# US 7,612,063 B2 · Substituted quinobenzoxazine analogs

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 7,612,063 B2
- Document ID: US7612063B2
- Status: Granted
- Kind: B2
- Application number: 12/013,961
- Filed: 2008-01-14
- Published: 2008-10-23
- Granted: 2009-11-03
- Earliest claimed: 2003-04-07
- Assignees: Cylene Pharmaceuticals, Inc.
- Inventors: Jeffrey P. Whitten; Michael Schwaebe; Adam Siddiqui-Jain; Terence Moran
- Web page: https://patentgrep.com/patent/US7612063B2

## CPC

- C07D 471/06: Peri-condensed systems
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- A61P 31/10: Antimycotics
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 513/04: 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 quinobenzoxazines analogs having the general formula: and pharmaceutically acceptable salts, esters and prodrugs thereof; wherein A, U, V, W, X and Z are substituents. The present invention also relates to methods for using such compounds.

## Claims

### Claim 1

A method for treating or ameliorating a cell proliferative disorder, comprising administering to a subject in need thereof an effective amount of a compound of formula 1
or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, wherein:
V is H, halo, NR1R2, NH2, or NR1—(CR12)n—NR3R4;
A is H, fluoro, or NR12;
Z is O;
U is selected from the group consisting of NR1—(CR12)n—NR3R4 and NR1R;
X is OR2, NR1R2, halo, azido, or SR2;
n is 1-6;
R is an optionally substituted 5-14 membered heterocyclic ring containing one or more N, O or S; or R is a C1-10 alkyl or C2-10 alkenyl optionally containing one or more non-adjacent heteroatoms selected from N, O, and S, and optionally substituted with an optionally substituted carbocyclic or heterocyclic ring;
R1 and R3 are independently H or an optionally substituted C1-6 alkyl, said alkyl optionally containing one or more non-adjacent heteroatoms selected from N, O, and S;
R2 and R4 are independently H or a C1-10 alkyl or C2-10 alkenyl optionally containing one or more non-adjacent heteroatoms selected from N, O, and S, and optionally substituted with an optionally substituted carbocyclic or heterocyclic ring; and wherein said C1-10 alkyl may be optionally substituted by one or more OH, C1-6 alkoxy, amino, amido, halo, ═O, aryl or heterocyclic groups;
or R2 is an optionally substituted heterocyclic ring, aryl or heteroaryl;
wherein R1 and R2 together with N in NR1R2, and/or R3 and R4 together with N in NR3R4, and/or R1 and R together with N in NR1R may independently form an optionally substituted 5-6 membered ring containing N, and optionally O or S;
W is selected from the group consisting of
wherein Q, Q1, Q2, and Q3 are independently CH or N;
Y is independently O, CH, ═O or NR1;
and R5 is a substituent at any position on the fused ring; and is H, OR2, C1-6 alkyl, or C2-6 alkenyl, each optionally substituted by halo, ═O or one or more heteroatoms; or R5 is an inorganic substituent; or two adjacent R5 are linked to obtain a 5-6 membered optionally substituted carbocyclic or heterocyclic ring, optionally fused to an additional optionally substituted carbocyclic or heterocyclic ring;
provided that U is not morpholinyl or 2,4-difluoroaniline when X is F or pyrrolidinyl; A is F; and W is phenylene;
wherein said cell proliferative disorder is a cancer selected from colorectal cancer, breast cancer, lung cancer, liver cancer, pancreatic cancer, prostate cancer, brain cancer, skin cancer, renal cancer, ovarian cancer, cervical cancer, leukemia, and lymphoma;
thereby treating or ameliorating said cell-proliferative disorder.

### Claim 2 (depends on 1)

The method of claim 1, wherein said subject is human or an animal.

### Claim 3 (depends on 1)

The method of claim 1, wherein V is H.

### Claim 4 (depends on 1)

The method of claim 1, wherein A is fluoro.

### Claim 5 (depends on 1)

The method of claim 1, wherein W is naphthalenyl.

### Claim 6 (depends on 1)

The method of claim 1, wherein U is NR1R and X is NR1R2.

### Claim 7 (depends on 6)

The method of claim 6, wherein R1 is H and R is a C1-10 alkyl optionally containing one or more non-adjacent heteroatoms selected from N, O and S, and optionally substituted with a C3-6 cycloalkyl, aryl or a 5-14 membered heterocyclic ring containing one or more N, O or S, each of which is optionally substituted.

### Claim 8 (depends on 7)

The method of claim 7, wherein said 5-14 membered heterocyclic ring is selected from the group consisting of tetrahydrofuran, 1,3-dioxolane, 2,3-dihydrofuran, tetrahydropyran, benzofuran, isobenzofuran, 1,3-dihydro-isobenzofuran, isoxazole, 4,5-dihydroisoxazole, piperidine, pyrrolidine, pyrrolidin-2-one, pyrrole, pyridine, pyrimidine, octahydro-pyrrolo[3,4-b]pyridine, piperazine, pyrazine, morpholine, thiomorpholine, imidazole, imidazolidine-2,4-dione, benzimidazole, 1,3-dihydrobenzimidazol-2-one, indole, thiazole, benzothiazole, thiadiazole, thiophene, tetrahydro-thiophene 1,1-dioxide, diazepine, triazole, guanidine, diazabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.1]heptane, and 2,3,4,4a,9,9a-hexahydro-1H-β-carboline.

### Claim 9 (depends on 6)

The method of claim 6, wherein R1 and R2 together with N in NR1R2 form an optionally substituted 5-14 membered ring containing one or more N, O or S.

### Claim 10 (depends on 9)

The method of claim 9, where NR1R2 is morpholine, thiomorpholine, imidazole, pyrrolidine, piperazine, pyridine, piperidine or diazepine, each of which is optionally substituted.

### Claim 11 (depends on 1)

The method of claim 1, wherein U is NR1R, where R is a C1-10 alkyl or C2-10 alkenyl optionally containing one or more non-adjacent heteroatoms selected from N, O, and S, and optionally substituted with an optionally substituted carbocyclic or heterocyclic ring.

### Claim 12 (depends on 1)

The method of claim 1, wherein X is NR1R2, wherein R1 and R2 together with N in NR1R form an optionally substituted 5-6 membered ring containing one or more N, and optionally O or S.

### Claim 13 (depends on 12)

The method of claim 12, wherein said optionally substituted 5-6 membered ring is selected from the group consisting of morpholine, thiomorpholine, imidazole, pyrrolidine, piperazine, pyridine and piperidine.

### Claim 14 (depends on 1)

The method of claim 1, wherein W is optionally substituted naphthalenyl.

### Claim 15 (depends on 1)

The method of claim 1, wherein X is NR1R2; and U has the formula
NR1—(CR12)n—NR3R4 (2)
wherein R1 and R2 are as defined in claim 1;
R3 is H or C1-6 alkyl;
n is 1-6; and
R4 is H or a C1-10 alkyl or C2-10 alkenyl optionally containing one or more non-adjacent heteroatoms selected from N, O and S, and optionally substituted with an optionally substituted carbocyclic or heterocyclic ring; and
wherein R1 and R2 together with N in NR1R2; and R3 and R4 together with N in NR3R4 each independently may form an optionally substituted 5-14 membered ring containing N, and optionally O or S.

### Claim 16 (depends on 1)

The method of claim 1, wherein W is benzene, pyridine, biphenyl, naphthalene, phenanthrene, quinoline, isoquinoline, quinazoline, cinnoline, phthalazine, quinoxaline, indole, benzimidazole, benzoxazole, benzthiazole, benzofuran, anthrone, xanthone, acridone, fluorenone, carbazolyl, pyrimido[4,3-b]furan, pyrido[4,3-b]indole, pyrido[2,3-b]indole, dibenzofuran, acridine or acridizine, each of which may be optionally substituted.

### Claim 17 (depends on 1)

The method of claim 1, wherein each optionally substituted moiety is substituted with one or more halo, OR2, NR1R2, carbamate, C1-10 alkyl, C2-10 alkenyl, each optionally substituted by halo, ═O, aryl or one or more heteroatoms; inorganic substituents, aryl, carbocyclic or a heterocyclic ring.

### Claim 18 (depends on 1)

The method of claim 1, wherein V is NH2 or NR1—(CR12)n—NR3R4;
wherein R1 and R3 are independently H or C1-6 alkyl;
n is 1-6; and
R4 is H, C1-6 alkyl optionally substituted with a carbocyclic or heterocyclic ring, or aryl; and
wherein R3 and R4 in NR3R4 may form an optionally substituted ring.

### Claim 19 (depends on 1)

The method of claim 1, wherein said compound is a compound having formula (1A)
or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and optionally with a chemotherapeutic agent.

### Claim 20 (depends on 1)

The method of claim 1, wherein said compound is a compound having formula
or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

### Claim 21 (depends on 1)

The method of claim 1, wherein said compound is a compound having formula
or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

### Claim 22 (depends on 1)

The method of claim 1, wherein said compound is a compound having formula
or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

### Claim 23 (depends on 1)

The method of claim 1, wherein said compound is a compound having formula
or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

### Claim 24 (depends on 1)

The method of claim 1, wherein said compound is a compound having formula (1A)
or a pharmaceutically acceptable salt or pharmaceutical composition thereof, which has a 50:50 ratio of RS and SS isomers.

### Claim 25 (depends on 1)

The method of claim 1, wherein said cancer is prostate cancer.

### Claim 26 (depends on 1)

The method of claim 1, wherein said cancer is colorectal cancer.

### Claim 27 (depends on 1)

The method of claim 1, wherein said cancer is pancreatic cancer.

### Claim 28 (depends on 1)

The method of claim 1, wherein said cancer is leukemia.