# US 2012/0238564 A1 · Imidazo pyrazines

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- Number: US 2012/0238564 A1
- Document ID: US20120238564A1
- Status: Published application
- Kind: A1
- Application number: 13/415,868
- Filed: 2012-03-09
- Published: 2012-09-20
- Earliest claimed: 2011-03-17
- Assignees: Hoffmann-La Roche Inc.
- Inventors: Kin-Chun Luk; Michael Soth
- Web page: https://patentgrep.com/patent/US20120238564A1

## CPC

- C07D 487/04: Ortho-condensed systems
- A61K 31/4985: Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- 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

## Abstract

Compounds of formula and pharmaceutically acceptable salts thereof are described, as well as the pharmaceutical compositions containing said compounds and their pharmaceutically acceptable salts, and the use of said compounds and pharmaceutical compositions for the treatment, control or amelioration of AML.

## Claims

### Claim 1

A compound of formula I
wherein
X is selected from CH or N,
R1 and R2 are independently selected from the group consisting of
(a) H,
(b) C1-4 alkyl,
(c) C1-4 alkyl substituted with up to 3 groups selected from cycloalkyl, heterocycle, OR5, NR5R6, SO2R7 or CN,
(d) heterocycle,
(e) heterocycle substituted with up to three groups selected from C1-4 alkyl, OR8, NR8R9 or CN,
(f) cycloalkyl, and
(g) cycloalkyl substituted with up to three groups selected from C1-4 alkyl, OR8, NR8R9 or CN; or
alternatively, NR1R2 together can be a heterocycle that optionally may be substituted with C1-4 alkyl;
R3 is selected from the group consisting of
(a) C1-6 alkyl
(b) C1-6 alkyl substituted with up to 3 groups selected from
aryl,
aryl substituted with Cl, F, CH3, or CF3,
heteroaryl,
cycloalkyl,
heterocycle,
OH,
OCH3,
NR8R9, and
CN;
(c) aryl,
(d) aryl substituted with Cl, F, C1-4 alkyl or CF3,
(e) heteroaryl,
(f) cycloalkyl optionally substituted with OR5, and
(g) heterocycle;
R4, R8 and R9 are independently selected from the group consisting of
(a) H, and
(b) C1-4 alkyl; or
alternatively, NR3R4 together can be a heterocycle that optionally is substituted with C1-4 alkyl;
R5 and R6 are independently selected from the group consisting of
(a) H, and
(b) C1-4 alkyl; and
R7 is selected from the group
(a) C1-4 alkyl, and
(b) cycloalkyl;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1 wherein either one of X is N, or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The compound of claim 1 wherein both X is CH, or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

The compound of claim 1, wherein R1 is C1-4 alkyl, or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 4)

The compound of claim 4 wherein R1 is C1-4 alkyl that optionally is substituted with heterocycle, or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 4)

The compound of claim 4 wherein R1 is C1-4 alkyl that optionally is substituted with OH, or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 4)

The compound of claim 4 wherein R1 is C1-4 alkyl that optionally is substituted with SO2R7 and R7 is C1-4 alkyl, or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 1)

The compound of claim 1, wherein R1 is cycolakyl that optionally is substituted with NR8R9, or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 8)

The compound of claim 8 wherein NR8R9 is NH2, or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 1)

The compound of claim 1, wherein R1 is a heterocycle, or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 10)

The compound of claim 10 wherein R1 is piperazine or morpholine, or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 1)

The compound of claim 1, wherein R2 is H, or a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 1)

The compound of claim 1, wherein R2 is C1-4 alkyl, or a pharmaceutically acceptable salt thereof.

### Claim 14 (depends on 1)

The compound of claim 1, wherein NR1R2 together are a heterocycle that optionally may be substituted with C1-4 alkyl, or a pharmaceutically acceptable salt thereof.

### Claim 15 (depends on 14)

The compound of claim 14 wherein NR1R2 is piperazine that optionally is substituted with methyl, or a pharmaceutically acceptable salt thereof.

### Claim 16 (depends on 1)

The compound of claim 1, wherein R3 is C1-6 alkyl that optionally may be substituted with aryl, heteroaryl, or herterocycle, or a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 16)

The compound of claim 16 wherein R3 is C1-6 alkyl that optionally is substituted with up to two groups selected from thiophene and phenyl, or a pharmaceutically acceptable salt thereof.

### Claim 18 (depends on 1)

The compound of claim 1, wherein R3 is cycloalkyl that optionally may be substituted with OR5, or a pharmaceutically acceptable salt thereof.

### Claim 19 (depends on 18)

The compound of claim 18 wherein R3 is cyclohexane that optionally may be substituted with OH.

### Claim 20 (depends on 1)

The compound of claim 1, wherein R3 is aryl, or a pharmaceutically acceptable salt thereof.

### Claim 21 (depends on 20)

The compound of claim 20 wherein R3 is phenyl, or a pharmaceutically acceptable salt thereof.

### Claim 22 (depends on 1)

The compound of claim 1, wherein R4 is H, or a pharmaceutically acceptable salt thereof.

### Claim 23 (depends on 1)

The compound of claim 1, wherein NR3R4 together are a heterocycle that optionally is substituted with C1-4 alkyl, or a pharmaceutically acceptable salt thereof.

### Claim 24 (depends on 23)

The compound of claim 23 wherein NR3R4 is morpholine or piperazine that optionally may be substituted with methyl, or a pharmaceutically acceptable salt thereof.

### Claim 25 (depends on 1)

The compound of claim 1, wherein R5 and R6 are independently H or CH3, or a pharmaceutically acceptable salt thereof.

### Claim 26 (depends on 1)

The compound of claim 1, wherein R7, R8 and R9 are independently selected from an C1-4 alkyl group, or a pharmaceutically acceptable salt thereof.

### Claim 27

A compound selected from the group comprising:
Isopropyl-[3-(2-phenylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine;
2-[3-(2-Phenylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-ethanol;
(2-Methanesulfonyl-ethyl)-{3-[2-(tetrahydro-pyran-4-ylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-amine;
(2-Methanesulfonyl-ethyl)-[3-(2-morpholin-4-yl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine;
[3-(2-Isopropylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-(2-methanesulfonyl-ethyl)-amine;
4-[4-(8-Isopropylamino-imidazo[1,2-a]pyrazin-3-yl)-pyrimidin-2-ylamino]-cyclohexanol;
Isopropyl-{3-[2-(tetrahydro-pyran-4-ylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-amine;
Isopropyl-[3-(2-morpholin-4-yl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine;
Methyl-[3-(2-phenylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine;
Methyl-[3-(2-morpholin-4-yl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine; and
Piperidin-4-yl-{3-[2-(tetrahydro-pyran-4-ylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-amine;
or a pharmaceutically acceptable salt of any of the foregoing compounds.

### Claim 28

A compound selected from the group comprising:
[3-(2-Morpholin-4-yl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-piperidin-4-yl-amine;
[3-(2-Isopropylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-piperidin-4-yl-amine;
Isopropyl-[3-(2-isopropylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine;
[3-(2-Methylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-piperidin-4-yl-amine;
4-{4-[8-(2-Methanesulfonyl-ethylamino)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamino}-cyclohexanol;
2-{3-[2-(Tetrahydro-pyran-4-ylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-ethanol;
2-[3-(2-Morpholin-4-yl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-ethanol;
2-[3-(2-Isopropylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-ethanol;
2-[3-(2-Methylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-ethanol;
Isopropyl-[3-(2-methylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine; and
(2-Methanesulfonyl-ethyl)-[3-(2-methylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine;
or a pharmaceutically acceptable salt of any of the foregoing compounds.

### Claim 29

A compound selected from the group comprising:
Methyl-{3-[2-(tetrahydro-pyran-4-ylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-amine;
Methyl-[3-(2-methylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine;
N1-{4-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-1-phenyl-ethane-1,2-diamine; hydrochloride;
N1-{4-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-1-phenyl-propane-1,3-diamine; hydrochloride;
N1-{6-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-yl}-1-phenyl-ethane-1,2-diamine; hydrochloride;
Benzyl-{6-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-yl}-amine;
Benzyl-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-amine;
(2-Chloro-benzyl)-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-amine; hydrochloride;
(4-Chloro-benzyl)-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-amine; hydrochloride;
N1-{6-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-yl}-1-phenyl-propane-1,3-diamine; hydrochloride; and
{4-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-thiophen-3-ylmethyl-amine;
or a pharmaceutically acceptable salt of any of the foregoing compounds.

### Claim 30

A compound selected from the group comprising:
1-(3-Chloro-phenyl)-N-1-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-propane-1,3-diamine; hydrochloride;
{4-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-thiophen-2-ylmethyl-amine; hydrochloride;
(2-Chloro-benzyl)-{6-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-yl}-amine; hydrochloride;
(3-Chloro-benzyl)-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-amine; hydrochloride;
N-{3-[2-(3-Chloro-benzylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine; hydrochloride;
N-[3-(2-Benzylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-cyclohexane-1,4-diamine; hydrochloride;
N1-{4-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-1-thiophen-3-yl-propane-1,3-diamine; hydrochloride;
(4-Chloro-benzyl)-{6-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-yl}-amine; hydrochloride;
[3-(2-Benzylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-(2-morpholin-4-yl-ethyl)-amine; hydrochloride;
N-[3-(6-Benzylamino-pyridin-2-yl)-imidazo[1,2-a]pyrazin-8-yl]-cyclohexane-1,4-diamine; hydrochloride;
N1-{4-[8-(4-Methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-1-thiophen-3-yl-ethane-1,2-diamine; hydrochloride;
N-{3-[2-(3-Amino-1-phenyl-propylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine; hydrochloride; and
N-{3-[2-(2-Amino-1-phenyl-ethylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine; hydrochloride;
or a pharmaceutically acceptable salt of any of the foregoing compounds.

### Claim 31

A compound selected from the group comprising:
1-(3-Chloro-phenyl)-N-1-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-ethane-1,2-diamine; hydrochloride;
N-{3-[6-(2-Amino-1-phenyl-ethylamino)-pyridin-2-yl}-imidazo[1,2-a]pyrazin-8-yl]-cyclohexane-1,4-diamine; hydrochloride;
N-{3-[6-(3-Amino-1-phenyl-propylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine; hydrochloride;
N-{3-[6-(3-Chloro-benzylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine; hydrochloride;
N-{3-[2-(2-Chloro-benzylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine; hydrochloride;
N-(3-{6-[(Thiophen-3-ylmethyl)-amino]-pyridin-2-yl}-imidazo[1,2-a]pyrazin-8-yl)-cyclohexane-1,4-diamine; hydrochloride;
N-{3-[6-(2-Chloro-benzylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine; hydrochloride;
N-{3-[6-(4-Chloro-benzylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine; hydrochloride;
N-(3-{6-[(Thiophen-2-ylmethyl)-amino]-pyridin-2-yl}-imidazo[1,2-a]pyrazin-8-yl)-cyclohexane-1,4-diamine; hydrochloride;
{3-[2-(2-Chloro-benzylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-(2-morpholin-4-yl-ethyl)-amine; hydrochloride;
{3-[2-(3-Chloro-benzylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-(2-morpholin-4-yl-ethyl)-amine; hydrochloride;
1-(3-Chloro-phenyl)-N-1-{6-[8-(2-morpholin-4-yl-ethylamino)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-yl}-propane-1,3-diamine hydrochloride; and
1-(3-Chloro-phenyl)-N-1-{6-[8-(2-morpholin-4-yl-ethylamino)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-yl}-ethane-1,2-diamine hydrochloride;
or a pharmaceutically acceptable salt of any the foregoing compounds.

### Claim 32 (depends on 1)

A pharmaceutical composition comprising any of the compounds according to claim 1, or a pharmaceutically acceptable salt thereof, as an active ingredient and a pharmaceutically acceptable carrier or excipient.