# US 8,541,407 B2 · Substituted benzo-pyrido-triazolo-diazepine compounds

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- Number: US 8,541,407 B2
- Document ID: US8541407B2
- Status: Granted
- Kind: B2
- Application number: 13/076,695
- Filed: 2011-03-31
- Published: 2011-10-06
- Granted: 2013-09-24
- Earliest claimed: 2010-03-31
- Assignees: ArQule, Inc.
- Applicants: Syed M. Ali; Mark A. Ashwell; Eugene Kelleher; Steffi Koerner; Jean-Marc Lapierre; Jeffrey S. Link; Yanbin Liu; Magdi Moussa; Rocio Palma; Manish Tandon; David Vensel; Neil Westlund; Hui Wu; Rui-Yang Yang
- Inventors: Syed M. Ali; Mark A. Ashwell; Eugene Kelleher; Steffi Koerner; Jean-Marc Lapierre; Jeffrey S. Link; Yanbin Liu; Magdi Moussa; Rocio Palma; Manish Tandon; David Vensel; Neil Westlund; Hui Wu; Rui-Yang Yang
- Web page: https://patentgrep.com/patent/US8541407B2

## CPC

- C07D 471/14: Ortho-condensed systems
- A61P 35/00: Antineoplastic agents
- C07D 487/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to substituted benzo-pyrido-triazolo-diazepine compounds and methods of synthesizing these compounds. The present invention also relates to pharmaceutical compositions containing substituted benzo-pyrido-triazolo-diazepine compounds and methods of treating cell proliferative disorders, such as cancer, by administering these compounds or pharmaceutical compositions to subjects in need thereof.

## Claims

### Claim 1

A compound of Formula I:
or a pharmaceutically acceptable salt or ester thereof, wherein:
X1 is CRX1 or N;
X2 is CRX2 or N;
RX1, RX2, RP1 and RP2 are each independently H, hydroxyl, halogen, cyano, nitro, amino, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 alkoxy, unsubstituted or substituted C6-C10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1- 4 heteroatoms selected from N, O and S, unsubstituted or substituted C3-C10 carbocycle or unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1- 4 heteroatoms selected from N, O and S;
Q is (CH2)z or a bond;
z is 1, 2, 3, 4, 5 or 6;
T is hydroxyl, halogen, cyano, nitro, amino, unsubstituted or substituted C6-C10 aryl or unsubstituted or substituted C3-C10 carbocycle;
RN is H or unsubstituted or substituted C1-C6 alkyl;
m is 0, 1, 2, 3 or 4; and
each R1 is independently hydroxyl, halogen, cyano, nitro, amino, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C6-C10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1- 4 heteroatoms selected from N, O and S, unsubstituted or substituted C3-C10 carbocycle or unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4heteroatoms selected from N, O and S.

### Claim 2 (depends on 1)

The compound of claim 1, wherein X1 is CH and X2 is CH, or X1 is N and X2 is CH, or X1 is CH and X2 is N.

### Claim 3 (depends on 1)

The compound of claim 1, wherein Q is (CH2)z and z is 1 or 2.

### Claim 4 (depends on 1)

The compound of claim 1, wherein Q is a bond.

### Claim 5 (depends on 1)

The compound of claim 1, wherein the compound is of Formula II:
or a pharmaceutically acceptable salt or ester thereof, wherein:
X1 is CRX1 or N;
X2 is CRX2 or N;
RX1, RX2, RP1 and RP2 are each independently H, hydroxyl, halogen, cyano, nitro, amino, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 alkoxy, unsubstituted or substituted C6-C10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4heteroatoms selected from N, O and S, unsubstituted or substituted C3-C10 carbocycle or unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4heteroatoms selected from N, O and S;
RN is H or unsubstituted or substituted C1-C6 alkyl;
m is 0, 1, 2, 3 or 4;
each R1 is independently hydroxyl, halogen, cyano, nitro, amino, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C6-C10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4heteroatoms selected from N, O and S, unsubstituted or substituted C3-C10 carbocycle or unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4heteroatoms selected from N, O and S;
n is 0, 1, 2, 3, 4 or 5;
each R2 is independently halogen, cyano, nitro, unsubstituted or substituted C1-C6 alkyl or (CH2)o—R2′;
o is 0, 1, 2, 3, 4, 5 or 6;
each R2′is independently unsubstituted or substituted C6- C10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4heteroatoms selected from N, O and S, unsubstituted or substituted C3-C10 carbocycle, unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4heteroatoms selected from N, O and S, OR3, NR4R4′, C(O)R5, C(O)OR5 or C(O)NR5R5′;
R3 is H, unsubstituted or substituted C1-C6 alkyl or S(O)2R6;
R4 is H, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C6-C10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1- 4 heteroatoms selected from N, O and S, unsubstituted or substituted C3-C10 carbocycle, unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1- 4 heteroatoms selected from N, O and S, C(O)R6, C(O)OR6, C(O)NR6R6′ or S(O)2R6;
R5 and R6 are each independently H, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C6- C10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4heteroatoms selected from N, O and S, unsubstituted or substituted C3-C10 carbocycle or unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4heteroatoms selected from N, O and S; and
R4′, R5′ and R6′ are each independently H or unsubstituted or substituted C1-C6 alkyl.

### Claim 6 (depends on 5)

The compound of claim 5, wherein X1 is CH and X2 is CH, or X1 is N and X2 is CH, or X1 is CH and X2 is N.

### Claim 7 (depends on 5)

The compound of claim 5, wherein RX1, RX2, RP1 and RP2 are each independently H, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl or phenyl.

### Claim 8 (depends on 5)

The compound of claim 5, wherein RN is H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl.

### Claim 9 (depends on 5)

The compound of claim 5, wherein each R1 is independently H, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl or phenyl.

### Claim 10 (depends on 5)

The compound of claim 5, wherein n is 1 or 2.

### Claim 11 (depends on 10)

The compound of claim 10, wherein n is 1 and R2 is at the para-position.

### Claim 12 (depends on 5)

The compound of claim 5, wherein each R2 is independently fluorine, chlorine, bromine, iodine, or unsubstituted or substituted methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl.

### Claim 13 (depends on 5)

The compound of claim 5, wherein o is 0, 1 or 2.

### Claim 14 (depends on 13)

The compound of claim 13, wherein each R2′ is independently unsubstituted or substituted C3-C10 carbocycle, unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4heteroatoms selected from N, O and S, or NR4R4′.

### Claim 15 (depends on 5)

The compound of claim 5, wherein the compound is of Formula IIa, IIb or IIc:
or a pharmaceutically acceptable salt or ester thereof, wherein:
o is 0, 1, 2, 3, 4, 5 or 6;
x is 0, 1, 2, 3 or 4;
R7 is H, hydroxyl, halogen, cyano, nitro, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C6-C10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4heteroatoms selected from N, O and S, unsubstituted or substituted C3-C10 carbocycle, unsubstituted or substituted heterocycle comprising one or two 5-or 6-member rings and 1-4heteroatoms selected from N, O and S, OR71, NR71R72, C(O)R71, C(O)OR71, C(O)NR71R72, NR72C(O)R71, NR72C(O)OR71, NR73C(O)NR71R72, NR72S(O)2R71 or S(O)2R71;
R8 is H, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C6-C10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1- 4 heteroatoms selected from N, O and S, unsubstituted or substituted C3-C10 carbocycle, unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1- 4 heteroatoms selected from N, O and S, C(O)R81, C(O)OR81 or C(O)NR81R82;
R9 is H, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C6-C10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1- 4 heteroatoms selected from N, O and S, unsubstituted or substituted C3-C10 carbocycle, unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1- 4 heteroatoms selected from N, O and S, C(O)R91, C(O)OR91, C(O)NR91R92 or S(O)2R91;
R71, R81 and R91 are each independently H, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C6-C10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4heteroatoms selected from N, O and S, unsubstituted or substituted C3-C10 carbocycle or unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4heteroatoms selected from N, O and S; and
R72, R73, R82 and R92 are each independently H or unsubstituted or substituted C1-C6 alkyl.

### Claim 16 (depends on 1)

The compound of claim 1, selected from the group consisting of:

### Claim 17 (depends on 1)

The compound of claim 1, wherein the compound is:

### Claim 18 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, or a salt, thereof, and a pharmaceutically acceptable carrier or excipient.