# US 11,299,480 B2 · 2-arylsulfonamido-N-arylacetamide derivatized STAT3 inhibitors

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 11,299,480 B2
- Document ID: US11299480B2
- Status: Granted
- Kind: B2
- Application number: 16/480,090
- Filed: 2018-01-23
- Published: 2019-12-26
- Granted: 2022-04-12
- Earliest claimed: 2017-01-23
- Assignees: University of Hawaii
- Applicants: University of Hawaii
- Inventors: James Turkson; Peibin Yue; Marcus Tius; Christine Brotherton-Pleiss; Francisco Javier Lopez Tapia
- Web page: https://patentgrep.com/patent/US11299480B2

## CPC

- C07D 207/48: Sulfur atoms
- C07D 403/14: containing three or more hetero rings
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61P 35/00: Antineoplastic agents
- C07D 205/04: having no double bonds between ring members or between ring members and non-ring members
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 405/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present disclosure provides pharmaceutical compositions comprising 2-arylsulfonamido-N-arylacetamide derivatized Stat3 inhibitors and certain pharmaceutically acceptable salts thereof, and methods of their use.

## Claims

### Claim 1

A compound represented by Formula I:
wherein R1 is selected from aryl or a 5 or 6-membered heteroaryl, where the heteroatoms are one or more O, N, S(A)2, where S is sulfur and A is selected from oxygen or an electron pair, the aryl or the 5 or 6-membered heteroaryl are optionally substituted with halo, CF3, C1-C6 alkyl, C1-C6 branched alkyl, aryl, heteroaryl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, three- to six-membered heterocycle, three- to seven-membered saturated heterocycle, fused C2-C5 alkylene, where one or more CH2 groups can be replaced with O, NR9, or S(A)2 where S is sulfur and A is selected from oxygen or an electron pair, the aryl or the 5 or 6-membered heteroaryl are optionally substituted naphthalene, optionally substituted indole, benzofuran, benzothiophene; R2 and R3 are independently selected from H or C1-C6 alkyl; where R2 and R3 can form a C3-C6 cycloalkane ring, where this C3-C6 cycloalkane ring can be substituted with 1 or more of C1-C6 alkyl, hydroxyl, NR9R10, or C1-C6 alkoxy; R5 is selected from H, (CH2)fNR9R10, (CH2)fOR9, (CH2)fCO2R9, or (CH2)fCO2NR9R10; R4 and R6 form a C3-C6 heterocycloalkane ring, where this C3-C6 heterocycloalkane ring can be substituted with 1 or more of C1-C6 alkyl, hydroxyl, NR9R10 and where one or more CH2 groups can be replaced with O, NR9, or S(A)2 where S is sulfur and A is selected from oxygen or an electron pair; or R4 and R6 form an optionally substituted pyrrole ring, wherein one or more CH groups of said pyrrole ring can be replaced with O, N, or S(A)2, where S is sulfur and A is selected from oxygen or an electron pair; R7 is selected from CF3, aryl or heteroaryl group where the aryl or heteroaryl group is substituted with 1-5 substituents selected from C1-C6 alkyl, halo, hydroxyl, CN, or CF3; R8 is substitution selected from one or more of H, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, halogen, OC(O)CH3, NR9R10, CN, CF3, CO2R9, CO2NR9R10, (CH2)fNR9R10, (CH2)fOR9, or (CH2)fCO2R9; R9 is selected from H or C1-C6 alkyl; R10 is selected from H, or C1-C6 alkyl; W is selected from CO2H, tetrazole, benzyl, C(O)NHOR10 or CF2OH; Q is C, CH, N, O, or S; where Q and R8 can form a heterocyclic ring; p is selected from 0 or 1, y is selected from 0 or 1, f is selected from 0 to 4; t is selected from 0 or 1;
or a solvate, hydrate, or pharmaceutically acceptable salt thereof.

### Claim 2

A compound represented by Formula II:
wherein R11 is selected from aryl or heteroaryl,
wherein the aryl or heteroaryl can be substituted with one or more of hydroxyl, carboxylic acid, carboxylate, benzohydroxamic acid, hydroxyl-substituted alkyl;
wherein R12 is selected from (R)—CH(CH3), (S)—CHCH3, (S)—CH(CH2CH3), (R)—CH(CH2CH3), bridging cylcopropyl
(S)—CH(CH2OH), (R)—CH(CH2OH), (R)—CH(CH2CH2OH), (S)—CH(CH2CH2OH), (S)—CH[(R)—CH(CH3)OH], (R)—CH[(S)—CH(CH3)OH], (S)—CH(CH2NH2), (R)—CH(CH2NH2), (S)—CH(CH2CO2H), or (R)—CH(CH2CO2H);
or a solvate, hydrate, or pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 2)

A compound of claim 2, wherein the compound is represented by Formula III:
wherein R11 is selected from aryl or heteroaryl,
wherein the aryl or heteroaryl can be substituted with one or more of hydroxyl, carboxylic acid, carboxylate, benzohydroxamic acid, nitroso, alkyl carboxylic acid, C1-C6 alkyl, or halo;
wherein R12 is (R)—CH(CH3);
or a solvate, hydrate, or pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 3)

A compound of claim 3 wherein R11 is selected from:
or a salt thereof.

### Claim 5

A compound represented by Formula IV:
wherein R14 is selected from a five- to seven-membered cycloalkyl or heteroxycloalkyl group, wherein the cycloalkyl group can be substituted with one or more of halo;
wherein R15 is selected from substituted aryl, wherein the substitution is one or more of hydroxy, carboxylic acid, or benzohydroxamic acid;
wherein R16 is (R)—CH(CH3);
wherein Y is selected from CH or N;
or a solvate, hydrate, or pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 5)

A compound of claim 5, wherein R14 is selected from:

### Claim 7 (depends on 5)

A compound of claim 5, wherein R15 is selected from:

### Claim 8 (depends on 5)

A compound of claim 5, wherein the compound is represented by Formula V:
wherein R17 is selected from CH2 or O;
wherein R18 is selected from hydrogen or halo;
wherein R19 is selected from hydrogen or hydroxyl;
wherein R20 is selected from —OH, —NHOH, or —(O′, Na+);
wherein R21 is CH3;
or a solvate, hydrate, or pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 1)

A compound of claim 1, wherein the compound is represented by Formula VI:
wherein n is selected from 1 to 3
wherein X is selected from CH or N;
wherein R17 is selected from CH2 or O;
wherein R18 is selected from hydrogen or halo;
wherein R19 is selected from hydrogen or hydroxyl;
wherein R20 is selected from —OH, NHOH, or —(O′, Na+),
or a solvate, hydrate, or pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 1)

A compound of claim 1, wherein the compound is selected from:
or a solvate, hydrate, or pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 1)

A compound of claim 1, wherein the compound is selected from:
or a solvate, hydrate, or pharmaceutically acceptable salt thereof.

### Claim 12

A compound represented by Formula VII:
wherein W, X, Y, and Z each independently can include or exclude CH or N,
wherein R21 is selected from optionally substituted aryl, optionally substituted heteroaryl, or an optionally substituted aryl fused with a heterocyclic ring,
wherein the substituted aryl or substituted heteroaryl or the substituted aryl fused with a heterocyclic ring can be substituted with one or more of hydroxyl, carboxylic acid, carboxylate, hydroxamic acid, amide, alkyl amide, dialkylamide, alkoxyamino, alkyl carboxylic acid, C1-C6 alkyl, or halo,
wherein n is selected from 1 to 3;
or a solvate, hydrate, or pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 12)

The compound of claim 12, wherein R21 is selected from any of the following moieties:

### Claim 14

A compound represented by Formula VIII:
wherein W, X, Y, Z, and Q each independently can include or exclude CH or N,
wherein d is selected from 0, 1, 2, 3, or 4,
wherein R21 is selected from optionally substituted aryl, optionally substituted heteroaryl, or an optionally substituted aryl fused with a heterocyclic ring, and wherein R22 is halogen.

### Claim 15 (depends on 14)

The compound of claim 14, wherein R21 is selected from any of the following moieties:

### Claim 16 (depends on 14)

The compound of claim 14, wherein halogen is fluorine.

### Claim 17 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16)

A pharmaceutical composition comprising a therapeutically effective amount of a compound, salt, crystal or polymorph in any one of claims 1-16, and a pharmaceutically acceptable excipient.

### Claim 18 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16)

A composition comprising a therapeutically effective amount of a compound of any one of claims 1-16 and a pharmaceutically acceptable carrier.

### Claim 19 (depends on 17)

A method of therapeutic treatment cancer, comprising administering to a subject in need thereof, a therapeutically effective dose of a composition of claim 17.

### Claim 20 (depends on 19)

The method of claim 19, wherein the therapeutically effective dose of the composition ranges from about 0.05 mg/kg to about 5 g/kg.

### Claim 21 (depends on 19)

The method of claim 19, wherein the therapeutically effective dose of the composition is given in one or more doses of about 0.05 mg/kg to about 5 g/kg.

### Claim 22 (depends on 19)

The method of claim 19, wherein the therapeutically effective dose of the composition is from about 0.08 mg/kg to about 0.5 mg/kg, from about 0.08 to about 0.24 mg/kg, or from about 0.24 to about 0.5 mg/kg, or from about 0.08 to 0.5 mg/kg.

### Claim 23 (depends on 19)

The method of claim 19, wherein the one or more therapeutically effective doses of the composition are administered orally.

### Claim 24 (depends on 19)

The method of claim 19, wherein the one or more therapeutically effective doses of the composition are administered subcutaneously, intravenously, or intramuscularly.

### Claim 25 (depends on 19)

The method of claim 19, wherein the cancer is a solid tumor.

### Claim 26 (depends on 25)

The method of claim 25, wherein the solid tumor comprises glioma, breast cancer or pancreatic cancer.

### Claim 27 (depends on 19)

The method of claim 19, wherein the cancer is selected from the group consisting of: lung, breast, prostate, pancreatic, ovarian, bladder, head and neck, thyroid, brain, skin and kidney.

### Claim 28 (depends on 19)

The method of claim 19, wherein the cancer is selected from the group consisting of: brain tumors, gliomas, breast, and malignant melanoma.

### Claim 29 (depends on 19)

The method of claim 19, wherein each therapeutically effective dose of the composition is between about 0.08 mg/kg and less than about 0.5 mg/kg, and said dose is administered by a delivery route selected from the group consisting of oral, intradermal, intramuscular, intraperitoneal, intravenous, topical, subcutaneous, and epidural routes.