# US 2014/0155477 A1 · Substituted biaryl sulfonamides and the use thereof

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- Number: US 2014/0155477 A1
- Document ID: US20140155477A1
- Status: Published application
- Kind: A1
- Application number: 14/092,425
- Filed: 2013-11-27
- Published: 2014-06-05
- Earliest claimed: 2012-11-30
- Assignees: NovoMedix, LLC
- Applicants: Novomedix, LLC
- Inventors: Leah M. Fung; Kyle W.H. Chan; Cathy A. Swindlehurst; Robert W. Sullivan
- Web page: https://patentgrep.com/patent/US20140155477A1

## CPC

- C07C 311/21: having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
- A61K 31/18: Sulfonamides (compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63)
- A61K 31/337: having four-membered rings, e.g. taxol
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 35/04: specific for metastasis
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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

Provided herein are substituted biaryl sulfonamide compounds, pharmaceutical compositions comprising the compounds, methods of their preparation, and methods of their use. The compounds provided herein are useful for the treatment, prevention, and/or amelioration of various disorders, including cancer and proliferative disorders. In one embodiment, the compounds provided herein modulate initiation of protein translation. In one embodiment, the compounds provided herein are used in combination with surgery, radiation therapy, immuno therapy and/or one or more additional anticancer drugs for the treatment, prevention, and/or amelioration of cancer and proliferative disorders.

## Claims

### Claim 1

A compound of formula (I):
or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof;
or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:
X is NH, and Y is S(O)2; or X is S(O)2, and Y is NH;
R′ is hydrogen, halogen, cyano, OH, OC(O)Ra, C(O)Ra, C(O)ORa, C(O)NRaRb, NRaC(O)Rb, NRaRb, OS(O)Ra, SRa, S(O)Ra, S(O)2Ra, S(O)2NRaRb, NRaS(O)2Rb, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C8)alkoxy, (C2-C8)alkenyloxy, (C2-C8)alkynyloxy, (C3-C8)cycloalkyl, or (C3-C8)cycloalkyloxy, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkyl, and cycloalkyloxy are each optionally substituted with one or more halogen;
n is 2, 3, or 4;
each occurrence of R is independently hydrogen, (C1-C6)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, or (C3-C8)cycloalkyl, each of which is optionally substituted with one or more halogen; and
Ra and Rb are each independently hydrogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C8)heteroalkyl, (C3-C8)cycloalkyl, (C7-C12)aralkyl, phenyl, (5 to 6 membered)heteroaryl, or (3 to 7 membered)heterocyclyl; or Ra and Rb together form a 3 to 10 membered ring.

### Claim 2 (depends on 1)

The compound of claim 1, wherein X is NH, and Y is S(O)2.

### Claim 3 (depends on 1)

The compound of claim 1, wherein X is S(O)2, and Y is NH.

### Claim 4 (depends on 1)

The compound of claim 1, wherein R′ is hydrogen, halogen, (C1-C4)alkyl, or (C1-C4)alkoxy, wherein the alkyl and alkoxyl are each optionally substituted with one or more halogen.

### Claim 5 (depends on 1)

The compound of claim 1, wherein R′ is hydrogen, halogen, or (C1-C4)alkyl optionally substituted with one or more halogen.

### Claim 6 (depends on 1)

The compound of claim 1, wherein R′ is hydrogen, F, Cl, Br, (C1-C4)alkyl, CF3, or OCF3.

### Claim 7 (depends on 1)

The compound of claim 1, wherein R′ is hydrogen, Cl, Br, or (C1-C4)alkyl.

### Claim 8 (depends on 1)

The compound of claim 1, wherein R′ is hydrogen, chloro, bromo, or methyl.

### Claim 9 (depends on 1)

The compound of claim 1, wherein R′ is hydrogen.

### Claim 10 (depends on 1)

The compound of claim 1, wherein R′ is methyl.

### Claim 11 (depends on 1)

The compound of claim 1, wherein R′ is chloro.

### Claim 12 (depends on 1)

The compound of claim 1, wherein R′ is bromo.

### Claim 13 (depends on 1)

The compound of claim 1, having formula (II):
or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof;
or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein:
R1 is independently (C1-C6)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, or (C3-C8)cycloalkyl, each of which is optionally substituted with one or more halogen;
R2 is independently hydrogen, (C1-C6)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, or (C3-C8)cycloalkyl, each of which is optionally substituted with one or more halogen; and
R3 is independently (C1-C6)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, or (C3-C8)cycloalkyl, each of which is optionally substituted with one or more halogen.

### Claim 14 (depends on 13)

The compound of claim 13, wherein R1, R2, and R3 are independently (C1-C6)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, or (C3-C8)cycloalkyl.

### Claim 15 (depends on 13)

The compound of claim 13, wherein R1 is (C1-C4)alkyl.

### Claim 16 (depends on 13)

The compound of claim 13, wherein R1 is methyl, ethyl, or isopropyl.

### Claim 17 (depends on 13)

The compound of claim 13, wherein R2 is hydrogen, or (C1-C4)alkyl.

### Claim 18 (depends on 13)

The compound of claim 13, wherein R2 is methyl, isopropyl, or tert-butyl.

### Claim 19 (depends on 13)

The compound of claim 13, wherein R3 is (C1-C4)alkyl.

### Claim 20 (depends on 13)

The compound of claim 13, wherein R3 is methyl, ethyl, or isopropyl.

### Claim 21 (depends on 13)

The compound of claim 13, having formula (II-A):
or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof;
or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

### Claim 22 (depends on 21)

The compound of claim 21, having formula (II-A-1):
or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof;
or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

### Claim 23 (depends on 22)

The compound of claim 22, wherein X is S(O)2, Y is NH, R′ is hydrogen, and R1, R2, and R3 are isopropyl.

### Claim 24 (depends on 22)

The compound of claim 22, having formula (III-A-1):
or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof;
or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

### Claim 25 (depends on 24)

The compound of claim 24, wherein the compound is:

### Claim 26 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1, or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and at least one pharmaceutically acceptable excipient or carrier.

### Claim 27 (depends on 26)

The pharmaceutical composition of claim 26, further comprising one or more additional active agents.

### Claim 28 (depends on 27)

The pharmaceutical composition of claim 27, further comprising paclitaxel or docetaxel.

### Claim 29 (depends on 26)

The pharmaceutical composition of claims 26, wherein the composition is formulated for single dose administration.

### Claim 30 (depends on 26)

The pharmaceutical composition of claim 26, wherein the composition is formulated as oral, parenteral, or intravenous dosage form.

### Claim 31 (depends on 29)

The pharmaceutical composition of claim 29, wherein the oral dosage form is a tablet or capsule.

### Claim 32 (depends on 1)

A method of treating, preventing, or ameliorating one or more symptoms of a disorder mediated by protein translation initiation, comprising administering a compound of claim 1, or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

### Claim 33 (depends on 1)

A method of treating, preventing, or ameliorating one or more symptoms of a disorder mediated by eIF4E, comprising administering a compound of claim 1, or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

### Claim 34 (depends on 32)

The method of claim 32, wherein the disorder is cancer, metastatic cancer, a proliferative disorder, breast cancer, triple negative breast cancer, ER+ breast cancer, ER− breast cancer, basal cell nevus syndrome (Gorlin syndrome), basal cell carcinoma, skin cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, brain cancer, medulloblastoma, glioblastoma, colorectal cancer, ovarian cancer, liver cancer, pancreatic cancer, pancreatic carcinoma, pancreatic angiosarcoma, pancreatic adenosarcoma, gastric cancer, gastroesophageal junction cancer, prostate cancer, cervical cancer, bladder cancer, head and neck cancer, lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, multiple myeloma, solid tumors that cannot be removed by surgery, locally advanced solid tumors, metastatic solid tumors, leukemia, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), or recurrent or refractory tumors.

### Claim 35 (depends on 1)

A method of treating, preventing, or ameliorating one or more symptoms of a disorder, comprising administering a compound of claim 1, or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein the disorder is cancer, metastatic breast cancer, a proliferative disorder, breast cancer, triple negative breast cancer, ER+ breast cancer, ER− breast cancer, basal cell nevus syndrome (Gorlin syndrome), basal cell carcinoma, skin cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, brain cancer, medulloblastoma, glioblastoma, colorectal cancer, ovarian cancer, liver cancer, pancreatic cancer, pancreatic carcinoma, pancreatic angiosarcoma, pancreatic adenosarcoma, gastric cancer, gastroesophageal junction cancer, prostate cancer, cervical cancer, bladder cancer, head and neck cancer, lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, multiple myeloma, solid tumors that cannot be removed by surgery, locally advanced solid tumors, metastatic solid tumors, leukemia, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), or recurrent or refractory tumors.

### Claim 36 (depends on 34)

The method of claim 34, wherein the cancer is resistant to conventional therapy.

### Claim 37 (depends on 34)

The method of claim 34, wherein the cancer is vincristine-resistant.

### Claim 38 (depends on 34)

The method of claim 34, wherein the cancer is taxol-resistant.

### Claim 39 (depends on 34)

The method of claim 34, wherein the cancer is cytarabine-resistant.

### Claim 40 (depends on 34)

The method of claim 34, wherein the cancer is doxorubicin-resistant.

### Claim 41 (depends on 1)

A method of treating, preventing, or ameliorating one or more symptoms of a disorder mediated by protein translation initiation, comprising administering a compound of claim 1, or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof together with one or more additional active agents.

### Claim 42 (depends on 41)

The method of claim 41, wherein the additional active agents comprises paclitaxel or docetaxel.

### Claim 43 (depends on 1)

A method of preventing metastasis comprising administering a compound of claim 1, or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

### Claim 44 (depends on 1)

A method of treating, preventing, or ameliorating fibrosis, comprising contacting a human fibroblast with a compound of claim 1, or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.