# US 8,785,658 B2 · Pyrrole compounds that modulate HSP90 activity

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- Number: US 8,785,658 B2
- Document ID: US8785658B2
- Status: Granted
- Kind: B2
- Application number: 13/902,290
- Filed: 2013-05-24
- Published: 2013-10-03
- Granted: 2014-07-22
- Earliest claimed: 2008-06-04
- Assignees: Synta Pharmaceuticals Corp.
- Applicants: Dinesh U. Chimmanamada; Weiwen Ying
- Inventors: Dinesh U. Chimmanamada; Weiwen Ying
- Web page: https://patentgrep.com/patent/US8785658B2

## CPC

- C07D 207/34: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- A61K 31/40: having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- C07D 207/335: Radicals substituted by nitrogen atoms not forming part of a nitro radical
- C07D 405/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 405/14: containing three or more hetero rings
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- 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
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The present invention relates to substituted pyrrole compounds and compositions comprising substituted pyrrole compounds. The invention further relates to methods of inhibiting the activity of Hsp90 in a subject in need thereof and methods for treating hyperproliferative disorders, such as cancer, in a subject in need thereof comprising administering to the subject a substituted pyrrole compound of the invention, or a pharmaceutical composition comprising such a compound.

## Claims

### Claim 1

A compound represented by the following structural formula:
or a pharmaceutically acceptable salt thereof,
wherein:
each R1 and R2 is independently —NR10R11, —OR7, or —SR7;
R3 is hydrogen, —X50R50, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, or heteraralkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, and heteraralkyl represented by R3 is optionally and independently substituted;
each R4 and R5 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, or heteraralkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, and heteraralkyl represented by R4 or R5 is optionally and independently substituted;
each R7 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, or heteraralkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, and heteraralkyl represented by R7 is optionally and independently substituted;
each R10 and R11 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, or heteraralkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, and heteraralkyl represented by R10 or R11 is optionally and independently substituted; or
R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R50 is an optionally substituted aryl or an optionally substituted heteroaryl;
X50 is a divalent group selected from a C1-C4 alkylene, NR7, C(O), C(S), C(NR7), and S(O)p;
Y is O or S;
each Z is independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, halo, cyano, nitro, guanadino, or alkoxy, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or heterocyclyl, represented by Z are optionally and independently substituted;
each optional substituent for an alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, aralkyl, heteroaryl, and heteroaralkyl is independently an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteraralkyl, heteroalkyl, alkoxy, halo, cyano, nitro, or guanadino;
each p is independently 0, 1 or 2; and
n is 0, 1, 2, or 3.

### Claim 2 (depends on 1)

The compound of any one of claim 1, wherein R1 and R2 are independently selected from —OH, —OR9, —SH and —NHR7, and R9 is a lower alkyl.

### Claim 3 (depends on 2)

The compound of claim 2, wherein R1 is —OR9; R2 is —OH; and R9 is —CH3 or —CH2CH3a and wherein Z is C1-C4 alkyl.

### Claim 4 (depends on 3)

The compound according to claim 3, wherein R3 is represented by the formula:
each X is independently N or CR21;
each R21 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halo, cyano, nitro, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —C(S)R7, —C(O)SR7, —C(S)OR7, —C(S)NR10R11, —C(NR7)OR7, —C(NR7)R7, —C(NR7)NR10R11, —C(NR7)SR7, —OC(O)R7, —OC(O)OR7, —OC(NR7)OR7, —OC(S)R7, —OC(O)NR10R11, —OC(NR7)NR10R11, —OC(NR7)R7, —C(O)NR10R11, —NR7C(O)R7, —NR7C(S)OR7, —NR7C(NR7)R7, —NR7C(O)OR7, —NR7C(NR7)OR7, —NR7C(O)NR10R11, —NR7C(NR7)NR10R11, —OS(O)pR7, —OS(O)pOR7, —OS(O)pNR10R11, —S(O)pOR7, —NR7S(O)pR7, —NR7S(O)pNR10R11, NR7S(O)pOR7, —S(O)pNR10R11, or —OP(O)(OR7)2, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl and heteroaralkyl represented by R21 is optionally and independently substituted;
or two adjacent R21 substituents, together with the atoms to which they are attached, form a cycloalkyl, heterocyclyl, aryl, or heteroaryl moiety, each of which may be optionally substituted;
n′ is an integer from 0 to 3;
q is an integer from 0 to 3; and
B is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halo, cyano, nitro, guanadino, —NR10R11, —C(O)R7, —C(O)OR7, —C(S)R7, —C(O)SR7, —C(S)OR7, —C(S)NR10R11, —C(NR7)OR7, —C(NR7)R7, —C(NR7)NR10R11, —C(NR7)SR7, —OC(O)R7, —OC(O)OR7, —OC(S)OR7, —OC(NR7)OR7, —SC(O)R7, —SC(O)OR7, —SC(NR7)OR7, —OC(S)R7, —SC(S)R7, —SC(S)OR7, —OC(O)NR10R11, —OC(S)NR10R11, —OC(NR7)NR10R11, —SC(O)NR10R11, —SC(NR7)NR10R11, —SC(S)NR10R11, —OC(NR7)R7, —SC(NR7)R7, —C(O)NR10R11, —NR7C(O)R7, —NR7C(S)R7, —NR7C(S)OR7, —NR7C(NR7)R7, —NR7C(O)OR7, —NR7C(NR7)OR7, —NR7C(O)NR10R11, —NR7C(S)NR10R11, —NR7C(NR7)NR10R11, —S(O)pR7, —OS(O)pR7, —OS(O)pOR7, —OS(O)pNR10R11, —S(O)pOR7, —NR7S(O)pR7, —NR7S(O)pNR10R11, —NR7S(O)pOR7, —S(O)pNR10R11, —SS(O)pR7, —SS(O)pOR7, —SS(O)pNR10R11, —OP(O)(OR7)2, or —SP(O)(OR7)2, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl and heteroaralkyl represented by B is optionally and independently substituted.

### Claim 5 (depends on 4)

The compound according to claim 4, wherein R3 is represented by the following formula:
wherein:
m is an integer from 0 to 2;
n′ is an integer from 0 to 1; and
q is an integer from 0 to 1.

### Claim 6 (depends on 1)

A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of claim 1.