# US 7,612,201 B2 · Pyrazole compounds

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- Number: US 7,612,201 B2
- Document ID: US7612201B2
- Status: Granted
- Kind: B2
- Application number: 10/536,899
- Filed: 2003-12-18
- Published: 2006-07-06
- Granted: 2009-11-03
- Earliest claimed: 2002-12-19
- Assignees: Vernalis (Cambridge) Limited; Cancer Research Technology Limited; The Institute of Cancer Research
- Inventors: Mandy Christine Beswick; Martin James Drysdale; Brian William Dymock; Edward McDonald
- Web page: https://patentgrep.com/patent/US7612201B2

## CPC

- C07D 231/38: Nitrogen atoms (nitro radicals C07D231/16)
- A61K 31/415: 1,2-Diazoles
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/06: Antiasthmatics
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/06: Antipsoriatics
- A61P 19/04: for non-specific disorders of the connective tissue
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 405/10: linked by a carbon chain containing aromatic rings
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- 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

Compounds of formula (IA) or (IB) or a salt, N-oxide, hydrate or solvate thereof are inhibitors of HSP90, and are of value in the treatment of diseases responsive to HSP90 inhibition such as cancers. In the formulae, Ar is an aryl, aryl(C1-C6 alkyl), aryl(C1-C6 alkyl), heteroaryl, heteroarylaryl(C1-C6 alkyl), or heteroarylaryl(C1-C6 alkyl) group, any of which being optionally substituted in the aryl or heteroaryl part thereof; R1, is hydrogen or optionally substituted C1-C6 alkyl; R2 is hydrogen, optionally substituted cycloalkyl, cycloalkenyl, C1-C6 alkyl, C1-C6 alkenyl, or C1-C6 alkynyl; or a carboxyl, carboxamide or carboxyl ester group; and ring A is a non aromatic carbocyclic or heterocyclic ring wherein (i) a ring carbon is optionally substituted, and/or (ii) a ring nitrogen is optionally substituted by a group of formula -(Alk1)p (Cyc)n-(Alk3)m-(Z)r (Alk2)s Q where Alk1, Alk2 and Alk3 are optionally substituted C1-C3 alkyl, Cyc is an optionally substituted carbocyclic or heterocyclic radical; m, n, p, r and s are independently 0 or 1, Z is -0-, —S—, —(C═O)—, —S02-, —C(═O)O—, —OC(═O)—, —NW—, —C(═O)NRA-, —NRAC(═O)—, —SO2NRA—, or —NRASO2— wherein RA is hydrogen or C1-C6 alkyl, and Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical.

## Claims

### Claim 1

A compound of formula (IA) or (IB) or a salt, or N-oxide thereof:
wherein
Ar is a 2,4-dihydroxyphenyl group which is optionally further substituted in the 5-position,
R1 and R2 are independently hydrogen, methyl, ethyl, n- or iso-propyl, hydroxyethyl, or benzyl;
ring A is a ring of formula (IIA)
wherein X represents N, and Y represents CH, O, S or NH,
wherein (i) a ring carbon is optionally substituted, and/or (ii) a ring nitrogen is optionally substituted by a group of formula -(Alk1)p-(Cyc)n-(Alk3)m-(Z)r-(Alk2)s-Q where
Alk1, Alk2 and Alk3 are optionally substituted C1-C3 alkyl,
Cyc is an optionally substituted phenylene radical;
m, n, p, r and s are independently 0 or 1,
Z is —O—, —S—, —(C═O)—, —SO2—, —C(═O)O—, —OC(═O)—, —NRA—, —C(═O)NRA—,
—NRAC(═O)—, —SO2NRA—, or —NRASO2— wherein RA is hydrogen or C1-C6 alkyl, and
Q is an optionally substituted phenyl, pyridyl, furyl, thienyl, oxadiazolyl, imidazolyl, or morpholinyl wherein “optionally substituted” means substituted with up to four substituents, each of which is independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy, hydroxy(C1-C6)alkyl, mercapto, mercapto(C1-C6)alkyl, (C1-C6)alkylthio, halo, trifluoromethyl, trifluoromethoxy, nitro, nitrile, oxo, phenyl, —COOH, —COORA, —CORA, —SO2RA, —CONH2, —CONHNH2; —CONHNHRA, —CONHNRARB, —SO2NH2, —CONHRA, SO2NHRA, —CONRARB, —SO2NRARB, —NH2, —NHRA, —NRARB, —OCONH2, —OCONHRA, —OCONRARB, —NHCORA, —NHCOORA, —NRBCOORA, —NHSO2ORA, —NRBSO2ORA, —NHCONH2, —NRACONH2, —NHCONHRB, —NRACONHRB, —NHCONRARB, and —NRACONRARB wherein RA and RB are independently a (C1-C6)alkyl group.

### Claim 2 (depends on 1)

A compound as claimed in claim 1 wherein R1 and R2 are each hydrogen.

### Claim 3 (depends on 2)

A compound as claimed in claim 2 wherein in the ring of formula (IIA), Y is —NRA—wherein RA is a radical of formula -(Alk1)s-Q, wherein Alk1 is a C1-C3 alkylene radical and Q is optionally substituted phenyl, pyridyl, furyl, thienyl, oxadiazolyl, imidazolyl or morpholinyl, wherein optionally substituted means substituted with up to four substituents, each of which is independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy, hydroxy(C1-C6)alkyl, mercapto, mercapto(C1-C6)alkyl, (C1-C6)alkylthio, halo, trifluoromethyl, trifluoromethoxy, nitro, nitrile, oxo, phenyl, —COOH, —COORA, —CORA, —SO2RA, —CONH2, —CONHNH2; —CONHNHRA, —CONHNRARB, —SO2NH2, —CONHRA, SO2NHRA, —CONRARB, —SO2NRARB, —NH2, —NHRA, —NRARB, —OCONH2, —OCONHRA, —OCONRARB, —NHCORA, —NHCOORA, —NRBCOORA, —NHSO2ORA, —NRBSO2ORA, —NHCONH2, —NRACONH2, —NHCONHRB, —NRACONHRB, —NHCONRARB, and —NRACONRARB wherein RA and RB are independently a (C1-C6)alkyl group.

### Claim 4 (depends on 2)

A compound as claimed in claim 2 wherein in the ring of formula (IIA), Y is —NRA— wherein RA is a radical of formula -(Alk1)p-(Cyc)n-(Alk3)m-(Z)r-(Alk2)s-Q wherein
Alk1, Alk2, and Alk3 are optionally substituted C1-C3 alkyl,
Cyc is an optionally substituted phenylene radical;
Z is —O—, —S—, —(C═O)—, —SO2—, —C(═O)O—, —OC(═O)—, —NRA—, —C(═O)NRA—,
—NRAC(═O)—, —SO2NRA—, or —NRASO2—wherein RA is hydrogen or C1-C6 alkyl, and
Q is an optionally substituted phenyl, pyridyl, furyl, thienyl, oxadiazolyl, imidazolyl, or morpholinyl wherein “optionally substituted” means substituted with up to four substituents, each of which is independently selected from (C1-C6)alkyl, (C1-C6) alkoxy, hydroxy, hydroxy(C1-C6)alkyl, mercapto, mercapto(C1-C6)alkyl, (C1-C6)alkylthio, halo, trifluoromethyl, trifluoromethoxy, nitro, nitrile, oxo, phenyl —COOH, —COORA, —CORA, —SO2RA, —CONH2, —CONHNH2; —CONHNHRA, —CONHNRARB, —SOsNH2, —CONHRA, SO2NHRA, —CONRARB, —SO2NRARB, —NH2, —NHRA, —NRARB, —OCONH2, —OCONHRA, —OCONRARB, —NHCORA, —NHCOORA, —NRBCOORA, —NHSO2ORA, —NRBSO2ORA, —NHCONH2, —NRACONH2, —NHCONHRB, —NRACONHRB, —NHCONRARB, and —NRACONRARB wherein RA and RB are independently a (C1-C6)alkyl group.

### Claim 5

A compound of formula (IC) or (ID) or a salt, or N-oxide thereof:
wherein R is hydrogen, chloro, bromo, or a phenylethyl group which is optionally substituted in the phenyl ring, and
R2 is independently hydrogen, methyl, ethyl, n- or iso-propyl, hydroxyethyl, or benzyl;
Alk2 and Alk3 are optionally substituted C1-C3 alkyl,
m, r and s are independently 0 or 1,
Z is —O—, —S—, —(C═O)—, —SO2—, —C(═O)O—, —OC(═O)—, —NRA—, —C(═O)NRA—,
—NRAC(═O)—, —SO2NRA—, or —NRASO2—wherein RA is hydrogen or C1-C6 alkyl, and
Q is an optionally substituted phenyl, pyridyl, furyl, thienyl, oxadiazolyl, imidazolyl, or morpholinyl,
wherein “optionally substituted” means substituted with up to four substituents, each of which is independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy, hydroxy(C1-C6)alkyl, mercapto, mercapto(C1-C6)alkyl, (C1-C6)alkylthio, halo, trifluoromethyl, trifluoromethoxy, nitro, nitrile, oxo, phenyl, —COOH, —COORA, —CORA, —SO2RA, —CONH2, —CONHNH2; —CONHNHRA, —CONHNRARB, —SO2NH2, —CONHRA, SO2NHRA, —CONRARB, —SO2NRARB, —NH2, —NHRA, —NRARB, —OCONH2, —OCONHRA, —OCONRARB, —NHCORA, —NHCOORA, —NRBCOORA, —NHSO2ORA, —NRBSO2ORA, —NHCONH2, —NRACONH2, —NHCONHRB, —NRACONHRB, —NHCONRARB, and —NRACONRARB wherein RA and RB are independently a (C1-C6)alkyl group.

### Claim 6 (depends on 5)

A compound as claimed in claim 5 wherein m is 0, r is 1, and Z is —C(═O)NH—.

### Claim 7

A compound of formula (IA) or (IB) or a salt, or N-oxide thereof:
wherein
Ar is a 2,4-dihydroxyphenyl group which is further substituted in the 5-position by chioro or bromo; or by optionally substituted phenyl or C1-C6 alkyl; or by a phenylethyl group which is optionally substituted in the phenyl ring thereof,
R1 and R2 are independently hydrogen, methyl, ethyl, n- or iso-propyl, hydroxyethyl, or benzyl;
ring A is a ring of formula (IIA)
wherein X represents N, and Y represents NRA wherein RA is a radical of formula -(Alk1)s-Q, wherein Alk1 is a C1-C3 alkylene radical and Q is optionally substituted phenyl, pyridyl, furyl, thienyl, oxadiazolyl, imidazolyl or morpholinyl, wherein optionally substituted means substituted with up to four substituents, each of which is independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy, hydroxy(C1-C6)alkyl, mercapto, mercapto(C1-C6)alkyl, (C1-C6)alkylthio, halo, trifluoromethyl, trifluoromethoxy, nitro, nitrile, oxo, phenyl, —COOH, —COORA, —CORA, —SO2RA, —CONH2, —CONHNH2; —CONHNHRA, —CONHNRARB, —SO2NH2, —CONHRA, SO2NHRA, —CONRARB, —SO2NRARB, —NH2, —NHRA, —NRARB, —OCONH2, —OCONHRA, —OCONRARB, —NHCORA, —NHCOORA, —NRBCOORA, —NHSO2ORA, —NRBSO2ORA, —NHCONH2, —NRACONH2, —NHCONHRB, —NRACONHRB, —NHCONRARB, and —NRACONRARB wherein RA and RB are independently a (C1-C6)alkyl group.