# US 8,569,331 B2 · Substituted benzo[f]lmidazo[1,2-d]pyrido[2,3-b][1,4]diazepine compounds

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- Number: US 8,569,331 B2
- Document ID: US8569331B2
- Status: Granted
- Kind: B2
- Application number: 13/286,294
- Filed: 2011-11-01
- Published: 2012-05-03
- Granted: 2013-10-29
- Earliest claimed: 2010-11-01
- Assignees: ArQule, Inc.
- Applicants: Mark A. Ashwell; Sudharshan Eathiraj; Anton Filikov; Steffi Koerner; Jean-Marc Lapierre; Yanbin Liu; Rocio Palma; David Vensel; Shin Iimura; Akiko Shiina; Kenichi Yoshida; Takanori Yamazaki; Akihisa Matsuda
- Inventors: Mark A. Ashwell; Sudharshan Eathiraj; Anton Filikov; Steffi Koerner; Jean-Marc Lapierre; Yanbin Liu; Rocio Palma; David Vensel; Shin Iimura; Akiko Shiina; Kenichi Yoshida; Takanori Yamazaki; Akihisa Matsuda
- Web page: https://patentgrep.com/patent/US8569331B2

## CPC

- C07D 471/14: Ortho-condensed systems
- A61K 31/551: having two nitrogen atoms, e.g. dilazep
- A61P 35/00: Antineoplastic agents
- 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 benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepine compounds and methods of synthesizing these compounds. The present invention also relates to pharmaceutical compositions containing substituted benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepine compounds and methods of treating cell proliferative disorders, such as cancer, by administering these compounds and pharmaceutical compositions to subjects in need thereof.

## Claims

### Claim 1

A compound of formula (I):
or a pharmaceutically acceptable salt or ester thereof, wherein:
Rz is H or C1-C6 alkyl;
R1 is H, halogen, cyano, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, or Q1-T1, wherein said substituted C1-C6 alkyl, substituted C2-C6 alkenyl, or substituted C2-C6 alkynyl is substituted with one or more groups independently selected from hydroxy, halogen, cyano, amino, and phenyl;
R2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Q2-T2;
Q1 and Q2 are each independently a bond or C1-C6 alkyl linker;
T1 is unsubstituted or substituted C6-C10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-membered 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-membered rings and 1-4 heteroatoms selected from N, O and S, ORt, SRt, C(O)NRt′Rt, C(O)Rt, C(O)ORt, NRt′C(O)NRt″Rt, NRt′C(O)ORt, NRt′C(O)Rt, S(O)2Rt, or NRt′S(O)2Rt, wherein said substituted C6-C10 aryl, substituted heteroaryl, substituted C3-C10 carbocycle, or substituted heterocycle is substituted with one or more Rp, wherein each Rp is independently selected from:
a) hydroxy, halogen, cyano, nitro,
b) C1-C6 alkyl,
c) C1-C6 alkoxy,
d) amino, C1-C6 alkylamino, di-C1-C6 alkylamino,
e) C6-C10 aryl,
f) heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S,
g) C3-C10 carbocycle,
h) heterocycle comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S,
i) OR5, NRs,R5, SR5, C(O)R5, C(O)OR5, C(O)NRsR5, NRs′C(O)R5, NRs′C(O)OR5, NRs′C(O)NRsR5, S(O)2R5, and NRs′S(O)2R5,
wherein R5 is H, C1-C6 alkyl, C6-C10 aryl-C1-C6 alkyl, C6-C10 aryl, heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, C3-C10 carbocycle, or heterocycle comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S; and
Rs and Rs′ are each independently H or C1-C6 alkyl;
T2 is unsubstituted or substituted C6-C10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-membered 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-membered rings and 1-4 heteroatoms selected from N, O and S, wherein said substituted C6-C10 aryl, substituted heteroaryl, substituted C3-C10 carbocycle, or substituted heterocycle is substituted with one or more groups independently selected from:
a) hydroxy, halogen, cyano, nitro,
b) C1-C6 alkyl,
c) C1-C6 alkoxy,
d) amino, C1-C6 alkylamino, di-C1-C6 alkylamino,
e) C6-C10 aryl,
f) heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S,
g) C3-C10 carbocycle, and
h) heterocycle comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S;
Rt is H, C1-C6 alkyl, C6-C10 aryl, heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, C3-C10 carbocycle, or heterocycle comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S;
Rt′ and Rt″ are each independently H or C1-C6 alkyl;
m is 0, 1, 2, or 3;
n is 0, 1, 2, 3, or 4;
each R3 is independently halogen, cyano, nitro, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, amino, C1-C6 alkylamino, or di-C1-C6 alkylamino; and
each R4 is independently halogen, cyano, nitro, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, amino, C1-C6 alkylamino, or di-C1-C6 alkylamino.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R1 is Q1-T1.

### Claim 3 (depends on 2)

The compound of claim 2, wherein Q1 is a bond, a methyl linker, or an ethyl linker.

### Claim 4 (depends on 3)

The compound of claim 3, wherein T1 is heterocycle comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S.

### Claim 5 (depends on 3)

The compound of claim 3, wherein T1 is ORt, SRt, C(O)Rt, C(O)ORt, or C(O)NRt′Rt.

### Claim 6 (depends on 3)

The compound of claim 3, wherein T1 is C3-C10 cycloalkyl or C3-C10 cycloalkenyl.

### Claim 7 (depends on 3)

The compound of claim 3, wherein T1 is phenyl or naphthyl.

### Claim 8 (depends on 7)

The compound of claim 7, wherein T1 is phenyl.

### Claim 9 (depends on 3)

The compound of claim 3, wherein T1 is heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S.

### Claim 10 (depends on 9)

The compound of claim 9, wherein said heteroaryl is selected from the group consisting of pyrrolyl, furanyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzoimidazolyl, benzothienyl, quinolinyl, isoquinolinyl, indolyl, purinyl, pyrrolopyridinyl, imidazopyridinyl, and benzofuranonyl.

### Claim 11 (depends on 1)

The compound of claim 1, wherein Rz is H; m is 0; and n is 0.

### Claim 12 (depends on 1)

The compound of claim 1, wherein each R3 is independently halogen or C1-C6 alkyl.

### Claim 13 (depends on 1)

The compound of claim 1, wherein each R4 is independently halogen or C1-C6 alkyl.

### Claim 14 (depends on 1)

The compound of claim 1, wherein R2 is Q2-T2; Q2 is a bond; and T2 is phenyl.

### Claim 15 (depends on 1)

The compound of claim 1, wherein R1 is halogen or cyano.

### Claim 16 (depends on 1)

The compound of claim 1, wherein R1 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

### Claim 17 (depends on 1)

The compound of claim 1, having formula (Ib):
or a pharmaceutically acceptable salt or ester thereof, wherein:
Rz, Rz′ and Rz″ are each independently H or C1-C6 alkyl;
Rs and Rs′ are each independently H or C1-C6 alkyl;
comprises one or two 5- or 6-membered rings and optionally 1-4 heteroatoms selected from N, O and S;
x and y are each independently 0, 1, 2, 3, or 4;
each Rp is independently hydroxy, halogen, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-C1-C6 alkylamino, C6-C10 aryl, heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, C3-C10 carbocycle, heterocycle comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, OR5, NRsR5, SR5, C(O)R5, C(O)OR5, C(O)NRsR5, NRs′C(O)R5, NRs′C(O)O R5, NRs′C(O)NRsR5, S(O)2R5, or NRs′S(O)2R5;
R5 is H, C1-C6 alkyl, C6-C10 aryl-C1-C6 alkyl, C6-C10 aryl, heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, C3-C10 carbocycle, or heterocycle comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S; and
each Rq is independently hydroxy, halogen, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-C1-C6 alkylamino C6-C10 aryl, heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, C3-C10 carbocycle, or heterocycle comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S.

### Claim 18 (depends on 1)

The compound of claim 1, selected from the group consisting of:
or a pharmaceutically acceptable salt or ester thereof.

### Claim 19 (depends on 1)

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