W are each independently selected from H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted heteroalkyl;

[0062] X 1 Selected from—CR X R Y —、—NR Z C(O)—、—NR Z C(O)CR X R Y —, —OC(O)—, —SC(O)—, —C(O)NR 1A —, —C(O)O—, -C(O)-, —(O)CS—, —NR 1A S(O)—,—S(O)NR 1A —、—NR 1A C(O)NR 1A —, —S(O)— and —S(O)2—;

[0063] R X , R Y , R Z and R 1A are each independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted heteroalkyl; or R X , R Y , R Z or R 1A With R D or R E and the atoms to which they are attached together form an optionally substituted cycloalkyl (such as a C3-C6 cycloalkyl) or an optionally substituted heterocycle (such as a 3- to 15-membered heterocycle);

[0064] R D and R E are each independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted cycloalkyl; or R D and R ETogether with the carbon to which they are attached, they form a substituted or unsubstituted cycloalkyl (such as a C3-C6 cycloalkyl) or a substituted or unsubstituted heterocycle (such as a 3- to 15-membered heterocycle);

[0065] R F , R G and R H are each independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted -C 6- C 10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted –CH2-C 5- C 10 Aryl and substituted or unsubstituted –CH2-C 5- C 10 heteroaryl; or alternatively, R F , R G and R H Two or three of them with their attached P + Together they form a + An optionally substituted heterocyclic group (such as a 3- to 15-membered heterocyclic ring) having zero, one or more heteroatoms in addition to , including but not limited to an optionally substituted heteroaromatic ring;

[0066] or R D , R E , R F , R G and R H Two or three of them with P + Together they form a + In addition to the optionally substituted heterocyclic ring having zero, one or more heteroatoms, including but not limited to heteroaromatic rings; for example, R E , R F and R G Two of them and P + Together they form a + The heterocyclic ring has zero, one or more heteroatoms.

[0067] The present invention further relates to phosphorus derivatives of sodium channel blocker compounds comprising an amine group (e.g., caine compounds), wherein the amine of the sodium channel blocker compound is substituted with phosphorus. Examples of sodium channel blocker compounds include, but are not limited to, lidocaine, bupivacaine, mapivacaine, etidocaine, prilocaine, tocainide, ropivacaine, proparacaine, allocaine, encainide, procainamide, metoclopramide, flecainide, tetracaine, benzocaine, oxybuprocaine, butambine, propoxycaine, dyclonine, pramoxine, chloroprocaine, proparacaine, piperocaine, hexacine, naphthene, cyclomethylcaine, and dibucaine, articaine, mexiletine, bupropion, ambroxol, procaine, tolperisone, and substituted derivatives thereof.

[0068] The present invention provides a compound represented by formula (IV):

[0069]

[0070] in:

[0071] Y - is a pharmaceutically acceptable anion;

[0072] R A and R B Each independently selected from H, 2 H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, OR I NR J R K NR L C(O)R M ,

[0073] S(O)R N 、S(O)2R N 、SO2R O R P 、SO2NR Q R R 、SO3R S 、CO2R T 、C(O)R U and

[0074] C(O)NR V R W ;

[0075] R I , R J , R K , R L , RM , R N , R O , R P , R Q , R R , R S , R T , R U , R V and R W Each independently selected from H, 2 H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyne

[0076] and substituted or unsubstituted heteroalkyl;

[0077] X 1 Selected from—CR X R Y —、—NR Z C(O)—、—NR Z C(O)CR X R Y —、—OC(O)—、—

[0078] SC(O)—,—C(O)NR 1A —, —C(O)O—, -C(O)-, —(O)CS—, —NR 1A S(O)—、—

[0079] S(O)NR 1A —、—NR 1A C(O)NR 1A —, —S(O)— and —S(O)2—;

[0080] R X , R Y , R Z and R 1A Each independently selected from H, 2 H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted heteroalkyl; or, R X , R Y , R Z or R 1A With R D or R E and the atoms to which they are attached together form an optionally substituted cycloalkyl (such as a C3-C6 cycloalkyl) or an optionally substituted heterocycle (such as a 3- to 15-membered heterocycle);

[0081] R D and R E Each independently selected from H, 2H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted cycloalkyl; or R D and R E Together with the carbon to which they are attached, they form a substituted or unsubstituted cycloalkyl (such as a C3-C6 cycloalkyl) or a substituted or unsubstituted heterocycle (such as a 3- to 15-membered heterocycle);

[0082] R F , R G and R H Each independently selected from H, 2 H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted –C 6- C 10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted –CH2-C 5- C 10 Aryl and substituted or unsubstituted –CH2-C 5- C 10 heteroaryl; or alternatively, R F , R G and R H Two or three of them with their attached P + Together they form a + An optionally substituted heterocyclic group (such as a 3- to 15-membered heterocyclic ring) having zero, one or more heteroatoms in addition to , including but not limited to an optionally substituted heteroaromatic ring;

[0083] or R D , R E , R F , R G and R H Two or three of them with their attached P + Together they form a + In addition to the optionally substituted heterocyclic ring having zero, one or more heteroatoms, including but not limited to heteroaromatic rings; for example, R E , R F and R G Two of them and P + Together they form a + The present invention provides a compound represented by formula (V):

[0084]

[0085] in:

[0086] Y -is a pharmaceutically acceptable anion;

[0087] R F and R G N + together form an optionally substituted heteroaryl ring having one or more heteroatoms or an optionally substituted bicyclic heteroaryl ring having one or more heteroatoms;

[0088] R A and R B are each independently selected from H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, nitrile, OR I NR J R K NR L C(O)R M 、S(O)R N 、SO2R O ,

[0089] S02R O R P 、SO2NR Q R R 、SO3R S 、CO2R T 、C(O)R U and C(O)NR V R W ;

[0090] R I , R J , R K , R L , R M , R N , R O , R P , R Q , R R , R S , R T , R U , R V and R W are each independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl

[0091] and substituted or unsubstituted heteroalkyl;

[0092] X 1 Selected from—CR X R Y —、—NR Z C(O)—、—NR Z C(O)CR X RY —, —OC(O)—,

[0093] —SC(O)—、—NR Z S(O)—,—S(O)NR Z —、—NR X C(O)NR Y —, —C(O)NR 1A —、

[0094] —C(O)O—, —C(O)—, —S(O)—, —S(O)2—, and —(O)CS—;

[0095] R X , R Y , R Z and R 1A are each independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted heteroalkyl; or may be combined with any other R X ,

[0096] R Y , R Z , R 1A , R D or R E Together with any intervening atoms, form a substituted or unsubstituted ring;

[0097] R D and R E R is each independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, optionally substituted with halogen, cyclic alkyl, aryl or heteroaryl, and cycloalkyl; or D and R E Together with the carbon to which they are attached, they form a substituted or unsubstituted 3-7 membered cycloalkyl (C3-C7 cycloalkyl) or a substituted or unsubstituted heterocyclic or heteroalkyl ring; or R D and R Z Together with the carbon to which they are attached and -NC(O)-, they form an optionally substituted 5-8 membered lactam.

[0098] In a preferred embodiment, X 1 In another preferred embodiment, X 1 It is —NHC(O)—.

[0099] In some embodiments, R A and R B are independently selected from H, D, halogen, OR I , substituted or unsubstituted C 1-C4 alkyl and CO2R T ; where R I and R T Independently selected from substituted and unsubstituted C 1- C4 alkyl.

[0100] In a preferred aspect, R A is CH3 and R B For CO2R T , where R T is selected from H and substituted or unsubstituted C 1-4 In another preferred embodiment, R A is CH3 and R B is selected from CO2CH3 and CO2CH2CH3. In a further preferred embodiment, R A is methyl and R B In yet another preferred aspect, R A is methyl and R B In yet another preferred aspect, R A is methyl and R B It is methyl.

[0101] In certain other embodiments, R D C 1-4 Alkyl, which is optionally substituted by a substituent selected from the group consisting of halogen, oxygen (oxo), C 3-8 (C3-C8) cycloalkyl, aryl and heteroaryl, and / or R E H or C 1-4 Alkyl, the C 1-4 The alkyl group is optionally substituted with a substituent selected from the group consisting of halogen, oxygen, C 3-8 Cycloalkyl, aryl and heteroaryl.

[0102] In a preferred embodiment, R D and R E Each is independently selected from -H, -CH3, -CH2CH3 and -(CH2)2CH3. In a more preferred embodiment, R E is hydrogen, and R D It is –H, –CH3, –CH2CH3 or –(CH2)2CH3.

[0103] In certain preferred embodiments, R D is selected from hydrogen and ethyl, and R E In another preferred embodiment, R D is selected from hydrogen and ethyl, and R Eis an alkyl group, such as a C1-C6 alkyl group or a C1-C4 alkyl group, including but not limited to methyl, ethyl, propyl and butyl. In a further aspect, R D is hydrogen, and R E In another preferred embodiment, R D is ethyl, and R E In certain other preferred embodiments, R D and R E Together with the carbon to which they are attached they form a C3-C6 cycloalkyl group including but not limited to cyclopropyl or cyclobutyl.

[0104] In some embodiments, Y - Including but not limited to halide, substituted or unsubstituted alkyl sulfonate, substituted or unsubstituted aryl sulfonate, aliphatic carboxylate, substituted aliphatic carboxylate, aryl carboxylate, substituted aryl carboxylate, heterocyclyl carboxylate or substituted heterocyclyl carboxylate.

[0105] In other aspects, Y - In one embodiment, Y - is a halide ion selected from bromide, chloride and iodide.

[0106] The present invention provides a compound represented by formula (VI):

[0107]

[0108] in:

[0109] Y - is a pharmaceutically acceptable anion;

[0110] R A and R B are each independently selected from H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, OR I NR J R K NR L C(O)R M 、S(O)R N 、S(O)2R N 、SO2R O R P 、SO2NR Q R R 、SO3R S 、CO2R T 、C(O)R U and C(O)NR V R W ;

[0111] R I , R J , R K , R L , R M , R N , R O , R P , R Q , R R , R S , R T , R U , R V and R W are each independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl

[0112] and substituted or unsubstituted heteroalkyl;

[0113] X 1 Selected from—CR X R Y —、—NR Z C(O)—, —OC(O)—, —SC(O)—, —C(O)NR 1A —、

[0114] —C(O)O—, -C(O)-, —(O)CS—, —NR 1A S(O)—,—S(O)NR 1A —、

[0115] —NR 1A C(O)NR 1A —, —S(O)— and —S(O)2—; X 1 Can also be -NR Z C(O)CR X R Y —;

[0116] R X , R Y , R Z and R 1A are each independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted heteroalkyl; or may be combined with any other R X , R Y , R Z , R 1A , R D or R E Together with any intervening atoms, form a substituted or unsubstituted ring;

[0117] R D and R Eare each independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted cycloalkyl; or R D and R E Together with the carbon to which they are attached, they form a substituted or unsubstituted 3-6 membered cycloalkyl (C3-C6 cycloalkyl), a substituted or unsubstituted heterocyclic ring, or a substituted or unsubstituted heteroalkyl ring; or R D and R Z The carbon and-

[0118] NC(O)-together form an optionally substituted 5-8 membered lactam;

[0119] R F and R G N + together form an optionally substituted heterocyclic ring having one or more nitrogen atoms; or R F and R G are each independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted C 3-6 Cycloalkyl; and

[0120] R H is a substituted or unsubstituted aromatic ring or a substituted or unsubstituted heteroaromatic ring.

[0121] In another embodiment, R H It may be a substituted alkyl. The substituent is preferably an ester group, such as -OC(O)R 1B , where R 1B R is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. 1B Preferably, it is a substituted or unsubstituted phenyl group. H Preferred is -CH2OC(O)-phenyl.

[0122] The present invention provides a compound represented by formula (VII):

[0123]

[0124] in:

[0125] Y - is a pharmaceutically acceptable anion;

[0126] R A For CO2R T ;

[0127] RT is a substituted or unsubstituted alkyl group (preferably a methyl group or an ethyl group);

[0128] R B is H, D, halogen or substituted or unsubstituted alkyl; preferably methyl or ethyl;

[0129] R C is selected from H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, OR I 、CN、NR J R K NR L C(O)R M 、S(O)R N 、S(O)2R N 、SO2R O R P 、SO2NR Q R R 、SO3R S 、CO2R T 、C(O)R U and C(O)NR V R W , (preferred

[0130] is H, F, Cl or CN, and more preferably is H);

[0131] R I , R J , R K , R L , R M , R N , R O , R P , R Q , R R , R S , R T , R U , R V and R W R is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; J and R K or R V and R W or R Q and R R They can also form with their attached nitrogen

[0132] a substituted or unsubstituted 5-, 6-, 7- or 8-membered ring;

[0133] X 1 Can be selected from—CR X R Y —、—NR Z C(O)—、—NR Z C(O)CR X R Y —、—OC(O)—、—

[0134] SC(O)—,—C(O)NR 1A —, —C(O)O—, -C(O)-, —(O)CS—, —NR 1A S(O)—、—

[0135] S(O)NR 1A —、—NR 1A C(O)NR 1A —, —S(O)— and —S(O)2—; and R X , R Y , R Z and

[0136] R 1A Each is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl and substituted or unsubstituted alkynyl. 1 For—NR Z C(O)—. In another preferred embodiment, R Z In another preferred embodiment, X 1 For—NR Z C(O)—and R Z For hydrogen.

[0137] In certain preferred embodiments, X 1 is —NHC(O)—;

[0138] R Z is H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl

[0139] and substituted or unsubstituted heteroalkyl (preferably H);

[0140] R D and R E are each independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted cycloalkyl;

[0141] or R Dand R E Together with the carbon to which they are attached, they form a substituted or unsubstituted cycloalkyl group (such as a C3-C6 cycloalkyl group).

[0142] or a substituted or unsubstituted heterocycle (such as a 3- to 15-membered heterocycle);

[0143] or R D and R Z Together with the carbon to which they are attached and —NC(O)—, they form a substituted or unsubstituted lactam;

[0144] R F , R G and R H are each independently selected from absent, H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted -C 6- C 10 Aryl, substituted or unsubstituted 5 to

[0145] 10-membered heteroaryl, substituted or unsubstituted –CH2-C 5- C 10 Aryl and substituted or unsubstituted –CH2-C 5- C 10 heteroaryl; or alternatively, R F , R G and R H Two or three of them with the N attached + Together they form N + An optionally substituted heterocyclic group (such as a 3- to 15-membered heterocyclic ring) having zero, one or more heteroatoms in addition to , including but not limited to an optionally substituted heteroaromatic ring;

[0146] or R D , R E , R F , R G and R H Two or three of N + Together they form N + In addition to the optionally substituted heterocyclic ring having zero, one or more heteroatoms, including but not limited to heteroaromatic rings; for example, R E , R F and R G Two of them and N + Together they form N + The heterocyclic ring has zero, one or more heteroatoms.

[0147] The present invention further relates to derivatives (e.g., caine compounds) of sodium channel blocker compounds comprising dimethylaniline, wherein the ortho-methyl of the sodium channel blocker compound is substituted with an ester. Examples of sodium channel blocker compounds include, but are not limited to, lidocaine, bupivacaine, mapivacaine, etidocaine, prilocaine, tocainide, ropivacaine, proparacaine, alocaine, encainide, procainamide, metoclopramide, flecainide, tetracaine, benzocaine, oxybuprocaine, butamine, propoxycaine, dyclonine, pramoxine, chloroprocaine, proparacaine, piperocaine, hexacane, naphthaine, cyclomethylcaine, and dibucaine, articaine, mexiletine, bupropion, ambroxol, procaine, tolperisone and substituted derivatives thereof.

[0148] The present invention provides a compound represented by formula (VIII):

[0149]

[0150] in:

[0151] Y - is a pharmaceutically acceptable anion;

[0152] n is 1, 2, 3 or 4;

[0153] R A , R B and R C are each independently selected from H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, OR I 、CN、NR J R K ,

[0154] NR L C(O)R M 、S(O)R N 、S(O)2R N 、SO2R O R P 、SO2NR Q R R 、SO3R S 、CO2R T ,

[0155] C(O)R U and C(O)NR V R W , (preferably R A and R B is methyl, and R C is H, F, Cl or CN,

[0156] and more preferably H);

[0157] R I , R J , R K , R L , R M , R N , R O , R P , R Q , R R , R S , R T , R U , R V and R W R is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; J and R K or R V and R W or R Q and R R They can also form with their attached nitrogen

[0158] a substituted or unsubstituted 5-, 6-, 7- or 8-membered ring;

[0159] R A , R B and / or R C Together with the benzene ring to which they are attached, they may form a fused bicyclic or tricyclic ring system such as naphthyl, indanyl, tetrahydronaphthyl, quinolinyl, indolyl, and the like;

[0160] X 1 Selected from—CR X R Y —、—NR Z C(O)—, —OC(O)—, —SC(O)—, —C(O)NR 1A —、—

[0161] C(O)O—, -C(O)-, —(O)CS—, —NR 1A S(O)—,—S(O)NR 1A —、—

[0162] NR 1A C(O)NR 1A —, —S(O)— and —S(O)2—; X 1 Can also be -NR Z C(O)CR X RY —;

[0163] R X , R Y , R Z and R 1A are each independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted heteroalkyl;

[0164] R D and R E are each independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted cycloalkyl; or R D and R E Together with the carbon to which they are attached, they form a substituted or unsubstituted 3-6 membered cycloalkyl (C3-C6 cycloalkyl), a substituted or unsubstituted heterocyclic ring, or a substituted or unsubstituted heteroalkyl ring;

[0165] or R D and R Z Together with the carbon to which they are attached and -NC(O)-, they form an optionally substituted 5-8 membered lactam;

[0166] R H is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; in certain aspects, R H may be substituted or unsubstituted aralkyl or heteroaralkyl; in another aspect, R H may be substituted or unsubstituted alkyl carboxylates, substituted or unsubstituted alkyl carboxamides; and

[0167] R 1B It is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group, and is preferably a substituted or unsubstituted phenyl group.

[0168] The present invention provides a compound represented by formula (IX):

[0169]

[0170] in:

[0171] Y - is a pharmaceutically acceptable anion;

[0172] R 1 Selected from the group consisting of: methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-propyl

[0173] butyl, isobutyl, tert-butyl and sec-butyl), cyclohexyl, phenyl and CH2C(O)NHR3;

[0174] R 2 is hydrogen or methyl; and

[0175] R 3 is hydrogen, methyl or ethyl.

[0176] In some embodiments, Y - is a halide ion, a sulfonate (including, for example, a substituted or unsubstituted alkyl sulfonate and a substituted or unsubstituted aryl sulfonate) or a carboxylate (including, for example, a substituted or unsubstituted alkyl or aliphatic carboxylate, a substituted or unsubstituted aryl carboxylate, or a substituted or unsubstituted heterocyclyl carboxylate).

[0177] In other aspects, Y - In one embodiment, Y - is a halide ion selected from bromide, chloride and iodide.

[0178] The present invention provides a compound represented by formula (X):

[0179]

[0180] in:

[0181] Y - is a pharmaceutically acceptable anion;

[0182] R 1 and R 2 One of them is hydrogen, and R 1 and R 2 The other one is selected from methyl, ethyl, unsubstituted benzene

[0183] Base, and C(O)OR 3 The group formed; and

[0184] R 3 is selected from the group consisting of hydrogen, methyl and ethyl.

[0185] In some embodiments, Y - is a halide ion, a sulfonate (including, for example, a substituted or unsubstituted alkyl sulfonate and a substituted or unsubstituted aryl sulfonate), a carboxylate (including, for example, a substituted or unsubstituted alkyl or aliphatic carboxylate, a substituted or unsubstituted aryl carboxylate or a substituted or unsubstituted heterocyclyl carboxylate).

[0186] In other aspects, Y - In one embodiment, Y - is a halide ion selected from bromide, chloride and iodide.

[0187] The present invention provides a compound represented by formula (XI):

[0188]

[0189] in:

[0190] Y - is a pharmaceutically acceptable anion;

[0191] q is 0, 1, 2, or 3; and

[0192] R D is hydrogen, methyl or ethyl.

[0193] The present invention provides a compound represented by formula (XII):

[0194]

[0195] in:

[0196] Y - is a pharmaceutically acceptable anion;

[0197] wherein R1, R2, R3, R4, R5 and R6 are independently selected from hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, aryl or heteroaryl;

[0198] n is 0, 1, 2, 3, 4, and 5;

[0199] q is 0, 1, 2, 3, 4 or 5.

[0200] The present invention provides a compound represented by formula (XIII):

[0201]

[0202] in:

[0203] Y - is a pharmaceutically acceptable anion;

[0204] R A , R B and R C are each independently selected from H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, OR I 、CN、CF3、NR J R K NR L C(O)R M 、S(O)R N、S(O)2R N 、SO2R O R P 、SO2NR Q R R 、SO3R S 、CO2R T 、C(O)R U and C(O)NR V R W ;

[0205] R I , R J , R K , R L , R M , R N , R O , R P , R Q , R R , R S , R T , R U , R V and R W are each independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; or R J and R K or R V and R W or R Q and R R They may also be taken together with the nitrogen to which they are attached to form a substituted or unsubstituted 5-, 6-, 7-, or 8-membered ring;

[0206] R A , R B and / or R C Together with the benzene ring to which they are attached, they may form a fused bicyclic or tricyclic ring system such as naphthyl, indanyl, tetrahydronaphthyl, quinolinyl, indolyl, and the like;

[0207] R1, R2, R3, R4, R5 and R6 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, cycloalkyl, aryl or heteroaryl, preferably hydrogen, methyl or ethyl;

[0208] n is 0, 1, 2, 3, 4, and 5;

[0209] or R1, R2, R3, R4, R5 and / or R6 together with the carbon to which they are attached form a substituted or unsubstituted cycloalkane

[0210] a cycloalkyl group (such as a C3-C6 cycloalkyl group) or a substituted or unsubstituted heterocycle (such as a 3- to 15-membered heterocycle);

[0211] R F and R G With N + Together they form N + In addition to the optionally substituted heterocyclic ring having zero, one or more heteroatoms, including but not limited to heteroaromatic rings; for example, R E , R F and R G Two of them and N + Together they form N + In addition to

[0212] a heterocyclic ring having zero, one or more heteroatoms;

[0213] R H is selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, such as -

[0214] CH2-cycloalkyl, -C2H4-cycloalkyl, substituted or unsubstituted –CH2-C 5- C 10 Aryl, substituted or unsubstituted –

[0215] C2H4-C 5- C 10 Aryl, substituted or unsubstituted –CH2-C 5- C 10 Heteroaryl, substituted or unsubstituted –C2H4-C 5-

[0216] C 10 Heteroaryl, -CH2 OC(O)R T 、-CH2CO2R T 、-CH2C(O)NR V R W 、-C2H4OCOR T 、-

[0217] C2H4OR I ;or

[0218] R F , R G and R H With N + Together they form a substituted or unsubstituted heteroaromatic ring (such as pyridyl or phenyl-pyridyl) or a bridged heterocyclic ring.

[0219] Charged sodium channel blockers are also described in WO2017 / 024037 to Bean et al., WO2011 / 006073 to Woolf et al., WO2008 / 063603 to Bean et al., and US8,865,741 to Thompson et al. (incorporated herein by reference in their entireties).

[0220] So far, the limitation of using molecules that block sodium channels as therapeutic agents is that most of these external molecules are hydrophobic and easily pass through the membrane. Because of this, they will enter all cells and therefore cannot selectively affect only nociceptors. This weakens their therapeutic potential because these agents are not limited to acting only on nociceptors. In addition, this behavior causes the risk of systemic mediated side effects because these molecules reach and affect cells throughout the body. In some cases, these macroporous cation channels (LPCCs) can be activated by exposure to endogenous inflammatory activators in the absence of exogenous agonists / ligands, such as those produced by tissue damage, infection, autoimmunity, allergy, ischemia, hypoxia, cell stress, immune cell activation, immune mediator production, and oxidative stress. These endogenous inflammation-related substances (including but not limited to prostaglandins, nitric oxide (NO), superoxide (H2O2), cysteine-responsive inflammatory mediators such as 4-hydroxynonenal, endogenous alkenyl aldehydes, endocannabinoids, and immune mediators (such as interleukin 1 (IL-1), nerve growth factor (NGF), and bradykinin)) can activate LPCCs expressed on nociceptors and open them, thereby allowing charged sodium channel blocking compounds that cannot cross the cell membrane to enter the nociceptors through the LPCCs to inhibit the activity of voltage-gated sodium channels, thereby preventing the initiation of action potentials.

[0221] We have identified compounds that are able to cross the LPCCs, which are selectively expressed on visceral nociceptors. Since inflammation opens the LPCCs, the ion channel blockers of the present invention can enter these channels on the nociceptors and block voltage-gated sodium channels. However, since the ion channel blocking compounds of the present invention are positively charged, they are not membrane permeable and therefore cannot enter cells without open LPCCs. Therefore, these compounds cannot cross normal cells.

[0222] In addition, the compound does not enter the systemic circulation after oral administration. Therefore, the ion channel blockers of the present invention can selectively target the visceral nociceptors activated in the intestinal cavity without affecting or passing through other types of cells. The ability to block the activity of intestinal visceral nociceptors allows these compounds to effectively treat pain mediated by visceral nociceptors, and further effectively treat the manifestation of neurogenic inflammation mediated by intestinal visceral nociceptors, thereby effectively treating one or more symptoms, signs or sequelae of IBD. Therefore, the present invention provides a method for treating intestinal inflammation such as IBD, UC or CD by administering an effective amount of a composition comprising Nocion (such as a compound with formula (I)-(XIII)) to a patient, wherein when one or more voltage-gated ion channels present in visceral nociceptors are activated by pre-existing inflammation (such as inflammation produced in IBD), the compound inhibits those channels. Preferably, the administration of the composition is oral administration, which allows the active ingredient to directly enter the infected area (when they face the intestinal cavity).

[0223] In an embodiment, LPCC is a transient receptor potential ion channel (TRP channel). In an embodiment, the channel is TRPA1, TRPV1-4, TRPM8, ASIC or P2X. In a specific embodiment, when the receptor / channel is activated, for example, by a local inflammatory process, the compound can enter the visceral nociceptor through TRPA1, TRPV1-4, TRPM8, ASIC or P2X receptor / channel. In an embodiment, the methods, compositions and preparations of the present invention treat both nociceptive pain mediated by visceral nociceptors and neurogenic inflammation mediated by visceral nociceptors.

[0224] Each embodiment described herein can be used in combination with one, any or all other embodiments, as presented herein in each arrangement. The composition of the present invention may include a racemic mixture, a pure enantiomer or an enantiomer in excess relative to another enantiomer. For example, the composition may include at least 5, 10, 20, 30, 40, 50, 60, 70, 80 or 90% enantiomeric excess. In one embodiment, the enantiomeric excess is at least 95%. The compound of the present invention includes all enantiomers that can be defined as (R)- or (S)- from an absolute stereochemical perspective, as well as their racemic and optically pure forms, and is not limited to those described herein in any pharmaceutically acceptable form thereof, including enantiomers, salts, solvates (solvate), polymorphs, solvatomorphs (solvatomorph), hydrates, anhydrous and other crystalline forms and combinations thereof. Similarly, all tautomeric forms are intended to be included. Preferably, the pharmaceutical composition comprises the compound of the invention in substantially pure form as the R enantiomer; alternatively, the pharmaceutical composition comprises the compound of the invention in substantially pure form as the S enantiomer; alternatively, the pharmaceutical composition comprises the compound of the invention as a mixture of enantiomers comprising an excess of the R enantiomer or an excess of the S enantiomer. Particularly preferably, the pharmaceutical composition comprises the compound of the invention as a substantially pure optical isomer. For the avoidance of doubt, the compound of the invention may be used in the form of a solvate, if desired.

[0225] Section 1: Definitions

[0226] As used herein, the words "a" and "an" are meant to include one or more, unless specifically stated otherwise.

[0227] As used herein, the term "affected area" refers to those anatomical sites affected by intestinal inflammation (such as IBD, UC or CD), including but not limited to areas of mucosal edema, atrophy, ulcers, erosions, ruptures, pits, aphthous lesions and similar abnormalities and tissue damage.

[0228] As used herein, the term "active ingredient" refers to those compositions disclosed herein that have biological activity for treating intestinal inflammation (such as IBD, UC or CD). A feature of the present invention is that such active ingredients are incorporated into formulations for oral administration. As used herein, the terms "treatment", "treating", "therapy", "therapeutic", etc. refer to interventions intended to cure, heal, alleviate, improve, remedy or otherwise beneficially affect a disorder or condition that affects the health of the patient. A disorder is a condition that alters the steady-state health of a patient, including but not limited to acute or chronic diseases, or a pathological condition that predisposes a mammal to acute or chronic diseases. UC and CD (both classified as IBD) are disorders that can be treated using the compositions and formulations of the present invention.

[0229] By "inflammation" is meant a localized response to injury, tissue damage, or other stimulation, such as that caused by the immune system (immune-mediated inflammation) and / or by the nervous system (neurogenic inflammation), typically causing symptoms including redness, heat, swelling, pain, tissue damage, and / or loss of function. By "neurogenic inflammation" is meant inflammation mediated or contributed to by neurons (such as nociceptors) or other components of the central or peripheral nervous system. As used herein, the term "inflammation" may refer to acute or chronic inflammation.

[0230] By "patient" is meant an animal. In one embodiment, the patient is a human. The methods, compositions, and kits of the invention can be used to treat other animals, including but not limited to non-human primates (e.g., monkeys, gorillas, chimpanzees), domesticated animals (e.g., horses, pigs, goats, rabbits, sheep, cattle, camels), and pets (e.g., guinea pigs, rats, mice, lizards, snakes, dogs, cats, fish, hamsters, and birds).

[0231] The compounds useful in the present invention include, but are not limited to, those described herein in any pharmaceutically acceptable form thereof, including isomers such as diastereomers and enantiomers, salts, esters, amides, thioesters, solvates and polymorphs, as well as racemic mixtures and pure isomers of the compounds described herein. The term "pharmaceutically acceptable" represents those substances that are suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and have a commensurate reasonable benefit / risk ratio within the scope of reasonable medical judgment. The compounds useful in the present invention include pharmaceutically acceptable anions and charged moieties thereof. The term "pharmaceutically acceptable anion" used herein refers to the conjugate base of a pharmaceutically acceptable acid. Such acids are described in Stahl, PH and Wermuth, CG (eds.) Handbook of Pharmaceutical Salts: Properties, Selection and Use, Wiley VCH (2008). Pharmaceutically acceptable acids include, but are not limited to, acetic acid, dichloroacetic acid, adipic acid, alginic acid, L-ascorbic acid, L-aspartic acid, benzenesulfonic acid, 4-acetamidobenzoic acid, benzoic acid, p-bromobenzenesulfonic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid, hexanoic acid, caprylic acid, carbonic acid, cinnamic acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, sulfuric acid, boric acid, citric acid, formic acid, fumaric acid, galactaric acid, quinonic acid, D-glucoheptonic acid, D-gluconic acid, D-glucuronic acid, glutamic acid, glutaric acid, 2-ketoglutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, isobutyric acid, DL-lactic acid, lactobionic acid, lauric acid, Maleic acid, (-)-L-malic acid, malonic acid, DL-mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, (-)-L-pyrroleglutamic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid. Pharmaceutically acceptable anions include conjugate bases of any of the above acids. The so-called "charged moiety" means a moiety that acquires a proton at physiological pH to become positively charged (such as ammonium, guanidine or amidine) or a moiety that includes a net formal positive charge without protonation (such as quaternary ammonium). The charged moiety is preferably permanently charged. The pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately prepared by reacting a free base function with a suitable organic acid.Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, isethionate, lactobionate, lactate, laurate, dodecylsulfate, malate, maleate, malonate, methanesulfonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate, and the like.

[0232] The compounds of the present invention, including salts of the compounds, can exist in non-solvated forms and solvated forms, including hydrated forms and non-hydrated forms. Generally speaking, the solvated form is equivalent to the non-solvated form and is encompassed within the scope of the present invention. Non-limiting examples of hydrates include: monohydrates, dihydrates, hemihydrates, etc. In some aspects, the compound is a hemihydrate. Non-limiting examples of solvates include: ethanol solvates, acetone solvates, etc. "Solvate" means a stoichiometric or non-stoichiometric solvent addition form containing a solvent. The compounds of the present invention can exist in a variety of crystalline or amorphous forms. Generally speaking, all physical forms are equivalent for the purposes contemplated by the present invention and are intended to fall within the scope of the present invention.

[0233] By "therapeutically effective amount" or "effective amount" is meant an amount sufficient to produce a desired result, e.g., to reduce or eliminate symptoms, signs, or sequelae associated with or caused by IBD, or to reduce the incidence of other diseases associated with IBD (such as colon cancer) or reduce the severity of other diseases associated with IBD (such as colon cancer). As used herein, the term "symptoms" refers to those manifestations of a disease or condition that a subject experiences, while "signs" are manifestations of a disease or condition perceived by an external observer, and "sequelae" are the long-term consequences of a disease or condition.

[0234] Section 2: Preparation

[0235] a. General preparations

[0236] Preparations comprising compounds of the present invention for treating intestinal inflammation (such as IBD, US or CD) can be prepared for oral administration. The dosage form prepared for oral administration may include a liquid or a solid. Advantageously, the oral dosage form will be prepared as a sustained-release preparation to delay the release of the active ingredient (Nocion) for a period of time, which is sufficient to allow the dosage form to pass through the intestinal tract via peristalsis until it reaches the local area in need of treatment. As used herein, the term "slow-release" refers to any preparation of an oral composition that releases an active ingredient from an oral dosage form at a rate slower than that of a quick-release or is controlled to be released at a specific position in the intestinal tract. The term "slow-release" can be applied to compositions having a controlled-release component or a delayed-release component or both, as described in more detail below.

[0237] Liquid preparations for oral use may incorporate aqueous solutions, appropriately flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils (such as cottonseed oil, sesame oil, coconut oil, or peanut oil), as well as elixirs and similar pharmaceutical vehicles. According to the present invention, Nocions may be dissolved or suspended in a liquid vehicle. A liquid oral sustained-release system may be produced that allows intracavitary delivery of the active ingredient to one or more infected areas so as to have a direct effect thereon. The techniques for preparing liquid oral sustained-release systems are familiar to those skilled in the art. When applied to the present invention, liquid sustained-release technologies may include, but are not limited to: the use of controlled-release spherical particles (including liposomes) containing Nocions suspended in a liquid vehicle; the use of ion exchange resins or sparingly soluble salts to produce colloids or suspensions having sustained-release properties; and the use of gelling systems having sustained-release properties, such as gels based on alginate or chitosan.

[0238] Solid dosage forms for oral use include tablets containing Nocion and non-toxic pharmaceutically acceptable excipients in a mixture. These excipients can be, for example, inert diluents or fillers (such as sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starch including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate or sodium phosphate); granulating and disintegrants (such as cellulose derivatives including microcrystalline cellulose, starch including potato starch, cross-linked sodium carboxymethyl cellulose, alginates or alginic acid); binders (such as sucrose, glucose, sorbitol, gum arabic, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinyl pyrrolidone or polyethylene glycol); and lubricants, glidants and anti-adherents (such as magnesium stearate, zinc stearate, stearic acid, silicon dioxide, hydrogenated vegetable oil or talc). Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffers, taste masking agents (such as hydroxypropyl methylcellulose, hydroxypropyl cellulose) and the like. One or more compounds of the present invention can be mixed together in tablets, capsules or other vehicles, or can be separated, and optionally combined with other bioactive agents that contribute to the treatment of IBD. The preparation for oral use can also be provided in chewable tablets or in hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent (such as potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or in soft gelatin capsules, wherein the active ingredient is mixed with water or an oil medium (such as peanut oil, liquid paraffin or olive oil). Powders, granules (granulate) and pellets (pellet) can be prepared in a conventional manner (such as using a mixer, a fluidized bed device or a spray drying device) using the ingredients mentioned above in tablets and capsule parts.

[0239] b. Exemplary sustained-release formulations

[0240] Solid oral sustained-release systems can be produced that allow intracavitary delivery of active ingredients to one or more infected areas so as to have a direct therapeutic effect thereon. Sustained release of active ingredients from solid dosage forms can be achieved by any means known in the art, including but not limited to the use of matrix dosage forms, multi-particulate dosage forms, reservoirs, and pulsatile dosage forms. Such dosage forms can also be prepared to delay the release of active ingredients. The characteristic properties of both delayed-release systems and controlled-release systems can be incorporated into the same dosage form.

[0241] In an embodiment, a matrix dosage form can be prepared for controlled release by incorporating the active ingredient into an appropriate matrix. As the matrix is ​​digested or degraded, it releases the active ingredient over time, resulting in controlled release. In general, the matrix material may include an erodible or non-erodible polymer matrix: an erodible matrix includes a water-swellable, water-soluble or water-erodible polymer that contains and supports the active ingredient. Then, as the water-swellable matrix passes through the intestinal tract, it gradually degrades, releasing the active ingredient it supports into the surrounding environment. Polymers suitable for forming such matrices are familiar in the art, including linear, branched or cross-linked homopolymers or copolymers, such as naturally occurring polysaccharides such as chitosan, dextran, pullulan, etc.; starches such as dextrin and maltodextrin; gums such as xanthan gum, guar gum, carrageenan, gum arabic, etc.; hydrophilic colloids similar to pectin; alginates; gelatin; collagen; polyvinyl pyrrolidone (PVP), polyvinyl alcohol, polyacrylamide, polyacrylates, glycerol fatty acid esters, etc.; polymers, including ethacrylic acid or methacrylic acid Or include other acrylic acid derivatives; and cellulose such as ethyl cellulose, methyl ethyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, etc. Exemplary matrix materials may include materials such as hydrated methyl cellulose, Kanava wax and stearyl alcohol, carbomer 934, silicone, tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene and / or halogenated fluorocarbons.

[0242] The erodible matrix system may contain other additives and excipients familiar to practitioners in the pharmaceutical field, including but not limited to: solubility enhancers or retarders, stability enhancers, permeabilizers, adhesives, buffers, etc. In a non-erodible matrix system, the active ingredient is distributed in an inert matrix and released into the surrounding environment by matrix diffusion. The materials used to form the inert matrix include various relatively insoluble polymer materials, including plastics such as copolymers of ethylene and vinyl acetate, methyl acrylate-methyl methacrylate copolymers, polyvinyl chloride and polyethylene; hydrophilic polymers such as cellulose acetate, ethyl cellulose and cross-linked PVP; waxes, triglycerides and fatty compounds. Further examples, as familiar to those skilled in the art, can be found in standard references such as Remington: The Science and Practice of Pharmacy, 23rd edition (2020).

[0243] Matrix can also be prepared to support a variety of particles comprising active ingredients, wherein the particles include a mixture of active ingredients and secondary matrix materials, wherein the secondary matrix material further changes the release of the active ingredient. This arrangement produces a multi-particulate dosage form. The secondary matrix material itself can be substantially water-soluble or water-insoluble, and in either case includes an agent that changes the active ingredient to release from the secondary matrix.

[0244] In an embodiment, the reservoir system can be prepared for controlled release of active ingredients such as Nocions. In the reservoir system, the reservoir containing the active ingredient is surrounded by a rate-limiting membrane. The active ingredient is distributed to the surrounding environment by passing through the membrane, which uses a mass transfer mechanism familiar in the art, such as diffusion through the membrane or dissolving in the holes filled with liquid in the membrane itself. The reservoir system can be formed by a single large reservoir in the dosage form (e.g., in a tablet), or it can involve multiple particles, such as a capsule containing multiple reservoir particles, each capsule is encapsulated by its own film. As understood by those skilled in the art, the film can be amorphous or crystalline, and can have any type of morphology or composition that allows it to provide controlled permeability to the active ingredient, such as a porous hydrophilic membrane, an interfacial polymerized membrane, a hydrogel membrane, an ionic membrane, etc. The release rate of the active ingredient can be controlled by designing various aspects of the reservoir system, such as the composition of the active ingredient deposit in the reservoir and the adhesive used, the nature and thickness of the membrane, the surface area and volume ratio of the reservoir element (whether it is a single cavity or multiple particles), etc.

[0245] Pulsatile dosage forms suitable for controlled release include a tablet or bead core loaded with the active ingredient surrounded by a semipermeable membrane that can be destroyed or ruptured by contact with the environment, resulting in essentially complete and immediate release of the active ingredient when the membrane is broken. Such systems fall into three categories: time-controlled release, in which degradation of the outer layer occurs as a function of time, for example when the surface corrodes or the system's internal environment accumulates water and swells; stimulus-induced release, in which degradation occurs in response to an environmental stimulus (such as pH or exposure to hydrolytic enzymes); and externally induced release, in which degradation occurs after exposure to an external stimulus (such as ultrasound or electromagnetic radiation). The art is familiar with techniques for producing such systems, which can allow the timing of the release of Nocions in the small or large intestine to be controlled so that they are in the best position to reach the area in need of treatment.

[0246] c. Coating

[0247] Any of the aforementioned sustained release methods can be adjusted or controlled by applying one or more external coatings. Coatings can be applied in one or more layers to the outer surface of the dosage form, and / or they can be applied in one or more layers to subcomponents within the dosage form, such as particles containing active ingredients that constitute part of a multiparticulate system.

[0248] Coatings facilitate the preparation of delayed release and controlled release dosage forms by applying the coating to the entire dosage form or to components of the dosage form that have the desired characteristics of sustained release. For example, a tablet can be formed that includes an active ingredient pressed into a core matrix that is coated with a first coating that controls the release of the active ingredient over time during transit through the intestine and a second coating that covers the entire dosage form and completely prevents the release of the active ingredient for a certain period of time or until a certain biological environment is reached. For example, if a tablet formulated to be twice coated with one or more Nocions is loaded with an outer coating selected to resist the acidic conditions of the stomach, the tablet can be ingested and pass through the stomach relatively intact, thereby keeping the underlying inner coating and tablet intact. The dosage form then enters the duodenum, where the higher pH can destroy (erode, dissolve, etc.) the acid-resistant outer coating to expose the inner coating. The inner coating can be formulated to produce controlled release of the active ingredient from the underlying tablet. Once the outer coating is destroyed, the controlled release properties of the inner coating can determine the release characteristics of the active ingredient. Alternatively, if only an outer coating is provided, it may be sufficient to protect the dosage form to completely delay the release of the active ingredient, with the controlled release of the active ingredient then being regulated by the properties of the matrix or vehicle in which it is loaded.

[0249] Suitable materials for the external delayed release coating are well known in the art, including those agents commonly referred to as enteric coatings for delayed release drug products. Enteric coatings known in the art are generally resistant to gastric acid and do not dissolve at a pH of less than 4; thus, they can prevent the underlying tablet from dissolving as the tablet passes through the stomach. Examples of enteric coatings suitable for use as external delayed release layers include cellulose derivatives such as cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate succinate, carboxymethyl ethyl cellulose, methylcellulose phthalate, hydroxypropyl methylcellulose phthalate, and ethylhydroxycellulose phthalate; vinyl polymers such as polyvinyl acetate phthalate, vinyl acetate-maleic anhydride copolymers; polyacrylates; and polymethacrylates such as methyl acrylate-methacrylic acid copolymers, methacrylate-methacrylic acid-octyl acrylate copolymers; and styrene-maleic acid monoester copolymers, any of which can be used alone or in combination. Some of these materials are pH sensitive, including, for example, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, and acrylic acid copolymers, such as The commercialized products of Rohm Pharma include L 100, S100 and L30-D55.

[0250] The controlled release coating can be designed to provide an appropriate delivery schedule for the active ingredient so that it allows it to reach the infected area or areas of the intestine. It should be understood that the infected area in the intestine is the therapeutic target of the active ingredient. In CD, the infected area is located in the colon; therefore, if the lesion is to be accessed and treated by an intraluminal method, the active ingredient needs to reach the colon without being absorbed more proximally. For CD, the lesion can involve the entire intestine, including both the small intestine and the large intestine. Therefore, it is ideal that the controlled release coating fully protects the active ingredient so that it can enter various parts affected by the disease, potentially including the entire length of the small intestine and the colon.

[0251] In an embodiment, release is specifically targeted at the vicinity of one or more infected areas. In other embodiments, active ingredient can be released at the proximal end and advance in the intestinal tract to treat the lesions encountered during the delivery period, provided that significant absorption of active ingredient does not occur. Controlled release coatings for these purposes include those agents that are familiar and safe for oral administration in pharmaceutical preparations, including but not limited to the following agents or combinations of agents: shellac, beeswax, sugar wax, castor wax, canava wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, stearyl palmitate, ethylcellulose, acrylic resin, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methyl methacrylate, 2-hydroxy methacrylate, methacrylate hydrogel, 1,3-butylene glycol, ethylene glycol methacrylate and / or polyethylene glycol.

[0252] Section 3: Treatment methods

[0253] Disclosed herein are methods for treating intestinal inflammation, such as IBD, UC, and CD, comprising orally administering to a patient in need thereof a therapeutically effective amount of one or more Nocions or a compound of the invention. Advantageously, oral administration involves providing a sustained-release formulation that can provide delayed release of the active ingredient, controlled release of the active ingredient, or both. The sustained-release formulation can be designed based on the clinical needs of the patient to maximize release at a selected location in the intestine. For example, a sustained-release formulation for an IBD patient with UC can target maximum release in the colon, wherein the formulation provides delayed release until most of the small intestine has been passed or the colon itself has been reached. A sustained-release formulation for an IBD patient with CD can target release along the length of the small intestine, wherein the delayed release is to ensure passage through the stomach, and the controlled release is to allow the active ingredient to enter a large number of infected areas along the length of the small intestine.

[0254] Generally, the oral dosage (dosage) of any compound of the present invention applied to a person depends on the properties of the compound, and can be easily determined by those skilled in the art. Typically, such dosage can be about 0.001mg to 2000mg per day, ideally about 1mg to 1000mg per day, and more ideally about 5mg to 500mg per day. It may be necessary to reach a dosage of 200mg per day or more. The administration of the compound can be daily, every other day or other intervals. The dosage can be provided once, twice, three times or four times a day or more frequently. The duration of treatment can be from a single day to a whole year or longer, recognizing that IBD is a lifelong disease, which may require long-term or lifelong treatment to prevent symptoms, pathological changes in intestinal tissue or sequelae such as colon cancer.

[0255] It should be understood that IBD itself is considered to be incurable, and its symptoms are variable and often worsen. However, clinical symptoms may not correspond linearly to the anatomical state or progression of the disease. Therefore, objective measures are useful for evaluating and monitoring the activity of the disease. At present, doctors rely on the combination of symptoms, radiological investigations, histological examinations of tissue specimens, endoscopic examinations and laboratory indicators to make treatment decisions. The technology of these current practices and the technology of future improvements can be collectively referred to as "monitoring" of IBD. The biomarkers allowed to be monitored have been found in blood, feces, urine, breath and tissues, and many other biomarkers are being studied. The use of monitoring technology can allow monitoring of disease activity, evaluation of therapeutic efficacy and prediction of the future course of the disease. The monitoring technology in current practice includes but is not limited to detection and measurement of serological antibodies such as autoantibodies and antimicrobial antibodies, detection and measurement of circulating non-coding RNA, serum metabolic analysis, serum protein analysis, detection and measurement of identified disease markers (such as tumor suppressor protein M, serum galactin, C-reactive protein, fecal calprotectin, proinflammatory cytokines, vitamin D levels, etc.).

[0256] Dosages and regimens may be arranged in response to clinical indications, such as the outbreak or persistence of symptoms. Dosages may also be arranged according to objective measures of disease persistence, disease progression, or disease regression. In an embodiment, a treatment regimen including a prearranged dosage schedule may be adapted to the clinical needs of a patient by reference to one or more objective measures, such as biomarkers that reflect the disease state or the inflammatory state that is considered to be attributed to the disease. In an embodiment, after obtaining a baseline objective measurement corresponding to the disease state, a predefined induction dose is administered for a first period of time, followed by obtaining a second set of objective measurements. Based on the second set of objective measurements, a second dose or dosing regimen is determined and administered. In an embodiment, the second dose or dosing regimen is less than the induction dose or the frequency is less than the induction dosing schedule, and in an embodiment, the second treatment regimen is intended to extend administration. In an embodiment, a third set of objective measurements is performed during the second treatment regimen, and the dose and / or dosing schedule may then be modified. In other embodiments, an induction dose is not administered, but objective measurements are performed regularly before and during the start of therapy, and dosing is adjusted accordingly.

[0257] Treatment of IBD using the methods of the present invention may include adjusting the amount of active ingredient in a single dose, the frequency or schedule of administration, the type of dosage form in which the active ingredient is delivered, or other parameters that affect the amount of active ingredient that reaches a specific infected area in the intestine within a predetermined time frame (collectively referred to as "modification" treatment regimen). As described above, the information obtained from monitoring can be used to modify the treatment regimen to optimize the treatment process. In an embodiment, changes in one or more monitoring parameters can be used to increase or decrease the amount of active ingredient administered in a single dose, or to change the frequency of administration within a single 24-hour period, or to change the duration of treatment (e.g., to allow intermittent treatment processes of various durations); those skilled in the art may envision other modifications to the treatment regimen based on monitoring parameters. Example

[0258] Example 1 :Anti-inflammatory activity of Nocion in the dextran sodium (DSS) model of ulcerative colitis

[0259] As an exemplary Nocion, a charged sodium channel blocker represented by the following formula (XIV) (referred to as "NTX 1170") was administered in a DSS mouse model of ulcerative colitis, where its anti-inflammatory effects were compared with those of tofacitinub and infliximab.

[0260] Formula (XIV)

[0261]

[0262] The anti-inflammatory efficacy of Nocion (exemplified by the compound of Formula XIV (NTX1170) (100 mg / kg QD PO)) was compared with infliximab (5 mg / kg QD IP) and tofacitinib (5 mg / kg BID PO) in mice given 2.5% DSS in drinking water for 6 days. Body weight, stool consistency, and the presence of blood in the stool were measured over 6 days and constituted the disease activity index (DAI). On day 7, the study was terminated and colon and plasma were collected for cytokine measurements, histological evaluation, and pharmacokinetic (PK) analysis.

[0263] The compound of formula XIV produced a 60% (P<0.001) improvement in DAI, compared to a 38% reduction with tofacitinib (P<0.05) and a 14% reduction with infliximab (NS). Several plasma cytokines (IP-10, MIG, TNF-α, G-CSF, and Mip-1β) were upregulated by DSS treatment and significantly reduced by NTX-1170. Tofacitinib significantly reduced MIG, TNF-α, G-CSF, and Mip-1β levels, while infliximab only reduced TNF-α, G-CSF, and Mip-1β levels. Colonic KC, IL-15, and RANTES levels were significantly increased by DSS treatment and significantly reduced by NTX-1170, while neither tofacitinib nor infliximab significantly reduced these cytokines. Histopathological analysis of the colon revealed that NTX-1170 significantly reduced the extent of inflammatory infiltrates, the number of layers to which the infiltrates extended, and the amount of crypt damage. Tofacitinib reduced only the extent of infiltration, while infliximab had no significant effect. Analysis of terminal plasma and colon samples showed low levels of the compound of Formula XIV in plasma, and high levels in the colon, with a colon / plasma ratio >3500.

[0264] These data indicate that charged sodium channel blocking compounds, exemplified by compounds shown in Formula II, inhibit neurogenic inflammation and provide significant efficacy in the DSS model of UC, thereby providing a therapeutic option for UC with a higher efficacy potential than current treatments such as infliximab and tofacitinib. Although the present invention has been specifically demonstrated and described with reference to its preferred embodiments, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the scope of the invention covered by the appended claims. Although specific embodiments of the present invention have been disclosed herein, the above description is illustrative only and non-limiting. After reading this specification, many variations of the present invention will become apparent to those skilled in the art; those changes in the described modes for implementing the present invention that are apparent to those skilled in the art of medicine, immunology, pharmacology, endocrinology or related fields are intended to be included within the scope of the present invention. Unless otherwise stated, all numerical values ​​representing reaction conditions, amounts of ingredients, etc., as used in the present specification and claims should be understood to be modified by the term "about" in all cases. Therefore, unless otherwise stated, the numerical parameters described herein are approximate values, which may vary according to the desired properties sought to be obtained by the present invention.

Claims

1. A method for treating intestinal inflammation comprising orally administering a pharmaceutical preparation comprising a therapeutically effective amount of a charged sodium channel blocker.

2. The method of claim 1, wherein the intestinal inflammation is selected from the group consisting of inflammatory bowel disease, ulcerative colitis and Crohn's disease.

3. The method of claim 1, wherein the formulation is designed to release the composition at a selected location in the intestinal tract.

4. The method according to claim 1, wherein the preparation is an enteric-coated tablet.

5. The method according to claim 1, wherein the compound has formula (I): in Y - is a pharmaceutically acceptable anion; R F and R G With N + together form an optionally substituted heteroaryl ring having one or more heteroatoms or an optionally substituted bicyclic heteroaryl ring having one or more heteroatoms; R A , R B and R C are each independently selected from H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, nitrile, OR I NR J R K NR L C(O)R M 、S(O)R N 、SO2R O 、SO2R O R P 、SO2NR Q R R 、SO3R S 、CO2R T 、C(O)R U and C(O)NR V R W ; or R B and adjacent R C Together with the carbon atom to which they are attached, they form a substituted or unsubstituted 3-7 membered cycloalkyl group (C3-C7 cycloalkyl) or a substituted or unsubstituted aryl group (e.g., phenyl); R I , R J , R K , R L , R M , R N , R O , R P , R Q , R R , R S , R T , R U , R V and R W are each independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted heteroalkyl; X 1 selected from —CR X R Y —, —NR Z C(O)—, —OC(O)—, —SC(O)—, —NR Z S(O)—, —S(O)NR Z —, —NR X C(O)NR Y —, —C(O)NR 1A —, —C(O)O—, —C(O)—, —S(O)—, —S(O)2— and —(O)CS—; X 1 may also be —NR Z C(O)CR X R Y —; R X , R Y , R Z and R 1A are each independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted heteroalkyl; and R D and R E R is each independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, optionally substituted with halogen, cyclic alkyl, aryl or heteroaryl, and cycloalkyl; or D and R E Together with the carbon to which they are attached, they form a substituted or unsubstituted 3-7 membered cycloalkyl (C3-C7 cycloalkyl) or a substituted or unsubstituted heterocyclic or heteroalkyl ring; or R D and R Z Together with the carbon to which they are attached and -NC(O)-, they form an optionally substituted 5-8 membered lactam.

6. The method according to claim 1, wherein the compound has formula (II): in: Y - is a pharmaceutically acceptable anion; R A , R B and R C are each independently selected from H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, OR I 、CN、NR J R K NR L C(O)R M 、S(O)R N 、S(O)2R N 、SO2R O R P 、SO2NR Q R R 、SO3R S 、CO2R T 、C(O)R U and C(O)NR V R W ; (preferably H, F, Cl or CN, and more preferably H); R I , R J , R K , R L , R M , R N , R O , R P , R Q , R R , R S , R T , R U , R V and R W R is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; J and R K or R V and R W or R Q and R R They may also be taken together with the nitrogen to which they are attached to form a substituted or unsubstituted 5-, 6-, 7-, or 8-membered ring; R A , R B and / or R C Together with the benzene ring to which they are attached, they may form a fused bicyclic or tricyclic ring system such as naphthyl, indanyl, tetrahydronaphthyl, quinolinyl, indolyl, and the like; X 1 selected from —CR X R Y —, —NR Z C(O)—, —OC(O)—, —SC(O)—, —C(O)NR 1A —, —C(O)O—, -C(O)-, —(O)CS—, —NR 1A S(O)—, —S(O)NR 1A —, —NR 1A C(O)NR 1A —, —S(O)— and —S(O)2—; X 1 may also be —NR Z C(O)CR X R Y —; R X , R Y , R Z and R 1A are each independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted heteroalkyl; R D and R E are each independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted cycloalkyl; or R D and R E Together with the carbon to which they are attached, they form a substituted or unsubstituted 3-6 membered cycloalkyl (C3-C6 cycloalkyl), a substituted or unsubstituted heterocyclic ring, or a substituted or unsubstituted heteroalkyl ring; or R D and R Z Together with the carbon to which they are attached and -NC(O)-, they form an optionally substituted 5-8 membered lactam; R F and R G With N + together form an optionally substituted heterocyclic ring having one or more nitrogen atoms; or R F and R G are each independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted C 3-6 Cycloalkyl; and R H is a substituted or unsubstituted aromatic ring or a substituted or unsubstituted heteroaromatic ring.

7. The method according to claim 1, wherein the compound has formula (III): in: Y - is a pharmaceutically acceptable anion; R A , R B and R C are each independently selected from H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, OR I NR J R K NR L C(O)R M 、CN、S(O)R N 、S(O)2R N 、SO2R O R P 、SO2NR Q R R 、SO3R S 、CO2R T 、C(O)R U and C(O)NR V R W ; R I , R J , R K , R L , R M , R N , R O , R P , R Q , R R , R S , R T , R U , R V and R W are each independently selected from H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted heteroalkyl; X 1 selected from —CR X R Y —, —NR Z C(O)—, —NR Z C(O)CR X R Y —, —OC(O)—, —SC(O)—, —C(O)NR 1A —, —C(O)O—, -C(O)-, —(O)CS—, —NR 1A S(O)—, —S(O)NR 1A —, —NR 1A C(O)NR 1A —, —S(O)— and —S(O)2—; R X , R Y , R Z and R 1A are each independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted heteroalkyl; or R X , R Y , R Z or R 1A With R D or R E and the atoms to which they are attached together form an optionally substituted cycloalkyl (such as a C3-C6 cycloalkyl) or an optionally substituted heterocycle (such as a 3- to 15-membered heterocycle); R D and R E are each independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted cycloalkyl; or R D and R E Together with the carbon to which they are attached, they form a substituted or unsubstituted cycloalkyl (such as a C3-C6 cycloalkyl) or a substituted or unsubstituted heterocycle (such as a 3- to 15-membered heterocycle); R F , R G and R H are each independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted -C 6- C 10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted –CH2-C 5- C 10 Aryl and substituted or unsubstituted –CH2-C 5- C 10 heteroaryl; or alternatively, R F , R G and R H Two or three of them with their attached P + Together they form a + An optionally substituted heterocyclic group (such as a 3- to 15-membered heterocyclic ring) having zero, one or more heteroatoms in addition to , including but not limited to an optionally substituted heteroaromatic ring; or R D , R E , R F , R G and R H Two or three of them with P + Together they form a + In addition to the optionally substituted heterocyclic ring having zero, one or more heteroatoms, including but not limited to heteroaromatic rings; for example, R E , R F and R G Two of them and P + Together they form a + The heterocyclic ring has zero, one or more heteroatoms.

8. The method of claim 1, wherein the compound has formula (IV): in: Y - is a pharmaceutically acceptable anion; R A and R B Each independently selected from H, 2 H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, OR I NR J R K NR L C(O)R M 、S(O)R N 、S(O)2R N 、SO2R O R P 、SO2NR Q R R 、SO3R S 、CO2R T 、C(O)R U and C(O)NR V R W ; R I , R J , R K , R L , R M , R N , R O , R P , R Q , R R , R S , R T , R U , R V and R W Each independently selected from H, 2 H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted heteroalkyl; X 1 selected from —CR X R Y —, —NR Z C(O)—, —NR Z C(O)CR X R Y —, —OC(O)—, —SC(O)—, —C(O)NR 1A —, —C(O)O—, -C(O)-, —(O)CS—, —NR 1A S(O)—, —S(O)NR 1A —, —NR 1A C(O)NR 1A —, —S(O)— and —S(O)2—; R X , R Y , R Z and R 1A Each independently selected from H, 2 H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted heteroalkyl; or R X , R Y , R Z or R 1A With R D or R E and the atoms to which they are attached together form an optionally substituted cycloalkyl (such as a C3-C6 cycloalkyl) or an optionally substituted heterocycle (such as a 3- to 15-membered heterocycle); R D and R E Each independently selected from H, 2 H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted cycloalkyl; or R D and R E Together with the carbon to which they are attached, they form a substituted or unsubstituted cycloalkyl (such as a C3-C6 cycloalkyl) or a substituted or unsubstituted heterocycle (such as a 3- to 15-membered heterocycle); R F , R G and R H Each independently selected from H, 2 H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted –C 6- C 10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted –CH2-C 5- C 10 Aryl and substituted or unsubstituted –CH2-C 5- C 10 heteroaryl; or alternatively, R F , R G and R H Two or three of them with their attached P + Together they form a + An optionally substituted heterocyclic group (such as a 3- to 15-membered heterocyclic ring) having zero, one or more heteroatoms in addition to , including but not limited to an optionally substituted heteroaromatic ring; or R D , R E , R F , R G and R H Two or three of them with their attached P + Together they form a + In addition to the optionally substituted heterocyclic ring having zero, one or more heteroatoms, including but not limited to heteroaromatic rings; for example, R E , R F and R G Two of them and P + Together they form a + The heterocyclic ring has zero, one or more heteroatoms.

9. The method of claim 1, wherein the compound has formula (V): in: Y - is a pharmaceutically acceptable anion; R F and R G N + together form an optionally substituted heteroaryl ring having one or more heteroatoms or an optionally substituted bicyclic heteroaryl ring having one or more heteroatoms; R A and R B are each independently selected from H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, nitrile, OR I NR J R K NR L C(O)R M 、S(O)R N 、SO2R O 、SO2R O R P 、SO2NR Q R R 、SO3R S 、CO2R T 、C(O)R U and C(O)NR V R W ; R I , R J , R K , R L , R M , R N , R O , R P , R Q , R R , R S , R T , R U , R V and R W are each independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted heteroalkyl; X 1 Selected from —CR X R Y —, —NR Z C(O)—, —NR Z C(O)CR X R Y —, —OC(O)—, —SC(O)—, —NR Z S(O)—, —S(O)NR Z —, —NR X C(O)NR Y —, —C(O)NR 1A —, —C(O)O—, —C(O)—, —S(O)—, —S(O)2— and —(O)CS—; R X , R Y , R Z and R 1A are each independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted heteroalkyl; or may be combined with any other R X , R Y , R Z , R 1A , R D or R E Together with any intervening atoms, form a substituted or unsubstituted ring; R D and R E R is each independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, optionally substituted with halogen, cyclic alkyl, aryl or heteroaryl, and cycloalkyl; or D and R E Together with the carbon to which they are attached, they form a substituted or unsubstituted 3-7 membered cycloalkyl (C3-C7 cycloalkyl) or a substituted or unsubstituted heterocyclic or heteroalkyl ring, or R D and R Z Together with the carbon to which they are attached and -NC(O)-, they form an optionally substituted 5-8 membered lactam.

10. The method of claim 1, wherein the compound has formula (VI), which is useful for treating or preventing pain, pruritus and neurogenic inflammation: in: Y - is a pharmaceutically acceptable anion; R A and R B are each independently selected from H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, OR I NR J R K NR L C(O)R M 、S(O)R N 、S(O)2R N 、SO2R O R P 、SO2NR Q R R 、SO3R S 、CO2R T 、C(O)R U and C(O)NR V R W ; R I , R J , R K , R L , R M , R N , R O , R P , R Q , R R , R S , R T , R U , R V and R W are each independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted heteroalkyl; X 1 selected from —CR X R Y —, —NR Z C(O)—, —OC(O)—, —SC(O)—, —C(O)NR 1A —, —C(O)O—, -C(O)-, —(O)CS—, —NR 1A S(O)—, —S(O)NR 1A —, —NR 1A C(O)NR 1A —, —S(O)— and —S(O)2—; X 1 may also be —NR Z C(O)CR X R Y —; R X , R Y , R Z and R 1A are each independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted heteroalkyl; or may be combined with any other R X , R Y , R Z , R 1A , R D or R E Together with any intervening atoms, form a substituted or unsubstituted ring; R D and R E are each independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted cycloalkyl; or R D and R E Together with the carbon to which they are attached, they form a substituted or unsubstituted 3-6 membered cycloalkyl (C3-C6 cycloalkyl), a substituted or unsubstituted heterocyclic ring, or a substituted or unsubstituted heteroalkyl ring; or R D and R Z Together with the carbon to which they are attached and -NC(O)-, they form an optionally substituted 5-8 membered lactam; R F and R G N + together form an optionally substituted heterocyclic ring having one or more nitrogen atoms; or, R F and R G are each independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted C 3-6 Cycloalkyl; and R H is a substituted or unsubstituted aromatic ring or a substituted or unsubstituted heteroaromatic ring.

11. The method according to claim 1, wherein the compound has formula (VII): in: Y - is a pharmaceutically acceptable anion; R A For CO2R T ; R T is a substituted or unsubstituted alkyl group (preferably a methyl group or an ethyl group); R B is H, D, halogen or substituted or unsubstituted alkyl; preferably methyl or ethyl; R C is selected from H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, OR I 、CN、NR J R K NR L C(O)R M 、S(O)R N 、S(O)2R N 、SO2R O R P 、SO2NR Q R R 、SO3R S 、CO2R T 、C(O)R U and C(O)NR V R W , (preferably H, F, Cl or CN, and more preferably H); R I , R J , R K , R L , R M , R N , R O , R P , R Q , R R , R S , R T , R U , R V and R W R is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; J and R K or R V and R W or R Q and R R They may also be taken together with the nitrogen to which they are attached to form a substituted or unsubstituted 5-, 6-, 7-, or 8-membered ring; X 1 Can be selected from—CR X R Y —、—NR Z C(O)—、—NR Z C(O)CR X R Y —, —OC(O)—, —SC(O)—, —C(O)NR 1A —, —C(O)O—, -C(O)-, —(O)CS—, —NR 1A S(O)—,—S(O)NR 1A —、—NR 1A C(O)NR 1A —, —S(O)— and —S(O)2—; and R X , R Y , R Z and R 1A Each is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl and substituted or unsubstituted alkynyl.

12. The method of claim 1, wherein the compound has formula (VIII): in: Y - is a pharmaceutically acceptable anion; n is 1, 2, 3 or 4; R A , R B and R C are each independently selected from H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, OR I 、CN、NR J R K NR L C(O)R M 、S(O)R N 、S(O)2R N 、SO2R O R P 、SO2NR Q R R 、SO3R S 、CO2R T ; C(O)R U and C(O)NR V R W , (preferably R A and R B is methyl, and R C is H, F, Cl or CN, and more preferably is H); R I , R J , R K , R L , R M , R N , R O , R P , R Q , R R , R S , R T , R U , R V and R W R is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; J and R K or R V and R W or R Q and R R They may also be taken together with the nitrogen to which they are attached to form a substituted or unsubstituted 5-, 6-, 7-, or 8-membered ring; R A , R B and / or R C Together with the benzene ring to which they are attached, they form a fused bicyclic or tricyclic ring system such as naphthyl, indanyl, tetrahydronaphthyl, quinolinyl, indolyl and the like; X 1 selected from —CR X R Y —, —NR Z C(O)—, —OC(O)—, —SC(O)—, —C(O)NR 1A —, —C(O)O—, -C(O)-, —(O)CS—, —NR 1A S(O)—, —S(O)NR 1A —, —NR 1A C(O)NR 1A —, —S(O)— and —S(O)2—; X 1 may also be —NR Z C(O)CR X R Y —; R X , R Y , R Z and R 1A are each independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted heteroalkyl; R D and R E are each independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted cycloalkyl; or R D and R E Together with the carbon to which they are attached, they form a substituted or unsubstituted 3-6 membered cycloalkyl (C3-C6 cycloalkyl), a substituted or unsubstituted heterocyclic ring, or a substituted or unsubstituted heteroalkyl ring; or R D and R Z Together with the carbon to which they are attached and -NC(O)-, they form an optionally substituted 5-8 membered lactam; R H is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; in certain aspects, R H may be substituted or unsubstituted aralkyl or heteroaralkyl; in another aspect, R H may be substituted or unsubstituted alkyl carboxylate, substituted or unsubstituted alkyl formamide; and R 1B It is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group, and is preferably a substituted or unsubstituted phenyl group.

13. The method of claim 1, wherein the compound has formula (IX): in: Y - is a pharmaceutically acceptable anion; R 1 Selected from the group consisting of methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, tert-butyl and sec-butyl), cyclohexyl, phenyl and CH2C(O)NHR3; R 2 is hydrogen or methyl; and R 3 is hydrogen, methyl or ethyl.

14. The method of claim 1, wherein the compound has formula (X): in: Y - is a pharmaceutically acceptable anion; R 1 and R 2 One of them is hydrogen, and R 1 and R 2 The other of which is selected from the group consisting of methyl, ethyl, unsubstituted phenyl and C(O)OR 3 ;and R 3 Selected from the group consisting of: hydrogen, methyl and ethyl.

15. The method of claim 1, wherein the compound has formula (XI): in: Y - is a pharmaceutically acceptable anion; q is 0, 1, 2, or 3; and R D is hydrogen, methyl or ethyl.

16. The method of claim 1, wherein the compound has formula (XII): in: Y - is a pharmaceutically acceptable anion; wherein R1, R2, R3, R4, R5 and R6 are independently selected from hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, aryl or heteroaryl; n is 0, 1, 2, 3, 4, and 5; q is 0, 1, 2, 3, 4 or 5.

17. The method of claim 1, wherein the compound has formula (XIII): in: Y - is a pharmaceutically acceptable anion; R A , R B and R C are each independently selected from H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, OR I 、CN、CF3、NR J R K NR L C(O)R M 、S(O)R N 、S(O)2R N 、SO2R O R P 、SO2NR Q R R 、SO3R S 、CO2R T 、C(O)R U and C(O)NR V R W ; R I , R J , R K , R L , R M , R N , R O , R P , R Q , R R , R S , R T , R U , R V and R W are each independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; or R J and R K or R V and R W or R Q and R R They may also be taken together with the nitrogen to which they are attached to form a substituted or unsubstituted 5-, 6-, 7-, or 8-membered ring; R A , R B and / or R C Together with the benzene ring to which they are attached, they may form a fused bicyclic or tricyclic ring system such as naphthyl, indanyl, tetrahydronaphthyl, quinolinyl, indolyl, and the like; R1, R2, R3, R4, R5 and R6 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, cycloalkyl, aryl or heteroaryl, preferably hydrogen, methyl or ethyl; n is 0, 1, 2, 3, 4, and 5; or R1, R2, R3, R4, R5 and / or R6 together with the carbon to which they are attached form a substituted or unsubstituted cycloalkyl (such as a C3-C6 cycloalkyl) or a substituted or unsubstituted heterocycle (such as a 3 to 15 membered heterocycle); R F and R G With N + Together they form N + In addition to the optionally substituted heterocyclic ring having zero, one or more heteroatoms, including but not limited to heteroaromatic rings; for example, R E , R F and R G Two of them and N + Together they form N + A heterocyclic ring having zero, one or more heteroatoms; R H is selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, such as -CH2-cycloalkyl, -C2H4-cycloalkyl, substituted or unsubstituted -CH2-C 5- C 10 Aryl, substituted or unsubstituted –C2H4-C 5- C 10 Aryl, substituted or unsubstituted –CH2-C 5- C 10 Heteroaryl, substituted or unsubstituted –C2H4-C 5- C 10 Heteroaryl, -CH2 OC(O)R T 、-CH2CO2R T 、-CH2C(O)NR V R W 、-C2H4OCOR T 、-C2H4OR I ;or R F , R G and R H With N + Together they form a substituted or unsubstituted heteroaromatic ring (such as pyridyl or phenylpyridyl) or a bridged heterocyclic ring.

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