# US 9,040,530 B2 · 1,2,4-triazine-6-carboxamide kinase inhibitors

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- Number: US 9,040,530 B2
- Document ID: US9040530B2
- Status: Granted
- Kind: B2
- Application number: 13/841,472
- Filed: 2013-03-15
- Published: 2013-12-26
- Granted: 2015-05-26
- Earliest claimed: 2012-06-22
- Assignees: Portola Pharmaceuticals, Inc.
- Applicants: Portola Pharmaceuticals, Inc.
- Inventors: Zhaozhong J. Jia; Brian Kane; Jack Rose; Shawn M. Bauer; Yonghong Song; Qing Xu; Anjali Pandey
- Web page: https://patentgrep.com/patent/US9040530B2

## CPC

- C07D 253/075: Two hetero atoms, in positions 3 and 5
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 7/06: Antianaemics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/06: Antiasthmatics
- A61P 13/12: of the kidneys
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/02: specific for leukemia
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 403/14: containing three or more hetero rings
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 405/14: containing three or more hetero rings
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 413/14: containing three or more hetero rings
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 471/04: Ortho-condensed systems
- C07D 495/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Provided are triazine compounds for inhibiting of Syk kinase, intermediates used in making such compounds, methods for their preparation, pharmaceutical compositions thereof, methods for inhibiting Syk kinase activity, and methods for treating conditions mediated at least in part by Syk kinase activity.

## Claims

### Claim 1

A compound of Formula (I):
or a tautomer or a pharmaceutically acceptable salt thereof, wherein
T is X1 where X1 is monocyclic heteroaryl comprising 1-4 heteroatoms selected from S, O and N, wherein heteroaryl are optionally substituted with 1 to 5 R1;
each R1 is independently selected from the group consisting of halo, C1-8alkyl, C2-8alkenyl, haloC1-8alkyl, (CH2)nSR1a, (CH2)nOR1a, O(CH2)jOR1a, (CH2)nNR1bR1c, (CH2)nCOR1e, (CH2)nCONR1bR1c, (CH2)nNR1bCOR1e, (CH2)nCONR1b(OR1a), (CH2)nCO2R1a, O(CH2)nCO2R1a, (CH2)nNR1bCO2R1a, (CH2)nSO2NR1bR1c, (CH2)nNR1bSO2R1e, (CH2)nSOR1e, (CH2)nSO2R1e, oxo, (CH2)nCN, N3, NO2, and -L-W, where n is 0, 1, 2, 3, 4, 5, or 6 and j is 1, 2, 3, 4, 5, or 6;
L is selected from the group consisting of
—O(CH2)b—, —SO—, —SO2—, —CO—, —NR1d—, —CONR1d(CH2)b—, —NR1dCO—, —NR1dSO2—, —SO2NR1d—, a bond, and —(CH2)z— where b is 0, 1, 2, 3, 4, or 5 and z is 1, 2, 3, 4, or 5;
W is selected from the group consisting of aryl, monocyclic or bicyclic heteroaryl comprising 1-4 heteroatoms selected from S, O and N, C3-8cycloalkyl, and 3-8 membered heterocyclyl comprising 1-4 heteroatoms selected from S, O and N, each optionally substituted with 1 to 3 R2;
each R2 is independently selected from the group consisting of halo, C1-8alkyl, C2-8alkenyl, haloC1-8alkyl, (CH2)mSR2a, (CH2)mOR2a, O(CH2)kOR2a, (CH2)mNR2bR2c, (CH2)mCOR2e, (CH2)mCONR2bR2c, (CH2)mNR2bCOR2e, (CH2)mCONR2b(OR2a), (CH2)mCO2R2a, O(CH2)mCO2R2a, (CH2)mNR2bCO2R2a, (CH2)mSO2NR2bR2c, (CH2)mNR2bSO2R2e, (CH2)mSOR2e, (CH2)mSO2R2e, oxo, (CH2)mCN, N3, and NO2, where m is 0, 1, 2, 3, 4, 5, or 6 and k is 1, 2, 3, 4, 5, or 6;
R1a, R1b, R1c, R1d, R2a, R2b, and R2c are independently selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, and haloC1-8alkyl;
R1e and R2e are independently selected from the group consisting of C1-8alkyl, C2-8alkenyl, and haloC1-8alkyl;
Y is (CH2)v(X2), wherein
v is 0, 1, 2, or 3;
X2 is selected from the group consisting of CH2CH3, (CH2)3NH2, C3-8cycloalkyl, 3-8 membered heterocyclyl comprising 1-4 heteroatoms selected from S, O and N, aryl, and monocyclic or bicyclic heteroaryl comprising 1-4 heteroatoms selected from S, 0 and N, wherein cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted with 1 to 3 R10;
R10 is independently selected from the group consisting of halo, C1-8alkyl, C2-8alkenyl, haloC1-8alkyl, (CH2)qSR10a, (CH2)qOR10a, (CH2)qNR10bR10c, (CH2)qCOR10d, (CH2)qCONR10bR10c, (CH2)qNR10bCOR10d, (CH2)qCONR10b(OR10a), (CH2)qCO2R10a, O(CH2)qCO2R10a, (CH2)qNR10bCO2R10a, (CH2)qSO2NR10bR10c, (CH2)qNR10bSO2R10d, (CH2)qSOR10d, (CH2)qSO2R10d, oxo, (CH2)qCN, N3, N═CH2, NO2, C(O)3-8 membered heterocyclyl comprising 1-4 heteroatoms selected from S, O and N, aryl, monocyclic or bicyclic heteroaryl comprising 1-4 heteroatoms selected from S, O and N, C3-8cycloalkyl, and 3-8 membered heterocyclyl comprising 1-4 heteroatoms selected from S, O and N, where aryl, cycloalkyl, heteroaryl, and heterocyclyl are each optionally substituted with 1 to 3 R11d and q is 0, 1, 2, 3, 4, 5, or 6;
R11d is selected from the group consisting of halo, C1-8alkyl, haloC1-8alkyl, OH, C1-8alkoxy, haloC1-8alkoxy, C(O)C1-8alkyl, CO2C1-8alkyl, and SO2C1-8alkyl;
R10a, R10b, and R10c are independently selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, and haloC1-8alkyl;
R10d is selected from the group consisting of C1-8alkyl, C2-8alkenyl, and haloC1-8alkyl.

### Claim 2 (depends on 1)

A compound of claim 1 or a tautomer or a pharmaceutically acceptable salt thereof, wherein at least one R1 is -L-W.

### Claim 3

A compound of Formula (Ib) or a tautomer or a pharmaceutically acceptable salt thereof
wherein
HET is monocyclic heteroaryl comprising 1-4 heteroatoms selected from S, O and N, optionally substituted with 1 to 3 R1; and
B1 is selected from the group consisting of CO—NRaRb, phenyl, monocyclic or bicyclic heteroaryl comprising 1-4 heteroatoms selected from S, O and N, and 3-8 membered heterocyclyl comprising 1-4 heteroatoms selected from S, O and N, wherein phenyl, heteroaryl, and heterocyclyl are each optionally substituted with 1 to 3 R2, and Ra and Rb together form a four to six membered heterocyclic ring optionally substituted with one to three groups independently selected from halo, C1-8alkyl, and haloC1-8alkyl; and wherein
each R1 is independently selected from the group consisting of halo, C1-8alkyl, C2-8alkenyl, haloC1-8alkyl, (CH2)nSR1a, (CH2)nOR1a, O(CH2)jOR1a, (CH2)nNR1bR1c, (CH2)nCOR1e, (CH2)nCONR1bR1c, (CH2)nNR1bCOR1e, (CH2)nCONR1b(OR1a), (CH2)nCO2R1a, O(CH2)nCO2R1a, (CH2)nNR1bCO2R1a, (CH2)nSO2NR1bR1c, (CH2)nNR1bSO2R1e, (CH2)nSOR1e, (CH2)nSO2R1e, oxo, (CH2)nCN, N3, NO2, and -L-W, where n is 0, 1, 2, 3, 4, 5, or 6 and j is 1, 2, 3, 4, 5, or 6;
L is selected from the group consisting of
—O(CH2)b—, —SO—, —SO2—, —CO—, —NR1d—, —CONR1d(CH2)b—, —NR1dCO—, —NR1dSO2—, —SO2NR1d—, a bond, and —(CH2)z— where b is 0, 1, 2, 3, 4, or 5 and z is 1, 2, 3, 4, or 5;
W is selected from the group consisting of aryl, monocyclic or bicyclic heteroaryl comprising 1-4 heteroatoms selected from S, O and N, C3-8cycloalkyl, and 3-8 membered heterocyclyl comprising 1-4 heteroatoms selected from S, O and N, each optionally substituted with 1 to 3 R2;
each R2 is independently selected from the group consisting of halo, C1-8alkyl, C2-8alkenyl, haloC1-8alkyl, (CH2)mSR2a, (CH2)mOR2a, O(CH2)kOR2a, (CH2)mNR2bR2c, (CH2)mCOR2e, (CH2)mCONR2bR2c, (CH2)mNR2bCOR2e, (CH2)mCONR2b(OR2a), (CH2)mCO2R2a, O(CH2)mCO2R2a, (CH2)mNR2bCO2R2a, (CH2)mSO2NR2bR2c, (CH2)mNR2bSO2R2e, (CH2)mSOR2e, (CH2)mSO2R2e, oxo, (CH2)mCN, N3, and NO2, where m is 0, 1, 2, 3, 4, 5, or 6 and k is 1, 2, 3, 4, 5, or 6;
R1a, R1b, R1c, R1d, R2a, R2b, and R2c are independently selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, and haloC1-8alkyl;
R1e and R2e are independently selected from the group consisting of C1-8alkyl, C2-8alkenyl, and haloC1-8alkyl;
Y is (CH2)v(X2), wherein
v is 0, 1, 2, or 3;
X2 is selected from the group consisting of CH2CH3, (CH2)3NH2, C3-8cycloalkyl, 3-8 membered heterocyclyl comprising 1-4 heteroatoms selected from S, O and N, aryl, and monocyclic or bicyclic heteroaryl comprising 1-4 heteroatoms selected from S, 0 and N, wherein cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted with 1 to 3 R10;
R10 is independently selected from the group consisting of halo, C1-8alkyl, C2-8alkenyl, haloC1-8alkyl, (CH2)qSR10a, (CH2)qOR10a, (CH2)qNR10bR10c, (CH2)qCOR10d, (CH2)qCONR10bR10c, (CH2)qNR10bCOR10d, (CH2)qCONR10b(OR10a), (CH2)qCO2R10a, O(CH2)qCO2R10a, (CH2)qNR10bCO2R10a, (CH2)qSO2NR10bR10c, (CH2)qNR10bSO2R10d, (CH2)qSOR10d, (CH2)qSO2R10d, oxo, (CH2)qCN, N3, N═CH2, NO2, C(O)3-8 membered heterocyclyl comprising 1-4 heteroatoms selected from S, O and N, aryl, monocyclic or bicyclic heteroaryl comprising 1-4 heteroatoms selected from S, O and N, C3-8cycloalkyl, and 3-8 membered heterocyclyl comprising 1-4 heteroatoms selected from S, O and N, where aryl, cycloalkyl, heteroaryl, and heterocyclyl are each optionally substituted with 1 to 3 R11d and q is 0, 1, 2, 3, 4, 5, or 6;
R11d is selected from the group consisting of halo, C1-8alkyl, haloC1-8alkyl, OH, C1-8alkoxy, haloC1-8alkoxy, C(O)C1-8alkyl, CO2C1-8alkyl, and SO2C1-8alkyl;
R10a, R10b, and R10c are independently selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, and haloC1-8alkyl; and
R10d is selected from the group consisting of C1-8alkyl, C2-8alkenyl, and haloC1-8alkyl.

### Claim 4 (depends on 1, 3)

A compound of claim 1 or 3 or a tautomer or a pharmaceutically acceptable salt thereof, wherein W or B1 is substituted with 1 to 3 R2.

### Claim 5 (depends on 3)

A compound of claim 3 or a tautomer or a pharmaceutically acceptable salt thereof wherein R1 and R2 are independently selected from the group consisting of halo, C1-8alkyl, haloC1-8alkyl, cyano, oxo, OH, O(C1-8alkyl), and O(haloC1-8alkyl).

### Claim 6 (depends on 1, 3)

A compound of claim 1 or 3 or a tautomer or a pharmaceutically acceptable salt thereof, wherein X1 or HET is selected from the group consisting of
where the wavy line indicates the point of attachment to the rest of the molecule.

### Claim 7 (depends on 1, 3)

A compound of claim 1 or 3 or a tautomer or a pharmaceutically acceptable salt thereof, wherein X1 or HET is selected from the group consisting of
where the wavy line indicates the point of attachment to the rest of the molecule.

### Claim 8 (depends on 1, 3)

A compound of claim 1 or 3 one a tautomer or a pharmaceutically acceptable salt thereof, wherein W or B1 is selected from the group consisting of
where the wavy line indicates the point of attachment to the rest of the molecule.

### Claim 9

A compound or a tautomer or a pharmaceutically acceptable salt thereof having a structure selected from
3-(((1R,2S)-2-aminocyclohexyl)amino)-5-((5-fluoropyridin-3-yl)amino)-1,2,4-triazine-6-carboxamide,
3-(((1R,2S)-2-aminocyclohexyl)amino)-5-((6-(dimethylcarbamoyl)pyridin-3-yl)amino)-1,2,4-triazine-6-carboxamide,
3-(((1R,2S)-2-aminocyclohexyl)amino)-5-((6-(azetidine-1-carbonyl)pyridin-3-yl)amino)-1,2,4-triazine-6-carboxamide,
3-(((1R,2S)-2-aminocyclohexyl)amino)-5-((6-fluoropyridin-3-yl)amino)-1,2,4-triazine-6-carboxamide,
3-(((1R,2S)-2-aminocyclohexyl)amino)-5-((2-methoxypyridin-4-yl)amino)-1,2,4-triazine-6-carboxamide,
3-(((1R,2S)-2-aminocyclohexyl)amino)-5-((1-methyl-1H-pyrazol-4-yl)amino)-1,2,4-triazine-6-carboxamide,
3-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-5-((1-methyl-1H-pyrazol-4-yl)amino)-1,2,4-triazine-6-carboxamide,
3-(((1R,2S)-2-aminocyclohexyl)amino)-5-(pyridin-3-ylamino)-1,2,4-triazine-6-carboxamide,
3-(((1R,2S)-2-aminocyclohexyl)amino)-5-((3-methylisothiazol-5-yl)amino)-1,2,4-triazine-6-carboxamide,
3-(((1R,2S)-2-aminocyclohexyl)amino)-5-((5-(4-fluorophenyl)isoxazol-3-yl)amino)-1,2,4-triazine-6-carboxamide,
3-(((1R,2S)-2-aminocyclohexyl)amino)-5-(thiazol-5-ylamino)-1,2,4-triazine-6-carboxamide,
3-(((1R,2S)-2-aminocyclohexyl)amino)-5-((3-phenyl-1,2,4-oxadiazol-5-yl)amino)-1,2,4-triazine-6-carboxamide,
3-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-5-((3-methylisothiazol-5-yl)amino)-1,2,4-triazine-6-carboxamide,
3-(((1R,2S)-2-aminocyclohexyl)amino)-5-(thiazol-5-ylamino)-1,2,4-triazine-6-carboxamide.

### Claim 10 (depends on 1)

A composition comprising a compound of claim 1 or a tautomer or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier or diluent.

### Claim 11 (depends on 1)

A method for inhibiting syk or JAK kinase or a signal transduction pathway mediated at least in part by syk kinase activity comprising contacting a cell with a compound of claim 1.

### Claim 12

The compound 3-(((1R,2S)-2-aminocyclohexyl)amino)-5-((3-methylisothiazol-5-yl)amino)-1,2,4-triazine-6-carboxamide or a pharmaceutically acceptable salt thereof.