HK1224572A1

HK1224572A1 - Sodium channel modulators for the treatment of pain and diabetes

Info

Publication number: HK1224572A1
Application number: HK16112915.9A
Authority: HK
Inventors: 奥尔加．巴比奇; 蒂娜．加里亚蒂斯; 罗伯特．Z．罗; 戴维．J．帕林; 斯里尼瓦桑．P．文卡塔查兰; 王艳林
Original assignee: 卓莫赛尔公司
Priority date: 2013-09-10
Filing date: 2014-09-09
Publication date: 2017-08-25

Description

Sodium channel modulators for the treatment of pain and diabetes

This application claims the benefit of U.S. provisional application No. 61/876,046 filed on 9/10/2013, the contents of which are incorporated herein by reference in their entirety.

1 technical field

Provided herein are sodium channel modulating compounds, particularly nav1.7 modulating compounds. In particular, provided herein are methods of making the compounds, intermediates used in making the compounds, pharmaceutical compositions comprising the compounds, and methods of treatment comprising administering the compounds. In particular, provided herein are compounds for the treatment or prevention of pain. In addition, provided herein are compounds for the treatment or prevention of diabetes.

2 background of the invention

Voltage-gated ion channels play a key role in the electrical activity of neurons and muscle cells. Many families of voltage-gated ion channels (e.g., sodium channels) have been identified. Due to their potential role in various pathological conditions, these ion channels have been the subject of important pharmacological studies.

Pain (due to cold or dampness)

Biophysical and pharmacological studies have established that the sodium channel subtypes nav1.3, nav1.7, nav1.8 and nav1.9 are particularly important in the pathophysiology of pain, especially neuropathic pain. Recently, gain-of-function mutations in SCN9A (gene encoding NaV1.7) have been associated with two human inherited pain syndromes, inherited erythromelalgia and paroxysmal megalgia, while loss-of-function mutations in SCN9A have been associated with complete insensitivity to pain (Dib-Hajj et al, Painmedicine 10 (7): 1260 and 1269(2009) (abstract)). Pain conditions affect nearly 1 million U.S. adults with a yearly direct medical cost and lost productivity of 5600-. Unfortunately, current treatment options typically provide only partial pain relief and are limited by inconvenient dosing and side effects such as lethargy, movement disorders, edema, gastrointestinal discomfort and respiratory depression. Thus, there is a need for new compounds to address the shortcomings of currently available treatment options.

Prediabetes and diabetes

Prediabetes and diabetes describe a group of metabolic diseases with elevated blood glucose levels over a prolonged period of time. Diabetes can be caused by an insufficient production of the peptide hormone insulin. In other cases, diabetes may be caused by insulin resistance, i.e., the inability of cells to respond properly to insulin. If the blood glucose level is higher than normal, but not so high as to diagnose diabetes, then the subject is prediabetic. There are three main types of diabetes: first, type 1 is caused by the body's inability to produce adequate levels of insulin. Second, type 2 is caused by insulin resistance. Third, gestational diabetes occurs when pregnant women without a history of diabetes develop high blood glucose levels. Another type of diabetes is Latent Autoimmune Diabetes of Adults (LADA). LADA is the most commonly used term to describe patients with type 2 diabetes phenotype and slow-progressing cell failure that bind to islet cell antibodies.

For example, type 2 diabetes is a serious and prevalent disease. Approximately 2580 million people in the united states alone have diabetes, whereby type 2 diabetes accounts for approximately 90% to 95% of all diagnosed cases of diabetes. U.S. patent application publication No. 2014/0228353A1, paragraph [0002 ]. From 1980 to 2008, the number of americans with diabetes has tripled. Diabetes is also becoming more prevalent in other parts of the world, for example, in certain asian countries (supra). Also, for example, in india and china, fast-paced lifestyle and economic changes have resulted in a sedentary lifestyle and poor diet throughout the population, causing diabetes to become a major health problem (supra). There is a continuing need for new and improved treatments that address this growing health problem.

Disclosure of the invention

Provided herein are compounds of formula (I), or a pharmaceutically acceptable salt, or a stereoisomeric or tautomeric form thereof,

wherein:

z is-O-or-S-;

y is-X-C (═ O) NR₄R₅、-(CH₂)₃-NR₉R₁₀Or 4,5,6, 7-tetrahydropyrazolo [1,5-a ]]Pyrimidin- (2-yl or 3-yl);

x is (C)₆-C₁₀) Aryl or 5-or 6-membered heteroaryl;

R₁is a partially unsaturated or aromatic 5-or 6-membered heterocycle;

R₂independently at each occurrence is-F, -Cl, -Br, -CH₃or-CN;

R₃independently at each occurrence-H, -F, -Cl, -Br, -CF₃、-OCF₃、-CN、(C₁-C₁₂) Alkyl, or (C)₁-C₁₂) An alkoxy group;

R₄and R₅Each independently of the other is H, (C)₁-C₉) Alkyl, (C)₄-C₁₂) Cycloalkyl, or R₄And R₅Together form a 5-to 7-membered heterocycloalkyl ring; with the following conditions:

R₄and R₅Neither is H; and is

R₄And R₅Is independently at least one of₄And R₅Said heterocycloalkyl ring being selected from the group consisting of-CO₂H、-CO₂R₆、-CN、-OH、-CONR₇R₈and-NR₇R₈1 or 2 substituents in the group; wherein:

R₆is (C)₁-C₁₂) An alkyl group;

R₇and R₈Each independently of the other is H, (C)₁-C₁₂) Alkyl, or R₇And R₈Together form a 4-to 7-membered heterocycloalkyl ring;

R₉is (C)₁-C₆) Alkyl, (C)₃-C₈) Cycloalkyl, pyrazolyl or pyridyl; wherein R is₉Optionally further selected from the group consisting of-COOH, -COOR₁₁、-CONR₁₁R₁₂、-SO₂R₁₁、-SO₂NR₁₁R₁₂、-OH、-CN、-OR₁₁and-NR₁₁R₁₂1 or 2 substituents in the group; wherein R is ₁₁And R₁₂May form a 6 membered heterocycloalkyl ring;

R₁₀is R₁₁、-COR₁₁、-COOR₁₁、-SO₂R₁₁5-methyl-2-oxo-1, 3-dioxolen-4-yl,-COO-CH(CH₃)OCOCH(CH₃)₂(ii) a Or R₉And R₁₀Together form a piperazinone or 4-to 8-membered heterocycloalkyl ring, wherein the heterocycloalkyl ring is selected from the group consisting of-COOH, -COOR₁₁、-CH₂-COOR₁₁、-OH、-NH₂-CN and (C)₁-C₈) 1 or 2 substituents in the group consisting of alkoxy;

R₁₁and R₁₂Independently is H or (C) optionally substituted with a 4-to 8-membered heterocycloalkyl ring₁-C₆) An alkyl group; and is

m and n are each independently 1, 2, 3 or 4.

In certain embodiments, the compounds of formula (I') are

Are the compounds wherein

R₁₀Is R₁₁、(C₃-C₆) Alkynyl, (C)₃-C₆) Alkenyl, -COR₁₁、-COOR₁₁、-SO₂R₁₁5-methyl-2-oxo-1, 3-dioxolen-4-yl,-COO-CH(CH₃)OCOCH(CH₃)₂(ii) a Or R9 and R10 together form a piperazinone or a 4-to 8-membered heterocycloalkyl ring, wherein the heterocycloalkyl ring is selected from the group consisting of-COOH, -COOR₁₁、-CH₂-COOR₁₁、-OH、-NH₂-CN and (C)₁-C₈) 1 or 2 substituents in the group consisting of alkoxy; or R₉And R₁₀Together form an unsubstituted 4-to 8-membered heterocycloalkyl ring, wherein the heterocycloalkyl ring is fused to a 5-membered heteroaryl; and is

Wherein all other substituents are as defined in paragraph [0009] above.

In certain embodiments, the compound of formula (I) or formula (I') is wherein Y is- (CH)₂)₃-NR₉R₁₀The compound of (1).

In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₁Is an aromatic 5-membered heterocycle or 6-membered heterocycle having 1-3 heteroatoms independently selected from the group consisting of N, O, and S.

In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₁A compound that is pyridyl or pyrimidinyl.

In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₁Is a compound of an aromatic 5-membered heterocyclic ring having 1 or 2 nitrogen atoms and optionally 1 or 2 sulfur atoms. In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₁A compound that is thiazolyl, isothiazolyl, or thiadiazolyl. In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₁A compound which is thiazolyl. In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₁Is a compound of 1,2, 4-thiadiazole-5-radical. In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₁A compound that is thiadiazol-4-yl.

In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₂A compound that is independently at each occurrence-F or-Cl.

In a particular embodiment, the compound of formula (I) or formula (I') is a compound wherein n is 1,2 or 3. In a particular embodiment, the compound of formula (I) or formula (I') is a compound wherein n is 2.

In a particular embodiment, the compound of formula (I) or formula (I') is a compound wherein Z is-O-.

In a particular embodiment, the compound of formula (I) or formula (I') is whereinR₃A compound that is independently at each occurrence-H, -F, -Cl, or-Br. In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₃A compound that is-H or-Cl. In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₃A compound which is-Cl.

In a particular embodiment, the compound of formula (I) or formula (I') is a compound wherein m is 1, 2 or 3. In a particular embodiment, the compound of formula (I) or formula (I') is a compound wherein m is 1.

In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₉Is (C)₁-C₆) A compound of an alkyl group; wherein R is₉Optionally further selected from the group consisting of-COOH, -COOMe, -CONH₂And NH₂1 or 2 substituents in the group. In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₉A compound that is methyl or ethyl. In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₉A compound further substituted with-COOH.

In a particular embodiment, the compound of formula (I) or formula (I') is wherein R ₁₀Is H and R₉Is (C)₁-C₆) A compound of an alkyl group; wherein R is₉is-CONR₁₁R₁₂Is further substituted, and wherein R₁₁And R₁₂Independently is H or (C)₁-C₆) An alkyl group. In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₉Is further substituted by-CONH₂A substituted compound. In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₉Is methyl and R₉Is further substituted by-CONH₂A substituted compound.

In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₁₀Compounds which are-H, -COMe, -COOEt. In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₁₀A compound which is-H or-COMe. In the specific implementationIn the formula (I) or (I') is where R₁₀A compound which is-H.

In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₉And R₁₀A compound which together form a 4-to 8-membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is selected from the group consisting of-COOH, -COOMe, -COOEt, -CH₂-COOH and-NH₂1 or 2 groups in the group. In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₉And R₁₀Compounds which together form a 4-to 8-membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is selected from the group consisting of-COOH, -CH ₂-COOH and-NH₂1 or 2 groups in the group.

In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₉And R₁₀Together form a group selected from the group consisting of-COOH, -COOMe, -COOEt, -CH₂-COOH、-CH₂-COOMe、-CH₂-COOEt and-NH₂A piperidine compound substituted with 1 or 2 groups of the group consisting. In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₉And R₁₀Together form a selected group consisting of-COOH, -CH₂-COOH and-NH₂A piperidine compound substituted with 1 or 2 groups of the group consisting.

In certain embodiments, the compound of formula (I) or formula (I') is wherein Y is-X-C (═ O) NR₄R₅The compound of (1).

In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₁Is an aromatic 5-membered heterocyclic ring or a 6-membered heterocyclic ring having 1 to 3 heteroatoms independently selected from the group consisting of N, O and S.

In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₁To be provided withA compound of an aromatic 5-membered heterocyclic ring of 1 or 2 nitrogen atoms and optionally 1 or 2 sulfur atoms. In a particular embodiment, the compound of formula (I) or formula (I') is wherein R ₁A compound that is thiazolyl, isothiazolyl, or thiadiazolyl. In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₁A compound which is thiazolyl. In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₁Is a compound of 1,2, 4-thiadiazole-5-radical.

In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₃A compound that is independently at each occurrence-H, -F, -Cl, or-Br. In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₃A compound that is-H or-Cl. In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₃A compound which is-Cl.

In a particular embodiment, the compound of formula (I) or formula (I') is a compound wherein m is 1,2 or 3. In a particular embodiment, the compound of formula (I) or formula (I') is a compound wherein m is 1.

In a particular embodiment, the compound of formula (I) or formula (I') is a compound wherein X is 5-membered heteroaryl or 6-membered heteroaryl. In a particular embodiment, the compound of formula (I) or formula (I') is a compound wherein X is pyridinyl or pyrimidinyl. In a particular embodiment, the compound of formula (I) or formula (I') is a compound wherein X is pyridinyl.

In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₄Is H and R₅Is (C)₁-C₉) Alkyl compounds.

In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₅Is selected from-CO₂H、-CO₂R₆and-CONR₇R₈Methyl or ethyl substituted with 1 or 2 substituents in the group.

In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₆Is (C)₁-C₆) Alkyl compounds.

In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₅Is a quilt-CO₂H-substituted methyl or ethyl compounds.

In certain embodiments, the compound of formula (I) or formula (I') is one wherein Y is 4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidin- (2-yl or 3-yl). In a particular embodiment, the compound of formula (I) or formula (I') is one wherein Y is 4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidin-3-yl).

In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₁Is a compound of an aromatic 5-membered heterocyclic ring having 1 or 2 nitrogen atoms and optionally 1 or 2 sulfur atoms. In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₁A compound that is thiazolyl, isothiazolyl, or thiadiazolyl. In a particular embodiment, a compound of formula (I) or formula (I')In which R is₁A compound which is thiazolyl. In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₁Is a compound of 1,2, 4-thiadiazole-5-radical.

In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₃A compound that is independently at each occurrence-H, -F, -Cl, or-Br. In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₃A compound that is-H or-Cl. In a particular embodiment, the compound of formula (I) is wherein R₃A compound which is-Cl.

In certain embodiments, the compound of formula (I) or formula (Γ) is the following compound:

3- (4- (2- (4- (N- (1,2, 4-thiadiazol-5-yl) sulfamoyl) -2-chloro-5-fluorophenoxy) -5-chlorophenyl) picolinamido) propionic acid,

2- (4- (2- (4- (N- (1,2, 4-thiadiazol-5-yl) sulfamoyl) -2-chloro-5-fluorophenoxy) -5-chlorophenyl) pyridine carboxamide) acetic acid,

5- (4- (2- (4- (N- (1,2, 4-thiadiazol-5-yl) sulfamoyl) -2-chloro-5-fluorophenoxy) -5-chlorophenyl) picolinamido) pentanoic acid,

4- (4- (2- (4- (N- (1,2, 4-thiadiazol-5-yl) sulfamoyl) -2-chloro-5-fluorophenoxy) -5-chlorophenyl) picolinamido) butanoic acid,

2- (4- (2- (4- (N- (1,2, 4-thiadiazol-5-yl) sulfamoyl) -2-chloro-5-fluorophenoxy) -5-chlorophenyl) picolinamido) propionic acid,

(R) -2- (4- (2- (4- (N- (1,2, 4-thiadiazol-5-yl) sulfamoyl) -2-chloro-5-fluorophenoxy) -5-chlorophenyl) picolinamido) propionic acid,

2- (6- (2- (4- (N- (1,2, 4-thiadiazol-5-yl) sulfamoyl) -2-chloro-5-fluorophenoxy) -5-chlorophenyl) picolinamido) acetic acid,

(S) -2- (4- (2- (4- (N- (1,2, 4-thiadiazol-5-yl) sulfamoyl) -2-chloro-5-fluorophenoxy) -5-chlorophenyl) picolinamido) propionic acid,

3- (4- (2- (4- (N- (1,2, 4-thiadiazol-5-yl) sulfamoyl) -2-cyanophenoxy) -5-chlorophenyl) pyridinecarboxamide) propionic acid,

3- (4- (2- (4- (N- (1,2, 4-thiadiazol-5-yl) sulfamoyl) -2, 5-difluorophenoxy) -5-chlorophenyl) picolinamido) propionic acid,

2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-4-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) acetic acid,

3- ((3- (2- (4- (N- (1,2, 4-thiadiazol-5-yl) sulfamoyl) -2-chloro-5-fluorophenoxy) -5-chlorophenyl) propyl) amino) propanoic acid,

2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) acetic acid,

1- (3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-4-yl) sulfamoyl) phenoxy) phenyl) propyl) piperidine) -4-carboxylic acid,

3- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-4-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) propanoic acid,

4-amino-1- (3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-4-yl) sulfamoyl) phenoxy) phenyl) propyl) piperidine) -4-carboxylic acid,

2-amino-4- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-4-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) butanoic acid,

2- ((3- (5-chloro-2- (2, 5-difluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) acetic acid,

1- (3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-4-yl) sulfamoyl) phenoxy) phenyl) propyl) piperidine) -3-carboxylic acid,

2- ((3- (2- (4- (N- (1,2, 4-thiadiazol-5-yl) sulfamoyl) -2-chloro-5-fluorophenoxy) phenyl) propyl) amino) acetic acid,

2- ((3- (5-chloro-2- (2, 5-difluoro-4- (N- (thiazol-4-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) acetic acid,

3- ((3- (5-chloro-2- (2, 5-difluoro-4- (N- (thiazol-4-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) propanoic acid,

3- ((3- (5-chloro-2- (2-cyano-4- (N- (thiazol-4-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) propanoic acid,

Methyl 2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-4-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) acetate,

3- ((3- (2- (2-chloro-5-fluoro-4- (N- (thiazol-4-yl) sulfamoyl) phenoxy) -5-fluorophenyl) propyl) amino) propanoic acid,

3- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-4-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) propanamide,

2- (N- (3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-4-yl) sulfamoyl) phenoxy) phenyl) propyl) acetamido) acetic acid,

2- (1- (3- (2- (4- (N- (1,2, 4-thiadiazol-5-yl) sulfamoyl) -2-chloro-5-fluorophenoxy) -5-chlorophenyl) propyl) piperidin-4-yl) acetic acid,

3- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) propanoic acid,

2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-4-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) -N-methylacetamide,

5-chloro-4- (4-chloro-2- (3- ((2- (methylsulfonyl) ethyl) amino) propyl) phenoxy) -2-fluoro-N- (thiazol-4-yl) benzenesulfonamide,

1- (3- (2- (4- (N- (1,2, 4-thiadiazol-5-yl) sulfamoyl) -2-chloro-5-fluorophenoxy) -5-chlorophenyl) propyl) piperidine-4-carboxylic acid,

5-chloro-4- (4-chloro-2- (4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidin-3-yl) phenoxy) -2-fluoro-N- (thiazol-4-yl) benzenesulfonamide,

2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) (carbethoxy) amino) acetic acid,

Ethyl 2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) acetate, or

4- (2- (3- ((1H-pyrazol-4-yl) amino) propyl) -4-chlorophenoxy) -5-chloro-2-fluoro-N- (thiazol-2-yl) benzenesulfonamide;

or a pharmaceutically acceptable salt, or a stereoisomeric or tautomeric form thereof.

3- ((3- (5-chloro-2- (2, 5-difluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) propanoic acid,

4- (2- (3- ((1H-pyrazol-3-yl) amino) propyl) -4-chlorophenoxy) -5-chloro-2-fluoro-N- (thiazol-4-yl) benzenesulfonamide,

2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-4-yl) sulfamoyl) phenoxy) phenyl) propyl) (methyl) amino) acetic acid,

5-chloro-4- (4-chloro-2- (3- (6, 7-dihydro-1H-pyrazolo [4,3-c ] pyridin-5 (4H) -yl) propyl) phenoxy) -2-fluoro-N- (thiazol-4-yl) benzenesulfonamide,

2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-4-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) acetamide,

Isoamyl 2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) acetate,

Acetic acid 2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) acetic acid isopropyl ester,

Methyl 2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-4-yl) sulfamoyl) phenoxy) phenyl) propyl) (methyl) amino) acetate,

2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) ((pentyloxy) carbonyl) amino) acetic acid,

2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) (prop-2-yn-1-yl) amino) acetic acid,

5-chloro-4- (4-chloro-2- (3- (5, 6-dihydroimidazo [1,2-a ] pyrazin-7 (8H) -yl) propyl) phenoxy) -2-fluoro-N- (thiazol-4-yl) benzenesulfonamide,

5-chloro-2-fluoro-4- (2- (4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidin-3-yl) phenoxy) -N- (thiazol-2-yl) benzenesulfonamide,

5-chloro-4- (4-chloro-2- (4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidin-3-yl) phenoxy) -2-fluoro-N- (thiazol-2-yl) benzenesulfonamide,

5-chloro-2-fluoro-4- (2- (4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidin-3-yl) phenoxy) -N- (thiazol-4-yl) benzenesulfonamide,

5-chloro-4- (4-chloro-2- (3- ((2- (methylsulfonyl) ethyl) amino) propyl) phenoxy) -2-fluoro-N- (thiazol-2-yl) benzenesulfonamide,

2- ((3- (2- (2-chloro-5-fluoro-4- (N- (thiazol-4-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) acetamide,

2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-4-yl) sulfamoyl) phenoxy) phenyl) propyl) (prop-2-yn-1-yl) amino) acetic acid,

2- (allyl (3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) acetic acid,

2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) acetamide,

2- (but-2-yn-1-yl) (3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) acetic acid,

2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) (propyl) amino) acetic acid,

3- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) (prop-2-yn-1-yl) amino) propionic acid,

2- ((3- (5-chloro-2- (2, 5-difluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) (prop-2-yn-1-yl) amino) acetic acid,

Ethyl 2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) (methyl) amino) acetate, or

2- ((3- (5-chloro-2- (2, 5-difluoro-4- (N- (thiazol-4-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) acetamide;

In particular embodiments, the compound of formula (I) or formula (Γ) is the following compound:

2- (4- (2- (4- (N- (1,2, 4-thiadiazol-5-yl) sulfamoyl) -2-chloro-5-fluorophenoxy) -5-chlorophenyl) picolinamido) propionic acid, or

3- ((3- (2- (4- (N- (1,2, 4-thiadiazol-5-yl) sulfamoyl) -2-chloro-5-fluorophenoxy) -5-chlorophenyl) propyl) amino) propanoic acid;

2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) ((pentyloxy) carbonyl) amino) acetic acid, or

2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) (prop-2-yn-1-yl) amino) acetic acid;

2- ((3- (5-chloro-2- (2, 5-difluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) (prop-2-yn-1-yl) amino) acetic acid, or

Provided herein are methods for treating neuropathic pain comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or formula (I'), or a pharmaceutically acceptable salt, solvate, or tautomeric form thereof.

Provided herein are methods for treating pain comprising using a compound of formula (I) or formula (Γ) as a voltage-gated sodium channel inhibitor. In particular embodiments, the methods are those wherein the pain is neuropathic pain, nociceptive pain, or inflammatory pain. In specific embodiments, these methods are those wherein the voltage-gated sodium channel is nav 1.7.

Provided herein are pharmaceutical compositions comprising a compound of formula (I) or formula (Γ) and a pharmaceutically acceptable carrier. In a specific embodiment, the pharmaceutical composition is one wherein the composition is suitable for topical, oral, subcutaneous, or intravenous administration.

Provided herein are methods for preventing or treating pain in a subject, wherein the methods comprise administering to a subject in need of such prevention or treatment a therapeutically effective amount of a compound of formula (I) or formula (Γ). In a specific embodiment, the method is one in which a therapeutically effective amount is effective to reduce pain in a subject, wherein the compound of formula (I) or formula (I') exhibits a reduction in pain response in the formalin assay (at phase 1 or phase 2, or both) (see section 5.1.2) at a dose of 0.1mg/kg to 1,000mg/kg, at a dose of 0.5mg/kg to 100mg/kg, at a dose of 1mg/kg to 50mg/kg, or at a dose of 5 mg/kg. In certain embodiments, a compound of formula (I) or formula (I') provided herein exhibits a reduction in pain response in the formalin assay (at phase 1 or phase 2, or both) by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99%, or 100%, or a reduction in the formalin relative to the vehicle control in a range between any range of the recited percentages (e.g., 10-20%, 10-30%, 10-40%, 20-30%, or 20-40%). In a specific embodiment, the method is a method wherein the pain is: nociceptive pain, such as pain resulting from physical trauma (e.g., cuts or contusions of the skin, including surgical or dental pain; or chemical or thermal burns), osteoarthritis, rheumatoid arthritis, or tendonitis; myofascial pain; neuropathic pain, such as that associated with stroke, diabetic neuropathy, syphilitic neuropathy, postherpetic neuralgia, trigeminal neuralgia, fibromyalgia, or painful neuropathy induced iatrogenically by a drug; or mixed pain (e.g., pain with both nociceptive and neuropathic components); visceral pain; headache (e.g., migraine); complex regional pain syndrome ("CRPS"); a CRPSI type; CRPSII type; reflex sympathetic dystrophy ("RSD"); reflex neurovascular dystrophy; reflex malnutrition; sympathetically maintained pain syndrome; burning pain; grandma atrophy of bone; hyperalgesic neurotrophism; shoulder-hand syndrome; post-traumatic malnutrition; autonomic dysfunction; autoimmune-related pain; pain associated with inflammation; pain associated with cancer; phantom limb pain; chronic fatigue syndrome; pain after surgery; pain associated with spinal cord injury; central post-stroke pain; a radiculopathy; sensitivity to temperature, light touch or color changes of the skin (allodynia); pain from a hyperthermic condition or hypothermia condition; and other painful conditions (e.g., diabetic neuropathy, syphilitic neuropathy, postherpetic neuralgia, trigeminal neuralgia); chronic pain; acute pain; neuroma pain, pain or itch associated with a channel disease, such as, for example, small fiber neuralgia, hereditary erythromelalgia ("IEM"), or raynaud's syndrome; or itch from various sources (e.g., allergic itch).

Provided herein are methods of modulating the activity of a voltage-gated sodium channel, wherein the method comprises contacting a cell expressing a voltage-gated sodium channel with a compound of formula (I) or formula (Γ). In a specific embodiment, the method is one wherein the voltage-gated sodium channel is nav 1.7. In a specific embodiment, the method is one in which inhibition of a voltage-gated sodium channel results.

Provided herein are methods for treating or preventing prediabetes, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or formula (I'), or a pharmaceutically acceptable salt, solvate, or tautomeric form thereof.

Provided herein are methods for treating or preventing diabetes, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or formula (I'), or a pharmaceutically acceptable salt, solvate, or tautomeric form thereof.

Also provided herein are methods for reducing blood or plasma glucose in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of formula (I) or formula (Γ), or a pharmaceutically acceptable salt, solvate, or tautomeric form thereof.

Further provided herein are methods for reducing blood or plasma glycated hemoglobin in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of formula (I) or formula (Γ), or a pharmaceutically acceptable salt, solvate, or tautomeric form thereof.

In one embodiment, the subject has pre-diabetes.

In another embodiment, the subject has diabetes. In certain embodiments, the diabetes is gestational diabetes, type 1 diabetes, type 2 diabetes, or latent autoimmune diabetes of adults.

Detailed description of the preferred embodiments

4.1 definition

As used herein, "compound" or "compounds" comprises a compound of formula (I), a compound of formula (I '), a compound of formula (Ia), a compound of formula (I' a), a compound of formula (Ib), a compound of formula (Ic), a compound of formula (Id), a compound listed in table 1, a compound listed in table 2, or a compound listed in table 3.

"pharmaceutically acceptable salt(s)" means a salt prepared from a pharmaceutically acceptable non-toxic acid or base including inorganic acids and inorganic bases as well as organic acids and organic bases. Suitable pharmaceutically acceptable base addition salts of compounds include, but are not limited to: metal salts made of aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc; or an organic salt made from lysine, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. Suitable non-toxic acids include, but are not limited to: inorganic and organic acids, such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric, and p-toluenesulfonic acids. Specific non-toxic acids include hydrochloric, hydrobromic, phosphoric, sulfuric, and methanesulfonic acids. Other non-toxic acids well known in the art are found, for example, in Remington pharmaceutical science, 18th edition, published by Mack press, easton, pa (1990) (Remington's pharmaceutical sciences,18 the. Science and practice of pharmacy,19th edition, published by Mack press, easton, pennsylvania (1995) (Remington: the science and practice of pharmacy,19 the.

"stereoisomer" or "stereoisomeric form" refers to a stereoisomer of a compound that is substantially free of other stereoisomers of the compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereoisomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound. Typical stereoisomerically pure compounds contain greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound. The compounds may have chiral centers and may occur as racemates, single enantiomers or diastereomers, and mixtures thereof. All such isomeric forms (including mixtures thereof) are included in the embodiments disclosed herein. Stereomerically pure forms using such compounds, as well as mixtures using these forms, are included in the embodiments disclosed herein. For example, mixtures comprising equal or unequal amounts of the enantiomers of a particular compound may be used in the methods and compositions disclosed herein. These isomers can be asymmetrically synthesized or resolved using standard techniques, such as chiral columns or chiral resolving agents. See, e.g., Jacques, j. et al, Enantiomers, racemates and resolution (enertiomers, racemes and resolutions) wiley interscience, new york, 1981; wilen, s.h. et al, Tetrahedron, (Tetrahedron)33:2725 (1977); eliel, e.l., the stereochemistry of carbon compounds (stereochemistriyof carbon compounds), (mcgrawhell, NY, 1962); and Wilen, s.h., list of resolving agents and optical resolutions (tablesof resolving agents and optical resolutions), page 268 (e.l.eliel, ed., univ.of notredamemepress, NotreDame, IN, 1972).

"tautomer" refers to isomeric forms of a compound that are in equilibrium with each other. The concentration of the isomeric forms will depend on the environment in which the compound is located and may vary depending on, for example, whether the compound is a solid or an organic or aqueous solution. For example, in aqueous solution, pyrazoles may appear in the following isomeric forms, which are referred to as tautomers of each other:

it is readily understood by those skilled in the art that a wide variety of functional groups and other structures can exhibit tautomerism and that all tautomers of the compounds provided herein are within the scope disclosed herein.

An "aryl" group is an aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthracenyl). In some embodiments, the aryl group contains 6 to 14 carbon atoms in the ring portion of the group, while in other embodiments the aryl group contains 6 to 12 or even 6 to 10 carbon atoms in the ring portion of the group. Specific aryl groups include, but are not limited to, phenyl, naphthyl, and the like.

A "heteroaryl" group is an aryl ring system having 1-4 heteroatoms as ring atoms in the heteroaromatic ring system, wherein the remaining atoms are carbon atoms. In some embodiments, heteroaryl groups contain 5 to 6 carbon atoms in the ring portion of the group, while in other embodiments heteroaryl groups contain 6 to 9 or even 6 to 10 atoms in the ring portion of the group. Suitable heteroatoms include oxygen, sulfur and nitrogen. In certain embodiments, the heteroaryl ring system is monocyclic or bicyclic. Examples include, but are not limited to, groups such as: pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2, 4-thiadiazolyl), pyrrolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl, azaindolyl (e.g., pyrrolopyridine or 1H-pyrrolo [2,3-b ] pyridyl), indazolyl, benzimidazolyl (e.g., 1H-benzo [ d ] imidazolyl), imidazopyridinyl, pyrazolopyridinyl, triazolopyridinyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, isoxazolopyridinyl, thianaphthyrenyl, purinyl, xanthine, adenine, guanine, quinolyl, isoquinolyl, Tetrahydroquinolinyl, quinoxalinyl and quinazolinyl.

"partially unsaturated or aromatic heterocycle" is a partially unsaturated or aromatic ring system having 1 to 4 heteroatoms as ring atoms in the heteroaromatic ring system, wherein the remaining atoms are carbon atoms. If the "partially unsaturated or aromatic heterocycle" is an aromatic heterocycle, the aromatic heterocycle is "heteroaryl" as defined above. In one embodiment, the partially unsaturated or aromatic heterocycle is a partially unsaturated or aromatic 5-or 6-membered heterocycle. Examples of partially unsaturated heterocycles include, but are not limited to, groups such as: 2, 5-dihydro-1H-pyrrolyl, 2, 5-dihydrofuranyl, 2, 5-dihydrothienyl, 4, 5-dihydrooxazolyl, 4, 5-dihydrothiazolyl, 4, 5-dihydro-1H-imidazolyl, 4, 5-dihydro-1H-1, 2, 3-triazolyl, 1,2,5, 6-tetrahydropyridinyl and 1,4,5, 6-tetrahydropyrimidinyl.

A "heterocycloalkyl" group is a non-aromatic cycloalkyl group in which 1 to 4 ring carbon atoms are independently substituted with a heteroatom from the group consisting of O, S and N. Examples of heterocycloalkyl groups include, but are not limited to, morpholinyl, pyrrolidinyl, piperazinyl, (1,4) -dioxanyl ((1,4) -dioxanyl), and (1,3) -dioxolanyl. The heterocycloalkyl group can also be attached at any ring atom (i.e., at any carbon or heteroatom of the heterocycle). In one embodiment, the heterocycloalkyl group is a 5-or 6-membered heterocycloalkyl group or a 4-to 8-membered heterocycloalkyl group.

An "alkyl" group is a saturated straight or branched chain acyclic hydrocarbon having, for example, 1 to 12 carbon atoms, 1 to 9 carbon atoms, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 2 to 6 carbon atoms. Representative alkyl groups include-methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and-n-hexyl; and branched alkyl groups include-isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like.

An "alkenyl" group is a partially unsaturated, straight-chain or branched, acyclic hydrocarbon having, for example, 3 to 6 carbon atoms, 3 to 4 carbon atoms, or 3 carbon atoms. Representative alkenyl groups include allyl, propenyl, and the like.

An "alkynyl" group is a partially unsaturated, straight-chain or branched, acyclic hydrocarbon having, for example, 3 to 6 carbon atoms, 4 to 6 carbon atoms, or 3 carbon atoms. Representative alkynyl groups include propynyl, butyl, and the like.

A "cycloalkyl" group is a saturated cyclic alkyl group of 3 to 12 carbon atoms having a single ring or multiple fused or bridged rings. In some embodiments, the cycloalkyl group has 4-12 ring members, while in other embodiments the number of ring carbon atoms is, for example, 3 to 5, 3 to 6, or 3 to 7. These cycloalkyl groups include, for example, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like, or polycyclic or bridged ring structures such as adamantyl, and the like.

By "subject in need thereof" is meant a mammal (e.g., a human, dog, horse, or cat) in need of treatment by any of the methods provided herein. In one embodiment, the subject is a patient.

"adult" refers to a person over the age of 30.

4.2 description of the drawings

Figure 1 shows the changes in food intake measured in a streptozotocin-induced diabetic rat model. Changes in food intake are shown for the diabetic vehicle group, the diabetic test compound treated group, and the sham operated group. The diabetes test compound treatment group received a 60 mg/kg/day dose of compound 49 over 9 days. The beginning and end of the treatment period are marked by dashed lines.

Fig. 2 shows the change in blood glucose levels measured in a streptozotocin-induced diabetic rat model. Changes in blood glucose levels are shown for the diabetic vehicle group, the diabetic test compound treated group, and the sham operated group. The diabetes test compound treatment group received a 60 mg/kg/day dose of compound 49 over 9 days. The beginning and end of the treatment period are marked by dashed lines.

Figure 3 shows the changes in water intake measured in a streptozotocin-induced diabetic rat model. Changes in water intake are shown for the diabetic vehicle group, the diabetic test compound treated group, and the sham operated group. The diabetes test compound treatment group received a 60 mg/kg/day dose of compound 49 over 9 days. The beginning and end of the treatment period are marked by dashed lines.

4.3 Compounds

Provided herein are compounds of formula (I),

or a pharmaceutically acceptable salt, or a stereoisomeric or tautomeric form thereof, wherein:

z is-O-or-S-;

x is (C)₆-C₁₀) Aryl or 5-or 6-membered heteroaryl;

R₁is a partially unsaturated or aromatic 5-or 6-membered heterocycle;

R₂independently at each occurrence is-F, -Cl, -Br, -CH₃or-CN;

R₄and R₅Each independently of the other is H, (C)₁-C₉) Alkyl, (C)₄-C₁₂) Cycloalkyl or R₄And R₅Taken together form a 5-membered to a 7-membered heterocycloalkyl ring; with the following conditions:

R₄and R₅Neither is H; and is

R₄And R₅Is independently or by R₄And R₅Said heterocycloalkyl ring being selected from the group consisting of-CO₂H、-CO₂R₆、-CN、-OH、-CONR₇R₈and-NR₇R₈1 or 2 substituents in the group; wherein:

R₆is (C)₁-C₁₂) An alkyl group;

R₇and R₈Each independently is H, (C)₁-C₁₂) Alkyl, or R₇And R₈Taken together form a 4-membered to a 7-membered heterocycloalkyl ring;

R₉is (C)₁-C₆) Alkyl, (C)₃-C₈) Cycloalkyl, pyrazolyl or pyridyl; wherein R is₉Optionally further selected from the group consisting of-COOH, -COOR ₁₁、-CONR₁₁R₁₂、-SO₂R₁₁、-SO₂NR₁₁R₁₂、-OH、-CN、-OR₁₁and-NR₁₁R₁₂1 or 2 substituents in the group; wherein R is₁₁And R₁₂May form a 6 membered heterocycloalkyl ring;

R₁₀is R₁₁、-COR₁₁、-COOR₁₁、-SO₂R₁₁5-methyl-2-oxo-1, 3-dioxolen-4-yl,-COO-CH(CH₃)OCOCH(CH₃)₂(ii) a Or R₉And R₁₀Together form a piperazinone or 4-membered to 8-membered heterocycloalkyl ring, wherein the heterocycloalkyl ring is selected from the group consisting of-COOH, -COOR₁₁、-CH₂-COOR₁₁、-OH、-NH₂-CN and (C)₁-C₈) 1 or 2 substituents in the group consisting of alkoxy;

R₁₁and R₁₂Independently is H or is optionally substituted with a 4-membered heterocycloalkyl ring to an 8-membered heterocycloalkyl ring (C)₁-C₆) An alkyl group; and is

m and n are each independently 1, 2, 3 or 4.

In certain embodiments, the compounds of formula (I') are

Are the compounds wherein

R₁₀Is R₁₁、(C₃-C₆) Alkynyl, (C)₃-C₆) Alkenyl, -COR₁₁、-COOR₁₁、-SO₂R₁₁5-methyl-2-oxo-1, 3-dioxolen-4-yl,-COO-CH(CH₃)OCOCH(CH₃)₂(ii) a Or R₉And R₁₀Together form a piperazinone or 4-to 8-membered heterocycloalkyl ring, wherein the heterocycloalkyl ring is selected from the group consisting of-COOH, -COOR₁₁、-CH₂-COOR₁₁、-OH、-NH₂-CN and (C)₁-C₈) 1 or 2 substituents in the group consisting of alkoxy; or R₉And R₁₀Together form an unsubstituted 4-to 8-membered heterocycloalkyl ring, wherein the heterocycloalkyl ring is fused to a 5-membered heteroaryl; and is

Wherein all other substituents are as defined in paragraph [0082] above.

In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₁Is an aromatic 5-membered heterocyclic ring or a 6-membered heterocyclic ring having 1-3 heteroatoms independently selected from the group consisting of N, O and S.

In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₁Is an aromatic 5-membered heterocyclic compound having 1 or 2 nitrogen atoms and optionally 1 or 2 sulfur atoms. In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₁Is thiazolyl, isothiazolyl,Or a thiadiazolyl compound. In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₁A compound which is thiazolyl. In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₁Is a compound of 1,2, 4-thiadiazole-5-radical. In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₁A compound that is thiadiazol-4-yl.

In a particular embodiment, the compound of formula (I) or formula (I') is wherein R ₂A compound that is independently at each occurrence-F or-Cl.

In a particular embodiment, the compound of formula (I) or formula (I') is a compound wherein n is 1, 2 or 3. In a particular embodiment, the compound of formula (I) or formula (I') is a compound wherein n is 2.

In a particular embodiment, the compound of formula (I) or formula (I') is a compound wherein m is 1, 2, or 3. In a particular embodiment, the compound of formula (I) or formula (I') is a compound wherein m is 1.

In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₉Is (C)₁-C₆) A compound of an alkyl group; wherein R is₉Optionally further selected from the group consisting of-COOH, -COOMe, -CONH₂And NH₂1 or 2 substituents in the group. In a particular embodiment, the compound of formula (I) or formula (I') is wherein R ₉A compound that is methyl or ethyl. In concrete embodimentsIn an embodiment, the compound of formula (I) or formula (I') is wherein R₉A compound further substituted with-COOH.

In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₁₀Is H and R₉Is (C)₁-C₆) A compound of an alkyl group; wherein R is₉Further by-CONR₁₁R₁₂Is substituted, and wherein R₁₁And R₁₂Independently is H or (C)₁-C₆) An alkyl group. In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₉Is further substituted by-CONH₂A substituted compound. In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₉Is methyl and wherein R₉Is further substituted by-CONH₂A substituted compound.

In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₁₀Compounds which are-H, -COMe, -COOEt. In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₁₀A compound which is-H or-COMe. In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₁₀A compound which is-H.

In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₉And R₁₀Together form a 4-to 8-membered heterocycloalkyl ring, wherein the heterocycloalkyl ring is selected from the group consisting of-COOH, -COOMe, -COOEt, -CH ₂-COOH, and-NH₂1 or 2 groups in the group. In a particular embodiment, the compound of formula (I) is wherein R₉And R₁₀Compounds which together form a 4-to 8-membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is selected from the group consisting of-COOH, -CH₂-COOH, and-NH₂1 or 2 groups in the group.

In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₉And R₁₀Together form a group selected from the group consisting of-COOH, -COOMe, -COOEt, -CH₂-COOH、-CH₂-COOMe、-CH₂-COOEt and-NH₂a piperidine compound substituted with 1 or 2 groups of the group consisting. In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₉And R₁₀Together form a selected group consisting of-COOH, -CH₂-COOH, and-NH₂A piperidine compound substituted with 1 or 2 groups of the group consisting.

In a particular embodiment, the compound of formula (I) or formula (I') is wherein R ₁A compound that is pyridyl or pyrimidinyl.

In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₁Is an aromatic 5-membered heterocyclic compound having 1 or 2 nitrogen atoms and optionally 1 or 2 sulfur atoms. In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₁A compound that is thiazolyl, isothiazolyl, or thiadiazolyl. In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₁A compound which is thiazolyl. In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₁Is a compound of 1,2, 4-thiadiazole-5-radical.

In a particular embodiment, the compound of formula (I) or formula (I') is a compound wherein n is 1,2, or 3. In a particular embodiment, the compound of formula (I) or formula (I') is a compound wherein n is 2.

In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₃A compound that is independently at each occurrence-H, -F, -Cl, or-Br. In a particular embodiment, the compound of formula (I) or formula (I') is wherein R ₃A compound that is-H or-Cl. In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₃A compound which is-Cl.

In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₅Is selected from the group consisting of-CO₂H、-CO₂R₆and-CONR₇R₈Methyl or ethyl substituted with 1 or 2 substituents in the group.

In a particular embodiment, the compound of formula (I) or formula (I') is wherein R ₅Is a quilt-CO₂H-substituted methyl or ethyl compounds.

In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₁Is a compound of an aromatic 5-membered heterocyclic ring having 1 or 2 nitrogen atoms and optionally 1 or 2 sulfur atoms. In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₁A compound that is thiazolyl, isothiazolyl, or thiadiazolyl. In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₁A compound which is thiazolyl. In a particular embodiment, the compound of formula (I) or formula (I') is wherein R ₁Is a compound of 1,2, 4-thiadiazole-5-radical.

In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₃A compound that is independently at each occurrence-H, -F, -Cl, or-Br. On toolIn an embodiment, the compound of formula (I) or formula (I') is wherein R₃A compound that is-H or-Cl. In a particular embodiment, the compound of formula (I) or formula (I') is wherein R₃A compound which is-Cl.

In a particular embodiment, the compound of formula (I) or formula (I') is a compound wherein m is 1,2, or 3. In a particular embodiment, the compound of formula (I) or formula (I') is a compound wherein m is 1.

In certain embodiments, the compound of formula (I) or formula (Γ) is a compound selected from the group consisting of the compounds in table 1, or a pharmaceutically acceptable salt, or a stereoisomeric or tautomeric form thereof.

TABLE 1

Chemical names were automatically generated by ChemDrawUltra, version 12.0.

In certain embodiments, the compound of formula (I) or formula (Γ) is a compound selected from the group consisting of the compounds in table 2, or a pharmaceutically acceptable salt, or a stereoisomeric or tautomeric form thereof.

TABLE 2

Chemical names were automatically generated by ChemDrawUltra, version 12.0.

In certain embodiments, the compound of formula (I) or formula (Γ) is a compound selected from the group consisting of the compounds in table 3, or a pharmaceutically acceptable salt, or a stereoisomeric or tautomeric form thereof.

TABLE 3

Chemical names were automatically generated by ChemDrawUltra, version 12.0.

For the purposes of this disclosure, tables 1,2, and 3 are used to define specific structures associated with specific names. Whenever a specific name is recited in the present disclosure or claims, the chemical structure associated with the specific name should be the structure identified in table 1, table 2, or table 3.

Further provided herein are compounds of formula (Ia),

z is-O-or-S-;

R₁is a partially unsaturated or aromatic 5-or 6-membered heterocycle;

R₂independently at each occurrence is-F, -Cl, -Br, -CH₃or-CN;

R₃independently at each occurrence-H, -F, -Cl, -Br, -CF ₃、-OCF₃、-CN、(C₁-C₁₂) Alkyl, or (C)₁-C₁₂) An alkoxy group;

R₉is (C)₁-C₆) Alkyl, (C)₃-C₈) Cycloalkyl, pyrazolyl or pyridyl; wherein R is₉Optionally further selected from the group consisting of-COOH, -COOR₁₁、-CONR₁₁R₁₂、-SO₂R₁₁、-SO₂NR₁₁R₁₂、-OH、-CN、-OR₁₁and-NR₁₁R₁₂1 or 2 substituents in the group; wherein R is₁₁And R₁₂May form a 6 membered heterocycloalkyl ring;

R₁₀is R₁₁、-COR₁₁、-COOR₁₁、-SO₂R₁₁5-methyl-2-oxo-1, 3-dioxolen-4-yl,-COO-CH(CH₃)OCOCH(CH₃)₂(ii) a Or R₉And R₁₀Together form piperazineA ketone or a 4-to 8-membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is selected from the group consisting of-COOH, -COOR₁₁、-CH₂-COOR₁₁、-OH、-NH₂-CN, and (C)₁-C₈) 1 or 2 substituents in the group consisting of alkoxy;

R₁₁and R₁₂Independently is H or optionally substituted with a 4-to 8-membered heterocycloalkyl ring₁-C₆) An alkyl group; and is

m and n are each independently 1, 2, 3 or 4.

In certain embodiments, the compound of formula (I' a)

Are the compounds wherein

R₁₀Is R₁₁、(C₃-C₆) Alkynyl, (C)₃-C₆) Alkenyl, -COR₁₁、-COOR₁₁、-SO₂R₁₁5-methyl-2-oxo-1, 3-dioxolen-4-yl,-COO-CH(CH₃)OCOCH(CH₃)₂(ii) a Or R₉And R₁₀Together form a piperazinone or 4 to 8 membered heterocycloalkyl ring, wherein the heterocycloalkyl ring is selected from the group consisting of-COOH, -COOR₁₁、-CH₂-COOR₁₁、-OH、-NH₂-CN, and (C)₁-C₈) 1 or 2 substituents in the group consisting of alkoxy; or R₉And R₁₀Taken together to form an unsubstituted 4-to 8-membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is fused to a 5-membered heteroaryl; and is

Wherein all other substituents are as defined in paragraph [00131] above.

In concrete embodimentsIn an embodiment, the compound of formula (Ia) or (I' a) is wherein R₁Is an aromatic 5-membered heterocycle or 6-membered heterocycle having 1-3 heteroatoms independently selected from the group consisting of N, O, and S.

In a particular embodiment, the compound of formula (Ia) or formula (I' a) is wherein R₁A compound that is pyridyl or pyrimidinyl.

In a particular embodiment, the compound of formula (Ia) or formula (I' a) is wherein R₁Is a compound of an aromatic 5-membered heterocyclic ring having 1 or 2 nitrogen atoms and optionally 1 or 2 sulfur atoms. In a particular embodiment, the compound of formula (Ia) or formula (I' a) is wherein R₁A compound that is thiazolyl, isothiazolyl, or thiadiazolyl. In a particular embodiment, the compound of formula (Ia) or formula (I' a) is wherein R₁A compound which is thiazolyl. In a particular embodiment, the compound of formula (Ia) or formula (I' a) is wherein R₁Is a compound of 1,2, 4-thiadiazole-5-radical. In a particular embodiment, the compound of formula (Ia) or formula (I' a) is wherein R₁A compound that is thiadiazol-4-yl.

In a particular embodiment, the compound of formula (Ia) or formula (I' a) is wherein R ₂A compound that is independently at each occurrence-F or-Cl.

In a particular embodiment, the compound of formula (Ia) or formula (I' a) is a compound wherein n is 1, 2, or 3. In a particular embodiment, the compound of formula (Ia) or formula (I' a) is a compound wherein n is 2.

In a particular embodiment, the compound of formula (Ia) or formula (I' a) is a compound wherein Z is-O-.

In a particular embodiment, the compound of formula (Ia) or formula (I' a) is wherein R₃A compound that is independently at each occurrence-H, -F, -Cl, or-Br. In a particular embodiment, the compound of formula (Ia) or formula (I' a) is wherein R₃A compound that is-H or-Cl. In a particular embodiment, the compound of formula (Ia) or formula (I' a) is wherein R₃A compound which is-Cl.

In a particular embodiment, the compound of formula (Ia) or formula (I' a) is a compound wherein m is 1, 2, or 3. In a particular embodiment, the compound of formula (Ia) or formula (I' a) is a compound wherein m is 1.

In a particular embodiment, the compound of formula (Ia) or formula (I' a) is wherein R₉Is (C)₁-C₆) A compound of an alkyl group; wherein R is₉Optionally further selected from the group consisting of-COOH, -COOMe, -CONH₂And NH₂1 or 2 substituents in the group. In a particular embodiment, the compound of formula (Ia) or formula (I' a) is wherein R ₉A compound that is methyl or ethyl. In a particular embodiment, the compound of formula (Ia) or formula (I' a) is wherein R₉A compound further substituted with-COOH.

In a particular embodiment, the compound of formula (Ia) or formula (I' a) is wherein R₁₀Is H and R₉Is (C)₁-C₆) A compound of an alkyl group; wherein R is₉Further by-CONR₁₁R₁₂Is substituted, and wherein R₁₁And R₁₂Independently is H or (C)₁-C₆) An alkyl group. In a particular embodiment, the compound of formula (Ia) or formula (I' a) is wherein R₉Is further substituted by-CONH₂A substituted compound. In a particular embodiment, the compound of formula (Ia) or formula (I' a) is wherein R₉Is methyl and R₉Is further substituted by-CONH₂A substituted compound.

In a particular embodiment, the compound of formula (Ia) or formula (I' a) is wherein R₁₀Compounds which are-H, -COMe, -COOEt. In a particular embodiment, the compound of formula (Ia) or formula (I' a) is wherein R₁₀A compound which is-H or-COMe. In a particular embodiment, the compound of formula (Ia) or formula (I' a) is wherein R₁₀A compound which is-H.

In a particular embodiment, the compound of formula (Ia) or formula (I' a) is wherein R₉And R₁₀A compound which together form a 4-to 8-membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is selected from the group consisting of-COOH, -COOMe, -COOEt, -CH ₂-COOH, and-NH₂1 or 2 groups in the group. In a particular embodiment, the compound of formula (Ia) is wherein R₉And R₁₀Compounds which together form a 4-to 8-membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is selected from the group consisting of-COOH, -CH₂-COOH, and-NH₂1 or 2 groups in the group.

In a particular embodiment, the compound of formula (Ia) or formula (I' a) is wherein R₉And R₁₀Together form a group selected from the group consisting of-COOH, -COOMe, -COOEt, -CH₂-COOH、-CH₂-COOMe、-CH₂-COOEt and-NH₂A piperidine compound substituted with 1 or 2 groups of the group consisting. In a particular embodiment, the compound of formula (Ia) or formula (I' a) is wherein R₉And R₁₀Together form a selected group consisting of-COOH, -CH₂-COOH, and-NH₂A piperidine compound substituted with 1 or 2 groups of the group consisting.

In particular embodiments, the compound of formula (Ia) or formula (I' a) is selected from the group consisting of:

Ethyl 2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) acetate, and

In a specific embodiment, the compound of formula (Ia) or formula (I' a) is selected from the group comprising:

ethyl 2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) (methyl) amino) acetate,

2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) ((5-methyl-2-oxo-1, 3-dioxol-4-yl) methyl) amino) acetic acid,

2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) ((1- (isobutyryloxy) ethoxy) carbonyl) amino) acetic acid,

2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) (((5-methyl-2-oxo-1, 3-dioxol-4-yl) methoxy) carbonyl) amino) acetic acid,

5-chloro-4- (4-chloro-2- (3- (3-oxopiperazin-1-yl) propyl) phenoxy) -2-fluoro-N- (thiazol-2-yl) benzenesulfonamide, and

5-chloro-4- (4-chloro-2- (3- ((3-morpholino-3-oxopropyl) amino) propyl) phenoxy) -2-fluoro-N- (thiazol-2-yl) benzenesulfonamide;

4- (2- (3- ((1H-pyrazol-3-yl) amino) propyl) -4-chlorophenoxy) -5-chloro-2-fluoro-N- (thiazol-4-yl) benzenesulfonamide;

Isopropyl 2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) acetate,

5-chloro-2- (4-chloro-2- (3- ((2- (methylsulfonyl) ethyl) amino) propyl) phenoxy) -2-fluoro-N- (thiazol-2-yl) benzenesulfonamide,

Ethyl 2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) (methyl) amino) acetate, and

Provided herein are compounds of formula (Ib),

z is-O-or-S-;

x is (C)₆-C₁₀) Aryl or 5-or 6-membered heteroaryl;

R₁Is a partially unsaturated or aromatic 5-or 6-membered heterocycle;

R₂independently at each occurrence is-F, -Cl, -Br, -CH₃or-CN;

R₄and R₅Each independently of the other is H, (C)₁-C₉) Alkyl, (C)₄-C₁₂) Cycloalkyl or R₄And R₅Together form a 5-to 7-membered heterocycloalkyl ring; with the following conditions:

R₄and R₅Neither is H; and is

R₆is (C)₁-C₁₂) An alkyl group;

R₇and R₈Each independently is H, (C)₁-C₁₂) Alkyl, or R₇And R₈Together form a 4-to 7-membered heterocycloalkyl ring; and is

m and n are each independently 1, 2, 3 or 4.

In a particular embodiment, the compound of formula (Ib) is wherein R₁Is an aromatic 5-membered heterocycle or 6-membered heterocycle having 1-3 heteroatoms independently selected from the group consisting of N, O, and S.

In a particular embodiment, the compound of formula (Ib) is wherein R₁A compound that is pyridyl or pyrimidinyl.

In a particular embodiment, the compound of formula (Ib) is wherein R₁Is a compound of an aromatic 5-membered heterocyclic ring having 1 or 2 nitrogen atoms and optionally 1 or 2 sulfur atoms. In a particular embodiment, the compound of formula (Ib) is wherein R ₁A compound that is thiazolyl, isothiazolyl, or thiadiazolyl. In a particular embodiment, the compound of formula (Ib) is wherein R₁A compound which is thiazolyl. In a particular embodiment, the compound of formula (Ib) is whereinR₁Is a compound of 1,2, 4-thiadiazole-5-radical.

In a particular embodiment, the compound of formula (Ib) is wherein R₂A compound that is independently at each occurrence-F or-Cl.

In a particular embodiment, the compound of formula (Ib) is a compound wherein n is 1,2, or 3. In a particular embodiment, the compound of formula (Ib) is a compound wherein n is 2.

In a particular embodiment, the compound of formula (Ib) is a compound wherein Z is-O-.

In a particular embodiment, the compound of formula (Ib) is wherein R₃A compound that is independently at each occurrence-H, -F, -Cl, or-Br. In a particular embodiment, the compound of formula (Ib) is wherein R₃A compound that is-H or-Cl. In a particular embodiment, the compound of formula (Ib) is wherein R₃A compound which is-Cl.

In a particular embodiment, the compound of formula (Ib) is a compound wherein m is 1,2, or 3. In a particular embodiment, the compound of formula (Ib) is a compound wherein m is 1.

In a specific embodiment, the compound of formula (Ib) is a compound wherein X is 5-membered heteroaryl or 6-membered heteroaryl. In a particular embodiment, the compound of formula (Ib) is a compound wherein X is pyridinyl or pyrimidinyl. In a particular embodiment, the compound of formula (Ib) is a compound wherein X is pyridinyl.

In a particular embodiment, the compound of formula (Ib) is wherein R₄Is H and R₅Is (C)₁-C₉) Alkyl compounds.

In a particular embodiment, the compound of formula (Ib) is wherein R₅Is selected from-CO₂H、-CO₂R₆and-CONR₇R₈Methyl or ethyl substituted with 1 or 2 substituents in the group.

In a particular embodiment, the compound of formula (Ib) is wherein R₆Is (C)₁-C₆) Alkyl compounds.

In a particular embodiment, the compound of formula (Ib) is wherein R₅Is a quilt-CO₂H-substituted methyl or ethyl compounds.

Provided herein are compounds of formula (Ic),

z is-O-or-S-;

R₁is a partially unsaturated or aromatic 5-or 6-membered heterocycle;

R₂independently at each occurrence is-F, -Cl, -Br, -CH₃or-CN;

R₄and R₅Neither is H; and is

R₆is (C)₁-C₁₂) An alkyl group;

m and n are each independently 1, 2, 3 or 4.

In a particular embodiment, the compound of formula (Ic) is wherein R₁A compound that is an aromatic 5-membered heterocycle or 6-membered heterocycle having 1-3 heteroatoms independently selected from the group consisting of N, O, and S.

In a particular embodiment, the compound of formula (Ic) is wherein R₁A compound that is pyridyl or pyrimidinyl.

In a particular embodiment, the compound of formula (Ic) is wherein R₁Is an aromatic 5-membered heterocyclic compound having 1 or 2 nitrogen atoms and optionally 1 or 2 sulfur atoms. In a particular embodiment, the compound of formula (Ic) is wherein R₁A compound that is thiazolyl, isothiazolyl, or thiadiazolyl. In a particular embodiment, the compound of formula (Ic) is R ₁A compound which is thiazolyl. In a particular embodiment, the compound of formula (Ic) is wherein R₁Is a compound of 1,2, 4-thiadiazole-5-radical.

In a particular embodiment, the compound of formula (Ic) is wherein R₂A compound that is independently at each occurrence-F or-Cl.

In a specific embodiment, the compound of formula (Ic) is a compound wherein n is 1,2, or 3. In a specific embodiment, the compound of formula (Ic) is a compound wherein n is 2.

In a particular embodiment, the compound of formula (Ic) is a compound wherein Z is-O-.

In the detailed descriptionWherein the compound of formula (Ic) is wherein R₃A compound that is independently at each occurrence-H, -F, -Cl, or-Br. In a particular embodiment, the compound of formula (I) is wherein R₃A compound that is-H or-Cl. In a particular embodiment, the compound of formula (Ic) is wherein R₃A compound which is-Cl.

In a specific embodiment, the compound of formula (Ic) is a compound wherein m is 1,2, or 3. In a specific embodiment, the compound of formula (Ic) is one wherein m is 1.

In a specific embodiment, the compound of formula (Ic) is a compound wherein X is 5-membered heteroaryl or 6-membered heteroaryl. In a specific embodiment, the compound of formula (Ic) is a compound wherein X is pyridinyl or pyrimidinyl. In a specific embodiment, the compound of formula (Ic) is a compound wherein X is pyridinyl.

In a particular embodiment, the compound of formula (Ic) is wherein R₄Is H and R₅Is (C)₁-C₉) Alkyl compounds.

In a particular embodiment, the compound of formula (Ic) is wherein R₅Is selected from-CO₂H、-CO₂R₆and-CONR₇R₈Methyl or ethyl substituted with 1 or 2 substituents in the group.

In a particular embodiment, the compound of formula (Ic) is wherein R₆Is (C)₁-C₆) Alkyl compounds.

In a particular embodiment, the compound of formula (Ic) is wherein R₅Is a quilt-CO₂H-substituted methyl or ethyl compounds.

In a specific embodiment, the compound of formula (Ic) is selected from the group consisting of:

3- (4- (2- (4- (N- (1,2, 4-thiadiazol-5-yl) sulfamoyl) -2-cyanophenoxy) -5-chlorophenyl) pyridinecarboxamide) propionic acid, and

3- (4- (2- (4- (N- (1,2, 4-thiadiazol-5-yl) sulfamoyl) -2, 5-difluorophenoxy) -5-chlorophenyl) picolinamido) propionic acid, or

A pharmaceutically acceptable salt thereof, or a stereoisomeric or tautomeric form.

Provided herein are compounds of formula (Id),

y is 4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidin- (2-yl or 3-yl);

z is-O-or-S-;

R₁is a partially unsaturated or aromatic 5-or 6-membered heterocycle;

R₂independently at each occurrence is-F, -Cl, -Br, -CH₃or-CN;

R₃independently at each occurrence-H, -F, -Cl, -Br, -CF₃、-OCF₃、-CN、(C₁-C₁₂) Alkyl, or (C)₁-C₁₂) An alkoxy group; and

m and n are each independently 1,2, 3 or 4.

In certain embodiments, the compound of formula (Id) is one wherein Y is 4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidin- (2-yl or 3-yl). In a particular embodiment, the compound of formula (Id) is one wherein Y is 4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidin-3-yl).

In a particular embodiment, the compound of formula (Id) is wherein R₁A compound that is an aromatic 5-membered heterocycle or 6-membered heterocycle having 1-3 heteroatoms independently selected from the group consisting of N, O, and S.

In a particular embodiment, the compound of formula (Id) is wherein R₁A compound that is pyridyl or pyrimidinyl.

In a particular embodiment, the compound of formula (Id) is wherein R₁Is an aromatic 5-membered heterocyclic compound having 1 or 2 nitrogen atoms and optionally 1 or 2 sulfur atoms. In a particular embodiment, the compound of formula (Id) is wherein R₁A compound that is thiazolyl, isothiazolyl, or thiadiazolyl. In a particular embodiment, the compound of formula (Id) is wherein R₁A compound which is thiazolyl. In a particular embodiment, the compound of formula (Id) is wherein R₁Is a compound of 1,2, 4-thiadiazole-5-radical.

In a particular embodiment, the compound of formula (Id) is wherein R₂At each time(ii) compounds that are independently in each occurrence-F or-Cl.

In a specific embodiment, the compound of formula (Id) is a compound wherein n is 1,2, or 3. In a specific embodiment, the compound of formula (Id) is a compound wherein n is 2.

In a particular embodiment, the compound of formula (Id) is a compound wherein Z is-O-.

In a particular embodiment, the compound of formula (Id) is wherein R₃A compound that is independently at each occurrence-H, -F, -Cl, or-Br. In a particular embodiment, the compound of formula (Id) is wherein R₃A compound that is-H or-Cl. In a particular embodiment, the compound of formula (Id) is wherein R₃A compound which is-Cl.

In a specific embodiment, the compound of formula (Id) is a compound wherein m is 1, 2, or 3. In a specific embodiment, the compound of formula (Id) is a compound wherein m is 1.

In a specific embodiment, the compound of formula (Id) is 5-chloro-4- (4-chloro-2- (4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidin-3-yl) phenoxy) -2-fluoro-N- (thiazol-4-yl) benzenesulfonamide; or a pharmaceutically acceptable salt, or a stereoisomeric or tautomeric form thereof.

In a specific embodiment, the compound of formula (Id) is:

5-chloro-4- (4-chloro-2- (4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidin-3-yl) phenoxy) -2-fluoro-N- (thiazol-2-yl) benzenesulfonamide, or

5-chloro-2-fluoro-4- (2- (4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidin-3-yl) phenoxy) -N- (thiazol-4-yl) benzenesulfonamide;

It should also be noted that the compounds provided herein may contain unnatural proportions of atomic isotopes at one or more atoms. For example, the compounds may be substituted with radioactive isotopes, such as for example tritium (A), (B), (C³H) Iodine-125 (¹²⁵I) Sulfur-35 (C)³⁵S), or carbon-14 (¹⁴C) Radiolabelling, or isotopically enriching for example deuterium (I)²H) Carbon 13 (C)¹³C) Or nitrogen 15(¹⁵N). As used herein, an "isotopic isomer" is an isotopically enriched compound. The term "isotopically enriched" refers to an atom having an isotopic composition different from the natural isotopic composition of the atom. "isotopically enriched" can also refer to compounds containing at least one atom with an isotopic composition different from the natural isotopic composition of the atom. The term "isotopic composition" refers to the amount of each isotope representing a given atom. Radiolabeled and isotopically enriched compounds are useful as therapeutic agents, for example, in the treatment of cancer and inflammation; research reagents, e.g., binding assay reagents; and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds described herein, whether radioactive or not, are intended to be encompassed within the scope of the embodiments provided herein. In some embodiments, isotopic isomers of compounds are provided, for example, isotopic isomers are compounds enriched in deuterium, carbon-13, or nitrogen-15.

In certain embodiments, the compounds provided herein modulate the activity of a sodium ion channel, such as a voltage-gated sodium ion channel. In a more specific embodiment, such a voltage-gated sodium ion channel is nav1.7 (whose alpha subunit is encoded by the human gene SCN 9A).

In certain embodiments, a compound provided herein reduces sodium ion flux through nav1.7 by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99%, or 100%, or by a range between any of the recited percentages (e.g., 10-20%, 10-30%, 10-40%, 20-30%, or 20-40%) relative to an activation channel in the absence of the compound.

In certain embodiments, the compounds provided herein desensitize nav1.7 response to membrane potential changes such that a channel requires at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% or a membrane potential change to be activated in a range between any of the recited percentages (e.g., 10-20%, 10-30%, 10-40%, 20-30%, or 20-40%) higher relative to a channel in the absence of the mixture.

In certain embodiments, the compounds provided herein affect a voltage-gated sodium ion channel (e.g., nav1.7) in one or more of the following states: rest (off), activate (on), or deactivate (off). In certain embodiments, the compounds provided herein affect the activation, inactivation, or deactivation of a voltage-gated sodium ion channel (e.g., nav 1.7).

In certain embodiments, a compound provided herein specifically modulates nav1.7, i.e., the compound modulates nav1.7 to a degree that is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000% greater than another voltage-gated sodium ion channel (e.g., nav1.1, nav1.2, nav1.3, nav1.4, nav1.5, nav1.6, nav1.8, and/or nav1.9), or to a degree that is between any of the enumerated percentages greater than another voltage-gated sodium channel (e.g., 10-20%, 10-30%, 10-40%, 20-30%, or 20-40%).

In certain embodiments, a compound provided herein binds nav1.7 with at least 5-fold, 10-fold, 50-fold, 100-fold, 500-fold, or 1000-fold greater affinity than it binds any or all of nav1.1, nav1.2, nav1.3, nav1.4, nav1.5, nav1.6, nav1.8, and nav 1.9. In certain embodiments, a compound provided herein binds to nav1.7 in the inactivated (off) state with at least 5-fold, 10-fold, 50-fold, 100-fold, 500-fold, or 1000-fold greater affinity than it binds to nav1.7 in any other state (i.e., the inactivated (off) and activated (on) states).

Any assay known to the skilled person may be used to test the effect of the compounds provided herein on voltage-gated sodium ion channels. In certain embodiments, a cell culture assay is used in which voltage-gated sodium ion channels are recombinantly expressed in cultured cells. In certain more specific embodiments, the α subunit of the voltage-gated sodium ion channel is expressed, but the helper protein is not recombinantly expressed in the same cell. In a specific embodiment, SCN9A and SCN9B1 and SCN9B2 are co-expressed in the same cell. In other embodiments, the α subunit of the voltage-gated sodium ion channel is expressed, and at least one helper protein (e.g., β subunit) is co-expressed in the same cell.

In certain embodiments, the FDSS membrane potential assay can be used to test the activity of voltage-gated sodium ion channels (see section entitled "FDSS membrane potential in vitro assay" below). In other embodiments, the current through the voltage-gated sodium ion channel is directly tested using the patch clamp method (patchclamp method) (see section entitled "Patchliner electrophysiological in vitro assay" below).

4.4 methods for preparing Compounds

Compounds of formula (Ia) or (I' a) were synthesized according to scheme 1. Make R ₃Reaction of a substituted 2-hydroxybenzaldehyde or 2-mercaptobenzaldehyde with formylmethylene-triphenylphosphine under Horner-Watts-Omns ("HWE") conditions to yield intermediate A, i.e., α, - β -unsaturated aldehyde intermediate A is reacted with HNR under reductive amination conditions using, for example, sodium borohydride₉R₁₀Reacted to give intermediate B. Intermediate B is then reduced in the presence of a metal catalyst (e.g., palladium on carbon) using, for example, hydrogen to yield intermediate C. Intermediate C is reacted with a fluoro-substituted phenylsulfonamide in the presence of a base, such as potassium carbonate, to provide intermediate D, wherein the sulfonamide nitrogen is optionally protected by a group ("PG"), such as tert-butoxycarbonyl ("BOC") or 2, 4-dimethoxybenzyl. The sulfonamide group of intermediate D is deprotected by using, for example, hydrochloric acid to give a compound of formula (Ia) or (I' a).

Scheme 1

The compounds of formula (Ib) may be prepared according to synthesis scheme 2. At R₃Suzuki coupling reactions between substituted 2-hydroxyboronic acids or derivatives of 2-mercaptoboronic acid and X, where X is, for example, (C) ₆-C₁₀) Aryl or 5-or 6-membered heteroaryl, such as 4-halocyanopyridine or 4-halopyridylmethyl (e.g., pyridine-2-carboxylate), wherein the halogen substituent is, for example, a chlorine or bromine substituent. Intermediate E is reacted with a base (e.g., potassium hydroxide) to provide intermediate F. Intermediate F is reacted with NHR using, for example, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide ("EDC") and 1-hydroxy-1H-benzotriazole ("HOBt₄R₅Reacted to form amide intermediate G. Intermediate G is reacted with a fluoro substituted phenylsulfonamide in the presence of a base, such as potassium carbonate, to provide intermediate H, wherein the sulfonamide nitrogen is optionally protected by a group, such as BOC or 2, 4-dimethoxybenzyl. The sulfonamide group of intermediate H is deprotected using, for example, hydrochloric acid to give a compound of formula (Ib).

Scheme 2

The compounds of formula (Ic) can be prepared according to synthesis scheme 3. At R₃The suzuki coupling reaction between a substituted 2-hydroxyboronic acid or 2-mercaptoboronic acid and a derivative of pyridine, such as a 4-halo-cyanopyridine or a 4-halo-picolyl ester (e.g., pyridine-2-carboxylic acid methyl ester), wherein the halogen substituent is, for example, a chlorine or bromine substituent, provides intermediate product I. Intermediate I is reacted with a base (e.g., potassium hydroxide) to give intermediate J. Intermediate J is prepared by using, for example, EDC and HOBt with NHR ₄R₅To form the amide intermediate K. Intermediate productK is reacted with a fluoro substituted phenylsulfonamide in the presence of a base, such as potassium carbonate, to provide intermediate product L, wherein the sulfonamide nitrogen is optionally protected by a group, such as BOC or 2, 4-dimethoxybenzyl. The sulfonamide group of intermediate L is deprotected using, for example, hydrochloric acid to give a compound of formula (Ic).

Scheme 3

The compounds of formula (Id) may be prepared according to scheme 4. Derivatives M of phenylacetonitrile with protected hydroxyl or thiol groups (e.g. methyl protected hydroxyl, i.e. -OMe groups) are formylated by using e.g. Na/ethyl formate or NaOEt/ethyl formate to give intermediates N. Intermediate N is reacted with hydrazine to provide intermediate O. Intermediate O under basic conditions, e.g. in the presence of NaH or Cs₂CO₃Under conditions to react with a dihaloalkane, for example, 1, 3-dibromopropane, to give an intermediate product P. After deprotection of the phenol or thiol, for example by contacting the methyl-protected hydroxyl group with BBr₃Reaction, intermediate P may be subjected to a synthetic sequence as depicted in scheme 1, scheme 2 or scheme 3 to yield compound S, i.e. a compound of formula (Id). Furthermore, the intermediate product W deprotected and subjected to the process described and mentioned in this paragraph to give the compound of formula (Id) may be obtained as follows: intermediate T is reacted with intermediate U or U 'in the presence of a base and a palladium catalyst under Suzukidition to give intermediate V, wherein R of intermediate U or U' is a nitro group or a suitably protected amino group. Intermediate V is subjected to conditions to reduce the nitro group to an amino group or to deprotect the nitrogen to release the amino group, such as zinc or hydrogen in acetic acid and Raney-Nickel (Raney-Nickel) to give intermediate W.

Scheme 4

4.5 methods of use

4.5.1 pain

Provided herein are methods for treating or preventing pain in a subject in need thereof, wherein the methods comprise administering a compound provided herein (i.e., a compound of formula (I), a compound of formula (I '), a compound of formula (Ia), a compound of formula (I' a), a compound of formula (Ib), a compound of formula (Ic), a compound of formula (Id), a compound listed in tables 1, 2, 3), or a pharmaceutically acceptable salt, solvate, or tautomeric form thereof to a subject in need of such treatment or prevention.

Provided herein are methods for delaying the onset of pain in a subject in need thereof, wherein the methods comprise administering to a subject in need of such treatment or prevention a compound provided herein, or a pharmaceutically acceptable salt, solvate, or tautomeric form thereof.

In one embodiment, the onset of pain is delayed for 10 minutes, 30 minutes, 60 minutes, 2 hours, 5 hours, 10 hours, 24 hours, 2 days, 5 days, 10 days, 20 days, 1 month, 3 months, 5 months, 6 months, 1 year or the entire treatment period and longer. In one embodiment, the compounds provided herein are not administered to a subject during a delay period.

Provided herein are methods for managing pain or reducing the frequency of recurrent pain, comprising administering to a subject in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate or tautomeric form thereof.

Provided herein are methods for treating neuropathic pain comprising administering to a subject in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate, or tautomeric form thereof.

Provided herein are methods for treating pain comprising using a compound as a voltage-gated sodium channel inhibitor. In a specific embodiment, the method is one wherein the pain is neuropathic pain, nociceptive pain, or inflammatory pain. In specific embodiments, these methods are those wherein the voltage-gated sodium channel is nav 1.7.

Provided herein are methods for treating or preventing a disorder associated with nav1.7 dysfunction, comprising administering to a subject in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate, or tautomeric form thereof.

Provided herein are methods for preventing or treating pain in a subject, wherein the methods comprise administering to a subject in need of such prevention or treatment a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate or tautomeric form thereof. In a specific embodiment, the method is one in which a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate, or tautomeric form thereof is effective to reduce pain in a subject, wherein the compound exhibits a reduced pain response in the formalin assay (at phase 1 or phase 2, or both) (see section 5.1.2) at a dose of 0.1mg/kg to 1,000mg/kg, at a dose of 0.5mg/kg to 100mg/kg, at a dose of 1mg/kg to 50mg/kg, or at a dose of 5 mg/kg. In certain embodiments, the compounds provided herein exhibit a reduction in pain response in the formalin assay (at phase 1 or phase 2, or both) by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99%, or 100%, or in a range between any of the recited percentages (e.g., 10-20%, 10-30%, 10-40%, 20-30%, or 20-40%) relative to the vehicle control. In a specific embodiment, the method is a method wherein the pain is: nociceptive pain, such as pain resulting from physical trauma (e.g., cuts or contusions of the skin, including surgical or dental pain; or chemical or thermal burns), osteoarthritis, rheumatoid arthritis, or tendonitis; myofascial pain; neuropathic pain, such as that associated with stroke, diabetic neuropathy, syphilitic neuropathy, postherpetic neuralgia, trigeminal neuralgia, fibromyalgia, or painful neuropathy induced iatrogenically by a drug; or mixed pain (i.e., pain with both nociceptive and neuropathic components); visceral pain; headache (e.g., migraine); CRPS; a CRPSI type; CRPSII type; RSD; reflex neurovascular dystrophy; reflex malnutrition; sympathetically maintained pain syndrome; burning pain; grandma atrophy of bone; hyperalgesic neurotrophism; shoulder-hand syndrome; post-traumatic malnutrition; autonomic dysfunction; autoimmune-related pain; pain associated with inflammation; pain associated with cancer; phantom limb pain; chronic fatigue syndrome; pain after surgery; pain associated with spinal cord injury; central post-stroke pain; a radiculopathy; sensitivity to temperature, light touch or color changes of the skin (allodynia); pain from hyperthermic or hypothermic conditions; and other painful conditions (e.g., diabetic neuropathy, syphilitic neuropathy, postherpetic neuralgia, trigeminal neuralgia); chronic pain; acute pain, neuroma pain, pain or itch associated with a pathway disease (e.g., fibromyalgia, IEM or raynaud's syndrome); or itch from various sources (e.g., allergic itch).

In particular embodiments, the methods are methods of treating, ameliorating, reducing and/or curing syndromes and diseases associated with or potentially associated with sodium-gated channel dysfunction and associated sensory and/or autonomic nervous system disorders, e.g., hereditary erythromelalgia, fibromyalgia, raynaud's phenomenon, CRPS; a CRPSI type; CRPSII type; RSD; reflex neurovascular dystrophy; reflex malnutrition, burning pain, migraine; shoulder-hand syndrome, skin sensitivity to temperature, light touch or color changes, symptoms of high or low body temperature, hyperhidrosis, postural hypotension, vagal vascular syndrome and other vegetative nerve disorders.

Provided herein are methods of modulating the activity of a voltage-gated sodium channel, wherein the methods comprise contacting a cell expressing a voltage-gated sodium channel with a compound, or a pharmaceutically acceptable salt, solvate, or tautomeric form thereof. In a specific embodiment, the method is one wherein the voltage-gated sodium channel is nav 1.7. In a specific embodiment, the method is a method that results in the inhibition of a voltage-gated sodium channel.

In certain embodiments, the compounds provided herein are administered to a population of patients having gain-of-function mutations in genes encoding the alpha subunit of voltage-gated sodium ion channels (e.g., nav 1.7).

In certain embodiments, the compounds provided herein are administered to a patient population diagnosed with erythromelalgia, primary erythromelalgia, Paroxysmal Extreme Pain Disorder (PEPD), or nav 1.7-associated fibromyalgia.

In certain embodiments, provided herein is a method for treating or preventing pain in a patient, wherein the method comprises administering to the patient a pharmaceutically effective amount of a compound provided herein, wherein the step of administering results in the reduction or prevention of pain sensation, and wherein the step of administering results in the reduction of sensation of non-nociceptive tactile mechanical stimulation by at most 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, at most 50%, or by no sensation of non-nociceptive tactile mechanical stimulation. In certain embodiments, the sensory extent of the non-nociceptive tactile mechanical stimulus is measured by using a von frey assay.

In certain embodiments, provided herein is a method for treating or preventing pain in a patient, wherein the method comprises administering to the patient a pharmaceutically effective amount of a compound provided herein, wherein the step of administering results in a reduction or prevention of pain sensation, and wherein the step of administering results in a reduction in motor function of at most 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, at most 50%, or no motor function. In some embodiments, the degree of motor function is measured by using a staggered test (FootFaulttest).

In certain embodiments, provided herein is a method for treating or preventing allodynia in a patient, wherein the method comprises administering to the patient a pharmaceutically effective amount of a compound provided herein, wherein the step of administering results in the reduction or prevention of pain sensation, and wherein the step of administering results in the reduction of motor function by at most 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, at most 50% or no motor function. In certain embodiments, burns or other tissue damage causes pain to the touch.

In certain embodiments, provided herein is a method for treating or preventing pain in a patient caused by arresting injury, wherein the method comprises administering a pharmaceutically effective amount of a compound provided herein to the patient, wherein the step of administering results in enriching at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 100% of the administered compound in the remainder of the patient at the site of tissue injury.

In certain embodiments, the compounds provided herein for use in the methods described herein are the following compounds: the reduction/inhibition of pain response is shown to be at least about 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 100% or any range resulting from a combination of any two of the aforementioned percentages in phase 1 of the formalin test (see subsection 5.1.2), e.g., at least about 10% to about 20% and at least about 15% to about 80%.

In certain embodiments, the compounds provided herein for use in the methods described herein are the following compounds: the reduction/inhibition of pain response is shown to be at least about 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 100% or any range resulting from a combination of any two of the aforementioned percentages in phase 2 of the formalin test (see subsection 5.1.2), e.g., at least about 10% to about 20% and at least about 15% to about 80%.

In certain embodiments, the compounds provided herein for use in the methods described herein are the following compounds: at least about 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 100%, or any range resulting from a combination of any two of the aforementioned percentages, e.g., at least about 10% to about 20% and at least about 15% to about 80%, is restored in a plantar test (see subsection 5.1.2) using a suitable animal model, e.g., a partial sciatic nerve ligation ("PSNL") model or a streptozotocin ("STZ") induced diabetic neuropathy model.

In certain embodiments, the compounds provided herein for use in the methods described herein are the following compounds: at least about 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 100%, or any range resulting from a combination of any two of the aforementioned percentages, e.g., at least about 10% to about 20% and at least about 15% to about 80%, is restored in a paw pressure test (see subsection 5.1.2) using a suitable animal model, e.g., a partial sciatic nerve ligation ("PSNL") model or a streptozotocin ("STZ") induced diabetic neuropathy model.

In certain embodiments, the compounds provided herein for use in the methods described herein are the following compounds: at least about 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 100% or any range resulting from a combination of any two of the aforementioned percentages, e.g., at least about 10% to about 20% and at least about 15% to about 80% in a von frey test (tactileodynia) using a suitable animal model, e.g., a partial sciatic nerve ligation ("PSNL") model or a streptozotocin ("STZ") induced diabetic neuropathy model (see subsection 5.1.2).

In certain embodiments, the compounds provided herein for use in the methods described herein are the following compounds: at least about 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 100%, or any range resulting from a combination of any two of the aforementioned percentages, e.g., at least about 10% to about 20% and at least about 15% to about 80%, is restored in a weight-bearing test using a suitable animal model, e.g., a partial sciatic nerve ligation ("PSNL") model or a streptozotocin ("STZ") induced diabetic neuropathy model (see subsection 5.1.2).

In certain embodiments, the compounds provided herein for use in the methods described herein are the following compounds: exhibit a reduction in pain of at least about 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 100%, or any range resulting from a combination of any two of the foregoing percentages in a writhing model (inflammatory abdominal pain) (see subsection 5.1.2), e.g., at least about 10% to about 20% and at least about 15% to about 80%.

In certain embodiments, the compounds provided herein for use in the methods described herein are the following compounds: the itch or scratch reduction is shown in the itch/itch model (Itching/puritism model) (see subsection 5.1.2) to be at least about 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 100%, or any range resulting from a combination of any two of the foregoing percentages, e.g., at least about 10% to about 20% and at least about 15% to about 80%.

In certain embodiments, the compounds provided herein for use in the methods described herein are the following compounds: the diabetic animals produced by a suitable method known in the art, e.g., streptozotocin ("STZ") injection (see section 5.1.2), exhibit at least about a 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 100%, or any range resulting from a combination of any two of the foregoing percentages, reduced one or more of food intake, glucose levels, and horizontal intake by at least about 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 100%, or a combination of any two of the foregoing percentages in comparison to non-diabetic sham group (sham) animals.

4.5.2 diabetes mellitus, lowering blood or plasma glucose and lowering blood or plasma glycated hemoglobin

Provided herein are methods for treating or preventing prediabetes, comprising administering to a subject in need thereof a therapeutically effective amount of a compound provided herein (i.e., a compound of formula (I), a compound of formula (I '), a compound of formula (Ia), a compound of formula (I' a), a compound of formula (Ib), a compound of formula (Ic), a compound of formula (Id), a compound listed in table 1, table 2, or table 3), or a pharmaceutically acceptable salt, solvate, or tautomeric form thereof.

Provided herein are methods for treating or preventing diabetes in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate, or tautomeric form thereof.

Provided herein are methods for maintaining or reducing blood or plasma glucose in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate, or tautomeric form thereof.

Also provided herein are methods for maintaining or reducing blood or plasma glycated hemoglobin in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate, or tautomeric form thereof.

In one embodiment, the subject has pre-diabetes.

In another embodiment, the subject has diabetes. In certain embodiments, the diabetes is gestational diabetes, type 1 diabetes, type 2 diabetes, or latent autoimmune diabetes in adults. In one embodiment, the diabetes is gestational diabetes. In one embodiment, the diabetes is type 1 diabetes. In one embodiment, the diabetes is type 2 diabetes. In one embodiment, type 2 diabetes is hyperinsulinemic type 2 diabetes. In one embodiment, wherein the diabetes is latent autoimmune diabetes of adults.

Blood or plasma glucose can be determined by any method known in the art, for example, a commercially available blood glucose meter, a lancet device with a three-edged needle, or a commercially available test strip.

Blood or plasma glycated hemoglobin can be determined by any method known in the art, for example, the A1C test using the method provided by NGSP ("national glycated hemoglobin standardization program"). Asp (last visit on 8/27/2014/8/25).

In one embodiment, the method of treating pre-diabetes or treating diabetes or reducing blood or plasma glucose reduces blood or plasma glucose in a subject in need thereof by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or any range resulting from a combination of any two of the aforementioned percentages, e.g., at least about 5% to about 10% or at least about 15% to about 50%, compared to blood or plasma glucose prior to administration of a compound provided herein. In one embodiment, blood or plasma glucose is continuously reduced or maintained at a reduced level after the compound has been discontinued from administration as compared to blood or plasma glucose prior to administration of a compound provided herein. In particular embodiments, after an administration period of at least about 1 day, 5 days, 10 days, 15 days, 20 days, 1 month, 3 months, 6 months or 1 year, blood or plasma glycated hemoglobin continues to decline or remains at a reduced level for at least about 5 days, 10 days, 15 days, 20 days, 1 month, 3 months, 6 months, 1 year, 2 years, 3 years or 5 years.

In one embodiment, the method of treating prediabetes or treating diabetes or reducing blood or plasma glycated hemoglobin reduces blood or plasma glycated hemoglobin in a subject in need thereof by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or any range resulting from a combination of any two of the aforementioned percentages, e.g., at least about 5% to about 10% or at least about 15% to about 50%, as compared to blood or plasma glycated hemoglobin prior to administration of the compound provided herein. In one embodiment, blood or plasma glycated hemoglobin continues to be reduced or maintained at a reduced level after the compound has been discontinued from administration as compared to blood or plasma glycated hemoglobin prior to administration of the compounds provided herein. In particular embodiments, after an administration period of at least about 1 day, 5 days, 10 days, 15 days, 20 days, 1 month, 3 months, 6 months or 1 year, blood or plasma glycated hemoglobin continues to decline or remains at a reduced level for at least about 5 days, 10 days, 15 days, 20 days, 1 month, 3 months, 6 months, 1 year, 2 years, 3 years or 5 years.

The diagnosis and classification of diabetes is described by the american diabetes association in diabetes care37 (american diabetes association diabetes care37, Supplement1, S67-S90(2014) ("ADA 2014"). "diagnosis and Classification of diabetes" ("survey error Table of Diagnosisan and Classification of Diabetes Mellitis", Diabetes Care37, Supplement1: S81-S90(2014) is published in Diabetes Care37,887 (2014)).

4.5.2.1 diagnosis of diabetes

In one embodiment, the subject is in need of: treating diabetes; or maintaining or reducing blood or plasma glucose; or maintaining or reducing blood or plasma glycated hemoglobin if the subject exhibits:

criteria 1-3 should be confirmed by repeated tests without definitive hyperglycemia.

A1C (also known as, among other things, hemoglobin A1c, HbA1c, glycohemoglobin (glycohemoglobin), glycated hemoglobin (glycohemoglobin), or glycosylated hemoglobin) is widely used as a marker of chronic hyperglycemia, reflecting average blood glucose levels over a 2-3 month period. This test plays a key role in managing diabetic subjects because it is associated with both microvascular and, to a lesser extent, macrovascular complications and is widely used as an appropriate biomarker for blood glucose management. At S87ADA2014, left column.

The FPG test measures the fasting blood glucose level of the subject. Fasting means that no food or drink (except water) is consumed at least 8 hours prior to testing. In one embodiment, the FPG test is performed in the morning, before the subject eats breakfast.

OGTT is the most commonly performed form of glucose tolerance test in which a standard dose of glucose is administered orally to a subject and blood samples are taken thereafter (after about 2 hours) to determine how quickly the blood will be treated with glucose. The random plasma glucose test measures how much glucose is in the subject's blood circulation. By "random" is meant that the subject is drawing blood at any time. The test was not affected whether the subject had fasted or had just had a meal.

In addition, in combination with item (4) of paragraph [00239] above, the symptoms of hyperglycemia or hyperglycemia risk include, but are not limited to: frequent micturition, thirst, blurred vision, fatigue, headache, fruity respiration, nausea, emesis, tachypnea, dry mouth, asthenia, blurred consciousness, coma and abdominal pain.

In one embodiment, the method of treating diabetes, or maintaining or reducing blood or plasma glucose, or maintaining or reducing blood or plasma glycated hemoglobin, maintains A1C level in a subject in need thereof or reduces A1C level in a subject in need thereof by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or any range resulting from a combination of any two of the aforementioned percentages, e.g., at least about 5% to about 10% or at least about 15% to about 50%, as compared to A1C level prior to administration of the compound provided herein. In particular embodiments, the method of treating diabetes, or reducing blood or plasma glucose, or reducing blood or plasma glycated hemoglobin, reduces A1C levels to at least about 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6.5%, 6.2%, 6.0%, 5.7%, 5.5%, 5.2%, 5.0%, 4.7%, 4.5%, 4.2%, 4.0%, 3.7%, 3.5%, 3.2%, or 3.0% or to at least one range formed by any two of the aforementioned percentages, for example, to a range of at least about 4.5% to about 6% or at least about 5.7% to 6.4%.

In one embodiment, the method of treating diabetes, or maintaining or reducing blood or plasma glucose, or maintaining or reducing blood or plasma glycated hemoglobin, maintains or reduces the FPG level in a subject in need thereof by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or any range resulting from a combination of any two of the aforementioned percentages, e.g., at least about 5% to about 10% or at least about 15% to about 50%, as compared to the FPG level prior to administration of the compound provided herein. In particular embodiments, the methods of treating diabetes, or lowering blood or plasma glucose, or lowering blood or plasma glycated hemoglobin lowers FPG levels to at least about 150mg/dL, 145mg/dL, 140mg/dL, 135mg/dL, 130mg/dL, 126mg/dL, 125mg/dL, 120mg/dL, 115mg/dL, 110mg/dL, 105mg/dL, 100mg/dL, 99mg/dL, 95mg/dL, 90mg/dL, 85mg/dL, 80mg/dL, 75mg/dL, 70mg/dL, or 60mg/dL or to at least one range formed by any two of the aforementioned percentages, for example, to at least about 70mg/dL to about 99mg/dL or to a range of at least about 100mg/dL to about 125 mg/dL.

In one embodiment, the method of treating diabetes, or maintaining or reducing blood or plasma glucose, or maintaining or reducing blood or plasma glycated hemoglobin, maintains or reduces two hour plasma glucose levels during an OGTT in a subject in need thereof by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or any range resulting from a combination of any two of the aforementioned percentages, e.g., at least about 5% to about 10% or at least about 15% to about 50%, compared to two hour plasma glucose levels during an OGTT prior to administration of a compound provided herein. In particular embodiments, methods of treating diabetes, or lowering blood or plasma glucose, or lowering blood or plasma glycated hemoglobin use a glucose load of, for example, 75g of anhydrous glucose in water to lower the two hour plasma glucose level during the OGTT to at least about 300mg/dL, 270mg/dL, 250mg/dL, 220mg/dL, 200mg/dL, 199mg/dL, 190mg/dL, 180mg/dL, 170mg/dL, 160mg/dL, 150mg/dL, 140mg/dL, 139mg/dL, 130mg/dL, 120mg/dL, 110mg/dL, or 100mg/dL or to at least one range formed by any two of the aforementioned percentages, for example, to a range of at least about 199mg/dL to about 140 mg/dL.

In one embodiment, the method of treating diabetes, or reducing blood or plasma glucose, or reducing blood or plasma glycated hemoglobin, reduces a level of A1C or FPG or A1C, or any combination thereof, in a subject in need thereof to such an extent that the subject is no longer diagnosed with diabetes for the criteria discussed in this section.

Prediabetes diagnosis

In one embodiment, the subject is in need of: treating prediabetes; or maintaining or reducing blood or plasma glucose; or maintaining or reducing blood or plasma glycated hemoglobin if the subject exhibits:

for all three tests, the risk was constant, extending below the lower end of the range and disproportionately larger at the upper end of the range.

The FPG test measures the fasting blood glucose level of the subject. Fasting means that no food or drink (except water) is consumed at least 8 hours prior to testing. OGTT is the most commonly performed form of glucose tolerance test in which a standard dose of glucose is administered orally to a subject and blood samples are taken thereafter (after about 2 hours) to determine how quickly the blood will be treated with glucose. A1C (also known as, among other things, hemoglobin A1c, HbA1c, glycohemoglobin, glycated hemoglobin, or glycosylated hemoglobin) is widely used as a marker of chronic hyperglycemia, reflecting average blood glucose levels over a 2-3 month period. At S87ADA2014, left column.

In one embodiment, the method of treating prediabetes, or maintaining or reducing blood or plasma glucose, or maintaining or reducing blood or plasma glycated hemoglobin maintains or reduces the FPG level in a subject in need thereof by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or any range resulting from a combination of any two of the aforementioned percentages, e.g., at least about 5% to about 10% or at least about 15% to about 50%, as compared to the FPG level prior to administration of the compound provided herein. In particular embodiments, the methods of treating prediabetes, or lowering blood or plasma glucose, or lowering blood or plasma glycated hemoglobin lowers FPG levels to at least about 125mg/dL, 120mg/dL, 115mg/dL, 110mg/dL, 105mg/dL, 100mg/dL, 99mg/dL, 95mg/dL, 90mg/dL, 85mg/dL, 80mg/dL, 75mg/dL, 70mg/dL, or 60mg/dL or to at least one range formed by any two of the aforementioned percentages, for example, to a range of at least about 99mg/dL to about 70 mg/dL.

In one embodiment, the method of treating pre-diabetes, or maintaining or reducing blood or plasma glucose, or maintaining or reducing blood or plasma glycated hemoglobin, maintains or reduces two hour plasma glucose levels during an OGTT in a subject in need thereof by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or any range resulting from a combination of any two of the aforementioned percentages, e.g., at least about 5% to about 10% or at least about 15% to about 50%, compared to two hour plasma glucose levels during an OGTT prior to administration of a compound provided herein. In particular embodiments, the methods of treating prediabetes, or lowering blood or plasma glucose, or lowering blood or plasma glycated hemoglobin use a glucose load of, for example, 75g of anhydrous glucose in water to lower the two hour plasma glucose level during the OGTT to at least about 199mg/dL, 190mg/dL, 180mg/dL, 170mg/dL, 160mg/dL, 150mg/dL, 140mg/dL, 139mg/dL, 130mg/dL, 120mg/dL, 110mg/dL, or 100mg/dL or to at least one range formed by any two of the aforementioned percentages, for example, to a range of at least about 139mg/dL to about 100 mg/dL.

In one embodiment, the method of treating prediabetes, or maintaining or reducing blood or plasma glucose, or maintaining or reducing blood or plasma glycated hemoglobin maintains a level of A1C in a subject in need thereof or reduces a level of A1C in a subject in need thereof by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or any range resulting from a combination of any two of the aforementioned percentages, e.g., at least about 5% to about 10% or at least about 15% to about 50%, as compared to the level of A1C prior to administration of the compounds provided herein. In particular embodiments, the method of treating prediabetes, or reducing blood or plasma glucose, or reducing blood or plasma glycated hemoglobin reduces A1C levels to at least about 5.7%, 5.6%, 5.5%, 5.2%, 5.0%, 4.7%, 4.5%, 4.2%, 4.0%, 3.7%, 3.5%, 3.2%, or 3.0% or to at least one range formed by any two of the aforementioned percentages, for example, to a range of at least about 5.6% to about 3.0%.

In one embodiment, the method of treating prediabetes, or reducing blood or plasma glucose, or reducing blood or plasma glycated hemoglobin reduces the FPG level or plasma glucose level or A1C, or any combination thereof, in a subject in need thereof to such an extent that the subject is no longer diagnosed with prediabetes for the criteria discussed in this section.

Diagnosis of gestational diabetes

In one embodiment, the subject is in need of: treating diabetes, wherein the diabetes is gestational diabetes; or maintaining or reducing blood or plasma glucose; or maintaining or reducing blood or plasma glycated hemoglobin if the subject exhibits:

one-step process (IADPSG ("international association for diabetes and pregnancy research group" consensus):

75gOGTT is performed on women about 24-28 weeks gestation who have not previously been diagnosed with overt diabetes, and plasma glucose is measured on an empty stomach and about 1 hour and about 2 hours after glycation. OGTT should be performed in the morning, after fasting for at least about 8 hours in the first night, and any plasma glucose value meets the following criteria for diagnosis of gestational diabetes:

(1) empty stomach: greater than or equal to about 92mg/dL (5.1 mmol/L);

(2)1 h: greater than or equal to about 180mg/dL (10.0 mmol/L); and

(3)2 h: greater than or equal to about 153mg/dL (8.5 mmol/L).

Two-step process (NIH (national institute of health) consensus):

approximately 50g GLT ("glucose stress test", non-fasting) was performed on women 24-28 weeks gestation who had not previously been diagnosed with overt diabetes, and plasma glucose was measured about 1 hour after taking the glucose. If the plasma glucose level measured about 1 hour after sugar loading is equal to or greater than 140mg/dL (7.8mmol/L), about 100g of OGTT is performed (step 2). The American society of obstetricians and gynecologists ("ACOG") advises a low threshold of about 135mg/dL (7.5mmol/L) in a population of high-risk ethnic groups with a high prevalence of gestational diabetes, and some experts also advise a low threshold of about 130mg/dL (7.2 mmol/L). An OGTT of about 100g should be performed on a patient on a fasting basis.

Gestational diabetes can be diagnosed when at least two of the following four plasma glucose levels (fasting, about 1h, about 2h, about 3h after OGTT determination) reach or exceed:

carpenter and Coursan, "screening test criteria for gestational diabetes mellitus (criterion of Criteriaforrest)," am. J. Obstet. Gynecol.44: 768-773 (1982).

The # American diabetes data group, "classification and diagnosis of diabetes and other classes of glucose tolerance (Classication and Diagnosis of diabetes mellitis and glucose tolerance). "Diabetes 28: 1039-.

In one embodiment, the method of treating diabetes (where the diabetes is gestational diabetes), or reducing blood or plasma glucose, or reducing blood or plasma glycated hemoglobin, reduces the plasma glucose level to such a level that the subject is no longer diagnosed with gestational diabetes using the one-step test or the two-step test, or both.

Diagnosis of latent autoimmune diabetes in adults

In one embodiment, the subject is in need of: treating diabetes, wherein the diabetes is latent autoimmune diabetes of adults; or maintaining or reducing blood or plasma glucose; or maintaining or reducing blood or plasma glycated hemoglobin if the subject exhibits at least two of the following characteristics:

Age at diagnosis of diabetes less than 50 years

Normal body weight (body mass index less than 25)

Acute symptoms when diagnosed with diabetes (e.g., extreme thirst, frequent urination, or involuntary weight loss)

Another autoimmune disease, e.g., autoimmune thyroid disease, rheumatoid arthritis and celiac disease

Family history of type 1 diabetes or other autoimmune diseases

In another embodiment, the subject is in need of: treating diabetes, wherein the diabetes is latent autoimmune diabetes of adults; or maintaining or reducing blood or plasma glucose; or maintain or reduce blood or plasma glycated hemoglobin if the subject exhibits high levels of pancreatic autoantibodies and has recently been diagnosed with diabetes, but does not require insulin. In particular embodiments, the presence of antibodies is measured using the GAD ("glutamate decarboxylase") antibody test. The GAD antibody test is a blood test that measures whether the subject's body produces one type of antibody that destroys its own GAD cells.

In one embodiment, the method of treating diabetes (where the diabetes is latent autoimmune diabetes in adults), or reducing blood or plasma glucose, or reducing blood or plasma glycated hemoglobin, lowers plasma glucose levels to such an extent that the subject is no longer diagnosed as having latent autoimmune diabetes.

Patient population

In one embodiment, the prediabetes or diabetes is caused by or accompanied by obesity. In certain embodiments, an obese subject has at least about 30kg/m²Body mass index ("BMI"). Diagnosis and management of obesity (diagnosis of obesity), the American family physician society, 2013, available at http:// www.aafp.org/dam/AAFP/documents/parent _ care/fixness/ease-diagnosis-management. pdf (last visit on 28/8/2014). BMI was calculated as follows:

BMI (weight kg)/(height of subject m) 2.

In one embodiment, a subject in need of treatment for prediabetes or diabetes, or in need of maintenance or reduction of blood or plasma glucose, or in need of maintenance or reduction of glycated hemoglobin has not previously received treatment for prediabetes or diabetes.

In one embodiment, a subject in need of treatment for prediabetes or diabetes, or in need of maintenance or reduction of blood or plasma glucose, or in need of maintenance or reduction of glycosylated hemoglobin, exhibits hypersensitivity and anaphylaxis, including but not limited to anaphylaxis, to insulin drugs such as HUMALOG (R).

In one embodiment, a subject in need of treatment for prediabetes or diabetes, or in need of maintenance or reduction of blood or plasma glucose, or in need of maintenance or reduction of glycated hemoglobin, is at risk of hypokalemia. All insulin products, e.g., humalog (r), cause potassium transfer from the extracellular space to the intracellular space, possibly resulting in hypokalemia. Untreated hypokalemia may cause, for example, respiratory paralysis, ventricular arrhythmias, and death. Subjects at risk of hypokalemia are, for example, subjects using potassium-lowering drugs, subjects taking drugs sensitive to serum potassium concentration, and subjects receiving intravenously administered insulin.

In one embodiment, the subject in need of treatment for prediabetes or diabetes, or in need of maintenance or reduction of blood or plasma glucose, or in need of maintenance or reduction of glycated hemoglobin is a female. In one embodiment, the subject in need of treatment for prediabetes or diabetes, or in need of maintenance or reduction of blood or plasma glucose, or in need of maintenance or reduction of glycosylated hemoglobin is a pregnant woman. In one embodiment, the subject in need of treatment for prediabetes or diabetes, or in need of maintenance or reduction of blood or plasma glucose, or in need of maintenance or reduction of glycosylated hemoglobin is a male.

In one embodiment, a subject in need of treatment for prediabetes or diabetes, or in need of maintenance or reduction of blood or plasma glucose, or in need of maintenance or reduction of glycosylated hemoglobin is at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 years old. In one embodiment, a subject in need of treatment for prediabetes or diabetes, or in need of maintenance or reduction of blood or plasma glucose, or in need of maintenance or reduction of glycosylated hemoglobin is less than about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 years old. In particular embodiments, the subject described in this paragraph is from about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, or 85, 90 years old ("first list") to about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 years old ("second list"), e.g., 10-45 years old, 30-90 years old, or any age range resulting from the combination of the numbers of the first list and the numbers of the second list, wherein the numbers of the second list are greater than the numbers of the first list.

In one embodiment, the subject in need of treatment for prediabetes or diabetes, or in need of maintenance or reduction of blood or plasma glucose, or in need of maintenance or reduction of glycosylated hemoglobin is a lactating subject (nursingsubject). Sulfonylureas mimic the beta cells of the pancreas to release insulin. Some sulfonylureas are known to be excreted in human milk. Because there is a potential for hypoglycemia in the infant, the use of sulfonylureas by lactating subjects should be avoided.

In one embodiment, the subject in need of treatment for prediabetes or diabetes, or in need of maintenance or reduction of blood or plasma glucose, or in need of maintenance or reduction of glycosylated hemoglobin is a subject with new york heart disease association ("NYHA") class III or IV heart failure. Physicians typically classify heart failure according to the severity of the subject's symptoms. The following table describes the most commonly used classification system, the NYHA functional classification. This system classifies patients into one of four categories depending on how limited the patients are during physical activity. Some diabetes drugs, e.g., rosiglitazone (avandia (r)), are contraindicated in subjects described in this paragraph.

http:// www.heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classes-of-Heart-Failure _ UCM _306328_ Archicle.jsp (last visit on 28/8/2014).

In one embodiment, a subject in need of treatment for prediabetes or diabetes, or in need of maintenance or reduction of blood or plasma glucose, or in need of maintenance or reduction of glycosylated hemoglobin is a subject having a hypersensitivity reaction to a dipeptidyl peptidase 4 ("DPP-4") inhibitor, e.g., sitagliptin (januvia (r)). These reactions include, but are not limited to, allergic reactions, angioedema, and exfoliative skin conditions, such as Stevens-Johnson syndrome.

In one embodiment, a subject in need of treatment for prediabetes or diabetes, or in need of maintenance or reduction of blood or plasma glucose, or in need of maintenance or reduction of glycated hemoglobin, is one having normal renal function (glomerular filtration rate ("GFR") at about 90mL/min/1.73m²Above, and without proteinuria), with chronic kidney disease (stage 1) (GFR at about 90mL/min/1.73m²Above, with evidence of renal injury), with chronic kidney disease (stage 2) (mild, GFR of about 60 to about 89mL/min/1.73m²With evidence of renal injury), with chronic kidney disease (stage 3) (moderate, GFR of about 30 to 59mL/min/1.73m ²) And chronic kidney disease (stage 4) (severe, GFR from about 15 to about 29mL/min/1.73m²) Or chronic kidney disease (stage 5) (renal failure, GFR less than about 15mL/min/1.73m²Where the subject may or may not require dialysis).

Pharmaceutical compositions and routes of administration

Provided herein are pharmaceutical compositions comprising a compound provided herein and a pharmaceutically acceptable carrier. In a specific embodiment, the pharmaceutical composition is one wherein the composition is suitable for topical, oral, subcutaneous, or intravenous administration.

Provided herein are compositions comprising an effective amount of a compound, as well as compositions comprising an effective amount of a compound and a pharmaceutically acceptable carrier or vehicle. In some embodiments, the pharmaceutical compositions described herein are suitable for oral, parenteral, mucosal, transdermal, or topical administration.

The compounds may be administered to a patient orally or parenterally in conventional dosage forms, for example, capsules, microcapsules, tablets, granules, powders, lozenges, pills, suppositories, injections, suspensions and syrups. Suitable formulations may be prepared by a conventionally employed method using a conventional organic or inorganic additive such as an excipient (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate), a binder (e.g., cellulose, methyl cellulose, hydroxymethyl cellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose or starch), a disintegrant (e.g., starch, carboxymethyl cellulose, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, sodium bicarbonate, calcium phosphate or calcium citrate), a lubricant (e.g., magnesium stearate, light anhydrous silicic acid, talc or sodium lauryl sulfate), a flavoring agent (e.g., citric acid, menthol, glycine or orange powder), a preservative (e.g., sodium benzoate, calcium phosphate or calcium citrate), a pharmaceutically acceptable carrier, a pharmaceutically, Sodium bisulfite, methyl or propyl paraben), stabilizers (e.g., citric acid, sodium citrate or acetic acid), suspending agents (e.g., methylcellulose, polyvinylpyrrolidone or aluminum stearate), dispersants (e.g., hydroxypropylmethylcellulose), diluents (e.g., water), and waxes (e.g., coconut oil, white petrolatum or polyethylene glycol). An effective amount of a compound in a pharmaceutical composition can be a level to achieve a desired effect, for example, in a unit dose of from about 0.1mg/kg to about 1000mg/kg or from about 0.5mg/kg to about 100mg/kg of patient body weight for oral and parenteral administration.

The dosage of the compound to be administered to a patient may vary quite widely and may be at the discretion of the health care practitioner. In general, the compound may be administered to a patient 1 to 4 times per day at a dose of about 0.1mg/kg to about 1000mg/kg of the patient's body weight, but the above dose may be appropriately changed depending on the age, body weight and medical condition of the patient and the type of administration. In one embodiment, the dose is from about 0.05mg/kg patient weight to about 500mg/kg patient weight, from 0.05mg/kg patient weight to about 100mg/kg patient weight, from about 0.5mg/kg patient weight to about 100mg/kg patient weight, from about 0.1mg/kg patient weight to about 50mg/kg patient weight, or from about 0.1mg/kg patient weight to about 25mg/kg patient weight. In one embodiment, one dose is administered per day. In another embodiment, two doses are administered per day. The amount of compound administered in any given case will depend on such factors as the solubility of the active ingredient, the dosage form used, and the route of administration.

In another embodiment, provided herein are methods for treating pain, pre-diabetes, and diabetes; and methods of maintaining or reducing blood or plasma glucose, and maintaining or reducing glycated hemoglobin; the method comprises administering to a patient in need thereof from about 7.5 mg/day to about 75 g/day, from about 3.75 mg/day to about 37.5 g/day, from about 3.75 mg/day to about 7.5 g/day, from about 37.5 mg/day to about 7.5 g/day, from about 7.5 mg/day to about 3.75 g/day, from about 3.75 mg/day to about 1.875 g/day, from about 3.75 mg/day to about 1,000 mg/day, from about 3.75 mg/day to about 800 mg/day, from about 3.75 mg/day to about 500 mg/day, from about 3.75 mg/day to about 300 mg/day, or from about 3.75 mg/day to about 150 mg/day of a compound. In specific embodiments, the methods disclosed herein comprise administering to a patient in need thereof 1 mg/day, 5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day, 30 mg/day, 40 mg/day, 45 mg/day, 50 mg/day, 60 mg/day, 75 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 200 mg/day, 250 mg/day, 300 mg/day, 400 mg/day, 600 mg/day, 800 mg/day, 1,000 mg/day, 1,500 mg/day, 2,000 mg/day, 2,500 mg/day, 5,000 mg/day, or 7,500 mg/day of the compound.

In another embodiment, provided herein is a unit dosage form comprising from about 7.5mg to about 75g, from about 3.75mg to about 37.5g, from about 3.75mg to about 7.5g, from about 37.5mg to about 7.5g, from about 7.5mg to about 3.75g, from about 3.75mg to about 1.875g, from about 3.75mg to about 1,000mg, from about 3.75mg to about 800mg, from about 3.75mg to about 500mg, from about 3.75mg to about 300mg, or from about 3.75mg to about 150mg of the compound.

In specific embodiments, provided herein are unit dosage forms comprising about 1mg, 5mg, 10mg, 15mg, 20mg, 30mg, 40mg, 45mg, 50mg, 60mg, 75mg, 100mg, 125mg, 150mg, 200mg, 250mg, 300mg, 400mg, 600mg, 800mg, 1,000mg, 1,500mg, 2,000mg, 2,500mg, 5,000mg, or 7,500mg of the compound.

In another embodiment, provided herein is a unit dosage form comprising a dose of a compound that achieves a target plasma concentration of the compound in a patient or animal model. In specific embodiments, provided herein are unit dosage forms that achieve a plasma concentration of the compound in a patient or animal model of about 0.001 μ g/mL to about 100mg/mL, about 0.01 μ g/mL to about 10mg/mL, about 0.1 μ g/mL to about 500 μ g/mL, about 0.1 μ g/mL to about 100 μ g/mL, or about 0.5 μ g/mL to about 10 μ g/mL. To achieve such plasma concentrations, the compounds or pharmaceutical compositions thereof may be administered at doses varying from 0.001 μ g to 100,000mg, depending on the route of administration. In certain embodiments, subsequent doses of the compound may be adjusted accordingly to the plasma concentration of the compound achieved with the initial dose of the compound or pharmaceutical composition thereof administered to the subject.

The compounds may be administered once, twice, three times, four times or more daily.

For convenience reasons, the compounds may be administered orally. In one embodiment, when administered orally, the compound is administered with the diet and water. In another embodiment, the compound is dispersed in water or fruit juice (e.g., apple juice or orange juice) and administered orally as a suspension. In another embodiment, when administered orally, the compound is administered in a fasted state.

The compounds may also be administered intradermally; intramuscular administration; intraperitoneal administration; transdermal administration (percutaneously); intravenous administration; subcutaneous administration; intranasal administration; epidural administration; sublingual administration; intracerebral administration; intravaginal administration; transdermal administration (transdermal); rectal administration; mucosal administration; administration by inhalation; or topically to the ear, nose, eye or skin. The mode of administration is discretionary to the health care practitioner and may depend in part on the site of the medical condition.

In one embodiment, provided herein are capsules comprising a compound without additional carriers, excipients, or vehicles.

In another embodiment, provided herein are compositions comprising an effective amount of a compound and a pharmaceutically acceptable carrier or vehicle, wherein the pharmaceutically acceptable carrier or vehicle can comprise an excipient, diluent, or mixture thereof. In one embodiment, the composition is a pharmaceutical composition.

The composition may be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, lozenges, suppositories, suspensions and the like. The compositions may be formulated to contain the daily dose in dosage units, or convenient aliquots of the daily dose, which may be in convenient volumes of individual tablets or capsules or liquids. In one embodiment, the solution is prepared from a water-soluble salt. In general, all compositions are prepared according to methods well known in pharmaceutical chemistry. Capsules may be prepared by mixing the compound with a suitable carrier or diluent and filling the correct amount of the mixture in the capsules. Commonly used carriers and diluents include, but are not limited to, inert powder materials such as many different kinds of starch, powdered cellulose, especially crystalline and microcrystalline cellulose; sugars such as fructose, mannitol and sucrose; cereal flour and similar edible powders.

Tablets may be prepared by direct compression, wet granulation or dry granulation. Their formulations typically incorporate diluents, binders, lubricants and disintegrants as well as compounds. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or calcium sulfate; inorganic salts, for example, sodium chloride; and powdered sugar. Powdered cellulose derivatives are also useful. In one embodiment, the pharmaceutical composition is free of lactose. Typical tablet binders are e.g. starch; gelatin; and sugars such as lactose, fructose, glucose, and the like. Natural and synthetic gums are also suitable, including gum arabic, alginates, methylcellulose, polyvinylpyrrolidone, and the like. Polyethylene glycols, ethyl cellulose and waxes may also be used as binders.

A lubricant may be required in the tablet formulation to prevent sticking of the tablet and sachet (pouch) to the die (die). Lubricants may be selected from such smooth solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils. Tablet disintegrants are materials that swell when wet to break up the tablet and release the compound. They include starches, clays, celluloses, algins, and gums. More specifically, for example, corn starch and potato starch, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation exchange resin, alginic acid, guar gum, citrus pulp and carboxymethyl cellulose, and sodium lauryl sulfate may be used. The tablets may be coated with sugar as a flavoring and sealing agent, or with a film protecting agent to modify the dissolution properties of the tablet. The composition may also be formulated as chewable tablets, for example, by using a substance such as mannitol in the formulation.

When it is desired to administer the compounds as suppositories, conventional bases may be used. Coconut oil is a traditional suppository base that may be modified by the addition of waxes to slightly raise its melting point. Water-miscible suppository bases are widely used, and include, in particular, polyethylene glycols of various molecular weights.

The effect of the compounds can be delayed or prolonged by appropriate formulations. For example, slowly soluble granules of the compounds may be prepared and incorporated into tablets or capsules, or as sustained release implantable devices. These techniques also include preparing several pellets of different dissolution rates and filling the capsule with a mixture of pellets. The tablets, capsules, or granules may be coated with a film that prevents dissolution for a predictable period of time (the coating may comprise, for example, polymethacrylate or ethylcellulose). Parenteral formulations can even be made long-acting by dissolving or suspending the compound in an oily or milky vehicle which allows the compound to be slowly dispersed in the serum.

5 examples

5.1 biological examples

5.1.1 in vitro assay

Recombinant NaV cell line

In vitro assays were performed on recombinant cell lines that stably expressed the heterotrimeric protein of interest starting from the introduced nucleic acids encoding the alpha subunit (hnav1.7, SCN9A), the beta subunit (SCNB1), and the beta subunit (SCNB 2). This cell line was engineered using human embryonic kidney 293 cells as the host background. Additional cell lines stably expressing recombinant Nav1.7 or Nav1.5. alpha. subunits, either alone or in combination with various β subunits, can also be used in vitro assays.

To generate the cells and cell lines provided herein, techniques such as those described in U.S. patent 6,692,965 and WO/2005/079462 may be used. Both of these documents are incorporated herein by reference in their entirety. This technique provides for the real-time assessment of millions of cells, so that any desired number of clones (from hundreds to thousands) expressing the desired gene can be selected. Using cell sorting techniques, such as flow cytometry cell sorting (e.g., using a FACS machine) or magnetic cell sorting (e.g., using a MACS machine), one cell per well is automatically deposited in a culture vessel (e.g., a 96-well culture plate) with high statistical confidence. The speed and automation of this technique allows for easy isolation of multigene recombinant cell lines.

FDSS Membrane potential in vitro assay

Cells stably expressing hNaV1.7 α, β 1, and β 2 subunits were maintained under standard cell culture conditions in Dulbecco's modified Eagles medium supplemented with 10% fetal bovine serum, glutamine, and HEPES, under assay conditionsThe day before, cells were harvested from stock culture plates using cell separation agents such as trypsin, CDB (GIBCO) or cell stripping agents (Mediatech) and plated in growth medium on 384-well culture plates at 10000-. Assay plates at 5% CO ₂Is maintained in a cell culture chamber at 37 ℃ for 22-48 hours. The medium was then removed from the assay plates and the loading buffer (137mM NaCl, 5mM KCl, 1.25mM CaCl) was added₂25 mhepes, 10mM glucose).

Membrane potential dyes: combining a blue membrane potential dye (molecular dynamics Inc.), or a membrane potential sensitive dye, HLB021-152(Anaspec), with a fluorescence quencher, e.g., bispicamide (DPA), acid Violet 17(AV17), Diazine Black (DB), HLB30818, FD and C-shadow (Blackde), Trypan blue (TrypanBlue), bromophenol blue, HLB30701, HLB30702, HLB30703, nitrazine yellow, nitro Red, DABCYL (molecular probes), FD and C Red NO.40, QSY (molecular probes), a metal ion quencher, e.g., Co, Red, DB, Red²⁺、Ni²⁺、Cu²⁺) And iodide ion.

Cells were incubated with membrane potential dye at 37 ℃ for 45-60 minutes. The dye-loaded assay plate was then placed in a high throughput fluorescence plate reader (HamamatsuFDSS). Kinetic energy readings begin with imaging the assay plate every second. After 10 seconds, assay buffer alone, or test compound diluted with assay buffer, was added to the cells (first addition step) and kinetic energy readings continued once every 2 seconds for a total of 2 minutes, after which time veratrine and scorpion venom diluted with assay buffer were used to stimulate the cells (second addition step) to assess the effect of the test compound.

Veratrine and scorpion venom protein modulate the activity of voltage-gated sodium channels through mechanistic recombination, including changes in the kinetics of inactivation. Activation of sodium channels in the resulting stable nav1.7 expressing cells alters the cell membrane potential and the fluorescence signal increases due to depolarization.

The control response elicited by veratrine and scorpion venom with buffer only (no test compound added) was taken as the maximal response. The assay results are expressed in Relative Fluorescence Units (RFU) and can be determined by using the maximum signal during the second addition/stimulation step or by calculating the difference of the maximum and minimum signals during the second addition/stimulation step. Signal inhibition was assessed in triplicate for each test compound concentration. Data were analyzed using GraphPadPrism software to determine IC50 values for test compounds.

Veratrine and scorpion venom from the Israeli japonica (Leiuusquinquestriatus) can be purchased from Sigma-Aldrich (St. Louis, Mo.). Stock solutions were prepared to 10mM (veratrine) in DMSO and 1mg/ml (scorpion venom) in demineralized water. The sodium channel agonist was diluted 4-fold with assay buffer, with a final concentration of veratrine of 2-25 μ M and scorpion venom of 2-20 μ g/ml.

Test compounds were prepared in DMSO as 2-10mM stock solutions. Stock solutionFurther dilutions were made in serial dilution steps with DMSO and then transferred to assay buffer as a 4-fold final assay concentration. The test compound was added during the first addition (pre-stimulation) step of kinetic energy reading. All test compound concentrations were evaluated in triplicate.

Compounds 1, 2, 3, 12, 13, 16, 26 and 32 showed nav1.7ic50 values of less than 0.13 μ M; compounds 4, 5, 6, 7, 8, 9, 10, 15, 18, 20 and 28 showed nav1.7ic50 values of 0.13 to 1.0 μ M; compounds 14, 17, 19, 21, 22 and 23 showed nav1.7ic50 values greater than 1.0 μ M and less than 20.0 μ M.

Compound 54 showed nav1.7ic50 values less than 0.1 μ M. Compounds 35, 43, 46, 49, 55, 57 and 59 showed nav1.7ic50 values of 0.1 μ M to 0.5 μ M. Compounds 34, 48, 49, 50, 51, 56 and 68 showed nav1.7ic50 values greater than 0.5 μ M and equal to or less than 1.0 μ M. Compounds 42, 45, 47, 52 and 58 showed nav1.7ic50 values greater than 1.0 μ M and less than 20.0 μ M.

Patchliner electrophysiological in vitro assay

In thatSodium currents from stable HEK293 cell lines expressing either nav1.7 or nav1.5 were recorded on the instrument (nanion technologies). Is a fully automated bench-top patch clamp platform and can simultaneously record up to 8 individual cells with a G Ω seal.

For patch clamp experiments, cells were grown in Dulbecco's modified Eagles medium supplemented with 10% fetal bovine serum, glutamine and HEPES under standard culture conditions. Cells were harvested and kept in suspension for up to 4 hours without significant change in the quality or capacity of the patch. According to aim atThe standard procedure of Nanion (R) for whole cell patch clamp recording. The experiments were performed at room temperature.

The voltage protocol was designed to establish for each of the 8 individual cells: 1) peak current amplitude (Imax), 2) test potential (Vmax) and 3) semi-inactivating potential (V)_1/2). To determine V_1/2A standard steady state inactivation protocol was performed using a series of 15 500ms depolarizing pre-pulses, in increments of 10mV (starting at-130 mV), followed by a 10ms test pulse to Vmax. To assess the affinity (Ki) of test compounds for the inactivated state of sodium channels, the maintenance potential of each cell was automatically set to V calculated from the steady state inactivation data_1/2. The current is activated with the following voltage scheme: at V_1/2Hold down for 2-5s, return to-120 mV for 5-10ms to mitigate rapid deactivation, step to test potential (Vmax) for 10-20 ms. This voltage protocol was repeated every 10s to establish a baseline by adding 2-3 times buffer followed by test compound. Dose-dependent inhibition was analyzed by using the Nanion data analysis package.

Compounds 1, 2, 5, 6, 8, 11, 12, 13, 15, 16, 20, 24, 26, 28, 29 and 32 showed nav1.7ic50 values of less than 0.1 μ M; compounds 14, 17, 18, 19, 21, 22, 23, 25 and 33 showed nav1.7ic50 values of 0.1 to 1.0 μ M.

Compounds 44, 49, 53, 54, 60, 61, 62, 63, 64, 65, 66, 67 and 69 showed nav1.7ic50 values of less than 0.1 μ M. Compounds 34 and 52 showed nav1.7ic50 values greater than 0.1 μ M and equal to or less than 0.5 μ M. Compounds 47 and 58 showed nav1.7ic50 values greater than 1.0 μ M and less than 10.0 μ M. Compounds 44, 49, 56 and 58 showed NaV1.7IC50 values greater than 10.0. mu.M (IC 50 measured according to the Patchliner electrophysiological assay described in the section beginning in paragraph [00305 ]).

In vitro cytochrome P450(CYP450) inhibition assay

We use a high-throughput compatible fluorescence-based CYP450 screening assay (CYP450, Invitrogen), the interaction of drug candidates with cytochrome P450 enzymes, which are the main determinants of drug clearance via oxidative metabolism, was evaluated according to manufacturer's instructions.

Briefly, four different concentrations (μ M-6.0, 2.0, 0.7, 0.2) of test compound, positive control (ketoconazole), and solvent control were incubated in a single well of a 96-well microtiter plate with the CYP3a4 enzyme complex for 20 minutes at room temperature. Tecan safire was used at the beginning of incubation ²Microplate reader-monochromator measures pre-read fluorescence (Ex-485nm/Em-530nm) to determine background fluorescence. At the end of the incubation time, the enzyme substrate and coenzyme were added and the reaction was monitored kinetically by measuring fluorescence every minute for 1 hour. The effect of the test compound on inhibition of CYP3a4 metabolism of the provided substrate was determined by calculating the ratio of the effective rate of reaction in the presence of the test compound to the effective rate of reaction in the absence of the inhibitor.

Compounds 9, 11, 13, 14, 15, 17, 18, 19, 21 and 22 showed 0-25% inhibition of CYP3a4 at the 6 μ M test concentration; compounds 5, 6, 8, 10 and 16 showed 25-50% inhibition of CYP3a4 at the 6 μ M test concentration; compounds 1, 2, 3, 4, 12, 20 and 32 showed 50-100% inhibition of CYP3a4 at the 6 μ M concentration tested.

5.1.2 in vivo assays

Formalin test

The formalin test (pain behavior) produces a two-phase response, with phase 1 (0 to 10 minutes after formalin injection) involving direct injury to nociceptors of sensory nerve endings and mimicking post-operative and wound pain, and phase 2 (11 to 40 minutes after formalin injection) involving neuroinflammatory pain mimicking inflammatory arthritis (joint pain).

Each animal was acclimated to the new environment for 2-3 days prior to testing. After acclimation, the test compound, positive control (e.g., mexiletine or lidocaine, which are well known to inhibit pain), or vehicle control (e.g., saline) is administered by intraperitoneal injection or oral gavage 15-20 minutes prior to formalin administration. The time of application of the test compound was recorded. Formalin solution in PBS (1.25%) was injected subcutaneously (s.c) in a volume of 50 μ L into the hind paw of each rat at time (T) 0 min. Each animal was then placed in a transparent observation room. Observations started at T ═ 1 min post injection and continued until 60 min post injection. Each animal was scored for the number of flinches (licks, bites or tremors) per minute by an automated nociception analyzer (Yaksh et al, "automated flinching detection system for formalin pain bioassay for formalin pain", "J.Appl.physiol.2001; 90: 2386-. This was achieved by measuring the movement of a small metal band (0.5g) placed on the ankle joint near the injected paw portion 15-30 minutes before the test compound was administered. Formalin was injected into the jaws with the metal strips and the animals were then placed unconstrained inside the observation room above the electromagnetic detector system. Paw flinches were detected by the system and counted automatically using a computer. At the end of the test, a file containing the identification information of each animal and the number of flinches per minute over time was written. The staggered test was performed 75 minutes after dosing. Changes in movement, e.g., immobility and other observations of sudden onset, were recorded throughout the study. At the end of the study, animals were euthanized.

For each compound tested, individual scores were obtained by calculating the cumulative number of flinches for the formalin test. The reduction in pain response obtained for each compound was then expressed as a percentage of inhibition (% inhibition) relative to vehicle (control) and calculated according to the following formula:

inhibition [ (% test compound score-vehicle score)/(vehicle score) ] × 100%.

Compounds 1, 2, 6, 8 and 12 showed a 24-78% (formalin assay, phase 1) and 29-73% (formalin assay, phase 2) reduction in pain response relative to vehicle control via intraperitoneal injection route at doses of 3-30 mg/kg.

Compound 1 showed a 14% (formalin assay, phase 1) and 17% (formalin assay, phase 2) reduction in pain response relative to vehicle control via the oral route at a dose of 75 mg/kg.

Compound 12 showed a 13-24% (formalin assay, phase 1) and 29-43% (formalin assay, phase 2) reduction in pain response relative to vehicle control via topical route of administration at a dose of 150 μ Ι _ of 1% or 2% w/v solution.

Partial Sciatic Nerve Ligation (PSNL) and Streptozotocin (STZ) -induced diabetes model

Part of the sciatic nerve ligation model is associated with neuropathic pain (e.g., a bulging of the intervertebral disc). The diabetes model is associated with diabetic nerve damage, which is one of the serious complications of diabetic patients.

Method for Partial Sciatic Nerve Ligation (PSNL)

250-350g male SD rats (Sprague-Dawleyratats) from appropriate animal sources were anesthetized with 2.5% isoflurane. The hind limbs were shaved and the skin was disinfected with 0.5% iodine and 75% alcohol. All surgical instruments were sterilized prior to surgery and between animals. An incision (1cm) was made in the middle of the thigh parallel to the muscle and sciatic nerve distribution. The muscle was left bare and incised at the junction of the two muscles (biceps femoris) as indicated by the light-colored (white) fascia line. The sciatic nerve is just below the muscle and then hooked out using an 18-20G feeding needle (90 degree bend); the sciatic nerve was laid flat on the feeding needle and approximately half of the diameter of the nerve was tightly ligated with a 7-0 suture. The ligation was successful as indicated by the tic response of the injured leg. After examination of hemostasis, 0.1-0.2ml (0.125%) of bupivacaine was administered to the incision area and the muscle and adjacent fascia were closed with 5-0 absorbable sutures. The skin is sutured with absorbable suture and tissue glue. Control animals (about 8-10 animals) using sham surgery underwent the same surgical procedure but without nerve ligation. Animals returned to their home cages after recovery from anesthesia.

Streptozotocin (STZ) -induced diabetic neuropathy model

Male SD rats from 250g to 350g from appropriate animal sources were used. Type I diabetes is induced by a single injection (intraperitoneal, intravenous or intramuscular) of 50-100mg/kg streptozotocin (STZ, sigma chemicals, st.louis, MO or VWR) freshly dissolved in sodium citrate (0.01M, ph 4.5). The animals in the sham group were injected with saline or vehicle of the same species. After a waiting period of about 2 days, the induction of diabetes in STZ-injected rats was confirmed by measuring plasma glucose concentration in blood from the tail vein after 6 hours of fasting. Glucose levels were determined by using a miniature blood glucose monitor (kit of AlphaTRAK2 available from AbbottLaboratories). Screening for hyperglycemia in STZ injected animals was done so that only animals with final blood glucose levels ≧ 300mg/dl were selected for study. The glucose levels in the sham group remained normal. Other parameters (water intake, food intake and body weight) were monitored before treatment with test compound and after treatment was stopped.

The analgesic effect of the test compounds was expressed as percent recovery (percent recovery) from sham-operated control baseline and was calculated according to the following formula:

Recovery rate { [ (sham group mean-test compound mean)/(sham group mean-vehicle mean) ] × 100% }100% }

Wherein "sham group mean" refers to the mean score in the sham group; "test compound mean" refers to the mean score of PSNL group (partially sciatic nerve ligated animals) or diabetic group (STZ treated animals) treated with test compound; "vehicle mean" refers to the mean score for the PSNL group or the diabetic group treated with vehicle only. The above formula was used to obtain the data for the following in vivo behavioral tests.

The following behavioral tests (i.e., plantar, paw pressure and von frey tests) were started after surgery or on day 3 after the use of diabetes-inducing agents, and once a week thereafter. Test compounds were tested to evaluate the effect of treatment on established neuropathic chronic pain starting at week 1 in the PSNL model and starting at week 5 in the diabetic neuropathy model.

Prevention or delay of onset of neuropathic pain

Treatment with a compound provided herein is initiated prior to and/or immediately after PSNL surgery to detect a compound provided herein and is continued for several days according to a daily oral dosing regimen to assess prevention and/or delay in onset of neuropathic pain prior to establishing pain or after cessation of dosing. To test whether a compound can prevent or delay the onset of neuropathic pain in the TPNL model, treatment with the compound was initiated on day 1 (3-4 hours after PSNL surgery) for two weeks until day 15. Pain responses were assessed prior to surgery and every three days post-surgery (e.g., on days 2, 5, 8, 11, and 14 post-surgery) by using behavioral tests, such as the von frey assay, plantar assay, or paw pressure test (all described below), and compared to sham, vehicle, and compound groups that began treatment with compound on day 7 after PSNL surgery and continued until day 15. Behavioral testing was performed every three days after dosing cessation (e.g., on days 18, 21, 24, and 27 post-surgery).

Diabetic neuropathy and anti-diabetic effect after long-term administration

The compounds provided herein were tested in the diabetic rat STZ model by chronic administration of the compounds for at least 7 days to evaluate the analgesic and antidiabetic effects of the compounds. The analgesic effect of a compound can be evaluated by using a behavioral test (e.g., the von frey test, plantar test, or paw pressure test described below). The anti-diabetic effect of the compounds can be evaluated based on the increase in glucose levels, food intake, water intake in the compound-treated group compared to the untreated vehicle group and the normal, non-diabetic sham-operated control group.

Thermal hyperalgesia (plantar test)：

The plantar test quantitatively assesses the thermal threshold of the hind paw.

Rats were placed on the glass surface of a thermal testing apparatus (model 336, IITC/life sciences instruments, woodland hills, CA) and allowed to acclimate to the new environment for 10 minutes before testing on the glass surface at room temperature. The animals were placed in an observation chamber and the temperature of the glass surface was kept constant at 30-32 ℃. A moving radiant heat source located below the glass was focused on the hind paw of each rat. The apparatus was set at 55% (heating rate-3 ℃/s) heating intensity, cut-off at 10 seconds. The paw withdrawal latency was recorded by a digital timer. The thermal threshold was determined as the average withdrawal latency of two to three consecutive trials of two hind paws. A 10 second cutoff is used to prevent potential tissue damage.

Mechanical hyperalgesia (paw pressure test)

The paw pressure test assesses nociceptive mechanical thresholds (in grams) and is measured with a ugobasil analytical instrument (varee, Italy).

The test is performed by applying harmful (painful) pressure on the hind limb. By depressing the pedal that starts the motor, the force increases in a linear proportion (32 g/s). When the animal expresses Pain by retracting the paw or sounding, the pedal is released immediately and the nociceptive Pain threshold (cutoff of 150g for avoiding tissue damage) is read on a scale (Courteix et al, study of the sensitivity of the rat diabetes-induced Pain model to a range of analgesics (StudyoftheSensitivityofheibies-induced Pain model of analgesics). Pain1994, month 5; 57(2): 153-160.1994). Both hind paws were used to assess mechanical hyperalgesia. At least two trials were performed per rat, 10 minutes apart, and the average was used. The testing process for a particular rat begins after 5 minutes of acclimation, or once the rat stops exploring and exhibits an acclimation testing environment.

Tactile allodynia (VonFrey assay)

The von frey test quantifies the mechanical sensitivity of the hind paw. This test utilizes non-noxious stimuli and is therefore considered a measure of tactile allodynia.

The animal is placed under a clear plastic box above the wire mesh floor, which allows full access to the paw. Allowing at least 5 minutes of behavioral adaptation. The mechanical Paw Withdrawal Threshold (PWT) was measured using the top and bottom test paradigm. Von frey filaments applied with logarithmically increasing force (2.0, 4.0, 6.0, 8.0, 10.0, 15.0, 26, 60g or a size of 4.31, 4.56, 4.74, 4.93, 5.07, 5.18, 5.46, 5.88) on the middle plantar paw of neuropathic pain (e.g., PSNL or diabetes) animals for 2-3 s. Applied to the central area of the plantar surface to avoid foot pad. First a stimulus of 4.0g was applied. Each time a withdrawal response is generated for a given probe, the next smaller von frey probe is applied. The next higher von frey probe is applied whenever a negative response is generated. The test continues until either (1) a response to more than 4 stimuli after the first change in response is obtained (3-5 trials in total), or (2) the upper/lower end of the von frey cilia is reached (flexion). If the animal did not respond to any von frey cilia, the value of 26g corresponding to the next logarithmically increased potential von frey filament was assigned as the threshold. This test continues until the cilia with the lowest force inducing the rapid paw are identified, or when a force of approximately 26g cutoff is reached. This cutoff force is used because it represents approximately 10% of the animal's body weight and serves to prevent lifting of the entire hind limb due to the use of stiffer cilia, which can alter the nature of the stimulus. The value of each cilia was confirmed once a week by measuring the size in grams that the cilia exert when placed on an electronic balance. Cilia were applied only when the rat was stationary and all four paws were standing. The retraction response is considered effective only when the hind paw is fully removed from the platform. Although rare, if the rat walks immediately after applying the cilia, rather than just lifting the claws, the cilia are reapplied. Occasionally, the hind paw is only distracted after a single application because the hind paw is not lifted from the platform, which is not considered a withdrawal response. The trial consisted of applying the von frey cilia 5 times at 5 second intervals on the hind paw, or once the hind paw was properly placed on the platform. If no recession occurs during 5 applications of a particular cilia, the next larger cilia in the series are applied in a similar manner. When the hind paw is retreated from a particular cilia in 4 or 5 of 5 applications, the cilia value in grams is considered to be the threshold of retreat. Once the threshold for the left hind paw was determined, the same test procedure was repeated for the right hind paw after 5 minutes.

Weight bearing (spontaneous pain)

Weight bearing tests were performed with a partial sciatic nerve ligation model as described herein. In a weight bearing test, rats were tested for hypersensitivity and spontaneous pain using an incapacitiance tester (LintonInstruments, Norfolk, UK). Rats were placed in the plastic box of the apparatus. During this time (1-2s), the integrated jaw pressure is displayed separately for the right and left legs. The ratio of the pressures of the right and left legs is calculated as the left/right rear leg weight distribution ratio. The load-bearing assay was repeated 3 times over a 5 minute period. The average distribution ratio of 3 measurements was calculated.

In the PSNL model, compounds 1 and 2 showed recovery rates of 49-62% (paw pressure test), 59-73% (plantar test) and 50-66% (weight bearing) relative to vehicle control via intraperitoneal injection route at a dose of 30 mg/kg. Compounds 1 and 2 had no significant effect in the tactile anomaly test measured 30-60 minutes after dosing.

In the PSNL model, compounds 49 and 54 showed a recovery rate of 28-32% (paw pressure test), 54-63% (plantar test) and 40-65% (weight bearing) by the oral route at a dose of 10mg/kg relative to vehicle control, and a recovery rate of 64-85% (paw pressure test), 81-90% (plantar test) and 64-75% (weight bearing) by the oral route at a dose of 30mg/kg relative to vehicle control. There was no significant effect in the tactile anomaly test compared to the vehicle control measured 30 minutes after dosing. At 2 hours post-dose, tactile abnormalities are generally expected to be reversed by up to 90% relative to vehicle control.

In the Streptozotocin (STZ) -induced diabetes model, compounds 15 and 49 showed recovery rates of 66-68% (paw pressure test), 93-100% (plantar test) relative to vehicle control at a dose of 30mg/kg by intraperitoneal or oral route, while there was no significant effect in the tactile abnormality test relative to vehicle control when measured 30 minutes after administration. After 9 days of repeated dosing, tactile abnormalities are expected to be reversed by up to 90% relative to vehicle control.

Torsion reaction model (inflammatory abdominal pain)

The writhing response model of acetic acid is associated with visceral pain (abdominal pain, such as stomach pain, and pain caused by, for example, bile duct congestion and kidney stones). Writhing response test to assess acute abdominal visceral pain.

After 2-3 days of acclimation, the test compound, positive control or vehicle control was administered by intraperitoneal injection (i.p.) or oral gavage 15-30 minutes prior to acetic acid administration. The time of administration of the test compound was recorded. For mice: the method A comprises the following steps: a10 ml/kg volume of 0.6% acetic acid in saline solution was injected intraperitoneally. The method B comprises the following steps: a5 ml/kg volume of 1.2% acetic acid in saline solution was injected intraperitoneally. For rats: a2 ml/kg volume of 4% acetic acid in saline solution was injected intraperitoneally at time T-0 minutes. Each animal was placed in a clear plastic cage. The number of writhing reaction movements was counted over a 45 minute period at T ═ 5 minutes. Alternatively, the writhing reaction movements were counted over 5 minutes and repeated every 5 minutes, starting at T-5 minutes over a 45 minute period.

For each compound tested, individual scores were obtained by calculating the cumulative writhing response movements over the time period studied. The reduction in pain obtained for each compound was then expressed as a percentage of inhibition (% inhibition) relative to vehicle (control) and calculated according to the following formula:

inhibition [ (% test compound score-vehicle score)/(vehicle score) ] × 100%.

Wherein "test compound score" refers to the group treated with the test compound or substance; "vehicle score" refers to the group treated with vehicle only.

Compound 2 tested in rats showed a 48-58% reduction in pain via the intraperitoneal route at a dose of 10-30mg/kg relative to vehicle control.

Compounds 49, 53 and 54 (method B) showed a 25-35% reduction in pain by the oral route at a dose of 10mg/kg (C57 mice). Compounds 2, 15, 49, 53 and 54 showed a 37-47% reduction in pain by the oral route and a 54-75% reduction in pain by the intraperitoneal route at a dose of 30mg/kg (C57 mice).

Model of itch/pruritus

The itching or scratching behavior of the animals studied can be used as a measure of pruritus.

The scratching was analyzed by counting the number of scratches from a video recording or live broadcast by direct visual observation, or by using an automatic analyzer (available from university of california, san diego, CA). Using an automatic analyzer, itch was measured by measuring the movement of a small metal band (0.5g) placed on the ankle near the animal's hind paw prior to injection of the itch agent. Itch agents, for example, histamine hydrochloride (5mg/ml saline, 20. mu.l/mouse or 50. mu.l/rat) or 5-hydroxytryptamine hydrochloride (5mg/ml saline, 20. mu.l/mouse, 50. mu.l/rat) are injected into the scapular area of the shaved hairs of animals to cause local skin itch.

The injection site was chosen such that only the hind paw wearing the metal band was accessible and when the animal used the hind paw to scratch the itchy area, a rhythmic scratching action (unlike the combing by the forelimbs) was recorded.

After percutaneous (i.d.) or subcutaneous (s.c.) injection of the pruritic agent, the animals were placed in a viewing chamber (typically 22 x 24cm) above the electromagnetic detection system without restraint. The number of scratches on the scapular region of the injection was detected by the system and automatically counted by using a computer over a period of 45 to 60 minutes. During the test period, observations are also recorded, for example, manually counting the number of scratches over time and comparing it with the number recorded by the automatic analyzer.

To measure the efficacy of a test compound as an inhibitor of itch, the compounds provided herein are dissolved in an appropriate vehicle, e.g., a mixture of PEG, Tween and water (typically 30% PEG/20% Tween/50% water), at a concentration of about 1-20% w/v, and about 100 μ Ι is applied over a circular area of shaved hair (about 20mm diameter) about 15 to 30 minutes prior to injection of the itch agent. For compounds administered orally, 10-30mg/kg of the test compound is dissolved in a vehicle, e.g., in water or PEG/water (typically 50% each of PEG/water), and administered by oral gavage 30-45 minutes prior to injection of the pruritic agent. In contrast to the compounds, positive controls, e.g., 20% benzocaine, and negative controls, e.g., saline or vehicle, were also administered separately and the results recorded.

For the in vivo model described above, the data obtained was analyzed using the two-tailed distribution of the student's t-test. All data are expressed as mean ± standard deviation. ANOVA (analysis of variance between groups) was used as a method to analyze the overall effect of the dose response of the tested compounds. For compounds that give a significant F-value at the time of testing, the Bonferonni test was subsequently applied.

Evaluation of antidiabetic Effect in vivo model of diabetes

Diabetes was induced in rats as described in paragraph [00327] above.

The animals selected for the study showed stable signs of diabetic condition, e.g., hyperglycemia, increased water and food intake, without weight gain or weight loss. Only animals with blood glucose levels ≧ 300mg/dl were used for the study ultimately (6-hour fasting from 8 AM to 2 PM), and no animals exhibiting hyperglycemia (blood glucose levels <300mg/dl) were excluded from the study. Baseline glucose levels, daily food and water intake, and behavioral tests (von frey, paw pressure and plantar tests) were measured once a week for 28 weeks for each animal, and once every 2-4 weeks for an additional 28-30 weeks. At the selected weeks (starting from week 6) for compound testing, diabetic rats were divided into two test groups: vehicle control group and test compound treatment group (n-10 per group). Sham (only saline without STZ, i.p. injection, n-10) was added as a normal non-diabetic control group. To minimize animal stress associated with repeated daily treatments, diabetic animals treated with the compounds received the test compound in their drinking water containing 2% PEG600 and 1% glycofurol at a daily dose of 60mg/kg (the concentration of the test compound in the drinking water depends on the average daily water consumption of the individual animals over the determined pre-dosing period, with an average of 0.1-0.11 mg/ml). The vehicle control group received drinking water containing 2% PEG600 and 1% glycogen without test compound. Treatment lasted 9 days. On day 10, drinking water with test compound or vehicle (2% PEG600 and 1% glycogen) was replaced with plain drinking water in all groups. Monitoring of glucose levels, food and water intake, and behavioral testing continued for an additional 28-30 weeks. Chronic treatment with the compound at a dose of 60 mg/kg/day in drinking water resulted in a rapid and sustained increase in mechanical pain (paw pressure test) and thermal pain (plantar test) without a rapid drug resistance response. A gradual significant reversal of up to 90% of mechanical allodynia (von frey test) was achieved after 9 days of treatment. Paw pressure test and plantar test thresholds returned to the pre-treatment baseline (measured on day 11, day 2 after compound withdrawal), while the tender threshold (von frey test) continued to be measured at levels significantly above the pre-treatment level baseline for up to 5 days after compound withdrawal.

Figures 1 to 3 show food intake, glucose levels and levels of intake for vehicle control, test compound treated (compound 49, 60 mg/kg/day) and sham groups, respectively. The test compound treated group exhibited an improvement in general appearance and/or health after treatment with compound 49 discontinued on day 9 (treatment period marked with dashed lines in each of fig. 1-3). In particular, fig. 1, 2 and 3 show that food intake, glucose levels and levels of intake (all of which are clinical manifestations of diabetes in animal models) are significantly reduced compared to the vehicle control group. The food intake, glucose levels and horizontal intake of the compound-treated group were significantly reduced from the vehicle control group for up to week 52. The sham group showed no significant changes in food intake, glucose levels or water intake during the experiment. Error bars are not shown since the standard deviation in the sham group is less than 5%.

5.2 examples of NaV modulators

5.2.1 general procedure

5.2.1.1LCMS method

Method A

LC-MS was performed on AcquistyH-ClassUPLC, PDA and SQ detectors. The column used was BEHC 1850X 2.1mm X1.7 μm and the column flow rate was 0.55 ml/min. Mobile phases (a) 0.1% formic acid +5mM ammonium acetate in water and (B) 0.1% formic acid in acetonitrile were used. The ultraviolet spectrum is recorded at its lambda maximum and the mass spectrum is recorded using ESI counts. The following gradient was used to monitor the progress of the reaction and to analyze the final product.

Time (minutes)	％A	％B
			0.01	95	05
0.40	95	05
			0.80	65	35
1.20	45	55
			2.50	00	100
3.30	00	100
			3.31	95	05
4.00	95	05

Method B

LC-MS was performed on waters lcalliance2995, PDA2996 and SQ detector. The column used was X-BRIDGEC 18150X 4.6mm X5 microns, and the column flow rate was 1.0 ml/min. Mobile phases (a) 0.1% ammonia in water and (B) 0.1% ammonia in acetonitrile were used. The ultraviolet spectrum is recorded at its lambda maximum and the mass spectrum is recorded using ESI counts. The following gradient was used to monitor the progress of the reaction and to analyze the final product.

Time (minutes)	％A	％B
			0.01	90	10
5.00	10	90
			7.00	00	100
11.00	00	100
			11.01	90	10
12.00	90	10

Method C

Time (minutes)	％A	％B
			0.01	100	00
7.00	50	50
			9.00	00	100
11.00	00	100
			11.01	100	00
12.00	100	00

Method D

LC-MS was performed on waters lcalliance2995, PDA2996 and SQ detector. The column used was X-BRIDGEC 18150X 4.6mm X5 microns, and the column flow rate was 1.0 ml/min. Mobile phases (a)20mM aqueous ammonium acetate solution and (B) 100% methanol were used. The ultraviolet spectrum is recorded at its lambda maximum and the mass spectrum is recorded using ESI counts. The following gradient was used to monitor the progress of the reaction and to analyze the final product.

5.2.1.2HPLC method

Method A

HPLC was performed on a Waterse2695, PDA detector. The column used was phenomenex gemini, C18150 × 4.6mm × 5 microns, and the column flow rate was 1.00 ml/min. Mobile phases (a) 0.1% formic acid in water and (B) 0.1% formic acid in acetonitrile were used. The ultraviolet spectrum is recorded at its lambda maximum. The following gradient was used.

Time (minutes)	％A	％B
			0.01	90	10
7.00	10	90
			9.00	00	100
13.00	00	100
			13.01	90	10
17.00	90	10

Method B

Time (minutes)	％A	％B
			0.01	100	00
7.00	50	50
			9.00	00	100
13.00	00	100
			13.01	100	00
17.00	100	00

Method C

HPLC was performed on a Waterse2695, PDA detector. The column used was X-BRIDGE, C18150X 4.6mm X5 microns, and the column flow rate was 1.00 ml/min. Mobile phases (a) 0.1% ammonia in water and (B) 0.1% ammonia in acetonitrile were used. The ultraviolet spectrum is recorded at its lambda maximum. The following gradient was used.

Method D

5.2.1.3PREPHPLC method

Method A

PREPHPLC was performed on ShimadzuUFLC, LC-20AP and UV detector. The column used was SunfireOBD, C18250X 19mm X5 microns, and the column flow rate was 18.00 ml/min. Mobile phases (a) 0.1% HCL in water and (B) 100% acetonitrile were used. The ultraviolet spectrum is recorded at its lambda maximum. The following gradient was used.

Method B

PREPHPLC was performed on ShimadzuUFLC, LC-20AP and UV detector. The column used was SunfireOBD, C18250X 19mm X5 microns, and the column flow rate was 18.00 ml/min. Mobile phases (a) 0.1% formic acid in water and (B) 0.1% formic acid in acetonitrile were used. The ultraviolet spectrum is recorded at its lambda maximum. The following gradient was used.

Method C

PREPHPLC was performed on ShimadzuUFLC, LC-20AP and UV detector. The column used was X-BRIDGE, C18250X 19mm X5 μm, and the column flow rate was 18.00 ml/min. Mobile phases (a) 0.1% ammonia in water and (B) 0.1% ammonia in acetonitrile were used. The ultraviolet spectrum is recorded at its lambda maximum. The following gradient was used.

5.2.1.4 list of abbreviations

Ac ═ acetyl group

EtOAc ═ ethyl acetate

Bn ═ benzyl

Boc ═ tert-butoxycarbonyl

Bzl ═ benzyl

DBU ═ 1, 8-diazabicyclo [5.4.0] undec-7-ene

DCC-1, 3-dicyclohexylcarbodiimide

DCM ═ dichloromethane

DEAD ═ azodicarboxylic acid diethyl ester

DIC ═ diisopropylcarbodiimide

DIPEA ═ diisopropylethylamine

Water is softened water

DME ═ 1, 2-dimethoxyethane

DMF ═ N, N-dimethylformamide

DMSO ═ dimethyl sulfoxide

EDC ═ 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride

Et2O ═ diethyl ether

HOBt ═ 1-hydroxybenzotriazole

IPA (isopropyl alcohol)

KHMDS ═ bis (trimethylsilyl) amino potassium

LAH ═ lithium aluminum hydride

LDA ═ lithium diisopropylamide

LHMDS lithium bis (trimethylsilyl) amide

MOM ═ methoxymethyl

NaHMDS sodium bis (trimethylsilyl) amide

NBS ═ N-bromosuccinimide

Ph ═ phenyl

PMB ═ p-methoxybenzyl

Py ═ pyridine

TEA ═ triethylamine

TFA ═ trifluoroacetic acid

THF ═ tetrahydrofuran

Tol ═ p-toluoyl

5.2.2 examples

Example 1: synthesis of 3- (4- (2- (4- (N-1,2, 4-thiadiazol-5-ylsulfamoyl) -2-chloro-5-fluorophenoxy) -5-chlorophenyl) picolinamido) propionic acid

Scheme 5

Step 1: preparation of (5-chloro-2-hydroxyphenyl) boronic acid.

A solution of 5-chloro-2-methoxyphenylboronic acid (10.0g, 53.6mmol) in dichloromethane (100ml) was cooled to a temperature of 5-10 ℃. To the above mixture was added dropwise 100ml of a 1M boron tribromide solution in DCM over a period of 30 minutes using a pressure equalizing dropping funnel. The resulting reaction mixture was then stirred at room temperature for 30 minutes. After completion of the reaction, the mixture was poured dropwise into an ice-cold saturated sodium bicarbonate solution (600 ml). The resulting mixture was allowed to stir at room temperature for 1 hour. The DCM layer was separated and the aqueous layer thus collected was cooled to a temperature of 10-15 ℃. A 1N dilute hydrochloric acid solution was then added to the above cooled aqueous layer and this resulted in the formation of a precipitate. The solid was filtered off under vacuum and dried to afford 9g (97% yield) of product. LC-MS: 170.9(M + H).

Step 2: preparation of 4- (5-chloro-2-hydroxyphenyl) cyanopyridine

(5-chloro-2-hydroxyphenyl) boronic acid (1.49g, 8.65mmol) and potassium carbonate (3.99g, 21.64mmol) were added sequentially to IPA of 4-chlorocyanopyridine (1.0g, 7.2mmol) at room temperature: toluene (7 ml: 7ml) solution. The resulting reaction mixture was degassed by purging with nitrogen for 15 minutes. Thereafter a calculated amount of Tetrakis (0.416g, 0.36mmol) was added to the reaction mixture and a nitrogen purge continued for a further 20 minutes. The resulting reaction mixture was then refluxed at 100 ℃ for 20 hours. After completion of the reaction, the mixture was concentrated under vacuum. To the resulting crude cake was added water (50ml), and the mixture was extracted with ethyl acetate (3X 25 ml). The combined organic extracts were washed with water (20ml), brine (20ml), dried over sodium sulfate and concentrated in vacuo to give the desired crude product. The crude product was purified by column chromatography using normal phase silica gel. The desired product was eluted in approximately 20-30% ethyl acetate in hexane. Evaporation of the product fractions gave 0.8g (yield 48%) of a solid, the desired product. LC-MS: m/z 231.1(M + H).

And step 3: preparation of 4- (5-chloro-2-hydroxyphenyl) picolinic acid)

To a solution of 4- (5-chloro-2-hydroxyphenyl) cyanopyridine (0.5g, 2.17mmol) in THF (20ml) was added a solution of potassium hydroxide (4.276g, 14mmol) in water (10 ml). The resulting reaction mixture was then refluxed at 100 ℃ for 5 hours. After completion of the reaction, the mixture was concentrated under vacuum. Ice-cold water was added to the reaction mixture, and the resulting mixture was acidified with 1n hcl to pH 3-6. The resulting solid precipitate was filtered and dried to provide 0.5g (yield 93%) of solid product. LC-MS: 249.8(M + H).

And 4, step 4: preparation of 3- (4- (5-chloro-2-hydroxyphenyl) -picolinamide) methyl propionate)

To a solution of 4- (5-chloro-2-hydroxyphenyl) picolinic acid (0.6g, 2.40mmol) in THF (20ml) at 0 deg.C were added EDC (0.69g, 3.61mmol) and HOBT (0.49g, 3.61mmol) in that order. The reaction mixture was stirred at 0 ℃ for 30 minutes. Beta-alanine methyl ester (0.40g, 2.88mol) was added at 0 ℃. The temperature of the reaction mixture was then allowed to rise to room temperature and stirred for 20 hours. After completion of the reaction, water (50ml) was added to the reaction mixture. The resulting mixture was then extracted with ethyl acetate (3X 25 ml). The combined organic extracts were washed with water (20ml), brine (20ml), dried over sodium sulfate and concentrated in vacuo to give the desired crude product. The crude product was purified by column chromatography using normal phase silica gel. The desired product was eluted in about 0-5% methanol in dichloromethane. Evaporation of the product fractions gave 0.72g (yield 89%) of the desired product. LC-MS: 335.6(M + H).

And 5: 3- (4- (5-chloro-2- (2-chloro-4- (N- (2, 4-dimethoxybenzyl) -N- (1,2, 4-thia-ethyl) Oxadiazole-5-yl) sulfamoyl) -5 fluorophenoxy) phenyl) picolinamido) methyl propionate) and their use in the treatment of diabetes Become into

To a solution of methyl 3- (4- (5-chloro-2-hydroxyphenyl) picolinamido) propionate) (0.72g, 2.15mmol) in DMF (10ml) under nitrogen at room temperature was added one portion of K₂CO₃(0.59g, 4.3 mol). The resulting reaction mixture was then allowed to stir at room temperature for 15 minutes. To the reaction mixture was then added a calculated amount of 5-chloro-N- (2, 4-dimethoxybenzyl) -2, 4-difluoro-N- (1,2, 4-thiadiazol-5-yl) benzenesulfonamide (1.0g, 2.15 mol). Further allowThe resulting reaction mixture was allowed to stir at room temperature for 3 hours after completion of the reaction, water (10ml) was added, then the resulting mixture was extracted with ethyl acetate (3 × 25ml), the combined organic extracts were washed with water (20ml), brine (20ml), dried over sodium sulfate, and concentrated under vacuum the crude product was purified by column chromatography using normal phase silica gel, the desired product was eluted in approximately 20-25% ethyl acetate in hexane solution, the product fractions were evaporated to give 1.0g (yield: 60%) of the desired product LC-MS: M/z 776.3(M + H).

Step 6: 3- (4- (5-chloro-2- (2-chloro-4- (N- (2, 4-dimethoxybenzyl) -N- (1,2, 4-thia-ethyl) Preparation of oxadiazol-5-yl) sulfamoyl) -5-fluorophenoxy) phenyl) picolinamido) propanoic acid)

To a solution of methyl 3- (4- (5-chloro-2- (2-chloro-4- (N- (2, 4-dimethoxybenzyl) -N- (1,2, 4-thiadiazol-5-yl) sulfamoyl) -5-fluorophenoxy) phenyl) picolinamido) propanoate) (1.0g, 1.28mmol) in THF (10mL) was added a solution of lithium hydroxide monohydrate (0.27g, 6.43mmol) in water (5 mL). The resulting reaction mixture was allowed to stir at room temperature for 3 hours. After completion of the reaction, ice-cold water was added to the reaction mixture, and the resulting mixture was acidified with 1n hcl to pH 4-6. The resulting acidic aqueous solution was extracted with ethyl acetate (3 × 25 ml). The combined organic extracts were washed with water (20ml), brine (20ml), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography using normal phase silica gel. The desired product was eluted in about 0-5% methanol in dichloromethane. The evaporation of the product fractions gave 1g (yield 99%) of the desired product. LC-MS: 762.8(M + H).

And 7: 3- (4- (2- (4- (N-1,2, 4-thiadiazole-5-ylsulfamoyl) -2-chloro-5-fluorophenoxy) Preparation of (E) -5-chlorophenyl) picolinamido) propionic acid

To a solution of 3- (4- (5-chloro-2- (2-chloro-4- (N- (2, 4-dimethoxybenzyl) -N- (1,2, 4-thiadiazol-5-yl) sulfamoyl) -5-fluorophenoxy) phenyl) picolinamido) propanoic acid) (1.0g, 1.3mmol) in DCM (10ml) was added dropwise a solution of 4N hydrochloric acid in ethyl acetate (0.5ml) at room temperature. The resulting reaction mixture was further stirred at room temperature for 2 hours. After completion of the reaction, pentane (20ml) was added to the reaction mixture to give a solid precipitate. The solid thus obtained was washed twice with pentane (15ml) and dried under vacuum. Aqueous solution of 0.1% HCl was used: the crude material obtained was further purified by preparative HPLC on acetonitrile mobile phase. The evaporation of the pure preparation fractions gives 0.29g (yield 34%) of the desired product, i.e. the salt of HCl. LC-MS: 612.9(M + H). 1HNMR (DMSO-d6),9.03(br,1H),8.71(d, J ═ 4.8Hz,1H),8.51(s,1H),8.20(s,1H),7.88(d, J ═ 7.2Hz,1H),7.80(br,2H),7.60(d, J ═ 8.4Hz,1H),7.28(d, J ═ 8.4Hz,1H),7.22(d, J ═ 10.8Hz,1H),4.01(br, 2H).

The following 9 compounds were synthesized according to the synthetic scheme described in example 1.

Scheme 6

Example 2: 2- (4- (2- (4- (N- (1,2, 4-thiadiazol-5-yl) sulfamoyl) -2-chloro-5-fluorophenoxy) -5-chlorophenyl) pyridine carboxamido) acetic acid

Compound 2 was synthesized according to the procedure described for the synthesis of example 1 by replacing β -alanine methyl ester with glycine methyl ester hydrochloride in step 4. LC-MS: 598.5(M + H). 1HNMR (DMSO-d6),9.03(t, J ═ 6.0Hz,1H),8.71(d, J ═ 4.8Hz,1H),8.53(s,1H),8.19(s,1H),7.88(d, J ═ 7.2Hz,1H),7.78-7.81(m,2H),7.60(dd, J ═ 2.4,8.8Hz,1H),7.29(d, J ═ 8.8Hz,1H),7.22(d, J ═ 10.8Hz,1H),4.00(br, 2H).

Example 3: 5- (4- (2- (4- (N- (1,2, 4-thiadiazol-5-yl) sulfamoyl) -2-chloro-5-fluorophenoxy) -5-chlorophenyl) picolinamido) pentanoic acid.

Compound 3 was synthesized according to the procedure described for the synthesis of compound 1 by replacing β -alanine methyl ester with 5-aminopentanoate methyl ester in step 4. LC-MS: 640.2(M + H).

Example 4: 4- (4- (2- (4- (N- (1,2, 4-thiadiazol-5-yl) sulfamoyl) -2-chloro-5-fluorophenoxy) -5-chlorophenyl) pyridine carboxamido) butanoic acid

Compound 4 was synthesized according to the procedure described for the synthesis of compound 1 by replacing β -alanine methyl ester with methyl 4-aminobutyrate in step 4. LC-MS: 626.6(M + H). 1HNMR (MeOH-d4),8.65(d, J ═ 4.8Hz,1H),8.27(s,1H),8.26(s,1H),7.91(d, J ═ 6.8Hz,1H),7.74(d, J ═ 4.4Hz,1H),7.71(d, J ═ 2.4Hz,1H),7.60(dd, J ═ 2.8,8.8Hz,1H),7.24(d, J ═ 8.8Hz,1H),6.94(s,1H),6.78(d, J ═ 10.8Hz,1H),3.75(br,2H),2.41(t, J ═ 7.2Hz,2H),1.97(t, J ═ 7.2Hz, 2H).

Example 5: (R) -2- (4- (2- (4- (N-1,2, 4-thiadiazole-5-sulfamoyl) -2-chloro-5-fluorophenoxy) -5-chlorophenyl) pyridine carboxamide) propionic acid

Compound 5 was synthesized according to the procedure described for the synthesis of compound 1 by replacing β -alanine methyl ester with DL-alanine methyl ester hydrochloride in step 4. LC-MS: 613.8(M + H). 1HNMR (MeOH-d4),8.65(d, J ═ 5.6Hz,1H),8.27(s,1H),8.25(s,1H),7.90(d, J ═ 6.8Hz,1H),7.74(dd, J ═ 1.6,4.8Hz,1H),7.70(d, J ═ 2.4Hz,1H),7.59(dd, J ═ 2.8,8.8Hz,1H),7.23(d, J ═ 8.8Hz,1H),6.78(d, J ═ 10.8Hz,1H),4.63(q, J ═ 7.2Hz,1H),1.56(d, J ═ 7.6Hz, 3H).

Example 6: (R) -2- (4- (2- (4- (N-1,2, 4-thiadiazole-5-sulfamoyl) -2-chloro-5-fluorophenoxy) -5-chlorophenyl) pyridine carboxamide) propionic acid

Compound 6 was synthesized according to the procedure described for the synthesis of compound 1 by replacing β -alanine methyl ester with DL-alanine methyl ester hydrochloride in step 4. LC-MS: 613.8(M + H). 1HNMR (MeOH-d4),8.67(d, J ═ 5.2Hz,1H),8.27(s,1H),8.25(s,1H),7.91(d, J ═ 7.2Hz,1H),7.75(dd, J ═ 2.0,5.2Hz,1H),7.71(d, J ═ 2.8Hz,1H),7.60(dd, J ═ 2.4,8.4Hz,1H),7.24(d, J ═ 8.8Hz,1H),6.78(d, J ═ 10.8Hz,1H),4.63(q, J ═ 7.2Hz,1H),1.56(d, J ═ 7.6Hz, 3H).

Example 7: 2- (6- (2- (4- (N- (1,2, 4-thiadiazol-5-yl) sulfamoyl) -2-chloro-5-fluorophenoxy) -5-chlorophenyl) pyridine carboxamido) acetic acid

Compound 7 was synthesized according to the procedure described for the synthesis of compound 1 by replacing 4-chlorocyanopyridine with 6-chlorocyanopyridine in step 2. LC-MS: 597.7(M + H). 1H-nmr (meod),8.19(s,1H),8.00-8.07(m,4H),7.9s (d, J ═ 6.8Hz,1H),7.59(dd, J ═ 2.4,8.8Hz,1H),7.25(d, J ═ 8.8Hz,1H),6.72(d, J ═ 10.4Hz,1H),4.09(s, 2H).

Example 8: (S) -2- (4- (2- (4- (N-1,2, 4-thiadiazole-5-sulfamoyl) -2-chloro-5-fluorophenoxy) -5-chlorophenyl) pyridine carboxamide) propionic acid

Compound 8 was synthesized according to the procedure described for the synthesis of compound 1 by substituting L-alanine methyl ester hydrochloride for β -alanine methyl ester in step 4. LC-MS: 612.6(M + H). 1HNMR (DMSO-d6),8.85(d, J ═ 7.6Hz,1H),8.71(d, J ═ 5.6Hz,1H),8.52(s,1H),8.19(s,1H),7.88(d, J ═ 7.2Hz,1H),7.78-7.80(m,2H),7.60(dd, J ═ 2.4,8.8Hz,1H),7.28(d, J ═ 8.8Hz,1H),7.22(d, J ═ 10.8Hz,1H),4.47(q, J ═ 7.2Hz,1H),1.42(d, J ═ 7.2Hz, 3H).

Example 9: 3- (4- (2- (4- (N- (1,2, 4-thiadiazol-5-yl) sulfamoyl) -2-cyanophenoxy) -5-chlorophenyl) pyridine carboxamide) propionic acid

Compound 9 was synthesized according to the procedure described for the synthesis of compound 1 by substituting 3-cyano-N- (2, 4-dimethoxybenzyl) -4-fluoro-N- (1,2, 4-thiadiazol-5-yl) benzenesulfonamide for 5-chloro-N- (2, 4-dimethoxybenzyl) -2, 4-difluoro-N- (1,2, 4-thiadiazol-5-yl) benzenesulfonamide in step 5. LC-MS: 584.8(M + H). 1H-nmr (meod),8.63(d, J ═ 4.81H),8.23(s,1H),8.19(s,1H),8.14(d, J ═ 2.0Hz,1H),7.95(dd, J ═ 2.4,8.8Hz,1H),7.74-7.76(m,2H),7.63(dd, J ═ 2.4,8.8Hz,1H),6.97(d, J ═ 10.0Hz,1H),3.68(t, J ═ 6.8Hz,2H),2.65(t, J ═ 6.8Hz, 2H).

Example 10: 3- (4- (2- (4- (N- (1,2, 4-thiadiazol-5-yl) sulfamoyl) -2, 5-difluorophenoxy) -5-chlorophenyl) pyridine carboxamide) propionic acid

Compound 10 was synthesized according to the procedure described for the synthesis of compound 1 by substituting N- (2, 4-dimethoxybenzyl) -2,4, 5-trifluoro-N- (1,2, 4-thiadiazol-5-yl) benzenesulfonamide for 5-chloro-N- (2, 4-dimethoxybenzyl) -2, 4-difluoro-N- (1,2, 4-thiadiazol-5-yl) benzenesulfonamide in step 5. LC-MS: 595.8(M + H). 1H-nmr (meod),8.66(d, J ═ 4.81H),8.28(s,1H),8.26(s,1H),7.69-7.77(m,3H),7.56(dd, J ═ 2.8,8.8Hz,1H),6.94(dd, J ═ 6.4,10.0Hz,1H),3.70(t, J ═ 6.4Hz,2H),2.67(t, J ═ 6.8Hz, 2H).

Example 11: preparation of 2- (3- (5-chloro-2- (2-chloro-5-fluoro-4- (N-thiazol-4-ylsulfamoyl) phenoxy) phenyl) propylamino) acetic acid

Scheme 7

Step 1: preparation of 3- (5-chloro-2-hydroxyphenyl) acrolein

To a solution of 5-chloro-2-hydroxybenzaldehyde (20g, 127mmol) in THF (300ml) was added (formylmethylene) triphenylphosphorane (43g, 140mmol) at room temperature. The resulting reaction mixture was refluxed at 100 ℃ for 20 hours. The reaction mixture was cooled to room temperature and extracted with water (200ml) and ethyl acetate (3X 250 ml). The combined organic phases were washed with water (200ml), brine (200ml), dried over sodium sulfate and concentrated in vacuo to give the desired crude product. The crude product was purified by column chromatography using normal phase silica gel. The desired product was eluted in approximately 20-30% ethyl acetate in hexane. The evaporation of the product fractions gave 20g (yield 87%) of a yellow solid, the desired compound. LC-MS: 183.4(M + H).

Step 2: preparation of methyl 2- (3- (5-chloro-2-hydroxyphenyl) allylamino) acetate

To a solution of 3- (5-chloro-2-hydroxyphenyl) acrolein (5g,27mmol) and glycine methyl ester hydrochloride (4.1g,32mmol) in dichloromethane (80ml) was added magnesium sulfate (6g,50mmol) and triethylamine (12ml,82mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. The resulting reaction mixture was then concentrated under vacuum. The concentrated cake thus obtained was dissolved in methanol (50ml) and cooled to a temperature of 5-10 ℃. To the above mixture was added a small portion of sodium borohydride (3.0g,82mmol) over a period of 20 minutes; the temperature of the reaction mixture during the addition is maintained at 10-20 ℃. The reaction mixture was stirred at room temperature for 2 hours and concentrated under vacuum. Water (100ml) was added to the above crude cake and the resulting mixture was extracted with ethyl acetate (3X 100 ml). The combined organic extracts were washed with water (50ml), brine (50ml), dried over sodium sulfate and concentrated in vacuo to give the desired crude product. The crude product was purified by column chromatography using normal phase silica gel. The desired product was eluted in about 1-5% methanol in dichloromethane. The evaporation of the product fractions gave 4g (yield, 58%) of a yellow solid, the desired compound. LC-MS: 256.43(M + H).

And step 3: preparation of methyl 2- (3- (5-chloro-2-hydroxyphenyl) propylamino) acetate

10% Palladium on carbon with 50% moisture (0.145g,1.3mmol) was carefully added to a solution of methyl 2- (3- (5-chloro-2-hydroxyphenyl) allylamino) acetate (3.5g,13.6mmol) in methanol (80 ml). Hydrogen was then bubbled into the reaction mixture at room temperature over a period of 30 minutes. After completion of the reaction, the reaction mixture was filtered through celite. The celite bed was carefully washed with a quantity of methanol. The filtrate thus obtained was concentrated under vacuum to provide 3g (yield 85%) of the compound as a colorless liquid and used directly in the next step. LC-MS: and M/z is 258.5(M + H).

And 4, step 4: 2- (3- (2- (4- (N- (tert-butoxycarbonyl) -N- (thiazol-4-yl) sulfamoyl) Preparation of methyl (E) -2-chloro-5-fluorophenoxy) -5-chlorophenyl) propylamino) acetate

To a solution of methyl 2- (3- (5-chloro-2-hydroxyphenyl) propylamino) acetate (0.7g,2.7mmol) in DMF (8ml) under a nitrogen atmosphere at room temperature was added a portion of K₂CO₃(1.2g,8.1 mmol.) the resulting reaction mixture was then stirred at room temperature for 15 minutes the resulting reaction mixture was added to the above compound at room temperature and the resulting reaction mixture was stirred at room temperature for 3 hours the resulting reaction mixture was stirred at room temperature after completion of the reaction water (10ml) was added and the resulting mixture was extracted with ethyl acetate (3 × 25ml) the combined organic extracts were washed with water (20ml), brine (20ml), dried over sodium sulfate and concentrated under vacuum the crude product was purified by column chromatography using normal phase silica gel the desired product was eluted in approximately 20-25% ethyl acetate in hexane solution the product fractions were evaporated to give 0.6g (yield 36%) of a solid, the desired compound LC-MS: M/z 648.4(M + H).

And 5: 2- (3- (2- (4- (N- (tert-butoxycarbonyl) -N- (thiazol-4-yl) sulfamoyl) Preparation of (E) -2-chloro-5-fluorophenoxy) -5-chlorophenyl) propylamino) acetic acid

To a solution of methyl 2- (3- (2- (4- (N- (tert-butoxycarbonyl) -N- (thiazol-4-yl) sulfamoyl) -2-chloro-5-fluorophenoxy) -5-chlorophenyl) propylamino) acetate (0.6g,0.9mmol) in THF (10mL) at room temperature was added a solution of lithium hydroxide monohydrate (0.0529,4.6mmol) in water (6 mL). The resulting reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction, ice-cold water (15ml) was added to the reaction mixture, and the resulting mixture was acidified to pH4-6 with aqueous 1N hydrochloric acid. The resulting acidic aqueous solution was extracted with ethyl acetate (3X 25 ml). The combined organic extracts were washed with water (20ml), brine (20ml), dried over sodium sulfate and concentrated in vacuo to afford 0.5g (yield 85%) of the compound as a white solid. This material was used directly in the next step.

Step 6: 2- (3- (5-chloro-2- (2-chloro-5-fluoro-4- (N-thiazol-4-ylsulfamoyl) phenoxy) Preparation of phenyl) propylamino) acetic acid

To a solution of 2- (3- (2- (4- (N- (tert-butoxycarbonyl) -N- (thiazol-4-yl) sulfamoyl) -2-chloro-5-fluorophenoxy) -5-chlorophenyl) propylamino) acetic acid (0.5g,0.78mmol) in dichloromethane (15ml) was added dropwise a 4N solution of hydrochloric acid in ethyl acetate (0.5ml) at room temperature. The resulting reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, pentane (20ml) was added to the reaction mixture to give a solid precipitate. The solvent layer was decanted, the solid thus obtained was washed twice with pentane (15ml) and dried under vacuum. Aqueous solution with 0.1% hydrochloric acid: acetonitrile mobile phase, the crude material obtained was further purified by preparative HPLC. Evaporation from the pure product fractions obtained by preparative HPLC provided the hydrochloride salt of the desired product (0.16g, 38% yield). LC-MS: 533.9(M + H). 1H-nmr (meod),8.77(d, J ═ 2.4Hz,1H),8.03(d, J ═ 6.8Hz,1H),7.49(d, J ═ 2.4Hz,1H),7.37(dd, J ═ 2.8,8.8Hz,1H),7.12(d, J ═ 2.4Hz,1H),7.03(d, J ═ 8.8Hz,1H),6.76(d, J ═ 10.8Hz,1H),3.8(s,2H),3.09-3.05(m,2H),2.68(t, J ═ 7.6Hz,2H),2.04-2.01(m, 2H).

Compounds 12-32 were synthesized according to the synthetic scheme described in example 11.

Scheme 8

Scheme 9

Example 12: 3- ((3- (2- (4- (N- (1,2, 4-thiadiazol-5-yl) sulfamoyl) -2-chloro-5-fluorophenoxy) -5-chlorophenyl) propyl) amino) propanoic acid

Compound 12 was synthesized according to the procedure described for the synthesis of compound 11 by replacing glycine methyl ester with β -alanine methyl ester in step 2 and 5-chloro-N- (2, 4-dimethoxybenzyl) -2, 4-difluoro-N- (1,2, 4-thiadiazol-5-yl) benzenesulfonamide in step 4 in place of tert-butyl 5-chloro-2, 4-difluorobenzenesulfonyl (thiazol-4-yl) carbamate. LC-MS: 549.6(M + H). 1H-nmr (meod),8.27(s,1H),8.05(d, J ═ 7.2Hz,1H),7.49(d, J ═ 2.4Hz,1H),7.36(dd, J ═ 2.8,8.8Hz,1H),7.03(d, J ═ 8.8Hz,1H),6.78(d, J ═ 6.4Hz,1H),3.26(t, J ═ 6.4Hz,2H),3.08(t, J ═ 7.6Hz,2H),2.68-2.75(m,4H),2.01-2.06(m, 2H).

Example 13: 2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) acetic acid

Compound 13 was synthesized according to the procedure described for the synthesis of compound 11 by substituting 5-chloro-N- (2, 4-dimethoxybenzyl) -2, 4-difluoro-N- (thiazol-2-yl) benzenesulfonamide for tert-butyl 5-chloro-2, 4-difluorophenylsulfonyl (thiazol-4-yl) carbamate in step 4. LC-MS: m/z 533.8(M + H). 1H-nmr (meod),7.94(d, J ═ 6.8Hz,1H),7.52(d, J ═ 5.8,1H),7.35-7.38(dd, J ═ 2.4,8.8Hz,1H),7.33(d, J ═ 4.4Hz,1H),7.11(d, J ═ 8.8Hz,1H),6.91-6.94(m,2H),3.60(s,2H),2.80(m,2H),2.56(m,2H),1.99(m, 2H).

Example 14: 1- (3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-4-yl) sulfamoyl) phenoxy) phenyl) propyl) piperidine) 4-carboxylic acid

Compound 14 was synthesized according to the procedure described for the synthesis of compound 11 by replacing glycine methyl ester with piperidine-4-carboxylic acid methyl ester in step 2. LC-MS: 589.8(M + H).

Example 15: 3- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-4-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) propanoic acid

Compound 15 was synthesized according to the procedure described for the synthesis of compound 11 by replacing the glycine methyl ester with β -alanine methyl ester in step 2. LC-MS: 547.8(M + H). 1H-nmr (meod),8.77(d, J ═ 2.0Hz,1H),8.03(d, J ═ 10.8Hz,1H),7.49(d, J ═ 2.4Hz,1H),7.35-7.38(m,1H),7.12(d, J ═ 2.8Hz,1H),7.03(d, J ═ 8.4Hz,1H),6.76(d, J ═ 10.4Hz,1H),3.26(br,2H),3.07(br,2H),2.67-2.76(m,4H),2.02(br, 2H).

Example 16: 4-amino-1- (3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-4-yl) sulfamoyl) phenoxy) phenyl) propyl) piperidine-4-carboxylic acid

Compound 16 was synthesized according to the procedure described for the synthesis of compound 11 by substituting methyl 4- ((tert-butoxycarbonyl) amino) piperidine-4-carboxylate for methyl glycinate in step 2. LC-MS: and M/z is 602.8(M + H). 1H-nmr (meod),8.77(d, J ═ 2.0Hz,1H),8.02(d, J ═ 7.2Hz,1H),7.52(d, J ═ 2.8Hz,1H),7.36-7.38(dd, J ═ 2.8,8.8Hz,1H),7.12(d, J ═ 2.0Hz,1H),7.03(d, J ═ 8.4Hz,1H),6.77(d, J ═ 10.4Hz,1H),3.25-3.70(m,6H)2.67-2.71(m,2H),2.50(br,2H),2.27(br,2H),2.12(br, 2H).

Example 17: 2-amino-4- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-4-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) butanoic acid

Scheme 10

Step 1: preparation of (S) -4-amino-2- (tert-butoxycarbonylamino) butanoic acid

To (S) -5-amino-2- (tert-butoxycarbonyl groupAmino group) -5-oxopentanoic acid (2g,8.1mmol) in DMF: water (1:1, v/v,18ml) pyridine (1.3ml,16.2mmol) was added then the resulting reaction mixture was stirred at room temperature for 5-10 min, iodobenzene diacetate (3.92g,12.1mmol) was added and stirred further for 4H after completion of the reaction demineralized water (100ml) was added then the resulting mixture was extracted with ethyl acetate (3 × 100ml) the combined organic extracts were washed with demineralized water (100ml), brine (100ml), dried over sodium sulfate and concentrated under vacuum to obtain the desired crude product which was purified by triturating with diethyl ether (trituating) the product fractions evaporated to give 1.1g (yield 62%) of a brown solid, i.e. the desired compound LC-MS M/z 219.1(M + H).

Step 2: (E) preparation of (E) -3- (5-chloro-2-hydroxyphenyl) acrolein

To a solution of 5-chloro-2-hydroxybenzaldehyde (20g, 127mmol) in THF (300ml) was added (formylmethylene) triphenylphosphorane (43g,140mmol) at room temperature. The resulting reaction mixture was then refluxed at 100 ℃ for 20 hours. After completion of the reaction, the reaction mixture was allowed to cool to room temperature. Demineralized water (200ml) was added, and the resulting mixture was extracted with ethyl acetate (3X 250 ml). The combined organic extracts were washed with demineralized water (200ml), brine (200ml), dried over sodium sulfate, and concentrated in vacuo to afford the desired crude product. The crude product was purified by column chromatography using normal phase silica gel. The desired product was eluted in approximately 20-30% ethyl acetate in hexane. The evaporation of the product fractions gave 20g (yield 87%) of a yellow solid, the desired compound. LC-MS: 183.4(M + H).

And step 3: (S, E) -2- (tert-Butoxycarbonylamino) -4- (3- (5-chloro-2-hydroxyphenyl) allyl Alkylamino) butanoic acid

To a solution of 3- (5-chloro-2-hydroxyphenyl) acrolein (0.5g,3.2mmol) and (S) -4-amino-2- (tert-butoxycarbonylamino) butyric acid (0.769g,3.52mmol) in dichloromethane (80ml) at room temperature were added magnesium sulfate (0.77g,6.4mmol) and triethylamine (1.34ml,9.615 mmol). The reaction mixture was stirred at room temperature for 12 hours. The resulting reaction mixture was then concentrated under vacuum. The concentrated cake thus obtained was dissolved in methanol (20ml) and cooled to a temperature of 5-10 ℃. To the above mixture was added a small portion of sodium borohydride (0.36g,9.61mmol) over a period of 10 minutes, the temperature of the reaction mixture being maintained at 10-20 ℃ during the addition. After the addition was complete, the resulting reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated under vacuum. Demineralized water (40ml) was added to the above crude cake and the resulting mixture was extracted with ethyl acetate (3 × 60 ml). The combined organic extracts were washed with demineralised water (50ml), brine (50ml), dried over sodium sulphate and concentrated under vacuum to give the desired crude product. The crude product was purified by column chromatography using normal phase silica gel. The desired product was eluted in about 1-5% methanol in dichloromethane. Evaporation of the product fractions gave 0.4g (yield 32.5%) of a brown liquid, the desired compound. LC-MS: and M/z is 385.2(M + H).

And 4, step 4: (S) -2- (tert-Butoxycarbonylamino) -4- (3- (5-chloro-2-hydroxyphenyl) propylamine Yl) butyric acid

10% Palladium on carbon with 50% moisture (0.120g,1.3mmol) was carefully added to a solution of (S, E) -2- (tert-butoxycarbonylamino) -4- (3- (5-chloro-2-hydroxyphenyl) allylamino) butanoic acid (0.4g, 13.6mmol) in methanol (10 ml). Hydrogen was then bubbled into the reaction mixture at room temperature over a period of 15-20 minutes. After completion of the reaction, the reaction mixture was filtered through celite (celitehyflow). The celite bed was carefully washed with a quantity of methanol. The filtrate thus obtained was concentrated under vacuum to provide 0.35g (yield 87.06%) of a colorless liquid, which was the desired compound. LC-MS: 387.4(M + H).

Note that: for this particular step we also observed that dechlorination occurred, with the ratio remaining changed. This step is therefore carefully monitored and post-treatment is carried out quickly when completed.

And 5: (S) -4- (3- (2- (4- (N- (tert-butoxycarbonyl) -N- (thiazol-4-yl) sulfamoyl) Acyl) -2-chloro-5-fluorophenoxy) -5-chlorophenyl) propylamino) -2- (tert-butoxycarbonylamino) butane Acid(s)

To a solution of (S) -2- (tert-butoxycarbonylamino) -4- (3- (5-chloro-2-hydroxyphenyl) propylamino) butanoic acid (0.350g,2.7mmol) in DMF (0.7ml) under a nitrogen atmosphere at room temperature was added one portion of K ₂CO₃(0.375g,2.7 mmol.) the resulting reaction mixture is then stirred at room temperature for 15 minutes.5-chloro-2, 4-difluorobenzenesulfonyl (thiazol-4-yl) carbamic acid tert-butyl-ester (0.408g,0.99mmol) is added to the above mixture and the resulting reaction mixture is stirred at room temperature for 3 hours after the reaction is complete demineralized water (20ml) is added and the resulting mixture is then extracted with ethyl acetate (3 × ml). the combined organic extracts are washed with ice-cold water (100ml), brine (50ml), dried over sodium sulfate and concentrated under vacuum.

Step 6: (S) -2-amino-4- (3- (5-chloro-2- (2-chloro-5-fluoro-4- (N-thiazol-4-ylsulfamoyl) amide Preparation of phenyl) phenoxy) propylamino) butanoic acid

To a solution of (S) -4- (3- (2- (4- (N- (tert-butoxycarbonyl) -N- (thiazol-4-yl) sulfamoyl) -2-chloro-5-fluorophenoxy) -5-chlorophenyl) propylamino) -2- (tert-butoxycarbonylamino) butyric acid (0.4g,0.78mmol) in dichloromethane (10ml) was added dropwise a 4N solution of hydrochloric acid in ethyl acetate (2ml) at room temperature. The resulting reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, pentane (20ml) was added to the reaction mixture, resulting in precipitation of a solid. The solvent layer was decanted, the solid thus obtained was washed twice with pentane (15ml) and dried under vacuum. Using 0.1% formic acid in water: the crude material obtained was further purified by preparative HPLC on acetonitrile mobile phase. Evaporation from the pure product fraction obtained by preparative HPLC afforded the desired product, i.e., the hydrochloride salt (0.0253g, 8.6% yield). LC-MS: 576.8(M + H).

Example 18: 2- ((3- (5-chloro-2- (2, 5-difluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) acetic acid

Compound 18 was synthesized according to the procedure described for the synthesis of compound 11 by substituting N- (2, 4-dimethoxybenzyl) -2,4, 5-trifluoro-N- (thiazol-2-yl) benzenesulfonamide for tert-butyl 5-chloro-2, 4-difluorobenzenesulfonyl (thiazol-4-yl) carbamate in step 4. LC-MS: 517.8(M + H). 1H-nmr (meod),7.81-7.85(dd, J ═ 6.4,10.4Hz,1H),7.46(d, J ═ 6.4,1H),7.31-7.34(dd, J ═ 2.8,8.8Hz,1H),7.17(d, J ═ 4.8Hz,1H),6.99(d, J ═ 8.4Hz,1H),6.86-6.90(dd, J ═ 6.4,10.0, 1H),6.81(d, J ═ 4.8Hz,1H),3.92(s,2H),3.08-3.12(m,2H),2.75(t, J ═ 8.0Hz,2H),2.03-2.08(m, 2H).

Example 19: 1- (3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-4-yl) sulfamoyl) phenoxy) phenyl) propyl) piperidine) 3-carboxylic acid

Compound 19 was synthesized according to the procedure described for the synthesis of compound 11 by replacing glycine methyl ester with piperidine-3-carboxylic acid methyl ester in step 2. LC-MS: 589.8(M + H).

Example 20: 2- ((3- (2- (4- (N- (1,2, 4-thiadiazol-5-yl) sulfamoyl) -2-chloro-5-fluorophenoxy) phenyl) propyl) amino) acetic acid

Compound 20 was synthesized according to the procedure described for the synthesis of compound 11 by substituting 2-hydroxybenzaldehyde for 5-chloro-2-hydroxybenzaldehyde in step 1. LC-MS: 500.8(M + H). 1H-nmr (meod),8.90(s,2H),8.51(s,1H),7.97(d, J ═ 7.2Hz,1H),7.41-7.44(dd, J ═ 1.6,7.2Hz,1H),7.26-7.34(m,2H),7.07(dd, J ═ 1.2,8.0Hz,1H),6.81(d, J ═ 10.8Hz,1H),3.89(s,2H),2.93(br,2H),2.57-2.61(m,2H),1.92(br, 2H).

Example 21: 2- ((3- (5-chloro-2- (2, 5-difluoro-4- (N- (thiazol-4-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) acetic acid

Compound 21 was synthesized according to the procedure described for the synthesis of compound 11 by replacing tert-butyl 5-chloro-2, 4-difluorobenzenesulfonyl (thiazol-4-yl) carbamate with tert-butyl 2,4, 5-trifluorophenylsulfonyl (thiazol-4-yl) carbamate in step 4. LC-MS: 517.8(M + H). 1H-nmr (meod),8.77(d, J ═ 2.0Hz,1H),7.79-7.83(dd, J ═ 6.4,10.0Hz,1H),7.47(d, J ═ 2.4Hz,1H),7.32-7.35(dd, J ═ 2.4,8.4Hz,1H),7.11(d, J ═ 2.4Hz,1H),7.02(d, J ═ 8.8Hz,1H),6.85-6.89(dd, J ═ 6.4,10.4Hz,1H),3.92(s,2H),3.09-3.16(m,2H),2.73(t, J ═ 7.6Hz,2H),1.99-2.07(m, 2H).

Example 22: 3- ((3- (5-chloro-2- (2, 5-difluoro-4- (N- (thiazol-4-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) propanoic acid

Compound 22 was synthesized according to the procedure described for the synthesis of compound 11 by replacing glycine methyl ester with β -alanine methyl ester in step 2 and 5-chloro-2, 4-difluorobenzenesulfonyl (thiazol-4-yl) carbamic acid tert-butyl ester with 2,4, 5-trifluorophenylsulfonyl (thiazol-4-yl) carbamic acid tert-butyl ester in step 4. LC-MS: 531.8(M + H). 1H-nmr (meod),8.78(d, J ═ 2.4Hz,1H),7.79-7.83(dd, J ═ 6.4,10.4Hz,1H),7.47(d, J ═ 2.4Hz,1H),7.32-7.35(dd, J ═ 2.4,8.4Hz,1H),7.11(d, J ═ 2.4Hz,1H),7.01(d, J ═ 8.8Hz,1H),6.85-6.90(dd, J ═ 6.4,10.4Hz,1H),3.27(t, J ═ 6.8Hz,2H),3.07(t, J ═ 8.0Hz,2H),2.71-2.78(m,4H),1.97-2.05(m, 2H).

Example 23: 3- ((3- (5-chloro-2- (2-cyano-4- (N- (thiazol-4-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) propanoic acid

Compound 23 was synthesized according to the procedure described for the synthesis of compound 11 by substituting β -alanine methyl ester for glycine methyl ester and tert-butyl (3-cyano-4-fluorophenyl) sulfonyl (thiazol-4-yl) carbamate for tert-butyl 5-chloro-2, 4-difluorophenylsulfonyl (thiazol-4-yl) carbamate in step 2. LC-MS: 520.9(M + H). 1H-nmr (meod),8.77(d, J ═ 2.0Hz,1H),8.30(d, J ═ 2.0Hz,1H),8.03(dd, J ═ 2.4,9.2Hz,1H),7.52(d, J ═ 2.4Hz,1H),7.39(dd, J ═ 2.8,8.8Hz,1H),7.16(d, J ═ 2.0Hz,1H),7.14(s,1H),6.96(d, J ═ 9.2Hz,1H),3.09(t, J ═ 6.8Hz,2H),3.09(t, J ═ 8.0Hz,2H),2.76(t, J ═ 6.4Hz,2H),2.69(t, J ═ 6.0, 2H), 2.99 (t, J ═ 2.07H).

Example 24: methyl 2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-4-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) acetate

Compound 24 was synthesized according to the procedure described for the synthesis of compound 11 without hydrolysis of the methyl ester (step 5). LC-MS: 548.4(M + H). 1H-nmr (meod),8.77(d, J ═ 2.4Hz,1H),8.02(d, J ═ 6.8Hz,1H),7.49(d, J ═ 2.4Hz,1H),7.35-7.38(dd, J ═ 2.4,8.4Hz,1H),7.12(d, J ═ 2.4Hz,1H),7.02(d, J ═ 8.8Hz,1H),6.75(d, J ═ 10.4Hz,1H),3.99(s,2H),3.85(s,3H),3.08-3.12(m,2H),2.68(t, J ═ 7.6Hz,2H),2.00-2.08(m, 2H).

Example 25: 3- ((3- (2- (2-chloro-5-fluoro-4- (N- (thiazol-4-yl) sulfamoyl) phenoxy) -5-fluorophenyl) propyl) amino) propanoic acid

Compound 25 was synthesized according to the procedure described for the synthesis of compound 11 by substituting 5-fluoro-2-hydroxybenzaldehyde for 5-chloro-2-hydroxybenzaldehyde in step 1 and β -alanine methyl ester for glycine methyl ester in step 2. LC-MS: 531.9(M + H). 1H-nmr (meod),8.77(d, J ═ 2.4Hz,1H),8.01(d, J ═ 6.8Hz,1H),7.23(dd, J ═ 2.4,8.8Hz,1H),7.11-7.13(m,3H),6.65(d, J ═ 10.8Hz,1H),3.25(t, J ═ 6.8Hz,2H),3.06(t, J ═ 8.0Hz,2H),2.73(t, J ═ 6.4Hz,2H),2.66(t, J ═ 7.6Hz,2H),1.99-2.03(m, 2H).

Example 26: 3- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-4-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) propanamide

Scheme 11

Step 1: preparation of 3- (5-chloro-2-hydroxyphenyl) acrolein

To a solution of 5-chloro-2-hydroxybenzaldehyde (20g, 127mmol) in THF (300ml) was added (formylmethylene) triphenylphosphorane (43g,140mmol) at room temperature. The resulting reaction mixture was then refluxed at 100 ℃ for 20 hours. After completion of the reaction, the reaction mixture was allowed to cool to room temperature. Demineralized water (200ml) was added, and the resulting mixture was extracted with ethyl acetate (3X 250 ml). The combined organic extracts were washed with water (200ml), brine (200ml), dried over sodium sulfate and concentrated in vacuo to give the desired crude product. The crude product was purified by column chromatography using normal phase silica gel. The desired product was eluted in approximately 20-30% ethyl acetate in hexane. The evaporation of the product fractions gave 20g (yield 87%) of a yellow solid, the desired compound. LC-MS: and M/z is 181.34 (M-H).

Step 2: 3- [3- (5-chloro-2-hydroxyphenyl) allylamino]Methyl propionate) preparation

To a solution of 3- (5-chloro-2-hydroxyphenyl) acrolein (1.0g,5.47mmol) and β -alanine methyl ester hydrochloride (0.917g,6.57mmol) in DCM (20ml) was added magnesium sulfate (1.317g,1.09mmol) and TEA (2.3ml,16.41mmol) at room temperature, and the resulting reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was then concentrated under vacuum. The concentrated cake thus obtained was dissolved in methanol (20ml) and cooled to 5-10 ℃. A small portion of sodium borohydride (0.620g,16.41mmol) was then added to the cooled reaction mixture over a period of 10-20 minutes, with the temperature maintained at 10-20 ℃ during the addition. After the addition was complete, the resulting reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated under vacuum. To the resulting crude material was added water (50ml) and the mixture was extracted with EtOAc (3X 25 ml). The combined organic extracts were washed with water (20ml), brine (20ml), dried over sodium sulfate and concentrated in vacuo to give the desired crude product. The crude product was purified by column chromatography using normal phase silica gel. The desired product was eluted in about 1-5% methanol in dichloromethane. Evaporation of the product fractions gave 0.9g (yield 61%) of a white solid, the desired compound. LC-MS: and M/z is 270.6(M + H).

And step 3: 3- [3- (5-chloro-2-hydroxyphenyl) propylamino group]Methyl propionate) preparation

To a solution of 3- [3- (5-chloro-2-hydroxyphenyl) allylamino ] propionate) (0.35g,1.3mmol) in methanol (20ml) was carefully added 10% palladium on carbon with 50% moisture (0.104g,0.065 mmol). Hydrogen was then bubbled into the reaction mixture at room temperature over a period of 30 minutes. The reaction mixture was monitored on TLC using ethyl acetate as mobile phase. After completion of the reaction, the reaction mixture was filtered through celite. The celite bed was carefully washed with a quantity of methanol. The filtrate thus obtained was concentrated under vacuum to provide 0.3g (yield 85%) of a colorless liquid, which was the desired compound. M/z 272.6(M + H).

And 4, step 4: 3- [3- (5-chloro-2-hydroxyphenyl) propylamino group]Propionamide) preparation

A solution of methyl 3- [3- (5-chloro-2-hydroxyphenyl) propylamino ] propionate) (0.3g,1.08mmol) in methanolic ammonia (10mL) was heated at 100 ℃ for 12 hours in a sealed tube (35 mL). After completion of the reaction, methanol was evaporated under vacuum. The crude product was purified by column chromatography using normal phase silica gel. The desired product was eluted in approximately 30-40% ethyl acetate in hexane. Evaporation of the product fractions gave 0.16g (yield 33.9%) of a colorless liquid, the desired compound. 257.2(M + H).

And 5: 3- (3- (2- (4- (N- (tert-butoxycarbonyl) -N- (thiazol-4-yl) sulfamoyl) Preparation of methyl (E) -2-chloro-5-fluorophenoxy) -5-chlorophenyl) propylamino) propionate

To 3- [3- (5-chloro-2-hydroxyphenyl) propylamino under nitrogen atmosphere at room temperature]A portion of K was added to a solution of propionate (0.09g,0.35mmol) in DMF (2ml)₂CO₃(0.145,1.05 mmol.) the resulting reaction mixture was stirred at room temperature for 15 minutes, 5-chloro-2, 4-difluorobenzenesulfonyl (thiazol-4-yl) carbamic acid tert-butyl ester (0.143g,0.35mmol) was added to the above mixture and the resulting mixture was stirred at room temperature for 3 hours after the reaction was complete water (10ml) was added and the resulting mixture was extracted with ethyl acetate (3 × 25 ml). the combined organic extracts were washed with water (20ml), brine (20ml), dried over sodium sulfate and concentrated under vacuum the crude product was purified by column chromatography using normal phase silica gel the desired product was eluted in a hexane solution of approximately 20-25% ethyl acetate the product fraction was evaporated to give 0.15g (66.2% yield) of solid, the desired compound.

Step 6: 3- (3- (5-chloro-2- (2-chloro-5-fluoro-4- (N-thiazol-4-ylsulfamoyl) phenoxy) Preparation of phenyl) propylamino) propionamide fluorophenylsulfonyl (thiazol-4-yl) carbamate

To a solution of 3- (3- (2- (4- (N- (tert-butoxycarbonyl) -N- (thiazol-4-yl) sulfamoyl) -2-chloro-5-fluorophenoxy) -5-chlorophenyl) propylamino) propionate (0.15g,0.23mmol) in dichloromethane (5ml) at room temperature was added dropwise a 4N solution of hydrochloric acid in ethyl acetate (0.5 ml). The resulting reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, pentane (20ml) was added to the reaction mixture, resulting in precipitation of a solid. The solvent layer was decanted, the solid thus obtained was washed twice with pentane (15ml) and dried under vacuum. Using 0.1% formic acid in water: acetonitrile mobile phase, the crude material obtained was further purified by preparative HPLC. Evaporation from the pure product fraction obtained by preparative HPLC provided the hydrochloride salt, the desired product (0.009g, 7.1% yield). LC-MS: 548.8(M + H). 1H-nmr (meod),8.75(d, J ═ 2.4Hz,1H),8.01(d, J ═ 7.2Hz,1H),7.48(d, J ═ 2.4Hz,1H),7.34-7.37(dd, J ═ 2.4,8.8Hz,1H),7.06(d, J ═ 2.4Hz,1H),7.01(d, J ═ 8.4Hz,1H),6.73(d, J ═ 10.4Hz,1H),3.22(t, J ═ 6.4Hz,2H),3.02-3.06(m,2H),2.62-2.70(m,4H),1.99-2.03(m, 2H).

Example 27: 2- (N- (3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-4-yl) sulfamoyl) phenoxy) phenyl) propyl) acetamido) acetic acid

Scheme 12

Step 1: (E) preparation of (E) -3- (5-chloro-2-hydroxyphenyl) acrolein

To a solution of 5-chloro-2-hydroxybenzaldehyde (20g, 127mmol) in THF (300ml) was added (formylmethylene) triphenylphosphorane (43g,140mmol) at room temperature. The resulting reaction mixture was then refluxed at 100 ℃ for 20 hours. After completion of the reaction, the reaction mixture was allowed to cool to room temperature. Demineralized water (200ml) was added, and the resulting mixture was extracted with ethyl acetate (3X 250 ml). The combined organic extracts were washed with water (200ml), brine (200ml), dried over sodium sulfate and concentrated in vacuo to give the desired crude product. The crude product was purified by column chromatography using normal phase silica gel. The desired product was eluted in approximately 20-30% ethyl acetate in hexane. The evaporation of the product fractions gave 20g (yield 87%) of a yellow solid, the expected compound. LC-MS: 183.4(M + H).

Step 2: (E) preparation of methyl (E) -2- (3- (5-chloro-2-hydroxyphenyl) allylamino) acetate

To a solution of (E) -3- (5-chloro-2-hydroxyphenyl) acrolein (1.0g,5.4mmol) and glycine methyl ester hydrochloride (0.590g,6.55mmol) in dichloromethane (20ml) was added magnesium sulfate (1.5g,10.9mmol) and triethylamine (2.28ml,16.38mmol) at room temperature. The reaction mixture was stirred at room temperature for 12 hours. The resulting reaction mixture was then concentrated under vacuum. The concentrated cake thus obtained was dissolved in methanol (20ml) and cooled to a temperature of 5-10 ℃. To the above mixture was added a small portion of sodium borohydride (0.606g,16.38mmol) over a period of 10 minutes, the temperature of the reaction mixture being maintained at 10-20 ℃ during the addition. After the addition was complete, the resulting reaction mixture was allowed to stir at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated under vacuum. Water (40ml) was added to the above crude cake and the resulting mixture was extracted with ethyl acetate (3 × 60 ml). The combined organic extracts were washed with water (50ml), brine (50ml), dried over sodium sulfate and concentrated in vacuo to give the desired crude product. The crude product was purified by column chromatography using normal phase silica gel. The desired product was eluted in about 2-3% methanol in dichloromethane. Evaporation of the product fractions gave 0.8g (yield 57.4%) of a brown liquid, the desired compound. LC-MS: 256.07(M + H).

To (E) -2- (3- (5-chloro-2-hydroxyphenyl) allylamino) acetic acidFirst of allPalladium hydroxide (0.199g,0.09mmol) was carefully added to a solution of the ester (0.8g,3.13mmol) in methanol (50 ml). Hydrogen was then bubbled into the reaction mixture at room temperature over a period of 30 minutes. After completion of the reaction, the reaction mixture was filtered through celite. The celite bed was carefully washed with a quantity of methanol. The filtrate thus obtained was concentrated under vacuum to provide 0.7g (yield 86.81%) of the compound as a colorless liquid. LC-MS: 258.07(M + H).

To a solution of methyl 2- (3- (5-chloro-2-hydroxyphenyl) propylamino) acetate (0.7g,2.72mmol) in DMF (7ml) under a nitrogen atmosphere at room temperature was added a portion of K₂CO₃(1.12g,8.17 mmol.) the resulting reaction mixture was then stirred at room temperature for 15 minutes.5-chloro-2, 4-difluorobenzenesulfonyl (thiazol-4-yl) carbamic acid tert-butyl ester (1.22g,2.996mmol) was added to the above mixture and the resulting reaction mixture was stirred at room temperature for 3 hours after the reaction was complete water (20ml) was added and the resulting mixture was extracted with ethyl acetate (3 × ml). the combined organic extracts were washed with water (20ml), brine (20ml), dried over sodium sulfate and concentrated under vacuum to provide 0.54g (30.64% yield) of compound as a white solid.

And 5: 2- (N- (3- (2- (4- (N- (tert-butoxycarbonyl) -N- (thiazol-4-yl) sulfamoyl) Acyl) -2-chloro-5-fluorophenoxy) -5-chlorophenyl) propyl) acetamido) acetic acid methyl ester.

To 2- (3- (2- (4- (N- (tert-butoxycarbonyl) -N- (thiazol-4-yl) sulfamoyl) -2-chloro-5-fluorophenoxy) -5-chlorophenyl) propylamino) acetic acidFirst of allTo a solution of the ester (0.35g,0.54mmol) in THF (5mL) was added triethylamine (0.22mL,1.62 mmol). The resulting reaction mixture was then stirred at 0 ℃ for 5-10 minutes. Acetic anhydride (0.102ml,1.08mmol) was added at 0 ℃. The resulting reaction mixture was then refluxed at 80 ℃ for 12 hours. Water (30ml) was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate (3 × 50 ml). The combined organic extracts were washed with water (30ml), brine (30ml), dried over sodium sulfate and concentrated in vacuo to give the desired crude product. The crude product was purified by trituration with diethyl ether. Evaporation of the product fractions gave 0.35g (yield 94.01%) of a brown solid, the desired compound. LC-MS: 690.5(M + H).

Step 6: 2- (N- (3- (2- (4- (N- (tert-butoxycarbonyl) -N- (thiazol-4-yl) sulfamoyl) Preparation of acyl) -2-chloro-5-fluorophenoxy) -5-chlorophenyl) propyl) acetamido) acetic acid

To a solution of methyl 2- (N- (3- (2- (4- (N- (tert-butoxycarbonyl) -N- (thiazol-4-yl) sulfamoyl) -2-chloro-5-fluorophenoxy) -5-chlorophenyl) propyl) acetamido) acetate (0.35g,0.50mmol) in THF (5ml) at room temperature was added an aqueous solution (0.5ml) of lithium hydroxide monohydrate (0.212g,5.07 mmol). The resulting reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction, ice-cold water (15ml) was added to the reaction mixture, and the resulting mixture was acidified to pH4-6 with aqueous 1N hydrochloric acid. The resulting aqueous acidic solution was extracted with ethyl acetate (3X 25 ml). The combined organic extracts were washed with water (20ml), brine (20ml), dried over sodium sulfate and concentrated in vacuo to afford 0.3g (yield 87.49%) of the compound as a white solid. This material was used directly in the next step without any further purification and analysis. LC-MS: 676.41(M + H).

And 7: 2- (N- (3- (5-chloro-2- (2-chloro-5-fluoro-4- (N-thiazol-4-ylsulfamoyl) phenoxy) Radical) phenyl) propyl) acetamido) acetic acid

To a solution of 2- (N- (3- (2- (4- (N- (tert-butoxycarbonyl) -N- (thiazol-4-yl) sulfamoyl) -2-chloro-5-fluorophenoxy) -5-chlorophenyl) propyl) acetamido) acetic acid (0.3g,0.44mmol) in dichloromethane (4ml) was added dropwise a 4N solution of hydrochloric acid in ethyl acetate (1ml) at room temperature. The resulting reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, pentane (20ml) was added to the reaction mixture, resulting in precipitation of a solid. The solvent layer was decanted, the solid thus obtained was washed twice with pentane (15ml) and dried under vacuum. Aqueous solution with 0.1% hydrochloric acid: the crude material obtained was further purified by preparative HPLC on acetonitrile mobile phase. Evaporation from the pure product fraction obtained by preparative HPLC provided the hydrochloride salt, the desired product (0.060g, 23.47% yield). LC-MS: 575.92(M + H).

Example 28: 2- (1- (3- (2- (4- (N- (1,2, 4-thiadiazol-5-yl) sulfamoyl) -2-chloro-5-fluorophenoxy) -5-chlorophenyl) propyl) piperidin-4-yl) acetic acid

Compound 28 was synthesized according to the procedure described for the synthesis of compound 11 by replacing glycine methyl ester with methyl 2- (piperidin-4-yl) acetate in step 2 and 5-chloro-N- (2, 4-dimethoxybenzyl) -2, 4-difluoro-N- (1,2, 4-thiadiazol-5-yl) benzenesulfonamide in step 4 in place of tert-butyl 5-chloro-2, 4-difluorobenzenesulfonyl (thiazol-4-yl) carbamate. LC-MS: m/z 601.2(M + H).

Example 29: 3- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) propanoic acid

Compound 29 was synthesized according to the procedure described for the synthesis of compound 11 by substituting glycine methyl ester with β -alanine methyl ester in step 2 and tert-butyl 5-chloro-2, 4-difluorobenzenesulfonyl (thiazol-4-yl) carbamate with 5-chloro-N- (2, 4-dimethoxybenzyl) -2, 4-difluoro-N- (thiazol-2-yl) benzenesulfonamide in step 4. LC-MS: 547.9(M + H). 1H-nmr (meod),8.05(d, J ═ 6.8Hz,1H),7.49(d, J ═ 2.8Hz,1H),7.34(dd, J ═ 2.4,8.4Hz,1H),7.17(d, J ═ 4.4Hz,1H),7.02(d, J ═ 8.4Hz,1H),6.80(d, J ═ 4.4Hz,1H),6.75(d, J ═ 10.4Hz,1H),3.14(t, J ═ 6.4Hz,2H),3.04(t, J ═ 8.0Hz,2H),2.71(t, J ═ 8.0Hz,2H),2.49(t, J ═ 6.4Hz,2H), 2.00-2.03 (m, 2H).

Example 30: 2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-4-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) -N-methylacetamide

Compound 30 was synthesized according to the procedure described for the synthesis of compound 11 by replacing glycine methyl ester with 2-amino-N-methylacetamide in step 2. LC-MS: 547.1(M + H). 1H-nmr (meod),8.77(d, J ═ 2.4Hz,1H),8.01(d, J ═ 7.2Hz,1H),7.48(d, J ═ 2.4Hz,1H),7.35(dd, J ═ 2.4,8.4Hz,1H),7.10(d, J ═ 2.0Hz,1H),7.02(d, J ═ 8.8Hz,1H),6.73(d, J ═ 10.4Hz,1H),3.70(s,2H),2.97-3.02(m,2H),2.80(s,3H),2.65-2.69(m,2H),1.96-2.06(m, 2H).

Example 31: 5-chloro-4- (4-chloro-2- (3- ((2- (methylsulfonyl) ethyl) amino) propyl) phenoxy) -2-fluoro-N- (thiazol-4-yl) benzenesulfonamide

Compound 31 was synthesized according to the procedure described for the synthesis of compound 11 by substituting 2- (methylsulfonyl) ethylamine for glycine methyl ester in step 2. LC-MS: m/z 581.8(M + H). 1H-nmr (meod),8.77(d, J ═ 2.4Hz,1H),8.02(d, J ═ 6.8Hz,1H),7.48(d, J ═ 2.4Hz,1H),7.36(dd, J ═ 2.8,8.8Hz,1H),7.10(d, J ═ 2.4Hz,1H),7.02(d, J ═ 8.4Hz,1H),6.73(d, J ═ 10.4Hz,1H),3.33 to 3.50(m,4H),3.03(s,3H),2.99 to 3.01(m,2H),2.65 to 2.68(m,2H),1.95 to 2.03(m, 2H).

Example 32: 1- (3- (2- (4- (N- (1,2, 4-thiadiazol-5-yl) sulfamoyl) -2-chloro-5-fluorophenoxy) -5-chlorophenyl) propyl) piperidine-4-carboxylic acid

Compound 32 was synthesized according to the procedure described for the synthesis of compound 11 by substituting piperidine-4-carboxylic acid methyl ester for glycine methyl ester in step 2 and 5-chloro-N- (2, 4-dimethoxybenzyl) -2, 4-difluoro-N- (1,2, 4-thiadiazol-5-yl) benzenesulfonamide for tert-butyl 5-chloro-2, 4-difluorobenzenesulfonyl (thiazol-4-yl) carbamate in step 4. LC-MS: m/z 589.6(M + H).

Example 33: 5-chloro-4- (4-chloro-2- (4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidin-3-yl) phenoxy) -2-fluoro-N- (thiazol-4-yl) benzenesulfonamide

Scheme 13

Step 1: preparation of 5-chloro-2-methoxybenzaldehyde

A solution of 5-chloro-2-hydroxybenzaldehyde (20g,128mmol) in DMF (70mL) was cooled to a temperature of 5-10 ℃. A small portion of sodium hydride (7.69g,192mmol) was added to the above solution over a period of 20 minutes. Methyl iodide (23.8ml,384mmol) was then added dropwise to the reaction mixture above while maintaining its temperature below 15 ℃. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. Thereafter, the reaction mixture was poured into a cold saturated ammonium chloride solution (250mL) to obtain a white precipitate. The precipitate thus formed is filtered off and dried under vacuum. The solid obtained was mixed with 100ml of pentane: diethyl ether (4:1) was triturated together to provide 18g (yield 82.58%) of a white solid, the desired compound. LC-MS: m/z 170.1(M + H).

Step 2：Preparation of (5-chloro-2-methoxyphenyl) methanol

A solution of 5-chloro-2-methoxybenzaldehyde (18g,105.8mmol) in methanol (100mL) was cooled to a temperature of 5-10 ℃. To the above solution was added a portion of sodium borohydride (11.8g,317mmol) over a period of 30 minutes. After the addition was complete, the resulting reaction mixture was allowed to stir at room temperature for an additional about 2 hours. Using ethyl acetate: hexane (1: 1) was used as mobile phase to monitor the reaction on TLC. After completion of the reaction, it was concentrated under vacuum. To the resulting crude cake was added cold water (200ml) to obtain a white precipitate. The precipitate thus formed was filtered and dried to provide 16g (yield 87.8%) of a white solid, which was the desired compound. This material was used directly in the next step.

And step 3: preparation of 4-chloro-2- (chloromethyl) -1-methoxybenzene

A solution of 5-chloro-2-methoxyphenyl) methanol (16g,94mmol) in DCM (100ml) was cooled to a temperature of 5-10 ℃. Thionyl chloride (11ml,140mmol) was added dropwise to the above solution over a period of 30 minutes. After the addition was complete, the resulting reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, it was concentrated under vacuum. To the resulting crude cake was added cold water (150ml) to obtain a white precipitate. The precipitate thus formed was filtered off and dried under vacuum to afford 12g (yield 67.9%) of a white solid, the desired compound. This material was used directly in the next step.

And 4, step 4: preparation of 2- (5-chloro-2-methoxyphenyl) acetonitrile

To a solution of 4-chloro-2- (chloromethyl) -1-methoxybenzene (12g,63.15mmol) in DMSO (60mL) was carefully added sodium cyanide (4.4g,95.6mmol) at room temperature. The reaction mixture was then heated to 100 ℃ and held for 3 hours. After cooling to room temperature, the reaction mixture was poured into cold water (200ml) to obtain a precipitate. The precipitate thus formed was filtered off and dried under vacuum to provide 10g (yield 87.46%) of a white solid, the desired compound. This material was used directly in the next step.

And 5: preparation of 2- (5-chloro-2-methoxyphenyl) -3-oxopropanenitrile

To a solution of 2- (5-chloro-2-methoxyphenyl) acetonitrile (10g,47.84mmol) in ethyl formate (50mL) was added metallic sodium (4.4g,95.6mmol) at room temperature. The resulting reaction mixture was heated to 100 ℃ and held for 3 hours. After the reaction was complete, it was cooled to room temperature, water (100ml) and dichloromethane (100ml) were added to the reaction mixture, and the solution was adjusted to pH-3 with the aid of concentrated hydrochloric acid. The layers were separated and the aqueous layer was extracted with dichloromethane (2X 100 ml). The combined organics were washed with saturated aqueous sodium chloride (150ml), dried over sodium sulfate, filtered under vacuum and evaporated. The crude product was purified by column chromatography using normal phase silica gel. The desired product was eluted in about 0.7-0.9% methanol in dichloromethane. Evaporation of the product fractions gave 9g (yield 77.94%) of a white solid, the desired compound. LC-MS: and M/z is 208.0 (M-H).

Step 6: preparation of 4- (5-chloro-2-methoxyphenyl) -1H-pyrazol-5-amine

To a solution of 2- (5-chloro-2-methoxyphenyl) -3-oxopropanenitrile (9g,43mmol) in ethanol (90mL) was added hydrazine hydrate (4.3g,86.12mmol) and glacial acetic acid (2.7mL,51.6mmol) at room temperature. The reaction mixture was then heated at reflux for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and quenched with aqueous sodium bicarbonate (150 ml). The resulting compound was extracted with dichloromethane (3X 100 ml). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography using normal phase silica gel. The desired product was eluted in about 0.9-1.1% methanol in dichloromethane. The evaporation of the product fractions gave 7g (yield 72.8%) of a white solid, the desired compound. LC-MS: m/z 224.1(M + H).

And 7: 3- (5-chloro-2-methoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a]Preparation of pyrimidines

A solution of 4- (5-chloro-2-methoxyphenyl) -1H-pyrazol-5-amine (3g,13.45mmol) in dry DMF (15mL) was cooled to a temperature of 5-10 ℃. Sodium hydride (0.806g,20.17mmol) was added to the above solution in small portions over a period of 30 minutes. The resulting reaction mixture was stirred at 5 to 10 ℃ for 30 minutes, after which 1, 3-dibromopropane (1.78ml,17.48mmol) was added dropwise to the above mixture. The resulting reaction mixture was heated at 100 ℃ for 4 hours. After the reaction was complete, the solution was diluted with cold water (100ml) and the product was extracted with ethyl acetate (3 × 100 ml). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography using normal phase silica gel. The desired product was eluted in about 1.2-1.5% methanol in dichloromethane. Evaporation of the product fractions gave 0.65g (yield 18.36%) of the desired compound as a semi-solid. LC-MS: m/z 264.2(M + H).

And 8: 4-chloro-2- (4,5,6, 7-tetrahydropyrazolo [1, 5-a)]Preparation of pyrimidin-3-yl) phenols

A solution of 3- (5-chloro-2-methoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine (0.65g,1.9mmol) in dichloromethane (30mL) was cooled to a temperature of 5-10 ℃. To the above solution was added dropwise a solution of boron tribromide in dichloromethane (4.7mL,4.75mmol) over a period of 30 minutes. After the addition was complete, the resulting reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, the solution was diluted with cold water (40mL) and the product was extracted with ethyl acetate (3X 30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford 0.65g (yield 81.24%) of a white solid, the desired compound. LC-MS: m/z 250.2(M + H).

And step 9: 5-chloro-4- (4-chloro-2- (4,5,6, 7-tetrahydropyrazolo [1, 5-a)]Pyrimidin-3-yl) phenoxy) Preparation of tert-butyl (thiazol-4-yl) -2-fluorophenylsulfonyl carbamate

4-chloro-2- (4,5,6, 7-tetrahydropyrazolo [1,5-a ] is reacted under nitrogen atmosphere at room temperature]Pyrimidin-3-yl) phenol (0.5g,2.008mmol) in DMF (8ml) was added K in small portions₂CO₃(0.556g,4.016 mmol)). the resulting reaction mixture was then stirred at room temperature for 15 minutes the resulting reaction mixture was added to the above mixture 5-chloro-2, 4-difluorobenzenesulfonyl (thiazol-4-yl) carbamic acid tert-butyl ester (0.989g,2.409mmol) and the resulting reaction mixture stirred at room temperature for 3 hours after the reaction was complete water (10ml) was added and the mixture was extracted with ethyl acetate (3 × 25ml) the combined organic extracts were washed with water (20ml), brine (20ml), dried over sodium sulfate and concentrated under vacuum the crude product was purified by column chromatography using normal phase silica gel the desired product was eluted in approximately 40-50% ethyl acetate in hexane solution the product fractions were evaporated to give 0.4g (yield 31.18%) of a yellow solid, the desired compound.

Step 10: 5-chloro-4- (4-chloro-2- (4,5,6, 7-tetrahydropyrazolo [1, 5-a)]Pyrimidin-3-yl) phenoxy) Preparation of (E) -2-fluoro-N- (thiazol-4-yl) benzenesulfonamide

To a solution of tert-butyl 5-chloro-4- (4-chloro-2- (4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidin-3-yl) phenoxy) -2-fluorophenylsulphonyl (thiazol-4-yl) carbamate (0.4g,0.626mmol) in dichloromethane (15ml) at room temperature was added dropwise a 4N solution of hydrochloric acid in ethyl acetate (0.8 ml). The resulting reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, pentane (20ml) was added to the reaction mixture, resulting in precipitation of a solid. The solvent layer was decanted, the solid thus obtained was washed twice with pentane (15ml) and dried under vacuum. Aqueous solution with 0.1% hydrochloric acid: the crude material obtained was further purified by preparative HPLC on acetonitrile mobile phase. Evaporation from the pure product fraction obtained by preparative HPLC provided the hydrochloride salt, the desired product (0.130g, 38.6% yield). LC-MS: 539.78(M + H). 1HNMR (400MHz, methanol-d 4)8.76(d, J ═ 2.4Hz,1H),8.02(s,1H),7.95(d, J ═ 7.2Hz,1H),7.61(d, J ═ 2.4Hz,1H),7.54(dd, J ═ 2.4,8.4Hz,1H),7.27(d, J ═ 8.4Hz,1H),7.09(d, J ═ 2.0Hz,1H),6.62(d, J ═ 10.8Hz,1H),4.14(t, J ═ 6.0Hz,2H),3.40(t, J ═ 5.6Hz,2H),2.14(p, J ═ 6.0Hz, 2H).

Example 34: 2- ((3- (5-2- (2-chloro-5-fluoro-4- (N- (thiazol-2-yl) sulfamoyl) benzene Oxy) phenyl) propyl) (ethoxycarbonyl) amino) acetic acid

Scheme 6

Step 1: preparation of 3- (5-chloro-2-hydroxyphenyl) acrolein

To a solution of 5-chloro-2-hydroxybenzaldehyde (20g, 127mmol) in THF (300ml) was added (formylmethylene) triphenylphosphorane (43g,140mmol) at room temperature. The resulting reaction mixture was refluxed at 100 ℃ for 20 hours. The reaction mixture was cooled to room temperature and extracted with water (200ml) and ethyl acetate (3X 250 ml). The combined organic phases were washed with water (200ml), brine (200ml), dried over sodium sulfate and concentrated in vacuo to give the desired crude product. The crude product was purified by column chromatography using normal phase silica gel. The desired product was eluted in approximately 20-30% ethyl acetate in hexane. The evaporation of the product fractions gave 20g (yield 87%) of a yellow solid, the desired compound. LC-MS: M/z 183.4(M + H).

To a solution of 3- (5-chloro-2-hydroxyphenyl) acrolein (5g,27mmol) and glycine methyl ester hydrochloride (4.1g,32mmol) in dichloromethane (80ml) was added magnesium sulfate (6g,50mmol) and triethylamine (12ml,82mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. The resulting reaction mixture was then concentrated under vacuum. The concentrated cake thus obtained was dissolved in methanol (50ml) and cooled to a temperature of 5-10 ℃. Sodium borohydride (3.0g,82mmol) was added to the above mixture in small portions over a period of 20 minutes, and the temperature of the reaction mixture was maintained at 10-20 ℃ during the reaction addition. The reaction mixture was allowed to stir at room temperature for 2 hours and concentrated under vacuum. Water (100ml) was added to the above crude cake and the resulting mixture was extracted with ethyl acetate (3 × 100 ml). The combined organic extracts were washed with water (50ml), brine (50ml), dried over sodium sulfate and concentrated in vacuo to give the desired crude product. The crude product was purified by column chromatography using normal phase silica gel. The desired product was eluted in about 1-5% methanol in dichloromethane. The evaporation of the product fractions gave 4g (yield 58%) of a yellow solid, the desired compound. LC-MS: M/z 256.43(M + H).

10% Palladium on carbon with 50% moisture (0.145g,1.3mmol) was carefully added to a solution of methyl 2- (3- (5-chloro-2-hydroxyphenyl) allylamino) acetate (3.5g,13.6mmol) in methanol (80 ml). Hydrogen was then bubbled into the reaction mixture at room temperature over a period of 30 minutes. After completion of the reaction, the reaction mixture was filtered through celite. The celite bed was carefully washed with a quantity of methanol. The filtrate thus obtained was concentrated under vacuum to provide 3g (yield 85%) of a colorless liquid compound and used directly in the next step. LC-MS: M/z 258.5(M + H).

And 4, step 4: (3- (5-chloro-2- (2-chloro-4- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) Preparation of sulfamoyl) -5-fluorophenoxy) phenyl) propyl) glycine methyl ester

To a solution of methyl 2- (3- (5-chloro-2-hydroxyphenyl) propylamino) acetate (1.1g,4.28mmol) in DMF (12ml) under a nitrogen atmosphere at room temperature was added a portion of K₂CO₃(1.77g,12.8 mmol.) the resulting reaction mixture was stirred at room temperature for 15 minutes.5-chloro-N- (2, 4-dimethoxybenzyl) -2, 4-difluoro-N- (thiazol-2-yl) benzenesulfonamide (1.96g,4.28mmol) was added to the above mixture and the resulting compound was stirred at room temperature for 4 hours after the reaction was complete, demineralized water (100ml) was added, then the resulting mixture was extracted with ethyl acetate (3 × 50 ml.) the combined organic extracts were washed with demineralized water (50ml) and brine (50ml) and concentrated under vacuum to afford 1.5g (50.2% yield) of the desired compound which was used directly in the next step.lc-MS: M/z 698.5(M + H).

And 5: n- (3- (5-chloro-2- (2-chloro-4- (N- (2, 4-dimethoxybenzyl) -N- (thiazole-2-) Preparation of methyl ester of phenyl) sulfamoyl) -5-fluorophenoxy) phenyl) propyl) -N- (ethoxycarbonyl) glycine Prepare for

To a solution of methyl (3- (5-chloro-2- (2-chloro-4- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -5-fluorophenoxy) phenyl) propyl) glycinate (1.0g, 1.43mmol) in dichloromethane (50ml) at room temperature was added triethylamine (0.596mmol, 4.29 mmol). The resulting reaction mixture was stirred at the same temperature for 10 minutes. Ethyl chloroformate (0.407ml,4.29mmol) was added to the reaction mixture at room temperature. The resulting reaction mixture was then refluxed at 80 ℃ for 12 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and poured into demineralized water (50 ml). The resulting compound was extracted with dichloromethane (3X 50 ml). The combined organic extracts were washed with demineralized water (50ml), brine (50ml), dried over sodium sulfate, and concentrated in vacuo to afford the desired crude product. The crude product was purified by trituration with diethyl ether to give 0.860g (yield 78.09%) of a brown solid, the desired compound. This material was used directly in the next step. LC-MS: M/z 770.2(M + H).

Step 6: n- (3- (5-chloro-2- (2-chloro-4- (N- (2, 4-)Dimethoxy benzyl) -N- (thiazole-2- Preparation of yl) sulfamoyl) -5-fluorophenoxy) phenyl) propyl) -N- (ethoxycarbonyl) glycine

To a solution of methyl N- (3- (5-chloro-2- (2-chloro-4- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -5-fluorophenoxy) phenyl) propyl) -N- (ethoxycarbonyl) glycinate (0.85g,1.10mmol) in THF (10ml) at room temperature was added a solution of lithium hydroxide monohydrate (0.135g,5.62mmol) in demineralized water (10 ml). The resulting reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction, ice-cold water (20ml) was added to the reaction mixture, and the resulting mixture was acidified to pH4-6 with aqueous 1N hydrochloric acid. The resulting aqueous acidic solution was extracted with ethyl acetate (3X 30 ml). The combined organic extracts were washed with demineralized water (20ml), brine (20ml), dried over sodium sulfate and concentrated in vacuo to afford 0.55g (yield 66.13%) of the compound as a white solid. This material was used directly in the next step.

And 7: n- (3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) Preparation of phenyl) propyl) -N- (ethoxycarbonyl) glycine

To a solution of N- (3- (5-chloro-2- (2-chloro-4- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -5-fluorophenoxy) phenyl) propyl) -N- (ethoxycarbonyl) glycine (0.5g,0.66mmol) in dichloromethane (10ml) was added dropwise a 4N solution of hydrochloric acid in ethyl acetate (5 ml). The resulting reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, pentane (15ml) was added to the reaction mixture, resulting in precipitation of a solid. The solvent layer was decanted, the solid thus obtained was washed twice with pentane (10ml) and dried under vacuum. By using 0.1% aqueous hydrochloric acid: preparative HPLC of acetonitrile mobile phase the crude material obtained was further purified. Evaporation from the pure product fraction obtained by preparative HPLC afforded the desired product (0.04g, yield 10%). LC-MS: M/z 606.16(M + H), 1H-nmr (meod), d8.00-8.06(M,1H),7.45(s,1H),7.28-7.35(M,1H),7.16(d, J4.6 Hz,1H),6.97-7.06(M,1H),6.80(d, J4.7 Hz,1H),6.61-6.71(M,1H),4.01-4.12(M,1H),3.95(d, J10.6 Hz,2H),2.52-2.63(M,2H),1.79-1.90(M,2H),1.14-1.25(M, 3H).

Example 35: ethyl 2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) acetate

Scheme 7

Step 1: (3- (5-chloro-2- (2-chloro-4- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) Preparation of sulfamoyl) -5-fluorophenoxy) phenyl) propyl) glycine methyl ester

To a solution of methyl 2- (3- (5-chloro-2-hydroxyphenyl) propylamino) acetate (1.6g,6.22mmol) (synthesized according to the procedure described for compound 11) in DMF (12ml) under nitrogen and at room temperature was added one portion of K₂CO₃(2.5g,18.6 mmol.) the resulting reaction mixture was stirred at room temperature for 15 minutes.5-chloro-N- (2, 4-dimethoxybenzyl) -2, 4-difluoro-N- (thiazol-2-yl) benzenesulfonamide (3.14g,6.8mmol) was added to the above mixture and the resulting mixture was stirred at room temperature for 4 hours after the reaction was complete demineralised water (100ml) was added and the mixture was then extracted with ethyl acetate (3 × 50 ml). the combined organic extracts were washed with demineralised water (50ml), brine (50ml) and concentrated under vacuum to give 1.0g (23.2% yield) of solid, the desired compound.

Step 2: (3- (5-chloro-2- (2-chloro-4- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) Preparation of sulfamoyl) -5-fluorophenoxy) phenyl) propyl) glycine

To a solution of methyl (3- (5-chloro-2- (2-chloro-4- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -5-fluorophenoxy) phenyl) propyl) glycinate (1g,1.43mmol) in THF (15ml) at room temperature was added a solution of lithium hydroxide monohydrate (0.3g,7.16mmol) in demineralized water (15 ml). The resulting reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction, ice-cold water (20ml) was added to the reaction mixture, and the resulting mixture was acidified to pH4-6 with aqueous 1N hydrochloric acid. The resulting aqueous acidic solution was extracted with ethyl acetate (3X 30 ml). The combined organic extracts were washed with demineralized water (20ml), brine (20ml), dried over sodium sulfate and concentrated in vacuo to afford 0.7g (yield 71.55%) of the compound as a white solid. This material was used directly in the next step without any further purification and analysis. LC-MS: M/z 684.15(M + H).

And step 3: (3- (5-chloro-2- (2-chloro-4- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) Preparation of sulfamoyl) -5-fluorophenoxy) phenyl) propyl) glycine ethyl ester

To a solution of (3- (5-chloro-2- (2-chloro-4- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -5-fluorophenoxy) phenyl) propyl) glycine (0.5g,0.73mmol) in ethanol (10ml) at 0 ℃ was added thionyl chloride (0.53ml,7.3 mmol). The resulting reaction mixture was then refluxed for 12 hours. After completion of the reaction, the reaction mixture was evaporated in vacuo and demineralized water (30ml) was added to the resulting residue. The resulting mixture was extracted with ethyl acetate (3X 50 ml). The combined organic extracts were washed with demineralized water (20ml), brine (20ml), dried over sodium sulfate, and concentrated in vacuo to afford the desired crude product. The crude product was purified by trituration with diethyl ether to give 0.4g (yield 76.9%) of the desired compound. This material was used directly in the next step. LC-MS: M/z 712.4(M + H).

And 4, step 4: (3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) Preparation of phenyl) propyl) glycine ethyl ester

To a solution of ethyl (3- (5-chloro-2- (2-chloro-4- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -5-fluorophenoxy) phenyl) propyl) glycinate (0.35g,0.49mmol) in dichloromethane (10ml) at room temperature was added dropwise a 4N solution of hydrochloric acid in ethyl acetate (5 ml). The resulting reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, pentane (15ml) was added to the reaction mixture, resulting in precipitation of a solid. The solvent layer was decanted, the solid thus obtained was washed twice with pentane (10ml) and dried under vacuum. By using 0.1% HCl in water: preparative HPLC of acetonitrile mobile phase (preparative HPLC method a) the resulting crude material was further purified. Evaporation of the pure product fractions from preparative HPLC afforded the desired product (0.045g, yield 16.32%). LC-MS: M/z 562.04(M + H).1H-nmr (meod), d8.03-8.08(M,1H)7.46-7.49(M,1H)7.33-7.38(M,1H)7.15-7.19(M,1H)7.00-7.04(M,1H)6.81-6.85(M,1H)6.75-6.79(M,1H)4.29-4.36(M,2H)3.97(s,2H)3.07-3.13(M,2H)2.67-2.74(M,2H)2.00-2.08(M,2H)1.29-1.37(M, 3H).

Example 42: 4- (2- (3- ((1H-pyrazol-4-yl) amino) propyl) -4-chlorophenoxy) -5-chloro-2-fluoro-N- (thiazol-2-yl) benzenesulfonamide

Compound 42 was synthesized according to the procedure described for the synthesis of compound 11 by replacing glycine methyl ester with 1H-pyrazol-4-amine in step 2 and omitting step 5. LC-MS: M/z 541.82(M + H).1H-nmr (meod), d8.78(d, J2.1 Hz,1H),8.02(d, J7.1 Hz,1H),7.89(s,2H),7.48(d, J2.4 Hz,1H),7.32-7.40(M,1H),7.12(d, J2.1 Hz,1H),7.01(d, J8.7 Hz,1H),6.74(d, J10.7 Hz,1H),3.36-3.44(M,2H),2.70(t, J7.7 Hz,2H),2.06(s, 2H).

Example 43: 3- ((3- (5-chloro-2- (2, 5-difluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) propanoic acid

Compound 43 was synthesized according to the procedure described for the synthesis of compound 11 by substituting β -alanine methyl ester for glycine methyl ester in step 2 and N- (2, 4-dimethoxybenzyl) -2,4, 5-trifluoro-N- (thiazol-2-yl) benzenesulfonamide for tert-butyl 5-chloro-2, 4-difluorophenylsulfonyl (thiazol-4-yl) carbamate in step 4. LC-MS: M/z 532.14(M + H), 1H-nmr (meod), d7.78-7.85(M,1H)7.44-7.51(M,1H)7.27-7.36(M,1H)7.13-7.19(M,1H)6.96-7.03(M,1H)6.83-6.91(M,1H)6.79(s,1H)3.11-3.18(M,2H)3.01-3.08(M,2H)2.71-2.80(M,2H)2.43-2.52(M,2H)1.97-2.08(M, 2H).

Example 44: 5-chloro-4- (4-chloro-2- (3- ((2- (methylsulfonyl) ethyl) amino) propyl) phenoxy) -2-fluoro-N- (thiazol-4-yl) benzenesulfonamide

Compound 44 was synthesized according to the procedure described for the synthesis of compound 11 by replacing glycine methyl ester with 2- (methylsulfonyl) ethylamine in step 2 and omitting step 5. LC-MS: M/z 581.83(M + H).1H-nmr (meod), d8.77(d, J2.2 Hz,1H),7.99-8.07(M,1H),7.46-7.53(M,1H),7.31-7.41(M,1H),7.10(d, J2.2 Hz,1H),7.04(s,1H),6.69-6.77(M,1H),3.46-3.52(M,2H),3.39-3.45(M,2H),3.09(s,3H),2.97-3.04(M,2H),2.63-2.71(M,2H),1.94-2.04(M, 2H).

Example 45: 4- (2- (3- ((1H-pyrazol-3-yl) amino) propyl) -4-chlorophenoxy) -5-chloro-2-fluoro-N- (thiazol-4-yl) benzenesulfonamide

Compound 45 was synthesized according to the procedure described for the synthesis of compound 11 by replacing glycine methyl ester with 1H-pyrazol-3-amine in step 2 and omitting step 5. LC-MS: M/z 541.99(M + H).1H-nmr (meod), d8.76(d, J2.2 Hz,1H),7.95(d, J7.2 Hz,1H),7.76-7.82(M,1H),7.45(d, J2.6 Hz,1H),7.33(dd, J8.6, 2.6Hz,1H),7.10(d, J2.2 Hz,1H),7.02(d, J8.7 Hz,1H),6.63(d, J10.8 Hz,1H),5.74(d, J2.9 Hz,1H),3.19(t, J6.7 Hz,2H),2.62-2.71, 2.82 (M,1H), 1.98(M, 2H).

Example 46: 2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-4-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) -N-methylacetamide

Compound 46 was synthesized according to the procedure described for the synthesis of compound 11 by replacing glycine methyl ester with 2-amino-N-methylacetamide in step 2 and omitting step 5. LC-MS: M/z 546.88(M + H).1H-nmr (meod), d8.74-8.81(M,1H),7.97-8.07(M,1H),7.46-7.51(M,1H),7.32-7.40(M,1H),7.09-7.15(M,1H),6.97-7.06(M,1H),6.68-6.82(M,1H),3.76(s,2H),3.01-3.09(M,2H),2.80(s,3H),2.63-2.72(M,2H),1.97-2.07(M, 2H).

Example 47: 2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-4-yl) sulfamoyl) phenoxy) phenyl) propyl) (methyl) amino) acetic acid

Compound 47 was synthesized according to the procedure described for the synthesis of compound 11 by replacing the glycine methyl ester with sarcosine methyl ester in step 2. LC-MS: M/z 548.04(M + H).1H-nmr (meod), d8.73(d, J2.1 Hz,1H),8.01(d, J7.1 Hz,1H),7.49(d, J2.5 Hz,1H),7.34(dd, J8.7, 2.6Hz,1H),6.99(d, J8.7 Hz,1H),6.94(d, J2.1 Hz,1H),6.74(d, J10.6 Hz,1H),3.61(s,2H),3.09-3.19(M,2H),2.84(s,3H),2.67(t, J7.7 Hz,2H),2.06(t, J0, 2H).

Example 48: 5-chloro-4- (4-chloro-2- (3- (6, 7-dihydro-1H-pyrazolo [4,3-c ] pyridin-5 (4H) -yl) propyl) phenoxy) -2-fluoro-N- (thiazol-4-yl) benzenesulfonamide

Compound 48 was synthesized according to the procedure described for the synthesis of compound 11 by replacing glycine methyl ester with 4,5,6, 7-tetrahydro-1H-pyrazolo [4,3-c ] pyridine in step 2 and omitting step 5. LC-MS: M/z 581.90(M + H).1H-nmr (meod), d8.76(br.s.,1H),8.02(br.s.,1H),7.67(br.s,1H),7.54(br.s,1H),7.35(br.s.,1H),7.13(br.s,1H),7.03(d, J ═ 6.7Hz,1H),6.73-6.79(M,1H),4.55-4.57(M,1H),4.19-4.21(M,1H),3.81(br.s,1H),3.66(br.s,1H),3.50(br.s,1H),3.29(s,1H),3.15(br.s,3H),2.68 (br.68, 2.72H), 2.72(M, 2H), 2.72(M, 1H).

Example 49: 2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-4-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) acetamide

Preparation of 2- ((3- (5-chloro-2-hydroxyphenyl) propyl) amino) acetamide

(3- (5-chloro-2-hydroxyphenyl) propyl) glycine methyl ester was synthesized as described for compound 11. A solution of (3- (5-chloro-2-hydroxyphenyl) propyl) glycine methyl ester (6.0g, 23.25mmol) in methanol (200ml) was cooled to-78 ℃ using an acetone/dry ice bath. Ammonia gas was then purged in this cold reaction mixture for 1-3 hours. The reaction assembly was then closed and the reaction mixture was allowed to warm to room temperature, whereupon it was stirred for a further 18 hours. The reaction mixture was monitored on TLC using pure ethyl acetate as mobile phase. After completion of the reaction, the reaction mixture was mixed and evaporated under vacuum to give a crude material which was further co-evaporated twice with diethyl ether. The crude product was triturated with diethyl ether (2 × 50ml) and pentane (50ml) and the resulting solid was filtered off under vacuum and used directly in the next step without any further purification. LC-MS: M/z 243.08(M + H).

2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-4-yl) sulfamoyl) phenoxy) benzene Group) propyl) amino) acetamide (49) preparation

Compound 49 was synthesized according to the procedure described for the synthesis of compound 11 by replacing methyl 2- (3- (5-chloro-2-hydroxyphenyl) propylamino) acetate with 2- ((3- (5-chloro-2-hydroxyphenyl) propyl) amino) acetamide in step 4 and omitting step 5. LC-MS, M/z 533.(M + H).1H-nmr (meod), d8.77(s,1H),8.03(d, J ═ 6.4Hz,1H),7.49(s,1H),7.37(d, J ═ 8.8Hz,1H),7.12(s,1H),7.03(d, J ═ 8.8Hz,1H),6.76(d, J ═ 10.4Hz,1H),3.80(s,2H),3.06(t, J ═ 8Hz,2H),2.68(t, J ═ 7.6Hz,2H),2.03(t, J ═ 8Hz, 2H).

Example 50: isoamyl 2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) acetate

Compound 50 was synthesized according to the procedure described for the synthesis of compound 35 by replacing ethanol with 3-methylbutan-1-ol in step 3. LC-MS: 604.14(M + H), 1H-nmr (dmso), d7.91-8.00(M,1H),7.50-7.56(M,1H),7.32-7.40(M,2H),7.06-7.14(M,1H),6.90-6.99(M,2H),4.16-4.25(M,2H),3.98-4.04(M,2H),2.90-2.97(M,2H),2.57-2.64(M,2H),1.87-1.96(M,2H),1.61-1.72(M,1H),1.45-1.55(M,2H),0.90(d, J ═ 6.6Hz, 6H).

Example 51: isopropyl 2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) acetate

Compound 51 was synthesized according to the procedure described for the synthesis of compound 35 by substituting isopropanol for ethanol in step 3. LC-MS: M/z 575.92(M + H).1H-nmr (meod), d1.31(s,3H)1.32(s,3H)2.01-2.09(M,2H)2.71(t, J7.63 Hz,2H)3.07-3.15(M,2H)3.95(s,2H)5.11-5.19(M,1H)6.76(d, J10.45 Hz,1H)6.82(d, J4.65 Hz,1H)7.01(d, J8.70 Hz,1H)7.18(d, J4.65 Hz,1H)7.35(dd, J8.70, 2.59Hz,1H)7.49(d, J2.52, J8.05H, 1H) 7.05 Hz, d, J10H).

Example 52: methyl 2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-4-yl) sulfamoyl) phenoxy) phenyl) propyl) (methyl) amino) acetate

Compound 52 was synthesized according to the procedure described for the synthesis of compound 11 by replacing glycine methyl ester with sarcosine methyl ester in step 2 and omitting step 5. LC-MS: M/z 562.14(M + H).1H-nmr (meod), d8.76(d, J2.2 Hz,1H),8.00(d, J7.2 Hz,1H),7.45(d, J2.6 Hz,1H),7.29-7.36(M,1H),6.97-7.10(M,2H),6.66(d, J10.8 Hz,1H),3.68(s,3H),3.24(s,2H),2.56(s,2H),2.48(d, J7.6 Hz,2H),2.28(s,3H),1.71-1.81(M, 2H).

Example 53: 2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) ((pentyloxy) carbonyl) amino) acetic acid

Scheme 8

To a solution of methyl 2- (3- (5-chloro-2-hydroxyphenyl) propylamino) acetate (0.6g,2.3mmol) (synthesized according to the procedure described for compound 11) in DMF (10ml) under nitrogen atmosphere and at room temperature was added one portion of K₂CO₃(0.96g,6.9 mmol.) the resulting reaction mixture is then stirred at room temperature for 15 minutes, 5-chloro-N- (2, 4-dimethoxybenzyl) -2, 4-difluoro-N- (thiazol-2-yl) benzenesulfonamide (1.17g,2.5mmol) is added to the above mixture and the resulting mixture is stirred at room temperature for 4 hours after the reaction is complete, demineralized water (100ml) is added, the resulting mixture is then extracted with ethyl acetate (3 × ml), the combined organic extracts are washed with demineralized water (50ml), brine (50ml), the combined organic layers are washed with brine, dried over sodium sulfate and concentrated under vacuum to afford 0.6g (37.36% yield) of the desired compound.

Step 2: n- (3- (5-chloro-2- (2-chloro-4- (N- (2, 4-dimethoxybenzyl) -N- (thiazole-2-) Yl) sulfamoyl) -5-fluorophenoxy) phenyl) propyl) -N- ((pentyloxy) carbonyl) glycine methyl ester Preparation of

To a solution of methyl (3- (5-chloro-2- (2-chloro-4- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -5-fluorophenoxy) phenyl) propyl) glycinate (0.6g,0.85mmol) in dichloromethane (30ml) at room temperature was added triethylamine (0.36ml,2.57 mmol). The resulting reaction mixture was then stirred at the same temperature for 10 minutes. N-pentyl chloroformate (0.38ml,2.57mmol) was added to the resulting reaction mixture at room temperature. The resulting reaction mixture was then refluxed at 80 ℃ for 12 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and poured into demineralized water (50 ml). The resulting mixture was extracted with dichloromethane (3X 50 ml). The combined organic extracts were washed with demineralized water (50ml), brine (50ml), dried over sodium sulfate, and concentrated in vacuo to afford the desired crude product. The crude product was purified by trituration with diethyl ether to give 0.6g (yield 86.9%) of a brown solid, the desired compound. MS: M/z 812.21(M + H).

And step 3: n- (3- (5-chloro-2- (2-chloro-4- (N- (2, 4-dimethoxybenzyl) -N- (thiazole-2-) Preparation of yl) sulfamoyl) -5-fluorophenoxy) phenyl) propyl) -N- ((pentyloxy) carbonyl) glycine Prepare for

To a solution of methyl N- (3- (5-chloro-2- (2-chloro-4- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -5-fluorophenoxy) phenyl) propyl) -N- ((pentyloxy) carbonyl) glycinate (0.6g,0.738mmol) in THF (20ml) at room temperature was added a solution of lithium hydroxide monohydrate (0.1g,4.43mmol) in demineralized water (10 ml). The resulting reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction, ice-cold water (20ml) was added to the reaction mixture, and the resulting mixture was acidified to pH4-6 with aqueous 1N hydrochloric acid. The resulting aqueous acidic solution was extracted with ethyl acetate (3X 30 ml). The combined organic extracts were washed with demineralized water (20ml), brine (20ml), dried over sodium sulfate and concentrated in vacuo to afford 0.5g (yield 84.89%) of the compound as a white solid. This material was used directly in the next step.

And 4, step 4: n- (3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) Preparation of phenyl) propyl) -N- ((pentyloxy) carbonyl) glycine

To a solution of N- (3- (5-chloro-2- (2-chloro-4- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -5-fluorophenoxy) phenyl) propyl) -N- ((pentyloxy) carbonyl) glycine (0.5g,0.626mmol) in dichloromethane (15ml) was added dropwise a 4N solution of hydrochloric acid in ethyl acetate (5ml) at room temperature. The resulting reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, pentane (10ml) was added to the reaction mixture, resulting in precipitation of a solid. The solvent layer was decanted, the solid thus obtained was washed twice with pentane (10ml) and dried under vacuum. By using 0.1% aqueous hydrochloric acid: preparative HPLC of acetonitrile mobile phase (preparative HPLC method a) the resulting crude material was further purified. Evaporation of the pure product fraction obtained from preparative HPLC provided the desired product (0.05g, yield 12.3%). LC-MS: M/z 648.14(M + H), 1H-nmr (dmso), d13.02(br.s,1H),12.63(br.s,1H),7.89-7.96(M,1H),7.44-7.51(M,1H),7.30-7.36(M,2H),7.05-7.13(M,1H),6.80-6.94(M,2H),3.83-3.93(M,4H),3.16-3.28(M,2H),1.66-1.81(M,2H),1.39-1.51(M,2H),1.12-1.28(M,4H),0.74-0.88(M, 3H).

Example 54: 2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) (prop-2-yn-1-yl) amino) acetic acid

Scheme 9

To a solution of methyl 2- (3- (5-chloro-2-hydroxyphenyl) propylamino) acetate (1.1g,4.28mmol) in DMF (12ml) under a nitrogen atmosphere at room temperature was added a portion of K₂CO₃(1.77g,12.8 mmol.) the resulting reaction mixture is then stirred at room temperature for 15 minutes, 5-chloro-N- (2, 4-dimethoxybenzyl) -2, 4-difluoro-N- (thiazol-2-yl) benzenesulfonamide (1.96g,4.28mmol) is added to the above mixture and the resulting mixture is stirred at room temperature for 4 hours after the reaction is complete, demineralised water (100ml) is added and the resulting mixture is then extracted with ethyl acetate (3 × 50ml), the combined organic extracts are washed with demineralised water (50ml), brine (50ml), the combined organic layers are washed with brine, dried over sodium sulphate and concentrated under vacuum to give 1.5g (yield 50.2%) of a solid, the desired compound.

Step 2: n- (3- (5-chloro-2- (2-chloro-4- (N- (2, 4-dimethoxybenzyl) -N- (thiazole-2-) Process for preparation of methyl ester of phenyl) sulfamoyl) -5-fluorophenoxy) phenyl) propyl) -N- (prop-2-yn-1-yl) glycine Preparation of

To a solution of methyl (3- (5-chloro-2- (2-chloro-4- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -5-fluorophenoxy) phenyl) propyl) glycinate (0.9g,1.28mmol) in dichloromethane (30mL) at room temperature was added triethylamine (0.54mL,3.86 mmol). The resulting reaction mixture was stirred at the same temperature for 10 minutes. 3-bromoprop-1-yne (0.346ml,3.86mmol) was added to the reaction mixture at room temperature. The resulting reaction mixture was then refluxed at 80 ℃ for 12 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and poured into demineralized water (50 ml). The resulting mixture was extracted with dichloromethane (3X 50 ml). The combined organic extracts were washed with demineralized water (50ml), brine (50ml), dried over sodium sulfate, and concentrated in vacuo to afford the desired crude product. The crude product was purified by trituration with diethyl ether to give 0.780g (77.8% yield) of a brown solid, the desired compound. LC-MS: M/z 736.15(M + H).

And step 3: n- (3- (5-chloro-2- (2-chloro-4- (N- (2, 4-dimethoxybenzyl) -N- (thiazole-2-) Preparation of yl) sulfamoyl) -5-fluorophenoxy) phenyl) propyl) -N- (prop-2-yn-1-yl) glycine

To a solution of methyl N- (3- (5-chloro-2- (2-chloro-4- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -5-fluorophenoxy) phenyl) propyl) -N- (prop-2-yn-1-yl) glycinate (0.7g,0.95mmol) in THF (30ml) was added a solution of lithium hydroxide monohydrate (0.2g,4.75mmol) in demineralized water (10ml) at room temperature. The resulting reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction, ice-cold water (20ml) was added to the reaction mixture, and the resulting mixture was acidified to pH4-6 with aqueous 1N hydrochloric acid. The resulting aqueous acidic solution was extracted with ethyl acetate (3X 30 ml). The combined organic extracts were washed with demineralized water (20ml), brine (20ml), dried over sodium sulfate and concentrated in vacuo to afford 0.43g (62.68% yield) of the compound as a white solid. This material was used directly in the next step.

And 4, step 4: n- (3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) Preparation of yl) phenyl) propyl) -N- (prop-2-yn-1-yl) glycine

To a solution of N- (3- (5-chloro-2- (2-chloro-4- (N- (2, 4-dimethoxybenzyl) -N- (thiazol-2-yl) sulfamoyl) -5-fluorophenoxy) phenyl) propyl) -N- (prop-2-yn-1-yl) glycine (0.4g,0.554mmol) in ethyl acetate (10ml) was added dropwise a 4N solution of hydrochloric acid in ethyl acetate (5ml) at room temperature. The resulting reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, pentane (10ml) was added to the reaction mixture, resulting in precipitation of a solid. The solvent layer was decanted, the solid thus obtained was washed twice with pentane (10ml) and dried under vacuum. By using 0.1% aqueous hydrochloric acid: preparative HPLC of acetonitrile mobile phase (preparative HPLC method a) the resulting crude material was further purified. Evaporation of the pure product fractions obtained from preparative HPLC provided the desired product (0.045g, yield 14.12%). LC-MS: M/z 572.09(M + H).1H-nmr (meod), d8.05(d, J7.1 Hz,1H),7.49(d, J2.6 Hz,1H),7.30-7.39(M,1H),7.17(d, J4.7 Hz,1H),7.01(d, J8.7 Hz,1H),6.81(d, J4.7 Hz,1H),6.75(d, J10.5 Hz,1H),4.07(d, J2.3 Hz,2H),3.87(s,2H),3.17-3.25(M,3H),2.64-2.73(M,2H),1.99-2.10(M, 2H).

Example 55: 5-chloro-4- (4-chloro-2- (3- (5, 6-dihydroimidazo [1,2-a ] pyridin-7 (8H) -yl) propyl) phenoxy) -2-fluoro-N- (thiazol-4-yl) benzenesulfonamide

Compound 55 was synthesized according to the procedure described for the synthesis of compound 11 by replacing glycine methyl ester with 5,6,7, 8-tetrahydroimidazo [1,2-a ] pyrazine in step 2 and omitting step 5. LC-MS: M/z 583(M + H).1H-nmr (meod), d8.72(d, J ═ 2.2Hz,1H),7.93-8.03(M,1H),7.45-7.52(M,1H),7.29-7.42(M,1H),7.00-7.10(M,2H),6.95(d, J ═ 1.4Hz,1H),6.61-6.69(M,1H),3.94-4.05(M,2H),3.63(s,2H),2.82-2.87(M,2H),2.72-2.77(M,2H),2.53-2.65(M,4H),1.79-1.92(M, 2H).

Example 56: 5-chloro-2-fluoro-4- (2- (4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidin-3-yl) phenoxy) -N- (thiazol-2-yl) benzenesulfonamide

Compound 56 was synthesized according to the procedure described for the synthesis of compound 33 by replacing 2- (5-chloro-2-methoxyphenyl) acetonitrile with 2- (2-methoxyphenyl) acetonitrile in step 5 and omitting steps 1 to 4. LC-MS: M/z 506.33(M + H).1H-nmr (dmso), d7.86(d, J7.2 Hz,1H),7.55(d, J7.6 Hz,1H),7.22-7.36(M,4H),7.14-7.19(M,1H),6.85(d, J4.3 Hz,1H),6.44(d, J10.9 Hz,1H),6.03(br.s.,1H),3.91(t, J5.6 Hz,2H),3.16(br.s.,2H),1.93(br.s., 2H).

Example 57: 5-chloro-4- (4-chloro-2- (4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidin-3-yl) phenoxy) -2-fluoro-N- (thiazol-2-yl) benzenesulfonamide

Compound 57 was synthesized according to the procedure described for the synthesis of compound 33 by substituting 5-chloro-N- (2, 4-dimethoxybenzyl) -2, 4-difluoro-N- (thiazol-2-yl) benzenesulfonamide for tert-butyl 5-chloro-2, 4-difluorophenylsulfonyl (thiazol-4-yl) carbamate in step 9. LC-MS: M/z 539.82(M + H).1H-nmr (dmso), d7.89(s,1H),7.56(d, J2.5 Hz,1H),7.48(s,1H),7.32(br.s.,1H),7.22(s,1H),6.88-6.94(M,1H),6.65-6.70(M,1H),3.95(t, J5.6 Hz,2H),3.18(t, J4.8 Hz,2H),1.90-2.00(M, 2H).

Example 58: 5-chloro-2-fluoro-4- (2- (4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidin-3-yl) phenoxy) -N- (thiazol-4-yl) benzenesulfonamide

Compound 58 was synthesized according to the procedure described for the synthesis of compound 33 by omitting steps 1 to 4, replacing 2- (5-chloro-2-methoxyphenyl) acetonitrile with 2- (2-methoxyphenyl) acetonitrile in step 5 and tert-butyl ((5-chloro-2, 4-difluorophenyl) sulfonyl) (thiazol-4-yl) carbamate in step 9 for tert-butyl 5-chloro-2, 4-difluorophenylsulfonyl (thiazol-4-yl) carbamate. LC-MS: M/z 505.87(M + H).1H-nmr (meod), d8.76(d, J2.2 Hz,1H),7.91-7.97(M,2H),7.51-7.62(M,2H),7.43-7.50(M,1H),7.25-7.32(M,1H),7.08(d, J2.2 Hz,1H),6.49(d, J10.8 Hz,1H),4.12(s,2H),3.35-3.43(M,2H),2.08-2.20(M,2H),1.32(s, 2H).

Example 59: 5-chloro-4- (4-chloro-2- (3- ((2- (methylsulfonyl) ethyl) amino) propyl) phenoxy) -2-fluoro-N- (thiazol-2-yl) benzenesulfonamide

Compound 59 was synthesized according to the procedure described for the synthesis of compound 11 by omitting step 5, replacing glycine methyl ester with 2- (methylsulfonyl) ethylamine in step 2, and replacing tert-butyl 5-chloro-2, 4-difluorobenzenesulfonyl (thiazol-4-yl) carbamate with 5-chloro-N- (2, 4-dimethoxybenzyl) -2, 4-difluoro-N- (thiazol-2-yl) benzenesulfonamide in step 4. LC-MS: M/z 584.44(M + H).1H-nmr (meod), d8.05(d, J7.1 Hz,1H),7.49(d, J2.5 Hz,1H),7.35(dd, J8.7, 2.6Hz,1H),7.18(d, J4.7 Hz,1H),7.01(d, J8.7 Hz,1H),6.71-6.86(M,2H),3.49-3.61(M,4H),3.09-3.18(M,5H),2.72(t, J7.7 Hz,2H),2.05(d, J1.8 Hz, 2H).

Example 60: 2- ((3- (2- (2-chloro-5-fluoro-4- (N- (thiazol-4-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) acetamide

Scheme 10

Step 1: preparation of 3- (2-hydroxyphenyl) acrolein

To a solution of 2-hydroxybenzaldehyde (10g,81.8mmol) in THF (150ml) was added (formylmethylene) triphenylphosphine (24.89g,81.8mmol) at room temperature. The resulting reaction mixture was refluxed at 100 ℃ for 20 hours. The reaction mixture was cooled to room temperature and extracted with water (200ml) and ethyl acetate (3X 150 ml). The combined organic phases were washed with water (150ml), brine (150ml), dried over sodium sulfate and concentrated in vacuo to give the desired crude product. The crude product was purified by column chromatography using normal phase silica gel. The desired product was eluted in approximately 20-30% ethyl acetate in hexane. The evaporation of the product fractions gave 8.7g (yield 71.86%) of a yellow solid, the desired compound. LC-MS: M/z 149.42(M + H).

Step 2: preparation of (3- (2-hydroxyphenyl) allyl) glycine methyl ester

To a solution of 3- (2-hydroxyphenyl) acrolein (8g, 56.7mmol) and glycine methyl ester hydrochloride (7.8g,62.4mmol) in dichloromethane (100ml) was added magnesium sulfate (10.21g, 85.1mmol) and triethylamine (16ml, 113.4mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. The resulting reaction mixture was concentrated under vacuum. The concentrated cake thus obtained was dissolved in methanol (50ml) and cooled to a temperature of 5-10 ℃. To the above mixture was added a small portion of sodium borohydride (6.4g,170.2mmol) over a period of 20 minutes, during which time the temperature of the reaction mixture was maintained at 10-20 ℃. The reaction mixture was allowed to stir at room temperature for 2 hours and concentrated under vacuum. Water (100ml) was added to the above crude cake and the resulting mixture was extracted with ethyl acetate (3 × 100 ml). The combined organic extracts were washed with water (50ml), brine (50ml), dried over sodium sulfate and concentrated in vacuo to give the desired crude product. The crude product was purified by column chromatography using normal phase silica gel. The desired product was eluted in about 1-5% methanol in dichloromethane. The evaporation of the product fractions gave 8g (yield 64.64%) of a yellow solid, the desired compound. LC-MS: M/z 222.33(M + H).

And step 3: preparation of (3- (2-hydroxyphenyl) propyl) glycine methyl ester

To a solution of (3- (2-hydroxyphenyl) allyl) glycine methyl ester (7.0g,31.6mmol) in methanol (70ml) was carefully added 10% palladium on carbon (0.335g,3.1mmol) with 50% moisture. Hydrogen was then bubbled into the reaction mixture at room temperature over a period of 30 minutes. After completion of the reaction, the reaction mixture was filtered through celite. The celite bed was carefully washed with a quantity of methanol. The filtrate thus obtained was concentrated under vacuum to provide 6g (yield 85.14%) of a colorless liquid compound, and was used directly in the next step. LC-MS: M/z 224.33(M + H).

And 4, step 4: preparation of 2- ((3- (2-hydroxyphenyl) propyl) amino) acetamide

A solution of (3- (2-hydroxyphenyl) propyl) glycine methyl ester (2g,8.96mmol) in methanol (60ml) was cooled to-78 ℃ using an acetone/dry ice bath. Ammonia gas was then purged in this cooled reaction mixture for 1-2 hours. The reaction assembly was then closed and the reaction mixture was allowed to warm to room temperature, whereupon it was stirred for a further 18 hours. The reaction mixture was monitored on TLC using pure ethyl acetate as mobile phase. After completion of the reaction, the reaction mixture was evaporated under vacuum and the obtained crude material was further co-evaporated twice with diethyl ether. This final crude material was used directly in the next step without purification. The above procedure gives 1.8g (yield 96.58%) of the desired compound. LC-MS: M/z 208.83(M + H).

And 5: ((4- (2- (3- ((2-amino-2-oxoethyl) amino) propyl) phenoxy) -5-chloro-2- Preparation of fluorophenyl) sulfonyl) (Thiazol-4-yl) carbamic acid Tert-butyl ester

To a solution of 2- ((3- (2-hydroxyphenyl) propyl) amino) acetamide (0.1g,0.48mmol) in DMF (3ml) under nitrogen and at room temperature was added one portion of K₂CO₃(0.13g,0.96 mmol.) the resulting reaction mixture was then stirred at room temperature for 15 minutes.Tert-butyl ((5-chloro-2, 4-difluorophenyl) sulfonyl) (thiazol-4-yl) carbamate (0.23g,0.576mmol) was added to the above reaction mixture and the resulting reaction mixture was stirred at room temperature for 4-8 hours after the reaction was complete, demineralized water (20ml) was added and the resulting mixture was then extracted with ethyl acetate (2 × 30 ml). the combined organic extracts were washed with demineralized water (20ml), brine (20ml), washed with sulfurThe sodium salt was dried and concentrated under vacuum. The crude product was purified by column chromatography using normal phase silica gel. The desired product was eluted in approximately 20-25% ethyl acetate in hexane. Evaporation of the product fractions gave 0.15g (yield 52.16%) of a solid, the desired compound. LC-MS: M/z 599.69(M + H).

Step 6: 2- ((3- (2- (2-chloro-5-fluoro-4- (N- (thiazol-4-yl) sulfamoyl) phenoxy) Preparation of phenyl) propyl) amino) acetamide

To a solution of tert-butyl ((4- (2- (3- ((2-amino-2-oxoethyl) amino) propyl) phenoxy) -5-chloro-2-fluorophenyl) sulfonyl) (thiazol-4-yl) carbamate (0.15g,0.25mmol) in dichloromethane (10ml) at room temperature was added dropwise a 4N solution of hydrochloric acid in ethyl acetate (5 ml). The resulting reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, pentane (15ml) was added to the reaction mixture, resulting in precipitation of a solid. The solvent layer was decanted off and the solid thus obtained was washed twice with pentane (15ml) and dried under vacuum. By using 0.1% formic acid in water: preparative HPLC of acetonitrile mobile phase (preparative HPLC method B) the crude material obtained was further purified. Evaporation of the pure product fraction obtained from preparative HPLC provided the desired product (0.025g, yield 20.04%). LC-MS: M/z 499.23(M + H), 1H-nmr (meod), d8.71-8.88(M,1H),7.96-8.08(M,1H),7.42-7.53(M,1H),7.25-7.40(M,2H),7.09-7.13(M,1H),7.00-7.07(M,1H),6.48-6.68(M,1H),3.73(s,2H),2.95-3.05(M,2H),2.62-2.72(M,2H),1.93-2.06(M, 2H).

Example 61: 2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-4-yl) sulfamoyl) phenoxy) phenyl) propyl) (prop-2-yn-1-yl) amino) acetic acid

Compound 61 was synthesized according to the procedure described for the synthesis of compound 54 by substituting 5-chloro-N- (2, 4-dimethoxybenzyl) -2, 4-difluoro-N- (thiazol-2-yl) benzenesulfonamide with tert-butyl 5-chloro-2, 4-difluorophenylsulfonyl (thiazol-4-yl) carbamate in step 1. LC-MS: M/z 572.20(M + H).1H-nmr (meod), d8.77(d, J2.1 Hz,1H),8.01(d, J7.1 Hz,1H),7.49(d, J2.4 Hz,1H),7.34(dd, J8.7, 2.5Hz,1H),7.11(d, J2.2 Hz,1H),7.02(d, J8.7 Hz,1H),6.73(d, J10.8 Hz,1H),3.91(br.s.,2H),3.59(br.s.,2H),2.98-3.07(M,3H),2.60-2.67(M,2H),1.92-2.02(M, 2H).

Example 62: 2- (allyl (3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) acetic acid

Compound 62 was synthesized according to the procedure described for the synthesis of compound 54 by substituting allyl bromide for 3-bromoprop-1-yne in step 2. LC-MS: M/z 573.86(M + H).1H-nmr (dmso), d12.66(s,1H),7.93(d, J ═ 7.2Hz,1H),7.50(br.s.,1H),7.32(br.s.,2H),7.09(d, J ═ 8.4Hz,1H),6.82-6.93(M,2H),5.66-5.78(M,1H),5.04-5.19(M,2H),3.22(br.s.,4H),2.60(br.s.,2H),2.52-2.57(M,2H),1.63-1.75(M, 2H).

Example 63: 2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) acetamide

Compound 63 was synthesized according to the procedure described for the synthesis of compound 60 by substituting 5-chloro-2-hydroxybenzaldehyde for 2-hydroxybenzaldehyde in step 1 and 5-chloro-N- (2, 4-dimethoxybenzyl) -2, 4-difluoro-N- (thiazol-2-yl) benzenesulfonamide for tert-butyl 5-chloro-2, 4-difluorobenzenesulfonyl (thiazol-4-yl) carbamate in step 5. LC-MS, M/z 532.92(M + H), 1H-nmr (meod), d7.97-8.10(M,1H),7.44-7.51(M,1H),7.29-7.41(M,1H),7.13-7.22(M,1H),6.98-7.08(M,1H),6.78-6.84(M,1H),6.71-6.77(M,1H),3.73(s,2H),2.95-3.08(M,2H),2.64-2.78(M,2H),1.92-2.10(M, 2H).

Example 64: 2- (but-2-yn-1-yl) (3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) acetic acid

Compound 64 was synthesized according to the procedure described for the synthesis of compound 54 by substituting 1-bromo-2-butyne for 3-bromoprop-1-yne in step 2. LC-MS, M/z 585.95(M + H), 1H-nmr (meod), d7.98-8.11(M,1H),7.46-7.54(M,1H),7.32-7.43(M,1H),7.13-7.25(M,1H),6.98-7.05(M,1H),6.72-6.85(M,2H),3.86-4.09(M,2H),3.68-3.80(M,2H),3.17-3.28(M,2H),2.60-2.75(M,2H),1.99-2.12(M,2H),1.87(s, 3H).

Example 65: 2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) (propyl) amino) acetic acid

Compound 65 was synthesized according to the procedure described for the synthesis of compound 54 by substituting 1-bromopropane for 3-bromoprop-1-yne in step 2. LC-MS: M/z 575.90(M + H), 1H-nmr (meod), d8.03-8.08(M,1H),7.48-7.52(M,1H),7.30-7.37(M,1H),7.17(d, J4.7 Hz,1H),7.02(d, J8.8 Hz,1H),6.81(d, J4.6 Hz,2H),3.65(s,2H),3.16-3.23(M,2H),3.05-3.13(M,2H),2.63-2.71(M,2H),2.01-2.11(M,2H),1.66-1.78(M,2H),0.98(t, J7.4 Hz, 3H).

Example 66: 3- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) (prop-2-yn-1-yl) amino) propanoic acid

Compound 66 was synthesized according to the procedure described for the synthesis of compound 54 by replacing methyl 2- (3- (5-chloro-2-hydroxyphenyl) propylamino) acetate with methyl 3- [3- (5-chloro-2-hydroxyphenyl) propylamino ] propionate in step 1. LC-MS: M/z 585.88(M + H).1H-nmr (dmso), d12.26-12.67(M,1H),7.93(d, J ═ 7.2Hz,1H),7.50(d, J ═ 2.6Hz,1H),7.29-7.36(M,2H),7.09(d, J ═ 8.7Hz,1H),6.85-6.93(M,2H),3.05(s,1H),2.61-2.68(M,2H),2.38-2.44(M,2H),2.27-2.36(M,2H),1.58-1.71(M, 2H).

Example 67: 2- ((3- (5-chloro-2- (2, 5-difluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) (prop-2-yn-1-yl) amino) acetic acid

Compound 67 was synthesized according to the procedure described for the synthesis of compound 54 by substituting N- (2, 4-dimethoxybenzyl) -2,4, 5-trifluoro-N- (thiazol-2-yl) benzenesulfonamide for 5-chloro-N- (2, 4-dimethoxybenzyl) -2, 4-difluoro-N- (thiazol-2-yl) benzenesulfonamide in step 1. LC-MS, M/z 555.93(M + H), 1H-nmr (meod), d7.77-7.86(M,1H),7.46(d, J2.6 Hz,1H),7.27-7.34(M,1H),7.17(d, J4.7 Hz,1H),6.99(d, J8.7 Hz,1H),6.78-6.89(M,2H),3.93(s,2H),3.59(s,2H),2.99-3.10(M,3H),2.66-2.76(M,2H),1.92-2.03(M, 2H).

Example 68: ethyl 2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) (methyl) amino) acetate

Compound 68 was synthesized according to the procedure described for the synthesis of compound 11 by replacing glycine methyl ester with sarcosine ethyl ester in step 2, replacing tert-butyl 5-chloro-2, 4-difluorobenzenesulfonyl (thiazol-4-yl) carbamate with N- (2, 4-dimethoxybenzyl) -2,4, 5-trifluoro-N- (thiazol-2-yl) benzenesulfonamide in step 4, and omitting step 5. LC-MS: M/z 575.85(M + H).1H-nmr (meod), d8.05(d, J7.0 Hz,1H),7.50(d, J2.5 Hz,1H),7.33-7.39(M,1H),7.18(d, J4.7 Hz,1H),7.01(d, J8.6 Hz,1H),6.81(d, J4.7 Hz,1H),6.77(d, J10.5 Hz,1H),4.32(d, J7.2 Hz,2H),4.07-4.22(M,2H),3.14-3.24(M,2H),2.96(s,3H),2.70(s,2H),2.05-2.15(M,2H), t (t, 1H), 1H, 3H).

Example 69: 2- ((3- (5-chloro-2- (2, 5-difluoro-4- (N- (thiazol-4-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) acetamide

Compound 69 was synthesized according to the procedure described for the synthesis of compound 49 by replacing tert-butyl 5-chloro-2, 4-difluorobenzenesulfonyl (thiazol-4-yl) carbamate with tert-butyl thiazol-4-yl ((2,4, 5-trifluorophenyl) sulfonyl) carbamate in step 4. LC-MS: M/z 516.8(M + H), 1H-NMR (DMSO-d6), d8.94(d, J2.0 Hz,1H),8.90(br,2H), 7.84-7.88 (M,2H),7.58(s,1H),7.50(d, J2.4 Hz,1H), 7.33-7.37 (dd, J2.8, 8.8Hz,1H), 7.09-7.13 (M,3H),3.66(s,2H),2.90(br,2H),2.62(t, J7.6 Hz,2H), 1.88-1.92 (M, 2H).

The embodiments described herein are intended to be merely exemplary, and those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific procedures described herein. All such equivalents are considered to be within the scope of the present invention and are encompassed by the following embodiments.

All references, including patent applications, patents, and publications, cited herein are hereby incorporated by reference in their entirety and for all purposes to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference in its entirety for all purposes.

Claims

1. A compound of the formula (I),

or a pharmaceutically acceptable salt thereof, or a stereoisomeric or tautomeric form thereof, wherein:

z is-O-or-S-;

y is-X-C (═ O) NR₄R₅、-(CH₂)₃-NR₉R₁₀Or 4,5,6, 7-tetrahydropyridineAzolo [1,5-a ]]Pyrimidin- (2-yl or 3-yl);

x is (C)₆-C₁₀) Aryl or 5-or 6-membered heteroaryl;

R₁is a partially unsaturated or aromatic 5-or 6-membered heterocycle;

R₂independently at each occurrence is-F, -Cl, -Br, -CH₃or-CN;

R₃independently at each occurrence-H, -F, -Cl, -Br, -CF₃、-OCF3、-CN、(C₁-C₁₂) Alkyl, or (C)₁-C₁₂) An alkoxy group;

R₄and R₅Neither is H; and is

R₆is (C)₁-C₁₂) An alkyl group;

R₉is (C)₁-C₆) Alkyl, (C)₃-C₈) Cycloalkyl, pyrazolyl or pyridyl; wherein R is₉Optionally further selected from the group consisting of-COOH, -COOR₁₁、-CONR₁₁R₁₂、-SO₂R₁₁、-SO₂NR₁₁R₁₂、-OH、-CN、-OR₁₁and-NR₁₁R₁₂1 or 2 substituents in the group; wherein R is ₁₁And R₁₂Can be shapedTo a 6 membered heterocycloalkyl ring;

m and n are each independently 1, 2, 3 or 4.

2. A compound of formula (I'):

z is-O-or-S-;

x is (C)₆-C₁₀) Aryl or 5-membered heteroaryl or 6-membered heteroaryl;

R₁is a partially unsaturated or aromatic 5-membered heteroaromatic ring or 6-membered heterocyclic ring;

R₂independently at each occurrence is-F, -Cl, -Br, -CH₃or-CN;

R₃independently at each occurrence-H, -F, -Cl, -Br,-CF₃、-OCF₃、-CN、(C₁-C₁₂) Alkyl or (C)₁-C₁₂) An alkoxy group;

R₄and R₅Neither is H; and is

R₆is (C)₁-C₁₂) An alkyl group;

R₁₀is R₁₁、(C₃-C₆) Alkynyl, (C)₃-C₆) Alkenyl, -COR₁₁、-COOR₁₁、-SO₂R₁₁5-methyl-2-oxo-1, 3-dioxolen-4-yl,-COO-CH(CH₃)OCOCH(CH₃)₂(ii) a Or R₉And R₁₀Together form a piperazinone or 4-to 8-membered heterocycloalkyl ring, wherein the heterocycloalkyl ring is selected from the group consisting of-COOH, -COOR₁₁、-CH₂-COOR₁₁、-OH、-NH₂-CN and (C)₁-C₈) 1 or 2 substituents in the group consisting of alkoxy; or R₉And R₁₀Taken together to form an unsubstituted 4-to 8-membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is fused to a 5-membered heteroaryl; and is

m and n are each independently 1, 2, 3 or 4.

3. The compound of any one of claims 1 or 2, wherein Y is- (CH) ₂)₃-NR₉R₁₀。

4. A compound according to claim 3, wherein R₁Is an aromatic 5-membered heterocycle or 6-membered heterocycle having 1-3 heteroatoms independently selected from the group consisting of N, O and S.

5. A compound according to any one of claims 3 or 4, wherein R₁Is pyridyl or pyrimidinyl.

6. A compound according to any one of claims 3 or 4, wherein R₁Is an aromatic 5-membered heterocyclic ring having 1 or 2 nitrogen atoms and optionally 1 or 2 sulfur atoms.

7. A compound according to any one of claims 3, 4 or 6, wherein R₁Is thiazolyl, isothiazolyl or thiadiazolyl.

8. The compound of any one of claims 3, 4, 6, or 7, wherein R₁Is thiazolyl.

9. The compound of any one of claims 3, 4, 6, 7, or 8, wherein R₁Is thiazol-4-yl

10. The compound of any one of claims 2, 3, 6, or 7, wherein R₁Is a 1,2, 4-thiadiazol-5-yl group.

11. The compound of any one of claims 3-10, wherein R₂Independently at each occurrence-F or-Cl.

12. The compound of any one of claims 3-11, wherein n is 1,2, or 3.

13. The compound of any one of claims 3-12, wherein n is 2.

14. The compound of any one of claims 3-13, wherein Z is-O-.

15. The compound of any one of claims 3-14, wherein R₃Independently at each occurrence-H, -F, -Cl, or-Br.

16. The compound of any one of claims 3-15, wherein R₃is-H or-Cl.

17. The compound of any one of claims 3-16, wherein R₃is-Cl.

18. The compound of any one of claims 3-17, wherein m is 1, 2, or 3.

19. The compound of any one of claims 3-18, wherein m is 1.

20. The compound of any one of claims 3-19, wherein R₉Is (C)₁-C₆) An alkyl group; wherein R is₉Optionally further selected from the group consisting of-COOH, -COOMe, -CONH₂and-NH₂1 or 2 substituents in the group.

21. The compound of any one of claims 3-20, wherein R₉Is methyl or ethyl.

22. The compound of any one of claims 3-21, wherein R₉Further substituted by-COOH.

23. The compound of any one of claims 3-22, wherein R₁₀is-H, -COMe, -COOEt.

24. The compound of any one of claims 3-22, wherein R ₁₀is-H or-COMe.

25. The compound of any one of claims 3-24, wherein R₁₀is-H.

26. The compound of any one of claims 3 to 19, wherein R₁₀Is H and R₉Is (C)₁-C₆) Alkyl radical, wherein R₉Further by-CONR₁₁R₁₂In which R is₁₁And R₁₂Independently is H or (C)₁-C₆) An alkyl group.

27. The compound of claim 26, wherein R₉Is further substituted by-CONH₂And (4) substitution.

28. The compound of claim 27, wherein R₉Is methyl.

29. The compound of any one of claims 3-19, wherein R₉And R₁₀Together form a 4-to 8-membered heterocycloalkyl ring, wherein the heterocycloalkyl ring is selected from the group consisting of-COOH, -COOMe, -COOEt, -CH₂-COOH and-NH₂1 or 2 groups in the group.

30. The compound of any one of claims 3-19, wherein R₉And R₁₀Together form a 4-to 8-membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is selected from the group consisting of-COOH, -CH₂-COOH and-NH₂1 or 2 groups in the group.

31. The compound of any one of claims 3-19, wherein R₉And R₁₀Together form a group selected from the group consisting of-COOH, -COOMe, -COOEt, -CH₂-COOH、-CH₂-COOMe、-CH₂-COOEt and-NH ₂Piperidine substituted with 1 or 2 groups of the group.

32. The compound of any one of claims 3-19, wherein R₉And R₁₀Together form a selected group consisting of-COOH, -CH₂-COOH and-NH₂Piperidine substituted with 1 or 2 groups of the group.

33. According to any one of claims 1 or 2Wherein Y is-X-C (═ O) NR₄R₅。

34. The compound of claim 33, wherein R₁Is an aromatic 5-membered heterocycle or 6-membered heterocycle having 1-3 heteroatoms independently selected from the group consisting of N, O, and S.

35. The compound of any one of claims 33 or 34, wherein R₁Is pyridyl or pyrimidinyl.

36. The compound of any one of claims 33 or 34, wherein R₁Is an aromatic 5-membered heterocyclic ring having 1 or 2 nitrogen atoms and optionally 1 or 2 sulfur atoms.

37. The compound of any one of claims 33, 34, or 36, wherein R₁Is thiazolyl, isothiazolyl or thiadiazolyl.

38. The compound of any one of claims 33, 34, 36, or 37, wherein R₁Is thiazolyl.

39. The compound of any one of claims 33, 34, 36, or 37, wherein R ₁Is a 1,2, 4-thiadiazol-5-yl group.

40. The compound of any one of claims 33-39, wherein R₂Independently at each occurrence-F or-Cl.

41. The compound of any one of claims 33-40, wherein n is 1,2, or 3.

42. The compound of any one of claims 33-41, wherein n is 2.

43. The compound of any one of claims 33-42, wherein Z is-O-.

44. The compound of any one of claims 33-43, wherein R₃Independently at each occurrence-H, -F, -Cl, or-Br.

45. The compound of any one of claims 33-44, wherein R₃is-H or-Cl.

46. The compound of any one of claims 33-45, wherein R₃is-Cl.

47. The compound of any one of claims 33-46, wherein m is 1,2, or 3.

48. The compound of any one of claims 33-47, wherein m is 1.

49. The compound of any one of claims 33-48, wherein X is 5-membered heteroaryl or 6-membered heteroaryl.

50. The compound of any one of claims 33-49, wherein X is pyridinyl or pyrimidinyl.

51. The compound of any one of claims 33-50, wherein X is pyridyl.

52. The compound of any one of claims 33-51, wherein R₄Is H and R₅Is (C)₁-C₉) An alkyl group.

53. The compound of any one of claims 33-52, wherein R₅Is selected from the group consisting of-CO₂H、-CO₂R₆and-CONR₇R₈Methyl or ethyl substituted with 1 or 2 substituents in the group.

54. The compound of any one of claims 33-53, wherein R₆Is (C)₁-C₆) An alkyl group.

55. The compound of any one of claims 33-53, wherein R₅Is a quilt-CO₂H substituted methyl or ethyl.

56. A compound according to any one of claims 1 or 2, wherein Y is 4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidin- (2-yl or 3-yl).

57. The compound of claim 56, wherein Y is 4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidin-3-yl.

58. The compound of any one of claims 56 or 57, wherein R₁Is an aromatic 5-membered heterocycle or 6-membered heterocycle having 1-3 heteroatoms independently selected from the group consisting of N, O and S.

59. The compound of any one of claims 56-58, wherein R₁Is pyridyl or pyrimidinyl.

60. The compound of any one of claims 56-58, wherein R₁Is an aromatic 5-membered heterocyclic ring having 1 or 2 nitrogen atoms and optionally 1 or 2 sulfur atoms.

61. The compound of any one of claims 56-58 or 60, wherein R₁Is thiazolyl, isothiazolyl or thiadiazolyl.

62. The compound of any one of claims 56-58, 60, or 61, wherein R₁Is thiazolyl.

63. The compound of any one of claims 56-58, 60, or 61, wherein R₁Is a 1,2, 4-thiadiazol-5-yl group.

64. The compound of any one of claims 56-63, wherein R₂Independently at each occurrence-F or-Cl.

65. The compound of any one of claims 56-64, wherein n is 1,2, or 3.

66. The compound of any one of claims 56-65, wherein n is 2.

67. The compound of any one of claims 56-66, wherein Z is-O-.

68. The compound of any one of claims 56-67, wherein R₃Independently at each occurrence-H, -F, -Cl, or-Br.

69. The compound of any one of claims 56-68, wherein R₃is-H or-Cl.

70. The method of any one of claims 56-69Wherein R is₃is-Cl.

71. The compound of any one of claims 56-70, wherein m is 1,2, or 3.

72. The compound of any one of claims 56-71, wherein m is 1.

73. The compound of any one of claims 1 or 2, wherein the compound is:

Ethyl 2- ((3- (5-chloro-2- (2-chloro-5-fluoro-4- (N- (thiazol-2-yl) sulfamoyl) phenoxy) phenyl) propyl) amino) acetate,

4- (2- (3- ((1H-pyrazol-4-yl) amino) propyl) -4-chlorophenoxy) -5-chloro-2-fluoro-N- (thiazol-2-yl) benzenesulfonamide,

or a pharmaceutically acceptable salt thereof, or a stereoisomeric or tautomeric form thereof.

74. The compound of any one of claims 1,2 or 73, wherein said compound is:

75. The compound of any one of claims 1,2 or 73, wherein said compound is

76. A method for treating neuropathic pain, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a compound of formula (Γ), or a pharmaceutically acceptable salt, solvate, or tautomeric form thereof.

77. A method for the treatment of pain comprising using a compound of formula (I) or a compound of formula (Γ) as a voltage-gated sodium channel inhibitor.

78. The method of claim 77, wherein the pain is neuropathic pain, nociceptive pain, or inflammatory pain.

79. The method of claim 77, wherein said voltage-gated sodium channel is NaV1.7.

80. A pharmaceutical composition comprising a compound according to any one of claims 1-75 and a pharmaceutically acceptable carrier.

81. The composition of claim 80, wherein the composition is suitable for topical, oral, subcutaneous, or intravenous administration.

82. A method for preventing or treating pain in a subject, wherein the method comprises administering to a subject in need of such prevention or treatment a therapeutically effective amount of a compound according to any one of claims 1-75.

83. The method of claim 82, wherein the therapeutically effective amount is effective to reduce pain in a subject, wherein the compound of any one of claims 1-69 exhibits a reduced pain response in phase 1 or phase 2 or both of the formalin assay at a dose of 0.1mg/kg to 1000mg/kg, at a dose of 0.5mg/kg to 100mg/kg, or at a dose of 1mg/kg to 50 mg/kg.

84. The method of claim 82, wherein the pain is nociceptive pain, such as pain resulting from physical trauma (e.g., an incision or contusion of the skin; or a chemical or thermal burn), osteoarthritis, rheumatoid arthritis, or tendonitis; myofascial pain; neuropathic pain, such as that associated with stroke, diabetic neuropathy, syphilitic neuropathy, postherpetic neuralgia, trigeminal neuralgia, fibromyalgia, or painful neuropathy induced iatrogenically by a drug; or mixed pain (i.e., pain with both nociceptive and neuropathic components); visceral pain; headache (e.g., migraine); CRPS; a CRPSI type; CRPSII type; RSD; reflex neurovascular dystrophy; reflex malnutrition; sympathetically maintained pain syndrome; burning pain; grandma atrophy of bone; hyperalgesic neurotrophism; shoulder-hand syndrome; post-traumatic malnutrition; autonomic dysfunction; autoimmune-related pain; pain associated with inflammation; pain associated with cancer; phantom limb pain; chronic fatigue syndrome; pain after surgery; pain associated with spinal cord injury; central post-stroke pain; a radiculopathy; sensitivity to temperature, light touch or color changes of the skin (allodynia); pain from a hyperthermic condition or hypothermia condition; and other painful conditions (e.g., diabetic neuropathy, syphilitic neuropathy, postherpetic neuralgia, trigeminal neuralgia); chronic pain; acute pain, neuroma pain, pain or itch associated with a pathway disease (e.g., fibromyalgia, IEM or raynaud's syndrome); or itch from various sources (e.g., allergic itch).

85. A method for modulating the activity of a voltage-gated sodium channel, wherein the method comprises contacting a cell expressing a voltage-gated sodium channel with a compound of any one of claims 1-75.

86. The method of claim 85, wherein said voltage-gated sodium channel is NaV1.7.

87. The method of claim 85, wherein said method results in the inhibition of a voltage-gated sodium channel.

88. A method for the treatment or prophylaxis of prediabetes, which method comprises administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 75, or a pharmaceutically acceptable salt, solvate or tautomeric form thereof.

89. A method for treating or preventing diabetes, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 75, or a pharmaceutically acceptable salt, solvate or tautomeric form thereof.

90. A method for maintaining or reducing blood or plasma glucose in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 75, or a pharmaceutically acceptable salt, solvate or tautomeric form thereof.

91. A method for maintaining or reducing blood or plasma glycated hemoglobin in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 75, or a pharmaceutically acceptable salt, solvate, or tautomeric form thereof.

92. The method of any one of claims 90 or 91, wherein the subject has prediabetes.

93. The method of any one of claims 90 or 91, wherein the subject has diabetes.

94. The method of any one of claims 89 or 93, wherein diabetes is gestational diabetes, type 1 diabetes, type 2 diabetes, or latent autoimmune diabetes in adults.

95. The method of claim 94, wherein diabetes is gestational diabetes.

96. The method of claim 94, wherein diabetes is type 1 diabetes.

97. The method of claim 94, wherein diabetes is type 2 diabetes.

98. The method of claim 97, wherein type 2 diabetes is hyperinsulinemic type 2 diabetes.

99. The method of claim 94, wherein diabetes is latent autoimmune diabetes of adults.

100. The method of any one of claims 88 or 92, wherein the prediabetes is caused by or accompanied by obesity.

101. The method of any one of claims 89 or 89, wherein the diabetes is caused by or accompanied by obesity.

102. The method of any one of claims 89 or 93, wherein the subject has not been previously treated for prediabetes.

103. The method of any one of claims 89 or 93, wherein the subject has not been previously treated for diabetes.