# US 10,245,265 B2 · Salts of 2-fluoro-N-methyl-4-[7-(quinolin-6-yl-methyl)-imidazo[1,2-B][1,2,4]triazin-2-yl]benzamide and processes related to preparing the same

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- Number: US 10,245,265 B2
- Document ID: US10245265B2
- Status: Granted
- Kind: B2
- Application number: 15/355,630
- Filed: 2016-11-18
- Published: 2017-09-14
- Granted: 2019-04-02
- Earliest claimed: 2008-05-21
- Assignees: Incyte Incorporation; Incyte Holdings Corporation
- Applicants: Incyte Corporation; Incyte Holdings Corporation
- Inventors: Lingkai Weng; Lei Qiao; Jiacheng Zhou; Pingli Liu; Yongchun Pan
- Web page: https://patentgrep.com/patent/US10245265B2

## CPC

- A61K 31/53: having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495})
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- 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 11/00: Drugs for disorders of the respiratory system
- A61P 13/12: of the kidneys
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 35/04: specific for metastasis
- A61P 37/02: Immunomodulators
- 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 253/07: with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D 401/10: linked by a carbon chain containing aromatic rings
- C07D 487/04: Ortho-condensed systems
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention is directed to dihydrochloric acid and dibenzenesulfonic acid salts of the c-Met kinase inhibitor 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)-imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide, and pharmaceutical compositions thereof, useful in the treatment of cancer and other diseases related to the dysregulation of kinase pathways. The present invention further relates to processes and intermediates for preparing 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide, and salts thereof.

## Claims

### Claim 1

A process of preparing a compound of Formula I:
or salt thereof;
comprising reacting a compound of Formula II:
with a compound of Formula III:
at a temperature from about 120° C. to about 150° C. to form a compound of Formula I, or salt thereof;
wherein X1 is chloro, bromo, or iodo.

### Claim 2 (depends on 1)

The process according to claim 1, further comprising reacting said compound of Formula I, or salt thereof, with a strong acid to form a compound of Formula IV:
or salt thereof.

### Claim 3 (depends on 2)

The process according to claim 2, wherein said acid is concentrated hydrochloric acid.

### Claim 4 (depends on 2)

The process according to claim 2, further comprising reacting the compound of Formula IV, or salt thereof, with CH3NH2 in the presence of a coupling agent to form a compound of Formula V:
or salt thereof.

### Claim 5 (depends on 4)

The process according to claim 4, wherein said coupling agent is selected from 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, N-hydroxybenzotriazole, (benzotriazol-1-yloxyl)tripyrrolidinophosphonium hexaflurophosphate, and salts thereof.

### Claim 6 (depends on 2)

The process according to claim 2, further comprising:
a) reacting the compound of Formula IV:
or salt thereof, with a halogenating agent, to form a compound of Formula VI:
or salt thereof; and
b) reacting said compound of Formula VI, or salt thereof, with CH3NH2 to form a compound of Formula V:
or salt thereof, wherein X2 is halogen.

### Claim 7 (depends on 6)

The process of claim 6, wherein said halogenating agent is thionyl chloride.

### Claim 8 (depends on 1)

The process of claim 1, further comprising preparing the compound of Formula II:
by a process comprising reacting a compound of Formula IIa:
with a compound of Formula IIb:
in the presence of a base,
wherein X1 is chloro, bromo, or iodo.

### Claim 9 (depends on 8)

The process of claim 8, wherein the reacting of the compound of Formula IIa with the compound of Formula IIb is carried out in the presence of proline.

### Claim 10 (depends on 8)

The process of claim 8, wherein X1 is chloro.

### Claim 11 (depends on 8)

The process of claim 8, further comprising preparing the compound of Formula IIa:
by a process comprising reacting a compound of Formula IIc:
with prop-2-en-1-ol in the presence of a palladium catalyst and a base;
wherein X3 is chloro, bromo, or iodo.

### Claim 12 (depends on 11)

The process of claim 11, further comprising preparing the compound of Formula IIa:
by a process comprising reacting a compound of Formula IId:
with an acid of formula HX;
wherein X′ is chloro, bromo, or iodo.

### Claim 13 (depends on 12)

A process of claim 12, further comprising preparing a compound of Formula IId:
by a process comprising reducing a compound of Formula IIe:
with hydrogen gas in the presence of a hydrogenation catalyst.

### Claim 14 (depends on 13)

A process of claim 13, wherein the hydrogenation catalyst is palladium-on-carbon.

### Claim 15 (depends on 13)

A process of claim 13, further comprising preparing a compound of Formula IIe by a process comprising reacting a compound of Formula IIc with a compound of Formula IIf:
in the presence of a coupling catalyst and a base.

### Claim 16 (depends on 15)

A process of claim 15, wherein the catalyst is a mixture of palladium acetate and CuI.

### Claim 17 (depends on 13)

A process of claim 13, further comprising preparing a compound of Formula IId:
by a process comprising reacting a compound of Formula IIg:
with 9-borabicyclo[3.3.1]nonane, followed by reacting with a compound of Formula IIc:
in the presence of a coupling catalyst to form the compound of Formula IId;
wherein X3 is chloro, bromo, or iodo.

### Claim 18 (depends on 17)

The process of claim 17, wherein the coupling catalyst is palladium(II)diacetate.

### Claim 19 (depends on 1)

The process of claim 1, further comprising preparing the compound of Formula III by a process comprising reacting a compound of Formula IIIa:
with a compound of Formula IIIb:
in the presence of a palladium catalyst and a base; wherein:
X4 is chloro, bromo or iodo; and
each Ra is, independently, C1-6 alkyl; or
each Ra, along with the two oxygen atoms and boron atom form a 5- or 6-membered heterocyclic ring; wherein said heterocyclic ring is optionally substituted with 1, 2, 3, or 4 independently selected C1-4 alkyl groups.

### Claim 20 (depends on 19)

The process of claim 19, wherein the compound of Formula IIIb has formula IIIb-1.

### Claim 21 (depends on 19)

The process of claim 19, further comprising preparing the compound of Formula IIIa by reacting 1,2,4-triazine-3-amine with a halogenating agent.

### Claim 22 (depends on 20)

The process of claim 20, further comprising preparing the compound of Formula IIIb-1 by a process comprising:
a) reacting a compound of Formula IIIc:
a reagent of formula R1MgY, followed by reacting with a compound of formula B(OR2)3 to form a compound of Formula IIId:
and
b) after the reacting in step a), reacting the compound of Formula IIId with an acid, followed by reacting with pinacol to form the compound of Formula IIIb-1;
wherein:
R1 is C1-6 alkyl;
each R2 is, independently, C1-6 alkyl; and
X5 is chloro, bromo, or iodo.

### Claim 23 (depends on 1)

The process of claim 1, wherein the polar protic solvent is ethylene glycol.

### Claim 24 (depends on 21)

The process of claim 21, wherein the halogenating agent is N-bromosuccinamide.