# US 2014/0194439 A1 · Methods of targeted drug development

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- Number: US 2014/0194439 A1
- Document ID: US20140194439A1
- Status: Published application
- Kind: A1
- Application number: 14/096,618
- Filed: 2013-12-04
- Published: 2014-07-10
- Earliest claimed: 2010-01-06
- Assignees: Joseph P. Errico
- Inventors: Joseph P. Errico; Benjamin Mugrage; Ignatius Turchi; Matthew Sills; Jane Ong; John Allocco; Pam Wines
- Web page: https://patentgrep.com/patent/US20140194439A1

## CPC

- C07D 215/26: Alcohols; Ethers thereof
- A61K 31/47: Quinolines; Isoquinolines
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/06: Antipsoriatics
- A61P 17/08: Antiseborrheics
- A61P 17/12: Keratolytics, e.g. wart or anti-corn preparations
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 335/26: Y being a hydrogen or a carbon atom, e.g. benzoylthioureas
- C07D 207/48: Sulfur atoms
- C07D 209/08: with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
- C07D 239/42: One nitrogen atom (nitro radicals C07D239/30)
- C07D 239/47: One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
- C07D 239/52: Two oxygen atoms
- C07D 285/135: Nitrogen atoms
- C07D 295/26: Sulfur atoms
- C07D 307/54: Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- 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 405/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 405/14: containing three or more hetero rings
- C07D 409/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 409/14: containing three or more hetero rings
- C07D 417/14: containing three or more hetero rings
- G16B 15/00: ICT specially adapted for analysing two-dimensional [2D] or three-dimensional [3D] molecular structures, e.g. structural or functional relations or structure alignment
- G16B 15/30: Drug targeting using structural data; Docking or binding prediction
- 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
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- G16B: BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY

## Abstract

Provided herein are compounds having anti-proliferative effect. Also provided are compounds that can modulate the activity of multi-domain proteins comprising a dimerization arm and interdomain tether, such as EGFR, where an untethered, extended conformation is the active state and a tethered conformation is the inactive state, resulting in an autoinhibited configuration. Also provided are methods and pharmacophores for identifying such compounds. Other aspects provide methods or therapeutic treatment for proliferative diseases, disorders, or conditions, such as those associated with EGFR.

## Claims

### Claim 1

A method of treating a proliferative disease, disorder, or condition comprising:
administering to a subject in need thereof a composition comprising a therapeutically effective amount of
(a) a compound having a formula of
or a stereoisomer or pharmaceutically acceptable salt thereof;
wherein,
X is selected from the group consisting of: hydrogen, 2-methyl, 5-chloro, 5-nitro, and 6-hydroxyl;
R1 is selected from the group consisting of:
(i) a 2-pyridyl ring of Formula (3)
wherein
R23 is selected from the group consisting of hydrogen; fluoro; chloro; trifluoromethyl; methyl; ethyl; and methoxy;
R3 is selected from the group consisting of hydrogen; fluoro; chloro; methyl; ethyl; methoxy; a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; a C-2 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; aryl comprising a phenyl or heteroaryl five or six membered ring containing from 1 to 4 N, O, or S atoms; and alkoxy —OR10 where R10 is a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation or a C-2 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
R24 is selected from the group consisting of: hydrogen; fluoro; chloro; and trifluoromethyl; and
R4 is selected from the group consisting of hydrogen; methyl; a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; a C-2 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; aryl comprising a phenyl or heteroaryl five or six membered ring containing from 1 to 4 N, O, or S atoms; and alkoxy —OR10 where R10 is a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation or a C-2 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(ii) a 3-pyridyl ring of Formula (4)
wherein R5, R6, and R7 are independently selected from the group consisting of: hydrogen, a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; a C-2 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; aryl comprising a phenyl or heteroaryl containing from 1 to 4 N, O, or S atoms; and alkoxy —OR10 where R10 is a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation or a C-2 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(iii) a 4-pyridyl ring of Formula (5)
wherein R8 and R9 are independently selected from the group consisting of: a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; a C-2 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; aryl comprising a phenyl or heteroaryl containing from 1 to 4 N, O, or S atoms; and alkoxy —OR10 where R10 is a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation or a C-2 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(iv) a phenyl ring substituted with one or more groups selected from a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; a C-2 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; aryl comprising a phenyl or heteroaryl containing from 1 to 4 N, O, or S atoms; alkoxy —OR10 where R10 is a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation or a C-2 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; trifluoromethyl; trifluoromethoxy; difluoromethoxy; 3,4-methylenedioxy; 2,3-methylenedioxy; nitro; and halogen;
(v) an unsubstituted heteroaryl five or six membered ring containing from 1 to 4 N, O, or S atoms; and
(vi) a substituted heteroaryl five or six membered ring containing from 1 to 4 N, O, or S atoms substituted with one or more groups selected from the group consisting of: straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; C-2 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; aryl comprising a phenyl or heteroaryl five or six membered ring containing from 1 to 4 N, O, or S atoms; and alkoxy —OR10 where R10 is a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation or a C-2 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; and
R2 is selected from the group consisting of:
(i) an unsubstituted phenyl ring or a phenyl ring substituted at the 2-, 3-, 4-, 5- or 6-position with one or more groups independently selected from the group consisting of: straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; C-2 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; aryl comprising a phenyl or heteroaryl five or six membered ring containing from 1 to 4 N, O, or S atoms; alkoxy —OR10 where R10 is a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation or a C-2 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; 2,3-methylenedioxy; 3,4-methylenedioxy; dialkylamino having formula —NR13R14 wherein R13 and R14 are independently selected from hydrogen or a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; trifluoromethyl; trifluoromethoxy; difluoromethoxy; 3,4-methylenedioxy; 2,3-methylenedioxy; nitro; and halogen;
(ii) a 2-thiophene ring of Formula (8) wherein R15, R16, and R′7 are independently selected from the group consisting of: hydrogen; straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; C-2 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; alkoxy —OR10 where R10 is a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation or a C-2 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; dialkylamino; trifluoromethyl; difluoromethyl; trifluoromethoxy; and halogen
(iii) a 3-thiophene ring of Formula (9) wherein R18, R19, and R20 are independently selected from the group consisting of: straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; C-2 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; alkoxy —OR10 where R10 is a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation or a C-2 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; dialkylamino; trifluoromethyl; difluoromethyl; trifluoromethoxy; and halogen
(iv) an unsubstituted 2-pyridyl ring or a 2-pyridyl ring substituted at 4- or 6-position of the pyridine ring with one or more groups independently selected from the group consisting of: straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation and C-2 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom;
(v) an unsubstituted 3-pyridyl ring or a 3-pyridyl ring substituted at the 2-, 4- or 6-position of the pyridine ring with one or more groups independently selected from the group consisting of: straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation and C-2 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; and
(vi) an unsubstituted 4-pyridyl ring or a 4-pyridyl ring substituted at the 2- or 6-position of the pyridine ring with one or more groups independently selected from the group consisting of: straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation and C-2 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; or
a stereoisomer or pharmaceutically acceptable salt thereof;
(b) a compound of Formula (1)
or
a stereoisomer or pharmaceutically acceptable salt thereof; or
(c) a compound selected from the group consisting of
or
a stereoisomer or pharmaceutically acceptable salt thereof; and
a pharmaceutically acceptable carrier or excipient.

### Claim 2 (depends on 1)

The method of claim 1, wherein the composition comprises a compound of Formula (2) wherein R1 is selected from the group consisting of:
(i) an 2-(1,3-thiazoyl) of Formula (6), wherein R11 and R12 are independently selected from the group consisting of: hydrogen; straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; C-2 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; alkoxy —OR10 where R10 is a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation or a C-2 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; dialkylamino; trifluoromethyl; difluoromethyl; trifluoromethoxy; and halogen,
and
(ii) a 2-(4,5-Dimethyl-1,3-thiazoyl) of Formula (7)

### Claim 3 (depends on 1)

The method of claim 1, wherein the composition comprises a compound of Formula (2) and wherein R1 is a 2-pyridyl ring of Formula (3) and R24 is chloro or R23 is methyl.

### Claim 4 (depends on 1)

The method of claim 1, wherein the composition comprises a compound of Formula (2) wherein (i) R1 is a 2-pyridyl ring of Formula (3) and (ii) one of the following:
R4 is hydrogen, R24 is fluoro, R3 is hydrogen, and R23 is fluoro;
R4 is methyl, R24 is chloro, R3 is hydrogen, and R23 is fluoro;
R4 is hydrogen, R24 is chloro, R3 is ethyl, and R23 is fluoro;
R4 is hydrogen, R24 is fluoro, R3 is methyl, and R23 is fluoro;
R4 is hydrogen, R24 is chloro, R3 is hydrogen, and R23 is ethyl;
R4 is methyl, R24 is chloro, R3 is hydrogen, and R23 is chloro;
R4 is hydrogen, R24 is chloro, R3 is methyl, and R23 is fluoro;
R4 is hydrogen, R24 is trifluoromethyl, R3 is hydrogen, and R23 is hydrogen;
R4 is hydrogen, R24 is chloro, R3 is hydrogen, and R23 is methyl;
R4 is hydrogen, R24 is chloro, R3 is hydrogen, and R23 is chloro;
R4 is hydrogen, R24 is chloro, R3 is methyl, and R23 is hydrogen; or
R4 is hydrogen, R24 is chloro, R3 is chloro, and R23 is hydrogen.

### Claim 5 (depends on 1)

The method of claim 1, wherein the composition comprises a compound of Formula (2) and wherein (i) R1 is a 2-pyridyl ring of Formula (3) and (ii) one of the following:
R24 is chloro and R3 is chloro or methyl or R23 is chloro or methyl;
R24 is chloro, R3 is hydrogen, and R23 is methyl;
R24 is chloro, R3 is methyl, and R23 is fluoro;
R24 is chloro, R3 is chloro, and R23 is hydrogen; or R24 is chloro, R3 is hydrogen, and R23 is chloro.

### Claim 6 (depends on 1)

The method of claim 1, wherein the composition comprises a compound of Formula (2) and wherein R2 is selected from the group consisting of:
a phenyl ring substituted at the 2- and 4-positions;
4-trifluoromethylphenyl;
2-fluoro,4-trifluoromethylphenyl; and
2,4-dichlorophenyl.

### Claim 7 (depends on 1)

The method of claim 1, wherein the composition comprises a compound of Formula (2) and wherein R2 is selected from the group consisting of:
4-chlorophenyl; 2-fluoro,4-trifluoromethylphenyl; 3-fluoro,4-chlorophenyl; 2-fluoro,4-chlorophenyl; 2,3-dichlorophenyl; 2,3,5-trichlorophenyl; 2,4-dichlorophenyl; 3,4-dichlorophenyl; and 3,5-dichlorophenyl.

### Claim 8 (depends on 1)

The method of claim 1, wherein the composition comprises a compound of Formula (2) and wherein R2 is selected from the group consisting of:
a phenyl ring substituted at the 4 position with chloro and substituted at the 2- or 3-position with chloro or fluoro;
2,4-dichlorophenyl; and
2-chloro,4-fluorophenyl.

### Claim 9 (depends on 1)

The method of claim 1, wherein the proliferative disease, disorder, or condition is associated with EGFR.

### Claim 10 (depends on 9)

The method of claim 9, wherein the proliferative disease, disorder, or condition associated with EGFR is stimulated by an EGFR ligand selected from the group consisting of EGF, TGF-alpha, heparin-binding growth factor (HBGF), β-cellulin, and Cripto-1.

### Claim 11 (depends on 1)

The method of claim 1, wherein the proliferative disease, disorder, or condition is selected from the group consisting of: cancer; a blood vessel proliferative disorder; a fibrotic disorder; a mesangial cell proliferative disorder; psoriasis; actinic keratoses; seborrheic keratoses; warts; keloid scars; eczema; papilloma virus infection; and hyperproliferative diseases caused by a viral infection.

### Claim 12 (depends on 1)

The method of claim 1, wherein the proliferative disease, disorder, or condition comprises cancer.

### Claim 13 (depends on 1)

The method of claim 1, wherein the subject is a mammal.

### Claim 14 (depends on 1)

The method of claim 1, wherein the subject is a horse, cow, dog, cat, sheep, pig, mouse, rat, monkey, guinea pig, chicken, or human.

### Claim 15 (depends on 1)

The method of claim 1, wherein the subject is a human.

### Claim 16 (depends on 1)

The method of claim 1, wherein administering to the subject comprises parenteral, pulmonary, oral, topical, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, ophthalmic, buccal, or rectal administration.

### Claim 17 (depends on 1)

The method of claim 1, wherein administering to the subject comprises multiple administrations of the composition.

### Claim 18 (depends on 1)

The method of claim 1, wherein the composition further comprises a second agent.

### Claim 19 (depends on 18)

The method of claim 18, wherein the second agent is selected from the group consisting of an anti-proliferative agent, a vascularization inhibitor, an agent that increases permeability of a tumor, and a chemotherapeutic agent.

### Claim 20 (depends on 18)

The method of claim 18, wherein the second agent is Tykerb, Iressa, Tarceva, or Erbitux.