# US 2013/0158041 A1 · Tyrosine Kinase Inhibitors

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- Number: US 2013/0158041 A1
- Document ID: US20130158041A1
- Status: Published application
- Kind: A1
- Application number: 13/818,312
- Filed: 2011-08-26
- Published: 2013-06-20
- Earliest claimed: 2010-08-31
- Inventors: Kevin Wilson; Matthew Daniels
- Web page: https://patentgrep.com/patent/US20130158041A1

## CPC

- C07D 403/14: containing three or more hetero rings
- A61P 35/00: Antineoplastic agents
- C07D 237/04: having less than three double bonds between ring members or between ring members and non-ring members
- C07D 237/18: Sulfur atoms
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/10: linked by a carbon chain containing aromatic rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to pyridazinthione derivatives that are useful for treating cellular proliferative diseases, for treating disorders associated with MET activity, and for inhibiting the receptor tyrosine kinase MET. The invention also relates to compositions which comprise these compounds, and methods of using them to treat cancer in mammals.

## Claims

### Claim 1

A compound of the formula:
wherein X is a bond, O, CR3′R4′, S or NR5;
R1 is heteroaryl or aryl, wherein said heteroaryl and aryl groups are optionally substituted with one to three groups independently selected from the group consisting of halo, cyano, C1-6 alkyl, (C1-6 alkyl)R7, heterocyclyl, OR10 and (C═O)N(R5)(R6);
R2 is heteroaryl or phenyl, wherein said heteroaryl group is optionally substituted with one to two groups independently selected from the group consisting of halo, cyano, N(R5)(R6), OR10, R9, heterocyclyl, (aryl)R9 and (heteroaryl)R9; and wherein said phenyl group is optionally substituted with one to two substituents independently selected from the group consisting of:
(1) halo,
(2) hydroxyl,
(3) cyano,
(4) heterocyclyl,
(5) heteroaryl, which is optionally substituted with N(R5)(R6), OR10, R9, heterocyclyl, (aryl)R9 or (heteroaryl)R9,
(6) NH(C═O)C1-5 alkyl, wherein said alkyl group is optionally substituted with one to three R8,
(7) NH(C═O)OC1-5 alkyl, wherein said alkyl group is optionally substituted with one to three R8, and
(8) NH(C═O)NHR11,
R3 is hydrogen, C1-6 alkyl or halo,
R4 is hydrogen, C1-6 alkyl or halo,
R3′ is hydrogen, C1-6 alkyl or halo,
R4′ is hydrogen, C1-6 alkyl or halo,
wherein R3 and R3′ can be taken together with the carbon atoms to which they are attached to form a C3-6 cycloalkyl ring,
R5 is hydrogen or C1-6 alkyl;
R6 is hydrogen or C1-6 alkyl;
R7 is hydrogen, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, heterocyclyl, OR10, (C═O)N(R5)(R6) or N(R5)(R6);
R8 is hydrogen, halo, hydroxyl, C1-6 alkyl, OR10, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 cycloalkyl(R5), N(R5)(R6), N(R5)-phenyl, (C═O)N(R5)(R6), phenyl, heteroaryl or heterocyclyl, wherein said heterocyclyl group is optionally substituted with one to three groups independently selected from the group consisting of halo, hydroxyl, C1-6 alkyl, (C1-6 alkyl)OR5, C1-6 haloalkyl, SO2 and (C═O)OH;
R9 is hydrogen, heterocyclyl, (C═O)N(R5)(R6), N(R5)(R6), C3-8 cycloalkyl or C1-6 alkyl, wherein said alkyl is optionally substituted with one to four groups independently selected from the group consisting of halo, hydroxyl, O(C1-6 alkyl), heterocyclyl, aryl and heteroaryl;
R10 is hydrogen, heterocyclyl, C3-8 cycloalkyl or C1-6 alkyl, wherein said alkyl is optionally substituted with one to four groups independently selected from the group consisting of halo, hydroxyl, O(C1-6 alkyl), heterocyclyl, aryl and heteroaryl;
R11 is hydrogen, C1-6 alkyl or C3-8 cycloalkyl, wherein said alkyl is optionally substituted with one to three R8;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1 wherein R1 is heteroaryl, wherein said heteroaryl group is optionally substituted with one to three groups independently selected from the group consisting of halo, cyano, C1-6 alkyl, (C1-6 alkyl)R7, heterocyclyl, OR10 and (C═O)N(R5)(R6); or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 2)

The compound of claim 2 wherein R1 is heteroaryl, wherein said heteroaryl group is optionally substituted with C1-6 alkyl, or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 2)

The compound of claim 2 wherein R3 is hydrogen, and R4 is hydrogen, or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1)

The compound of claim 1 wherein R2 is phenyl, wherein said phenyl group is optionally substituted with one to two substituents independently selected from the group consisting of:
(1) halo,
(2) hydroxyl,
(3) cyano,
(4) heterocyclyl,
(5) heteroaryl, which is optionally substituted with N(R5)(R6), OR10, R9, heterocyclyl, (aryl)R9 or (heteroaryl)R9,
(6) NH(C═O)C1-5 alkyl, wherein said alkyl group is optionally substituted with one to three R8,
(7) NH(C═O)OC1-5 alkyl, wherein said alkyl group is optionally substituted with one to three R8,
(8) NH(C═O)NHR11,
or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 5)

The compound of claim 5 wherein R2 is phenyl, wherein said phenyl group is substituted with heteroaryl, which is optionally substituted with OR10 or R9, or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1)

The compound of claim 1 wherein X is O.

### Claim 8 (depends on 1)

The compound of claim 1 selected from:
3-[3-(5-Ethoxypyrimidin-2-yl)benzyl]-1-(1-methyl-1H-pyrazol-4-yl)pyridazin-4(1H)-one;
3-[3-(5-methoxypyrimidin-2-yl)benzyl]-1-(1-methyl-1H-pyrazol-4-yl)pyridazin-4(1H)-thione;
3-{3-[5-(2-methoxyethoxy)pyrimidin-2-yl]benzyl}-1-(1-methyl-1H-pyrazol-4-yl)pyridazin-4(1H)-thione;
3-[3-[3-(5-ethoxypyrimidin-2-yl)benzyl]-4-thioxopyridazin-1(4H)-yl]benzonitrile;
1-(1-ethyl-1H-pyrazol-4-yl)-3-[3-(1-propyl-1H-1,2,4-triazol-3-yl)benzyl]pyridazin-4(1H)-thione;
3-(3-aminobenzyl)-1-(3,4-difluorophenyl)pyridazine-4(1H)-thione;
N-(3-{[1-(3,4-difluorophenyl)-4-thioxo-1,4-dihydropyridazin-3-yl]methyl}phenyl)-2,2,2-trifluoroacetamide;
N-(3-{[1-(3,4-difluorophenyl)-4-thioxo-1,4-dihydropyridazin-3-yl]methyl}phenyl)-2,2,2-trifluoroacetamide;
2-methoxyethyl (3-{[1-(1-methyl-1H-pyrazol-4-yl)-4-thioxo-1,4-dihydropyridazin-3-yl]methyl}phenyl)carbamate;
ethyl (3-{[1-(3-cyanophenyl)-4-thioxo-1,4-dihydropyridazin-3-yl]methyl}phenyl)carbamate;
isobutyl (3-{[1-(3-cyanophenyl)-4-thioxo-1,4-dihydropyridazin-3-yl]methyl}phenyl)carbamate;
methyl (3-{[4-thioxo-1-(3,4,5-trifluorophenyl)-1,4-dihydropyridazin-3-yl]methyl}phenyl)carbamate;
propyl (3-{[4-thioxo-1-(3,4,5-trifluorophenyl)-1,4-dihydropyridazin-3-yl]methyl}phenyl)carbamate;
benzyl (3-{[4-thioxo-1-(3,4,5-trifluorophenyl)-1,4-dihydropyridazin-3-yl]methyl}phenyl)carbamate;
N-(3-{[4-thioxo-1-(3,4,5-trifluorophenyl)-1,4-dihydropyridazin-3-yl]methyl}phenyl)acetamide;
3-phenyl-N-(3-{[4-thioxo-1-(3,4,5-trifluorophenyl)-1,4-dihydropyridazin-3-yl]methyl}phenyl)propanamide;
1-(3-Bromophenyl)-3-[(quinolin-6-yloxy)methyl]pyridazin-4(1H)-thione;
1-(1-Methyl-1H-pyrazol-4-yl)-3-[(quinolin-6-yloxy)methyl]pyridazin-4(1H)-thione;
1-(1-methyl-1H-pyrazol-4-yl)-3-[(quinoxalin-6-yloxy)methyl]pyridazine-4(1H)-thione;
3-{[(3-Ethoxyquinolin-6-yl)oxy]methyl}-1-(1-methyl-1H-pyrazol-4-yl)pyridazin-4(1H)-thione;
1-(3,5-difluorophenyl)-3-{[(3-ethoxyquinolin-6-yl)oxy]methyl}pyridazin-4(1H)-thione;
1-(1-methyl-1H-pyrazol-4-yl)-3-({[3-(1-methyl-1H-pyrazol-4-yl)quinolin-6-yl]oxy}methyl)pyridazine-4(1H)-thione;
1-(1-Methyl-1H-pyrazol-4-yl)-3-[2-(quinolin-6-yl)ethyl]pyridazin-4(1H)-thione;
or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 1)

A pharmaceutical composition that is comprised of a compound in accordance with claim 1 and a pharmaceutically acceptable carrier.

### Claim 10 (depends on 1)

A method of treating or preventing cancer in a mammal in need of such treatment that is comprised of administering to said mammal a therapeutically effective amount of a compound of claim 1.

### Claim 11

A compound which is:
1-(1-methyl-1H-pyrazol-4-yl)-3-({[3-(1-methyl-1H-pyrazol-4-yl)quinolin-6-yl]oxy}methyl)pyridazine-4(1H)-thione
or a pharmaceutically acceptable salt thereof.

### Claim 12

A compound which is:
3-{3-[5-(2-methoxyethoxy)pyrimidin-2-yl]benzyl}-1-(1-methyl-1H-pyrazol-4-yl)pyridazin-4(1H)-thione
or a pharmaceutically acceptable salt thereof.

### Claim 13

A compound which is:
2-methoxyethyl (3-{[1-(1-methyl-1H-pyrazol-4-yl)-4-thioxo-1,4-dihydropyridazin-3-yl]methyl}phenyl)carbamate
or a pharmaceutically acceptable salt thereof.

### Claim 14

A compound which is:
3-[3-(5-Ethoxypyrimidin-2-yl)benzyl]-1-(1-methyl-1H-pyrazol-4-yl)pyridazin-4(1H)-thione
or a pharmaceutically acceptable salt thereof.

### Claim 15

A compound which is:
3-[3-(5-methoxypyrimidin-2-yl)benzyl]-1-(1-methyl-1H-pyrazol-4-yl)pyridazin-4(1H)-thione
or a pharmaceutically acceptable salt thereof.