IP Library › Granted Patent US 8,524,712
Granted Patent B2
US 8,524,712 · App. 12/593,147 · Granted Sep 3, 2013

Triazinone and diazinone derivatives useful as HSP90 inhibitors

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Quick Facts
Patent No.
US 8,524,712
App. No.
12/593,147
Granted
Sep 3, 2013
Kind
B2
Abstract

The present invention relates to compounds according to formulae (IA) to (ID) and compositions that inhibit the activity of Hsp90. The invention further relates to methods of inhibiting the activity of Hsp90 in a subject in need thereof and methods for preventing or treating hyperproliferative disorders, such as cancer, in a subject in need thereof comprising administering to the subject a compound of the invention, or a composition comprising such a compound.

Claims (54)

1. A compound represented by the following structural formula:

or a tautomer, pharmaceutically acceptable salt, or a prodrug thereof, wherein:

X is —C(R 7 ) 2 —, —NH—, —O—, or —S—;

X 1 is O or S;

X 20 is a C1-C4 alkyl, NR 7 , C(O), C(S), C(NR 8 ), or S(O) p ;

Z is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, an optionally substituted haloalkyl, an optionally substituted heteroalkyl, optionally substituted alkoxy, —C(O)NR 28 R 29 , —C(S)NR 28 R 29 , —C(NR 32 )NR 28 R 29 , —NR 33 C(O)R 31 , —NR 33 C(S)R 31 , —NR 33 C(NR 32 )R 31 , halo, —OR 33 , cyano, nitro, haloalkoxy, —C(O)R 33 , —C(S)R 33 , —C(NR 32 )R 33 , —NR 28 R 29 , —C(O)OR 33 , —C(S)OR 33 , —C(NR 32 )OR 33 , —OC(O)R 33 , —OC(S)R 33 , —OC(NR 32 )R 33 , —NR 30 C(O)NR 28 R 29 , —NR 33 C(S)NR 28 R 29 , —NR 33 C(NR 32 )NR 28 R 29 , —OC(O)NR 28 R 29 , —OC(S)NR 28 R 29 , —OC(NR 32 )NR 28 R 29 , —NR 33 C(O)OR 31 , —NR 33 C(S)OR 31 , —NR 33 C(NR 32 )OR 31 , —S(O) h R 33 , —OS(O) p R 33 , —NR 33 S(O) p R 33 , —S(O) p NR 28 R 29 , —OS(O) p NR 28 R 29 , or —NR 33 S(O) p NR 28 R 29 guanadino, —C(O)SR 31 , —C(S)SR 31 , —C(NR 32 )SR 31 , —OC(O)OR 31 , —OC(S)OR 31 , —OC(NR 32 )OR 31 , —SC(O)R 33 , —SC(O)OR 31 , —SC(NR 32 )OR 31 , —SC(S)R 33 , —SC(S)OR 31 , —SC(O)NR 28 R 29 , —SC(NR 32 )NR 28 R 28 , —SC(S)NR 28 R 29 , —SC(R 32 )R 33 , —OS(O) p OR 31 , —S(O) p OR 31 , —NR 30 S(O) p OR 31 , —SS(O) p R 33 , —SS(O) p OR 31 , —SS(O) p NR 28 R 29 , —OP(O)(OR 31 ) 2 , or —SP(O)(OR 31 ) 2 ;

R 2 and R 3 are each independently —NR 7 H, —OR 7 , —SR 7 , —O(CH 2 ) m OH, —O(CH 2 ) m SH, —O(CH 2 ) m NR 7 H, —S(CH 2 ) m OH, —S(CH 2 ) m SH, —S(CH 2 ) m NR 7 H, —OC(O)NR 10 R 11 , —SC(O)NR 10 R 11 , —NR 7 C(O)NR 10 R 11 , —OC(O)R 7 , —SC(O)R 7 , —NR 7 C(O)R 7 , —OC(O)OR 7 , —SC(O)OR 7 , —NR 7 C(O)OR 7 , —OCH 2 C(O)R 7 , —SCH 2 C(O)R 7 , —NR 7 CH 2 C(O)R 7 , —OCH 2 C(O)OR 7 , —SCH 2 C(O)OR 7 , —NR 7 CH 2 C(O)OR 7 , —OCH 2 C(O)NR 10 R 11 , —SCH 2 C(O)NR 10 R 11 , —NR 7 CH 2 C(O)NR 10 R 11 , —OS(O)R 7 , —SS(O)R 7 , —S(O) p OR 7 , —NR 7 S(O) p R 7 , —OS(O) p NR 10 R 11 , —SS(O) p NR 10 R 11 , —NR 7 S(O) p NR 10 R 11 , —OS(O) p OR 7 , —SS(O) p OR 7 , —NR 7 S(O) p OR 7 , —OC(S)R 7 , —SC(S)R 7 , —NR 7 C(S)R 7 , —OC(S)OR 7 , —SC(S)OR 7 , —NR 7 C(S)OR 7 , —OC(S)NR 10 R 11 , —SC(S)NR 10 R 11 , —NR 7 C(S)NR 10 R 11 , —OC(NR 8 )R 7 , —SC(NR 8 )R 7 , —NR 7 C(NR 8 )R 7 , —OC(NR 8 )OR 7 , —SC(NR 8 )OR 7 , —NR 7 C(NR 8 )OR 7 , —OC(NR 8 )NR 10 R 11 , —SC(NR 8 )NR 10 R 11 , —NR 7 C(NR 8 )NR 10 R 11 , —OP(O)(OR 7 ) 2 , or —SP(O)(OR 7 ) 2 ;

R 5 is —X 20 R 50 , an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;

R 7 and R 8 , for each occurrence, are independently, —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;

R 10 and R 11 , for each occurrence, are independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R 10 and R 11 , taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;

R 28 and R 29 , for each occurrence is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;

R 33 and R 31 for each occurrence is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; and

R 32 , for each occurrence is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, —C(O)R 33 , —C(O)NR 28 R 29 , —S(O) p R 33 , or —S(O) p NR 28 R 29 ;

R 50 is an optionally substituted aryl or an optionally substituted heteroaryl;

h is 0, 1 or 2;

p, for each occurrence, is independently, 0, 1 or 2;

m for each occurrence, is independently 1, 2, 3, or 4; and

n is 0, 1, 2, or 3.

2. The compound of claim 1 , wherein the compound is represented by the following structure:

wherein:

X 41 is O, S, or NR 42 ;

X 42 is CR 44 or N;

Y 40 is N or CR 43 ;

Y 41 is N or CR 45 ;

Y 42 , for each occurrence, is independently N, C or CR 46 ;

R 41 is —H, —OH, —SH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, an alkoxy or cycloalkoxy, a haloalkoxy, —NR 10 R 11 , —OR 7 , —C(O)R 7 , —C(O)OR 7 , —C(S)R 7 , —C(O)SR 7 , —C(S)SR 7 , —C(S)OR 7 , —C(S)NR 10 R 11 , —C(NR 8 )OR 7 , —C(NR 8 )R 7 , —C(NR 8 )NR 10 R 11 , —C(NR 2 )SR 7 , —OC(O)R 7 , —OC(O)OR 7 , —OC(S)OR 7 , —OC(NR 8 )OR 7 , —SC(O)R 7 , —SC(O)OR 7 , —SC(NR 8 )OR 7 , —OC(S)R 7 , —SC(S)R 7 , —SC(S)OR 7 , —OC(O)NR 10 R 11 , —OC(S)NR 10 R 11 , —OC(NR 8 )NR 10 R 11 , —SC(O)NR 10 R 11 , —SC(NR 8 )NR 10 R 11 , —SC(S)NR 10 R 11 , —OC(NR 8 )R 7 , —SC(NR 8 )R 7 , —C(O)NR 10 R 11 , —NR 8 C(O)R 7 , —NR 7 C(S)R 7 , —NR 7 C(S)OR 7 , —NR 7 C(NR 8 )R 7 , —NR 7 C(O)OR 7 , —NR 7 C(NR 8 )OR 7 , —NR 7 C(O)NR 10 R 11 , —NR 7 C(S)NR 10 R 11 , —NR 7 C(NR 8 )NR 10 R 11 , —SR 7 , —S(O)R 7 , —OS(O) p R 7 , —OS(O)OR 7 , —OS(O) p NR 10 R 11 , —S(O)OR 7 , —NR 8 S(O) p R 7 , —NR 7 S(O) p NR 10 R 11 , —NR 7 S(O) p OR 7 , —S(O) p NR 10 R 11 , —SS(O) p R 7 , —SS(O)OR 7 , —SS(O) p NR 10 R 11 , —OP(O)(OR 7 ) 2 , or —SP(O)(OR 7 ) 2 ;

R 42 is —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, a haloalkyl, a heteroalkyl, —C(O)R 7 , —(CH 2 ) m C(O)OR 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)NR 10 R 11 , —S(O) p R 7 , —S(O)OR 7 , or —S(O) p NR 10 R 11 ;

R 43 and R 44 are, independently, —H, —OH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)NR 10 R 11 , —NR 8 C(O)R 7 , —SR 7 , —S(O)R 7 , —OS(O) p R 7 , —S(O)OR 7 , —NR 8 S(O) p R 7 , —S(O) p NR 10 R 11 , or R 43 and R 44 taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl;

R 45 is —H, —OH, —SH, —NR 7 H, —O(CH 2 ) m OH, —O(CH 2 ) m SH, —O(CH 2 ) m NR 7 H, —S(CH 2 ) m OH, —S(CH 2 ) m SH, —S(CH 2 ) m NR 7 H, —OC(O)NR 10 R 11 , —SC(O)NR 10 R 11 , —NR 7 C(O)NR 10 R 11 , —OC(O)R 7 , —SC(O)R 7 , —NR 7 C(O)R 7 , —OC(O)OR 7 , —SC(O)OR 7 , —NR 7 C(O)OR 7 , —OCH 2 C(O)R 7 , —SCH 2 C(O)R 7 , —NR 7 CH 2 C(O)R 7 , —OCH 2 C(O)OR 7 , —SCH 2 C(O)OR 7 , —NR 7 CH 2 C(O)OR 7 , —OCH 2 C(O)NR 10 R 11 , —SCH 2 C(O)NR 10 R 11 , —NR 7 CH 2 C(O)NR 10 R 11 , —OS(O) p R 7 ,—SS(O) p R 7 , —NR 7 S(O) p R 7 , —OS(O) p NR 10 R 11 , —SS(O) p NR 10 R 11 , —NR 7 S(O) p NR 10 R 11 , —OS(O)OR 7 , —SS(O)OR 7 , —NR 7 S(O) p OR 7 , —OC(S)R 7 , —SC(S)R 7 , —NR 7 C(S)R 7 , —OC(S)OR 7 , —SC(S)OR 7 , —NR 7 C(S)OR 7 , —OC(S)NR 10 R 11 , —SC(S)NR 10 R 11 , —NR 7 C(S)NR 10 R 11 , —OC(NR 8 )R 7 , —SC(NR 8 )R 7 , —NR 7 C(NR 8 )R 7 , —OC(NR 8 )OR 7 , —SC(NR 8 )OR 7 , —NR 7 C(NR 8 )OR 7 , —OC(NR 8 )NR 10 R 11 , —SC(NR 8 )NR 10 R 11 , or —NR 7 C(NR 8 )NR 10 R 11 ; and

R 46 , for each occurrence, is independently, selected from the group consisting of H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —NR 10 R 11 , —OR 7 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)NR 10 R 11 , —NR 8 C(O)R 7 , —SR 7 , —S(O)R 7 , —OS(O) p R 7 , —S(O) p OR 7 , —NR 8 S(O) p R 7 , or —S(O) p NR 10 R 11 .

3. The compound of claim 2 , wherein the compound is represented by the following structural formula:

or a tautomer, pharmaceutically acceptable salt, or prodrug thereof.

4. The compound of claim 2 , wherein the compound is represented by the following structural formula:

5. A compound represented by the following structural formula:

or a tautomer, pharmaceutically acceptable salt, or a prodrug thereof, wherein:

X is —C(R 7 ) 2 —, —N—, —O—, or —S—;

X 20 is a C1-C4 alkyl, NR 7 , C(O), C(S), C(NR 8 ), or S(O) p ;

R 2 and R 3 are each independently —NR 7 H, —OR 7 , —SR 7 , —O(CH 2 ) m OH, —O(CH 2 ) m SH, —O(CH 2 ) m NR 7 H, —S(CH 2 ) m OH, —S(CH 2 ) m SH, —S(CH 2 ) m NR 7 H, —OC(O)NR 10 R 11 , —SC(O)NR 10 R 11 , —NR 7 C(O)NR 10 R 11 , —OC(O)R 7 , —SC(O)R 7 , —NR 7 C(O)R 7 , —OC(O)OR 7 , —SC(O)OR 7 , —NR 7 C(O)OR 7 , —OCH 2 C(O)R 7 , —SCH 2 C(O)R 7 , —NR 7 CH 2 C(O)R 7 , —OCH 2 C(O)OR 7 , —SCH 2 C(O)OR 7 , —NR 7 CH 2 C(O)OR 7 , —OCH 2 C(O)NR 10 R 11 , —SCH 2 C(O)NR 10 R 11 , —NR 7 CH 2 C(O)NR 10 R 11 , —OS(O) p R 7 , —SS(O) p R 7 , —S(O) p OR 7 , —NR 7 S(O) p R 7 , —OS(O) p NR 10 R 11 , —SS(O) p NR 10 R 11 , —NR 7 S(O) p NR 10 R 11 , —OS(O) p OR 7 , —SS(O) p OR 7 , —NR 7 S(O) p OR 7 , —OC(S)R 7 , —SC(S)R 7 , —NR 7 C(S)R 7 , —OC(S)OR 7 , —SC(S)OR 7 , —NR 7 C(S)OR 7 , —OC(S)NR 10 R 11 , —SC(S)NR 10 R 11 , —NR 7 C(S)NR 10 R 11 , —OC(NR 8 )R 7 , —SC(NR 8 )R 7 , —NR 7 C(NR 8 )R 7 , —OC(NR 8 )OR 7 , —SC(NR 8 )OR 7 , —NR 7 C(NR 8 )OR 7 , —OC(NR 8 )NR 10 R 11 , —SC(NR 8 )NR 10 R 11 , —NR 7 C(NR 8 )NR 10 R 11 , —OP(O)(OR 7 ) 2 , or —SP(O)(OR 7 ) 2 ;

R 4 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;

R 5 is —X 20 R 50 , an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;

R 7 and R 8 , for each occurrence, are independently, —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionallys ubstituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;

R 10 and R 11 , for each occurrence, are independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R 10 and R 11 , taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;

R 50 is an optionally substituted aryl or an optionally substituted heteroaryl;

p, for each occurrence, is independently, 1 or 2; and

m for each occurrence, is independently 1, 2, 3, or 4.

6. A compound selected from the group consisting of

3-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4,5-dihydro-1,2,4-triazin-6(1H)-one;

4-(benzo[d][1,3]dioxol-5-ylmethyl)-3-(2,4-dihydroxy-5-isopropylphenyl)-4,5-dihydro-1,2,4-triazin-6(1H)-one;

3-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholinophenyl)-4,5-dihydro-1,2,4-triazin-6(1H)-one;

3-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(dimethylamino)phenyl)-4,5-dihydro-1,2,4-triazin-6(1H)-one; or

3-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-methoxybenzyl)-4,5-dihydro-1,2,4-triazin-6(1H)-one;

or, a tautomer, pharmaceutically acceptable salt, or a prodrug thereof.

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

8. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of claim 6 .

Assignments (1)
SECURITY INTEREST Recorded Jul 17, 2025
From: MADRIGAL PHARMACEUTICALS, INC.
To: LSI FINANCING LLC, AS ADMINISTRATIVE AGENT
Reel/Frame 072038/0693 →