Compounds of the Invention

In a first aspect, the present invention provides a compound of formula (I)

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- or a pharmaceutically acceptable salt thereof, wherein:
- X¹is N or C—R⁶;
- X²is N or C—R⁷;
- X³is N or C—R¹¹;
- X⁴is N or C—R¹²;
- provided that at most one of X¹to X⁴is N;
- R¹, R², and R³are each independently selected from hydrogen, hydroxy, amino, halogen, cyano, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, cyano-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, amino-C₁-C₆-alkyl, carbamoyl-C₁-C₆-alkyl, carboxy-C₁-C₆-alkyl, C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy, and a group

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- R⁴is hydrogen or C₁-C₆-alkyl;
- R⁵is selected from hydrogen, halogen, cyano, C₁-C₆-alkyl, C₁-C₆-alkoxy, halo-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, and halo-C₁-C₆-alkoxy;
- R⁶, R⁷, R¹¹, and R¹²are each independently selected from is hydrogen, hydroxy, amino, halogen, cyano, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, cyano-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, amino-C₁-C₆-alkyl, C₁-C₆-alkoxy, and halo-C₁-C₆-alkoxy;
- R⁸, R⁹, and R¹⁰are each independently selected from hydrogen, halogen, cyano, amino, hydroxy, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, cyano-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, amino-C₁-C₆-alkyl, C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy, and C₁-C₆-alkoxy-C₁-C₆-alkyl;
- R¹³, R¹⁴, and R¹⁵are each independently selected from hydrogen, halogen, cyano, amino, hydroxy, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, cyano-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, amino-C₁-C₆-alkyl, C₁-C₆-alkoxy, and halo-C₁-C₆-alkoxy;
- A and C are each independently a 3- to 14-membered heterocycle;
- B is a 5- to 14-membered heteroaryl; and
- L¹and L²are each independently selected from a covalent bond, carbonyl, and C₁-C₆-alkyldiyl.

In one embodiment, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (II):

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In one embodiment, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (III):

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In one embodiment, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (IV):

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In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- X¹is C—R⁶.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- X²is N or C—R⁷.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- X³is C—R¹¹.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- X⁴is C—R¹².

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- R¹is selected from hydrogen, C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, carbamoyl-C₁-C₆-alkyl, carboxy-C₁-C₆-alkyl, and a group

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In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- R¹is a group

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In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- R²is selected from hydrogen, C₁-C₆-alkyl, and carboxy-C₁-C₆-alkyl.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- R²is selected from C₁-C₆-alkyl, and carboxy-C₁-C₆-alkyl.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- R²is selected from methyl, and carboxymethyl.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- R³is hydrogen.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- R⁴is hydrogen.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- R⁵is alkyl.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- R⁵is ethyl.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- R⁶is hydrogen or halogen.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- R⁶is halogen.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- R⁶is fluoro.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- R⁷is hydrogen or halogen.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- R⁷is halogen.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- R⁷is fluoro.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- R⁸is selected from C₁-C₆-alkyl, halo-C₁-C₆-alkyl, cyano-C₁-C₆-alkyl, and C₁-C₆-alkoxy-C₁-C₆-alkyl.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- R⁸is C₁-C₆-alkyl or C₁-C₆-alkoxy-C₁-C₆-alkyl.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- R⁸is methyl or 2-methoxyethyl.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- R⁹is hydrogen or C₁-C₆-alkyl.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- R⁹is hydrogen or methyl.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- R¹⁰is hydrogen or C₁-C₆-alkyl.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- R¹⁰is hydrogen or methyl.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- R¹¹is hydrogen or halogen.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- R¹¹is hydrogen.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- R¹²is hydrogen or C₁-C₆-alkyl.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- R¹²is hydrogen.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- R¹³is hydrogen.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- R¹⁴is hydrogen.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- R¹⁵is hydrogen.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- L¹is C₁-C₆-alkyldiyl.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- L¹is —CH₂—.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- L²is C₁-C₆-alkyldiyl.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- L²is —CH₂—.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- A is piperidyl.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- B is pyrazolyl.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- C is azetidinyl.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- X¹is C—R⁶;
- X²is N or C—R⁷;
- X³is C—R¹¹;
- X⁴is C—R¹²;
- R⁶, R⁷, and R¹¹are each independently hydrogen or halogen; and
- R¹²is hydrogen or C₁-C₆-alkyl.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- X¹is C—R⁶;
- X²is N or C—R⁷;
- X³is C—R¹¹;
- X⁴is C—R¹²
- R⁶and R⁷are halogen; and
- R¹¹and R¹²are hydrogen.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- X¹is C—R⁶;
- X²is N or C—R⁷;
- X³is C—R¹¹;
- X⁴is C—R¹²;
- R⁶and R⁷are fluoro; and
- R¹¹and R¹²are hydrogen.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- R¹is selected from hydrogen, C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, carbamoyl-C₁-C₆-alkyl, carboxy-C₁-C₆-alkyl, and a group

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- R²is selected from hydrogen, C₁-C₆-alkyl, and carboxy-C₁-C₆-alkyl;
- R³, R¹³, R¹⁴, and R¹⁵are hydrogen;
- L¹and L²are each independently C₁-C₆-alkyldiyl; and
- A and C are each independently a 3- to 14-membered heterocycle.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- R¹is a group

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- R²is C₁-C₆-alkyl or carboxy-C₁-C₆-alkyl;
- R³, R¹³, R¹⁴, and R¹⁵are hydrogen;
- L¹and L²are each independently C₁-C₆-alkyldiyl; and
- A and C are each independently a 3- to 14-membered heterocycle.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- R¹is a group

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- R²is methyl or carboxymethyl;
- R³, R¹³, R¹⁴, and R¹⁵are hydrogen;
- L¹and L²are —CH₂—;
- A is piperidyl; and
- C is azetidinyl.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- X¹is C—R⁶;
- X²is N or C—R⁷;
- X³is C—R¹¹;
- X⁴is C—R¹²;
- R¹is selected from hydrogen, C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, carbamoyl-C₁-C₆-alkyl, carboxy-C₁-C₆-alkyl, and a group

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- R²is selected from hydrogen, C₁-C₆-alkyl, and carboxy-C₁-C₆-alkyl;
- R³, R⁴, R¹³, R¹⁴, and R¹⁵are hydrogen;
- R⁵is C₁-C₆-alkyl;
- R⁶, R⁷, and R¹¹are each independently hydrogen or halogen;
- R⁸is selected from C₁-C₆-alkyl, halo-C₁-C₆-alkyl, cyano-C₁-C₆-alkyl, and C₁-C₆-alkoxy-C₁-C₆-alkyl;
- R⁹, R¹⁰, and R¹²are each independently hydrogen or C₁-C₆-alkyl;
- A and C are each independently a 3- to 14-membered heterocycle;
- B is a 5- to 14-membered heteroaryl; and
- L¹and L²are each independently C₁-C₆-alkyldiyl.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- X¹is C—R⁶;
- X²is N or C—R⁷;
- X³is C—R¹¹;
- X⁴is C—R¹²;
- R¹is a group

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- R²is C₁-C₆-alkyl or carboxy-C₁-C₆-alkyl;
- R³, R⁴, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵are hydrogen;
- R⁵is C₁-C₆-alkyl;
- R⁶and R⁷are halogen;
- R⁸is C₁-C₆-alkyl or C₁-C₆-alkoxy-C₁-C₆-alkyl;
- R⁹and R¹⁰are each independently hydrogen or C₁-C₆-alkyl;
- A and C are each independently a 3- to 14-membered heterocycle;
- B is a 5- to 14-membered heteroaryl; and
- L¹and L²are each independently C₁-C₆-alkyldiyl.

In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

- X¹is C—R⁶;
- X²is N or C—R⁷;
- X³is C—R¹¹;
- X⁴is C—R¹²;
- R¹is a group

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- R²is methyl or carboxymethyl;
- R³, R⁴, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵are hydrogen;
- R⁵is ethyl;
- R⁶and R⁷are fluoro;
- R⁸is methyl or 2-methoxyethyl;
- R⁹and R¹⁰are each independently hydrogen or methyl;
- A is piperidyl;
- B is pyrazolyl;
- C is azetidinyl; and
- L¹and L²are —CH₂—.

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from:

N-[[1-(azetidin-3-ylmethyl)-4-piperidyl]methyl]-4-[[3-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide;

N-[[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]-4-[[3-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide;

2-[1-(azetidin-3-ylmethyl)-4-[[[4-[[3-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]methyl]piperidin-1-ium-1-yl]acetic acid;

2-[4-[[[4-[[3-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]methyl]-1-piperidyl]acetic acid;

2-[4-[[[4-[[3-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]methyl]-1-methyl-piperidin-1-ium-1-yl]acetic acid;

N-[[1-(azetidin-3-ylmethyl)-4-piperidyl]methyl]-4-[[3-[2,3-difluoro-4-[3-(trifluoromethyl)-1H-pyrazol-4-yl]phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide;

N-[[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]-4-[[3-[2,3-difluoro-4-[3-(trifluoromethyl)-1H-pyrazol-4-yl]phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide;

N-[[1-(2-amino-2-oxo-ethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]-4-[[3-[4-[1-(cyanomethyl)-3-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide;

N-[[1-(2-amino-2-oxo-ethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]-4-[[3-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide;

2-[1-(2-amino-2-oxo-ethyl)-4-[[[4-[[3-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]methyl]piperidin-1-ium-1-yl]acetic acid;

2-[1-(carboxymethyl)-4-[[[4-[[3-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]methyl]piperidin-1-ium-1-yl]acetic acid;

N-[[1-(azetidin-3-ylmethyl)-4-piperidyl]methyl]-2-ethyl-4-[[3-[2-fluoro-6-(3-methyl-1H-pyrazol-4-yl)-3-pyridyl]imidazo[1,2-a]pyrazin-8-yl]amino]benzamide;

N-[[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]-2-ethyl-4-[[3-[2-fluoro-6-(3-methyl-1H-pyrazol-4-yl)-3-pyridyl]imidazo[1,2-a]pyrazin-8-yl]amino]benzamide;

N-[[1-(azetidin-3-ylmethyl)-4-piperidyl]methyl]-4-[[3-[6-(3,5-dimethyl-1H-pyrazol-4-yl)-2-fluoro-3-pyridyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide;

N-[[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]-4-[[3-[6-(3,5-dimethyl-1H-pyrazol-4-yl)-2-fluoro-3-pyridyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide;

N-[[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]-2-ethyl-4-[[3-[5-fluoro-6-(3-methyl-1H-pyrazol-4-yl)-3-pyridyl]imidazo[1,2-a]pyrazin-8-yl]amino]benzamide;

N-[[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]-2-ethyl-4-[[3-[4-methyl-6-(3-methyl-1H-pyrazol-4-yl)-3-pyridyl]imidazo[1,2-a]pyrazin-8-yl]amino]benzamide;

N-[[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]-2-ethyl-4-[[3-[4-(3-methyl-1H-pyrazol-4-yl)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]benzamide;

4-[[3-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-N-(4-piperidylmethyl)benzamide;

N-[[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]-4-[[3-[2,3-difluoro-4-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide;

N-[[1-(2-amino-2-oxo-ethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]-4-[[3-[2,3-difluoro-4-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide;

4-[[3-[2,3-difluoro-4-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-N-[[1-(2-hydroxyethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]benzamide;

4-[[3-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-N-[(1,1-dimethylpiperidin-1-ium-4-yl)methyl]-2-ethyl-benzamide;

N-[[1-(2-amino-2-oxo-ethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]-4-[[3-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide;

4-[[3-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-N-[[1-(2-hydroxyethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]benzamide; and

N-[[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]-4-[[3-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide.
- In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from:

N-[[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]-4-[[3-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide;

2-[1-(azetidin-3-ylmethyl)-4-[[[4-[[3-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]methyl]piperidin-1-ium-1-yl]acetic acid;

N-[[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]-4-[[3-[6-(3,5-dimethyl-1H-pyrazol-4-yl)-2-fluoro-3-pyridyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide; and

N-[[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]-4-[[3-[2,3-difluoro-4-[1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl]phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide.

In one embodiment, the present invention provides pharmaceutically acceptable salts of the compounds of formula (I) as described herein, especially pharmaceutically acceptable salts selected from hydrochlorides, fumarates, lactates (in particular derived from L-(+)-lactic acid), tartrates (in particular derived from L-(+)-tartaric acid) and trifluoroacetates. In yet a further particular embodiment, the present invention provides compounds according to formula (I) as described herein (i.e., as “free bases” or “free acids”, respectively).

In some embodiments, the compounds of formula (I) are isotopically-labeled by having one or more atoms therein replaced by an atom having a different atomic mass or mass number. Such isotopically-labeled (i.e., radiolabeled) compounds of formula (I) are considered to be within the scope of this disclosure. Examples of isotopes that can be incorporated into the compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, and iodine, such as, but not limited to, ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I, respectively. Certain isotopically-labeled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. ³H, and carbon-14, i.e., ¹⁴C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. For example, a compound of formula (I) can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99 percent of a given isotope.

Substitution with heavier isotopes such as deuterium, i.e. ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.

Processes of Manufacturing

The preparation of compounds of formula (I) of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses of the compounds of the invention are shown in the following schemes. The skills required for carrying out the reactions and purifications of the resulting products are known to those skilled in the art. The substituents and indices used in the following description of the processes have the significance given hereinbefore unless indicated to the contrary. In more detail, the compounds of formula (I) can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art. Also, for reaction conditions described in literature affecting the described reactions see for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Edition, Richard C. Larock. John Wiley & Sons, New York, NY. 2018). We find it convenient to carry out the reactions in the presence or absence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. The described reactions can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. It is convenient to carry out the described reactions in a temperature range between −78° C. to reflux temperature. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 h to several days will usually suffice to yield the described intermediates and compounds. The reaction sequence is not limited to the one displayed in the schemes, however, depending on the starting materials and their respective reactivity the sequence of reaction steps can be freely altered. Starting materials are either commercially available or can be prepared by methods analogous to the methods given below, by methods described in references cited in the description or in the examples, or by methods known in the art.

[Image Omitted]

- wherein R⁹and R¹⁰are as defined herein, preferably H or Me;
- X is halogen or H;
- R⁸is as defined herein, preferably C_1-6alkyl, C_1-6alkoxy, or is a protective group, such as Boc or MOM.

Compound of Intermediate B can be prepared according to route in Scheme 1. Alkylation R⁸X with substituted pyrazole analogues (I) to give Intermediate A, which can couple with building block (II) to give Building block III. Bronic ester (Intermediate B) can be achieved using palladium catalysts and phosphine ligands then.

[Image Omitted]

- wherein R⁵is as defined herein, preferably Me, Et or halogen;
- R¹is as defined herein, preferably C_1-6alkyl, C_1-6alkoxy, C_1-6amine or C_1-6aminocarbonyl, or is a protective group, such as Boc, MOM.

Compound of Intermediate C can be prepared according to route in Scheme 2. 8-chloro-3-iodo-imidazo[1,2-a]pyrazine (IV) can react with 4-aminobenzoic acid analogues (V) to give building block VI, which can couple with amine building block VII with condensing agent, such as HATU/DIPEA in DMSO to give the compound of formula Intermediate C1.

Remove protect group under acid condition to get Intermediate C2, which can be further be alkylated with R⁸X to get Intermediate C.

[Image Omitted]

- wherein R⁹and R¹⁰are as defined herein, preferably H or Me;
- X is halogen or H;
- R⁸is as defined herein, preferably C_1-6alkyl or C_1-6alkoxy, or is a protective group, such as Boc or MOM;
- R¹is as defined herein, preferably C_1-6alkyl, C_1-6alkoxy, C_1-6amine or C_1-6aminocarbonyl or is a protective group, such as Boc or MOM;
- R⁵is as defined herein, preferably Me, Et or halogen.

Intermediate D can be prepared according to route in Scheme 3. Suziki coupling of Intermediate C with bronic ester (Intermediate B) can be achieved using palladium catalysts and phosphine ligands to give compound of formula Intermediate D.

[Image Omitted]

- wherein R⁹and R¹⁰are as defined herein, preferably H or Me;
- R⁸is as defined herein, preferably C_1-6alkyl or C_1-6alkoxy, or is a protective group, such as Boc or MOM;
- R¹is as defined herein, preferably C_1-6alkyl, C_1-6alkoxy, C_1-6amine or C_1-6aminocarbonyl or is a protective group, such as Boc or MOM;
- R⁵is as defined herein, preferably Me, Et or halogen.

Intermediate F can be prepared according to route in Scheme 4. Suzuki coupling of Intermediate C with Aza-Aryl bronic ester (VIII) can be achieved using palladium catalysts and phosphine ligands to give compound of formula (Intermediate E). Then further Suzuki coupling of Intermediate I using classical palladium catalysts system to get compound of formula Intermediate F.

[Image Omitted]

- wherein R⁹and R¹⁰are as defined herein, preferably H or Me;
- X is halogen or H;
- R⁸is as defined herein, preferably C_1-6alkyl or C_1-6alkoxy, or is a protective group, such as Boc or MOM;
- R¹is as defined herein, preferably C_1-6alkyl, C_1-6alkoxy, C_1-6amine or C_1-6aminocarbonyl or is a protective group, such as Boc or MOM;
- R⁵is as defined herein, preferably Me, Et or halogen.

The Example A-D can be prepared according to the route in Scheme 5. The methylation of Intermediate D and Intermediate F can be achieved at mild conditions like Mel with DIPEA in acetonitrile at room temperature. The removal of the protective group can be before or after the methylation step, based on different substitution.

In one aspect, the present invention provides a process of manufacturing the compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, comprising:

- (iii) Suzuki coupling of a heteroaryl halide C1, wherein R¹to R⁵, A, and L¹are as defined herein and “Hal” is a halogen, preferably iodine,

[Image Omitted]

- - with a boronic acid (ester) B1, wherein X¹to X⁴, R⁸to R¹⁰and ring B are as defined herein, and each R is independently hydrogen or alkyl, wherein the two R groups, taken together with the oxygen and boron atoms to which they are attached, may form a cyclic boronic acid ester;

[Image Omitted]

- - in the presence of a transition metal catalyst, such as 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex or Tris(dibenzylideneacetone)dipalladium(0), to afford said compound of formula (I); or
- (iv) Suzuki coupling of an aryl/heteroaryl halide E1, wherein R¹to R⁵, A, L¹, and X¹to X⁴are as defined herein and “Hal” is a halogen, preferably chlorine,

[Image Omitted]

- - with a boronic acid (ester) I1, wherein R⁸to R¹⁰and ring B are as defined herein, and each R is independently hydrogen or alkyl, wherein the two R groups, taken together with the oxygen and boron atoms to which they are attached, may form a cyclic boronic acid ester;

[Image Omitted]

- - in the presence of a transition metal catalyst, such as 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex or Tris(dibenzylideneacetone)dipalladium(0), to afford said compound of formula (I); to afford said compound of formula (I).

In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, when manufactured according to the processes disclosed herein.

Using the Compounds

As illustrated in the experimental section, the compounds of formula (I) and their pharmaceutically acceptable salts possess valuable pharmacological properties for the treatment or prevention of infections and resulting diseases, particularly bacteremia, pneumonia, meningitis, urinary tract infection, and wound infection, caused by pathogens, particularly by bacteria, more particularly by Acinetobacter species, most particularly by Acinetobacter baumannii.

The compounds of formula (I) and their pharmaceutically acceptable salts exhibit activity as antibiotics, particularly as antibiotics against Acinetobacter species, more particularly as antibiotics against Acinetobacter baumannii, most particularly as pathogen-specific antibiotics against Acinetobacter baumannii.

The compounds of formula (I) and their pharmaceutically acceptable salts can be used as antibiotics, i.e. as antibacterial pharmaceutical ingredients suitable in the treatment and prevention of bacterial infections, particularly in the treatment and prevention of bacterial infections caused by Acinetobacter species, more particularly in the treatment and prevention of bacterial infections caused by Acinetobacter baumannii.

The compounds of the present invention can be used, either alone or in combination with other drugs, for the treatment or prevention of infections and resulting diseases, particularly bacteremia, pneumonia, meningitis, urinary tract infection, and wound infection, caused by pathogens, particularly by bacteria, more particularly caused by Acinetobacter species, most particularly by Acinetobacter baumannii.

In one aspect, the present invention provides compounds of formula (I) or their pharmaceutically acceptable salts as described herein for use as therapeutically active substances.

In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use as antibiotic.

In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of nosocomial infections and resulting diseases.

In a particular embodiment, said nosocomial infections and resulting diseases are selected from bacteremia, pneumonia, meningitis, urinary tract infection and wound infection, or a combination thereof.

In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of infections and resulting diseases caused by Gram-negative bacteria.

In a particular embodiment, said infections and resulting diseases caused by Gram-negative bacteria are selected from bacteremia, pneumonia, meningitis, urinary tract infection and wound infection, or a combination thereof.

In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of infections and resulting diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or E. coli, or a combination thereof.

In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of infections and resulting diseases caused by Acinetobacter baumannii or Pseudomonas aeruginosa or a combination thereof.

In a further preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of infections and resulting diseases caused by Pseudomonas aeruginosa.

In a further preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of infections and resulting diseases caused by Acinetobacter baumannii.

In a further aspect, the present invention provides a method for the treatment or prevention of infections and resulting diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or E. coli, or a combination thereof, which method comprises administering a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, to a mammal.

In a further aspect, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, as an antibiotic.

In a further aspect, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of infections and resulting diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or E. coli, or a combination thereof.

In a further aspect, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of medicaments useful for the treatment or prevention of infections and resulting diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or E. coli, or a combination thereof.

In a particular embodiment, said infections and resulting diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or E. coli, or a combination thereof, are selected from bacteremia, pneumonia, meningitis, urinary tract infection and wound infection, or a combination thereof.

In a further aspect, the present invention provides compounds of formula (I) or their pharmaceutically acceptable salts as defined above for use in the treatment or prevention of infections and resulting diseases, particularly bacteremia, pneumonia, meningitis, urinary tract infection, and wound infection, caused by pathogens, particularly by bacteria, more particularly caused by Acinetobacter species, most particularly by Acinetobacter baumannii.

In a further aspect, the present invention provides a method for the treatment or prevention of infections and resulting diseases, particularly bacteremia, pneumonia, meningitis, urinary tract infection, and wound infection, caused by pathogens, particularly by bacteria, more particularly caused by Acinetobacter species, most particularly by Acinetobacter baumannii, which method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above to a mammal.

In a further aspect, the present invention provides the use of compounds of formula (I) or their pharmaceutically acceptable salts as defined above for the treatment or prevention of infections and resulting diseases, particularly bacteremia, pneumonia, meningitis, urinary tract infection, and wound infection, caused by pathogens, particularly by bacteria, more particularly caused by Acinetobacter species, most particularly by Acinetobacter baumannii.

In a further aspect, the present invention provides the use of compounds of formula (I) or their pharmaceutically acceptable salts as defined above for the preparation of medicaments for the treatment or prevention of infections and resulting diseases, particularly bacteremia, pneumonia, meningitis, urinary tract infection, and wound infection, caused by pathogens, particularly by bacteria, more particularly caused by Acinetobacter species, most particularly by Acinetobacter baumannii. Such medicaments comprise compounds of formula (I) or their pharmaceutically acceptable salts as defined above.

Pharmaceutical Compositions and Administration

In one aspect, the present invention provides pharmaceutical compositions comprising compounds of formula (I) or their pharmaceutically acceptable salts as defined above and one or more pharmaceutically acceptable excipients. Exemplary pharmaceutical compositions are described in Examples 1 to 4.

In a further aspect, the present invention relates to pharmaceutical compositions comprising compounds of formula (I) or their pharmaceutically acceptable salts as defined above and one or more pharmaceutically acceptable excipients for the treatment or prevention of infections and resulting diseases, particularly bacteremia, pneumonia, meningitis, urinary tract infection, and wound infection, caused by pathogens, particularly by bacteria, more particularly caused by Acinetobacter species, most particularly by Acinetobacter baumannii.

The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments (e.g. in the form of pharmaceutical preparations). The pharmaceutical preparations can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays) or rectally (e.g. in the form of suppositories). However, the administration can also be effected parentally, such as intramuscularly or intravenously (e.g. in the form of injection solutions or infusion solutions).

The compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic excipients for the production of tablets, coated tablets, dragées and hard gelatin capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such excipients for tablets, dragées and hard gelatin capsules.

Suitable excipients for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols, etc.

Suitable excipients for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc.

Suitable excipients for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, etc.

Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.

The dosage can vary in wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 0.1 mg to 20 mg per kg body weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g. about 300 mg per person), divided into preferably 1-3 individual doses, which can consist, for example, of the same amounts, should be appropriate. It will, however, be clear that the upper limit given herein can be exceeded when this is shown to be indicated.

Co-Administration of Compounds of Formula (I) and Other Agents

The compounds of formula (I) or salts thereof or a compound disclosed herein or a pharmaceutically acceptable salt thereof may be employed alone or in combination with other agents for treatment. For example, the second agent of the pharmaceutical combination formulation or dosing regimen may have complementary activities to the compound of formula (I) such that they do not adversely affect each other. The compounds may be administered together in a unitary pharmaceutical composition or separately. In one embodiment a compound or a pharmaceutically acceptable salt can be co-administered with an antibiotic, in particular with an antibiotic for the treatment or prevention of infections and resulting diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or E. coli, or a combination thereof.

The term “co-administering” refers to either simultaneous administration, or any manner of separate sequential administration, of a compound of formula (I) or a salt thereof or a compound disclosed herein or a pharmaceutically acceptable salt thereof and a further active pharmaceutical ingredient or ingredients, including antibiotic agents. If the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered intravenously and another compound may be administered orally.

Typically, any agent that has antimicrobial activity may be co-administered. Particular examples of such agents are Carbapenems (meropenem), Fluoroquinolone (Ciprofloxacin), Aminoglycoside (amikacin), Tetracyclines (tigecycline), Colistin, Sulbactam, Sulbactam+Durlobactam, Cefiderocol (Fetroja), macrocyclic peptides as exemplified e.g. in WO 2017072062 A1, WO 2019185572 A1 and WO 2019206853 A1, and Macrolides (erythromycin).

In one aspect, the present invention provides a pharmaceutical composition described herein, further comprising an additional therapeutic agent.

In one aspect, the present invention provides a pharmaceutical combination comprising a compound of formula (I) described herein and an additional therapeutic agent.

In one embodiment, said additional therapeutic agent is an antibiotic agent.

In one embodiment, said additional therapeutic agent is an antibiotic agent that is useful for the treatment or prevention of infections and resulting diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or E. coli, or a combination thereof.

In one embodiment, said additional therapeutic agent is an antibiotic agent selected from Carbapenems (meropenem), Fluoroquinolone (Ciprofloxacin), Aminoglycoside (amikacin), Tetracyclines (tigecycline), Colistin, Sulbactam, Sulbactam+Durlobactam, Cefiderocol (Fetroja), macrocyclic peptides as exemplified in WO 2017072062 A1, WO 2019185572 A1 and WO 2019206853 A1, and Macrolides (erythromycin).

EXAMPLES

The invention will be more fully understood by reference to the following examples. The claims should not, however, be construed as limited to the scope of the examples.

In case the preparative examples are obtained as a mixture of enantiomers, the pure enantiomers can be separated by methods described herein or by methods known to the man skilled in the art, such as e.g., chiral chromatography (e.g., chiral SFC) or crystallization.

All reaction examples and intermediates were prepared under an argon atmosphere if not specified otherwise.

Abbreviations used herein are as follows:

- ACN or MeCN acetonitrile
- BINAP 2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene
- CFU colony-forming unit
- d day
- DCM dichloromethane
- DIPEA N,N-diisopropylethylamine
- EtOAc or EA ethyl acetate
- FA formic acid
- h(s) or hr(s) hour
- HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate
- HPLC: high performance liquid chromatography
- HPLC-UV: high performance liquid chromatography with ultraviolet detector
- IC50 half maximal inhibitory concentration
- IC90 90% inhibitory concentration
- PE petroleum ether
- PdCl₂(DPPF) 1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)
- Pd₂(dba)₃Tris(dibenzylideneacetone)dipalladium(0)
- PG Protect group
- Precat precatalyst
- prep-HPLC preparative high performance liquid chromatography
- rt room temperature
- sat saturated
- SEM 2-methoxyethyl(trimethyl)silane
- FA Formic acid
- TFA Trifluoroacetic Acid
- wt weight
- X-PHOS 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

Intermediate A1
1-(2-Methoxyethyl)-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole

To a 25 mL microwave vial was added 3-methyl-4-(4.4.5.5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-1H-pyrazole (2 g, 9.61 mmol), 1-bromo-2-methoxyethane (1.74 g, 12.5 mmol), K₂CO₃(1.73 g, 12.5 mmol) and potassium iodide (319 mg, 1.92 mmol) in DMF (15 mL). The vial capped and heated in the microwave at 100° C. for 15 h. The reaction mixture filtered through glass fiber paper. The filtrate was concentrated in vacuum. The crude material purified by flash chromatography (silica gel, 40 g, 10% to 40% EtOAc in hexanes) to afford 2 g of crude product, the crude product was purified by preparative HPLC. to afford 1-(2-methoxyethyl)-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (550 mg, 2.07 mmol, 21.5% yield) and 1-(2-methoxyethyl)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (316 mg, 1.19 mmol, 12.4% yield). MS [M+H]⁺: 280.3.

Intermediate A2
1-(2-Methoxyethyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole

To a 25 mL microwave vial was added 3, 5-dimethyl-4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-1H-pyrazole (2 g, 9.01 mmol), 1-bromo-2-methoxyethane (1.63 g, 11.7 mmol), K₂CO₃(1.62 g, 11.7 mmol) and potassium iodide (299 mg, 1.8 mmol) in DMF (15 mL). The vial capped and heated in the microwave at 100° C. for 15 h. The reaction mixture filtered through glass fiber paper. The filtrate was concentrated in vacuum. The crude material purified by flash chromatography (silica gel, 40 g, 10% to 40% EtOAc in hexanes), to afford 1-(2-methoxyethyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.5 g, 5.35 mmol, 59.5% yield). MS [M+H]⁺: 281.1.

Intermediate A3
Trimethyl-[2-[[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]methoxy]ethyl]silane

In a 100 mL round-bottomed flask, 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.5 g, 7.21 mmol), SEM-C1 (1.56 g, 1.66 mL, 9.37 mmol) and DIPEA (2.8 g, 3.78 mL, 21.6 mmol) were combined with DCM (30 mL) to give a colorless solution. The reaction stirred at room temperature for 2 h. The crude reaction mixture was concentrated in vacuum. The crude material purified by flash chromatography (silica gel, 40 g, 0% to 30% DCM in PE). To afford trimethyl-[2-[[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]methoxy]ethyl]silane (2.4 g, 98.4% yield). MS[M+H]⁺: 339.4.

Intermediate B1
2-[[4-[2,3-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-methyl-pyrazol-1-yl]methoxy]ethyl-trimethyl-silane
Step 1: 2-[[4-(4-bromo-2,3-difluoro-phenyl)-3-methyl-pyrazol-1-yl]methoxy]ethyl-trimethyl-silane

To a 25 mL microwave vial was added 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1 g, 2.96 mmol), 1,4-dibromo-2,3-difluorobenzene (1.61 g, 5.91 mmol), 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (193 mg, 296 μmol) and Na₂CO₃(940 mg, 8.87 mmol) in dioxane (15 mL)/water (1.5 mL). The vial capped and heated at 100° C. for 2 h under N₂. The reaction mixture filtered through glass fiber paper. The filtrate was concentrated in vacuum. The crude material was purified by flash chromatography (silica gel, 40 g, 25% to 80% DCM in PE), to afford 2-[[4-(4-bromo-2,3-difluoro-phenyl)-3-methyl-pyrazol-1-yl]methoxy]ethyl-trimethyl-silane(324 mg, 803 μmol, 27.2% yield). MS [M+H]⁺: 405.1.

Step 2: 2-[[4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-methyl-pyrazol-1-yl]methoxy]ethyl-trimethyl-silane

In a 100 mL round-bottomed flask, bis(pinacolato)diboron (265 mg, 1.04 mmol), 4-(4-bromo-2,3-difluorophenyl)-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (324 mg, 803 μmol), PdCl₂(dppf)-CH₂Cl₂adduct (58.8 mg, 80.3 μmol) and potassium acetate (237 mg, 2.41 mmol) combined with dioxane (10 mL) to give a dark red solution. The reaction mixture heated to 80° C. and stirred for 15 h under N₂. The crude reaction mixture was concentrated in vacuum. The crude material purified by flash chromatography (silica gel, 40 g, 30% to 80% PE in DCM). to afford 2-[[4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-methyl-pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (350 mg, 777 μmol, 96.7% yield). MS [M+H]⁺: 451.3.

The following intermediates were prepared in analogy:

MS
Starting

Int.
Name
ESI [M + H]⁺
Material

Intermediate
3-methyl-4-[4-(4,4,5,5-
285.9
1-bromo-4-iodobenzene and 3-

B2
tetramethyl-1,3,2-

methyl-4-(4,4,5,5-tetramethyl-

dioxaborolan-2-

1,3,2-dioxaborolan-2-yl)-1H-

yl)phenyl]-1H-

pyrazole; B₂pin₂

pyrazole

Intermediate
4-[2,3-difluoro-4-
321.2
1-bromo-2,3-difluoro-4-

B3
(4,4,5,5-tetramethyl-

iodobenzene and 3-methyl-4-

1,3,2-dioxaborolan-2-

(4,4,5,5-tetramethyl-1,3,2-

yl)phenyl]-3-methyl-

dioxaborolan-2-yl)-1H-pyrazole;

1H-pyrazole

B₂pin₂

Intermediate
4-(2,3-difluoro-4-
375.3
1-bromo-2,3-difluoro-4-

B4
(4,4,5,5-tetramethyl-

iodobenzene and 4-(4,4,5,5-

1,3,2-dioxaborolan-2-

tetramethyl-1,3,2-dioxaborolan-

yl)phenyl)-3-

2-yl)-3-(trifluoromethyl)-1H-

(trifluoromethyl)-1H-

pyrazole; B₂pin₂

pyrazole

Intermediate
4-[2,3-difluoro-4-
393.2
1-bromo-2,3-difluoro-4-

B5
(4,4,5,5-tetramethyl-

iodobenzene and intermediate

1,3,2-dioxaborolan-2-

A2; B₂pin₂

yl)phenyl]-1-(2-

methoxyethyl)-3,5-

dimethyl-pyrazole

Intermediate
4-[2,3-difluoro-4-
379.3
1-bromo-2,3-difluoro-4-

B6
(4,4,5,5-tetramethyl-

iodobenzene and intermediate

1,3,2-dioxaborolan-2-

A1; B₂pin₂

yl)phenyl]-1-(2-

methoxyethyl)-3-

methyl-pyrazole

Intermediates C1 & C2
tert-Butyl 4-[[[2-ethyl-4-[(3-odoimidazo[1,2-a]pyrazin-8-yl)amino]benzoyl]amino]methyl]piperidine-1-carboxylate (Intermediate C1)
2-Ethyl-4-[(3-iodoimidazo[1,2-a]pyrazin-8-yl)amino]-N-(4-piperidylmethyl)benzamide (Intermediate C2)
Step 1: 2-ethyl-4-[(3-iodoimidazo[1,2-a]pyrazin-8-yl)amino]benzoic acid

4-Amino-2-ethylbenzoic acid (3 g, 18.2 mmol) and 8-chloro-3-iodoimidazo[1,2-a]pyrazine (5.33 g, 19.1 mmol) was suspended in MeCN (33 mL) and AcOH (3.3 mL). The mixture heated in a sealed microwave tube at 100° C. for 18 h, and then cooled to room temperature. The precipitate collected by filtration and washed with ether (30 mL×3). The cake was dried in vacuum to afford the product 2-ethyl-4-((3-iodoimidazo[1,2-a]pyrazin-8-yl)amino)benzoic acid (7.08 g, 95.5% yield).

Step 2: tert-butyl 4-((2-ethyl-4-((3-iodoimidazo[1,2-a]pyrazin-8-yl)amino)benzamido) methyl)piperidine-1-carboxylate

In a 50 mL round-bottomed flask, 2-ethyl-4-((3-iodoimidazo[1,2-a]pyrazin-8-yl)amino)benzoic acid (287 mg, 703 μmol), tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (196 mg, 914 μmol), HATU (348 mg, 914 μmol) and DIPEA (273 mg, 368 μl, 2.11 mmol) were combined with DMF (5 mL) to give a light brown solution. The reaction stirred at room temperature for 30 min. The reaction mixture was poured into 25 mL H₂O and extracted with EtOAc (25 mL×3). Combined the organic, washed with sat. NaCl (25 mL), dried over Na₂SO₄and concentrated in vacuum. The crude material purified by flash chromatography (silica gel, 12 g, 0% to 5% MeOH in DCM) to afford tert-butyl 4-((2-ethyl-4-((3-iodoimidazo[1,2-a]pyrazin-8-yl)amino)benzamido)methyl)piperidine-1-carboxylate (363 mg, 601 μmol, 85.4% yield). MS [M+H]⁺: 605.4.

Step 3: 2-ethyl-4-[(3-iodoimidazo[1,2-a]pyrazin-8-yl)amino]-N-(4-piperidylmethyl) benzamide

In a 50 mL round-bottomed flask, tert-butyl 4-((2-ethyl-4-((3-iodoimidazo[1,2-a]pyrazin-8-yl)amino)benzamido)methyl)piperidine-1-carboxylate (240 mg, 397 μmol) was combined with THE (4 mL) to give a light yellow solution. HCl (in water) (1.65 mL, 19.9 mmol) was added. The reaction stirred at room temperature for 1 h. The crude reaction mixture was concentrated in vacuum. The crude product was directly used to the next step to afford 2-ethyl-4-[(3-iodoimidazo[1,2-a]pyrazin-8-yl)amino]-N-(4-piperidylmethyl)benzamide (200 mg, 397 μmol, 99.9% yield). MS [M+H]⁺: 505.0

Intermediate C3
tert-Butyl3-[[4-[[[2-ethyl-4-[(3-iodoimidazo[1,2-a]pyrazin-8-yl)amino]benzoyl]amino]methyl]-1-piperidyl]methyl]azetidine-1-carboxylate

In a 100 mL round-bottomed flask, 2-ethyl-4-((3-iodoimidazo[1,2-a]pyrazin-8-yl)amino)-N-(piperidin-4-ylmethyl)benzamide (200 mg, 397 μmol), tert-butyl 3-formylazetidine-1-carboxylate (220 mg, 1.19 mmol) and NaBH₃CN (125 mg, 1.98 mmol) were combined with MeOH (10 mL) to give a light brown solution. The reaction mixture heated to 45° C. and stirred for 3 h. The crude reaction mixture was concentrated in vacuum. The reaction mixture was poured into 25 mL H₂O and extracted with EtOAc (25 mL×3). Combined the organic layers were, washed with sat. NaCl (25 mL), dried over Na₂SO₄and concentrated in vacuum to afford tert-butyl 3-[[4-[[[2-ethyl-4-[(3-iodoimidazo[1,2-a]pyrazin-8-yl)amino]benzoyl]amino]methyl]-1-piperidyl]methyl]azetidine-1-carboxylate (160 mg, 238 μmol, 59.9% yield). MS [M+H]⁺: 674.2.

Intermediate C4
tert-Butyl 2-[4-[[[2-ethyl-4-[(3-iodoimidazo[1,2-a]pyrazin-8-yl)amino]benzoyl]amino]methyl]-1-piperidyl]acetate

In a 50 mL round-bottomed flask, 2-ethyl-4-((3-iodoimidazo[1,2-a]pyrazin-8-yl)amino)-N-(piperidin-4-ylmethyl)benzamide (120 mg, 238 μmol) and DIPEA (40 mg, 54 μl, 309 μmol) were combined with DMF (3 mL) to give a light brown solution, tert-butyl 2-bromoacetate (60.3 mg, 309 μmol) added. The reaction stirred at room temperature for 1 h. The reaction mixture was poured into 25 mL H₂O and extracted with EtOAc (25 mL×3). The organic layers were combined, washed with sat NaCl (25 mL). The organic layers were dried over Na₂SO₄and concentrated in vacuum to afford tert-butyl 2-[4-[[[2-ethyl-4-[(3-iodoimidazo[1,2-a]pyrazin-8-yl)amino]benzoyl]amino]methyl]-1-piperidyl]acetate (112 mg, 181 μmol, 76.1% yield). MS [M+H]⁺: 619.2.

Intermediate C5
N-[[1-(2-Amino-2-oxo-ethyl)-4-piperidyl]methyl]-2-ethyl-4-[(3-iodoimidazo[1,2-a]pyrazin-8-yl)amino]benzamide

In a 50 mL round-bottomed flask, 2-ethyl-4-((3-iodoimidazo[1,2-a]pyrazin-8-yl)amino)-N-(piperidin-4-ylmethyl)benzamide (140 mg, 278 μmol) and DIPEA (46.6 mg, 63 μl, 361 μmol) were combined with DMF (3 mL) to give a light brown solution. 2-iodoacetamide (56.5 mg, 305 μmol) was added. The reaction stirred at room temperature for 1 h. The reaction mixture was poured into 25 mL H₂O and extracted with EtOAc (25 mL×3). The organic layers were combined, washed with sat NaCl (25 mL). The organic layers dried over Na₂SO₄and concentrated in vacuum. The crude material purified by flash chromatography (silica gel, 12 g, 0% to 10% MeOH in DCM) to afford N-[[1-(2-amino-2-oxo-ethyl)-4-piperidyl]methyl]-2-ethyl-4-[(3-iodoimidazo[1,2-a]pyrazin-8-yl)amino]benzamide (112 mg, 199 μmol, 71.9% yield). MS[M+H]⁺: 562.2.

Intermediate D1
tert-Butyl 3-[[4-[[[4-[[3-[2,3-difluoro-4-[3-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]methyl]-1-piperidyl]methyl]azetidine-1-carboxylate

To a 25 mL microwave vial, tert-butyl 3-((4-((2-ethyl-4-((3-iodoimidazo[1,2-a]pyrazin-8-yl)amino)benzamido)methyl)piperidin-1-yl)methyl)azetidine-1-carboxylate (75 mg, 111 μmol), 4-(2,3-difluoro-4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)phenyl)-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (100 mg, 223 μmol), PdCl₂(dppf)-CH₂Cl₂adduct (8.15 mg, 11.1 μmol) and Na₂CO₃(35.4 mg, 334 μmol) was added with Dioxane (10 mL)/Water (1 mL). The vial capped and heated at 100° C. for 2 h under N₂. The crude reaction mixture concentrated in vacuum. The crude material purified by flash chromatography (silica gel, 40 g, 0% to 10% MeOH in DCM) to afford tert-butyl 3-[[4-[[[4-[[3-[2,3-difluoro-4-[3-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]methyl]-1-piperidyl]methyl]azetidine-1-carboxylate (39 mg, 44.8 μmol, 40.3% yield). MS [M+H]⁺: 870.6.

The following intermediates were prepared in analogy:

MS
Starting

Int.
Name
ESI [M + H]⁺
Material

Intermediate
N-[[1-(2-amino-2-oxo-ethyl)-4-
772.8
Intermediate B1;

D2
piperidyl]methyl]-4-[[3-

Intermediate C5

[2,3-difluoro-4-[3-methyl-1-(2-

trimethylsilylethoxymethyl)pyrazol-4-

yl]phenyl]imidazo[1,2-a]pyrazin-8-

yl]amino]-2-ethyl-benzamide

Intermediate
tert-butyl 3-[[4-[[[4-[[3-
870.6
Intermediate B1;

D3
[2,3-difluoro-4-[3-methyl-1-(2-

Intermediate C3

trimethylsilylethoxymethyl)pyrazol-4-

yl]phenyl]imidazo[1,2-a]pyrazin-8-

yl]amino]-2-ethyl-

benzoyl]amino]methyl]-1-

piperidyl]methyl]azetidine-1-carboxylate

Intermediate
tert-butyl 2-[4-[[[4-[[3-
815.7
Intermediate B1;

D4
[2,3-difluoro-4-[3-methyl-1-(2-

Intermediate C4

trimethylsilylethoxymethyl)pyrazol-4-

yl]phenyl]imidazo[1,2-a]pyrazin-8-

yl]amino]-2-ethyl-

benzoyl]amino]methyl]-1-

piperidyl]acetate

Intermediate
tert-butyl 4-[[[4-[[3-[2,3-
671.6
Intermediate B3;

D5
difluoro-4-(3-methyl-1H-pyrazol-4-

Intermediate C1

yl)phenyl]imidazo[1,2-a]pyrazin-8-

yl]amino]-2-ethyl-

benzoyl]amino]methyl]piperidine-1-

carboxylate

Intermediate
tert-butyl 4-((4-((3-(2,3-difluoro-4-(1-(2-
729.4
Intermediate B6;

D6
methoxyethyl)-3-methyl-1H-pyrazol-4-

Intermediate C1

yl)phenyl)imidazo[1,2-a]pyrazin-8-

yl)amino)-2-

ethylbenzamido)methyl)piperidine-1-

carboxylate

Intermediate
tert-butyl 4-((4-((3-(2,3-difluoro-4-(1-(2-
743.5
Intermediate B5;

D7
methoxyethyl)-3,5-dimethyl-1H-pyrazol-

Intermediate C1

4-yl)phenyl)imidazo[1,2-a]pyrazin-8-

yl)amino)-2-

ethylbenzamido)methyl)piperidine-1-

carboxylate

Intermediate
tert-butyl 3-((4-((2-ethyl-4-((3-(4-(3-
704.9
Intermediate B2;

D8
methyl-1H-pyrazol-4-

Intermediate C3

yl)phenyl)imidazo[1,2-a]pyrazin-8-

yl)amino)benzamido)methyl)piperidin-1-

yl)methyl)azetidine-1-carboxylate

Intermediate
tert-butyl 3-((4-((4-((3-(2,3-difluoro-4-
794.6
Intermediate B4;

D9
(3-(trifluoromethyl)-1H-pyrazol-4-

Intermediate C3

yl)phenyl)imidazo[1,2-a]pyrazin-8-

yl)amino)-2-

ethylbenzamido)methyl)piperidin-1-

yl)methyl)azetidine-1-carboxylate

Intermediate E1
tert-Butyl 3-[[4-[[[4-[[3-(6-chloro-2-fluoro-3-pyridyl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]methyl]-1-piperidyl]methyl]azetidine-1-carboxylate

To a 25 mL microwave vial was added tert-butyl 3-((4-((2-ethyl-4-((3-iodoimidazo[1,2-a]pyrazin-8-yl)amino)benzamido)methyl)piperidin-1-yl)methyl)azetidine-1-carboxylate (100 mg, 148 μmol) and (6-chloro-2-fluoropyridin-3-yl)boronic acid (28.6 mg, 163 μmol), PdCl₂(DPPF)-CH₂Cl₂adduct (21.7 mg, 29.7 μmol) and Na₂CO₃(47.2 mg, 445 μmol) in Dioxane (10 mL)/Water (1 mL). The vial capped and heated at 100° C. for 2 h under N₂. The reaction was directly used to the next step. MS [M+H]⁺: 677.5.

The following intermediates were prepared in analogy:

MS
Starting

Int.
Name
ESI [M + H]⁺
Material

Intermediate
tert-butyl 3-[[4-[[[4-[[3-(6-
673.5
Intermediate C3;

E2
chloro-4-methyl-3-

(6-chloro-4-methylpyridin-3-

pyridyl)imidazo[1,2-

yl)boronic

a]pyrazin-8-yl]amino]-2-

ethyl-

benzoyl]amino]methyl]-1-

piperidyl]methyl]azetidine-1-

carboxylate

Intermediate
tert-butyl 3-[[4-[[[4-[[3-(6-
677.6
Intermediate C3;

E3
chloro-5-fluoro-3-

(6-chloro-5-fluoropyridin-3-

pyridyl)imidazo[1,2-

yl)boronic acid

a]pyrazin-8-yl]amino]-2-

ethyl-

benzoyl]amino]methyl]-1-

piperidyl]methyl]azetidine-1-

carboxylate

Intermediate F1
tert-Butyl 3-[[4-[[[2-ethyl-4-[[3-[2-fluoro-6-(3-methyl-1H-pyrazol-4-yl)-3-pyridyl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]amino]methyl]-1-piperidyl]methyl]azetidine-1-carboxylate

To a 25 mL microwave vial, tert-butyl 3-((4-((4-((3-(6-chloro-2-fluoropyridin-3-yl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)methyl)piperidin-1-yl)methyl)azetidine-1-carboxylate (101 mg, 149 μmol), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (46.5 mg, 224 μmol), 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (9.72 mg, 14.9 μmol) and Na₂CO₃(31.6 mg, 298 μmol) was added with Dioxane (10 mL)/Water (1 mL). The microwave vial capped and heated at 110° C. for 2 h under N₂. The reaction mixture filtered through glass fiber paper. The crude filtrate was concentrated in vacuum. The crude material purified by flash chromatography (silica gel, 20 g, 0% to 20% MeOH in DCM) to afford tert-butyl 3-[[4-[[[2-ethyl-4-[[3-[2-fluoro-6-(3-methyl-1H-pyrazol-4-yl)-3-pyridyl]imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]amino]methyl]-1-piperidyl]methyl]azetidine-1-carboxylate (60 mg, 83 μmol, 55.7% yield). MS[M+H]⁺: 723.5.

The following intermediates were prepared in analogy:

MS
Starting

Int.
Name
ESI [M + H]⁺
Material

Intermediate
tert-butyl 3-[[4-[[[2-ethyl-
719.7
Intermediate E2;

F2
4-[[3-[4-methyl-6-(3-

3-methyl-4-(4,4,5,5-tetramethyl-

methyl-1H-pyrazol-4-yl)-

1,3,2-dioxaborolan-2-yl)-1H-

3-pyridyl]imidazo[1,2-

pyrazole

a]pyrazin-8-

yl]amino]benzoyl]amino]

methyl]-1-

piperidyl]methyl]azetidine-

1-carboxylate

Intermediate
tert-butyl 3-[[4-[[[2-ethyl-
723.7
Intermediate E3;

F3
4-[[3-[5-fluoro-6-(3-

3-methyl-4-(4,4,5,5-tetramethyl-

methyl-1H-pyrazol-4-yl)-

1,3,2-dioxaborolan-2-yl)-1H-

3-pyridyl]imidazo[1,2-

pyrazole

a]pyrazin-8-

yl]amino]benzoyl]amino]

methyl]-1-

piperidyl]methyl]azetidine-

1-carboxylate

Intermediate
tert-butyl 3-[[4-[[[4-[[3-[6-
737.6
Intermediate E1;

F4
(3,5-dimethyl-1H-pyrazol-

3,5-dimethyl-4-(4,4,5,5-

4-yl)-2-fluoro-3-

tetramethyl-1,3,2-dioxaborolan-

pyridyl]imidazo[1,2-

2-yl)-1H-pyrazole

a]pyrazin-8-yl]amino]-2-

ethyl-

benzoyl]amino]methyl]-1-

piperidyl]methyl]azetidine-

1-carboxylate

Intermediate G1
4-[[3-[2,3-Difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-N-[(1-methyl-4-piperidyl)methyl]benzamide
Step 1: 4-[[3-[2,3-difluoro-4-[l-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-N-(4-piperidylmethyl)benzamide

In a 50 mL round-bottomed flask, tert-butyl 4-((4-((3-(2,3-difluoro-4-(1-(2-methoxyethyl)-3-methyl-1H-pyrazol-4-yl)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)methyl)piperidine-1-carboxylate (275 mg, 377 μmol) was combined with THE (2 mL) to give a light brown solution. HCl (1.89 mL, 22.6 mmol) added. The reaction stirred at room temperature for 20 min. The crude reaction mixture was concentrated in vacuum, the crude product was directly used to the next step to afford 4-[[3-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-N-(4-piperidylmethyl)benzamide (237 mg, 377 μmol, 99.9% yield). MS [M+H]⁺: 629.5.

Step 2: 4-[[3-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]-imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-N-[(1-methyl-4-piperidyl)methyl]benzamide

In a 50 mL round-bottomed flask, 4-((3-(2,3-difluoro-4-(1-(2-methoxyethyl)-3-methyl-1H-pyrazol-4-yl)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethyl-N-(piperidin-4-ylmethyl)benzamide (237 mg, 377 μmol), formaldehyde (153 mg, 1.88 mmol) and NaBH₃CN (118 mg, 1.88 mmol) were combined with MeOH (6 mL) to give a light brown solution. The reaction mixture heated to 50° C. and stirred for 20 min. The crude reaction mixture was concentrated in vacuum. The reaction mixture was poured into 25 mL sat NaHCO₃and extracted with EtOAc (25 mL×3). The organic layers were combined, washed with sat NaCl (25 mL). Dried over Na₂SO₄and concentrated in vacuum to afford 4-((3-(2,3-difluoro-4-(1-(2-methoxyethyl)-3-methyl-1H-pyrazol-4-yl)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethyl-N-((1-methylpiperidin-4-yl)methyl)benzamide (242 mg, 377 μmol, 99.9% yield) MS[M+H]⁺: 643.4.

The following intermediates were prepared in analogy:

MS
Starting

Int.
Name
ESI [M + H]⁺
Material

Intermediate
4-[[3-[2,3-difluoro-4-[1-(2-
657.3
Intermediate D7

G2
methoxyethyl)-3,5-dimethyl-pyrazol-4-

yl]phenyl]imidazo[1,2-a]pyrazin-8-

yl]amino]-2-ethyl-N-[(1-methyl-4-

piperidyl)methyl]benzamide

Example A1
N-[[1-(Azetidin-3-ylmethyl)-4-piperidyl]methyl]-4-[[3-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide; formic acid

[Image Omitted]

In a 100 mL round-bottomed flask, tert-butyl 3-((4-((4-((3-(2,3-difluoro-4-(3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)methyl)piperidin-1-yl)methyl)azetidine-1-carboxylate (39 mg, 44.8 μmol) was combined with DCM (3 mL) to give a light brown solution. 2,2,2-trifluoroacetic acid (1.02 g, 8.96 mmol) was added. The reaction stirred at room temperature for 1 h. The crude reaction mixture was concentrated in vacuum. The crude material was purified by preparative HPLC, to obtain N-[[1-(azetidin-3-ylmethyl)-4-piperidyl]methyl]-4-[[3-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide; formic acid (9 mg, 10.2 μmol, 22.7% yield). MS [M+H]+. 640.2.

Example A2
N-[[1-(Azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]-4-[[3-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide; formic acid; formate

[Image Omitted]

Step 1: tert-butyl 3-[[4-[[[4-[[3-[2,3-difluoro-4-[3-methyl-1-(2-trimethylsilylethoxymethyl) pyrazol-4-yl]phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]methyl]-1-methyl-piperidin-1-ium-1-yl]methyl]azetidine-1-carboxylate; iodide

In a 50 mL round-bottomed flask, tert-butyl 3-((4-((4-((3-(2,3-difluoro-4-(3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)methyl)piperidin-1-yl)methyl)azetidine-1-carboxylate (29 mg, 33.3 μmol) and Mel (23.7 mg, 167 μmol) and DIPEA (21.5 mg, 167 μmol) were combined with MeCN (3 mL) to give a light brown solution. The reaction stirred at room temperature for 2 h. The crude reaction mixture was concentrated in vacuum to afford tert-butyl 3-[[4-[[[4-[[3-[2,3-difluoro-4-[3-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]methyl]-1-methyl-piperidin-1-ium-1-yl]methyl]azetidine-1-carboxylate; iodide (29.5 mg, 33.3 μmol, 100% yield). MS [M+H]⁺: 884.9.

Step 2: N-[[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]-4-[[3-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide; formic acid; formate

In a 50 mL round-bottomed flask, 1-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)-4-((4-((3-(2,3-difluoro-4-(3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)methyl)-1-methylpiperidin-1-ium (29.5 mg, 33.3 μmol) and HCl (in water) (1.11 mL, 13.3 mmol) were combined with THE (2 mL) to give a light brown solution. HCl (in water) (1.11 mL, 13.3 mmol) added. The reaction stirred at room temperature for 1 h. The crude reaction mixture was concentrated in vacuum. The crude material purified by preparative HPLC to afford N-[[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]-4-[[3-[2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide; formic acid; formate (9.4 mg, 12.4 μmol, 37.1% yield). MS: 654.8.

The following compounds were prepared in analogy:

MS

ESI
Starting

Ex.
Name
Structure
[M + H]⁺
Material

Example A3
2-[4-[[[4-[[3-[2,3- difluoro-4-(3-methyl- 1H-pyrazol-4- yl)phenyl]imidazo[1,2- a]pyrazin-8-yl]amino]-2- ethyl- benzoyl]amino]methyl]- 1-piperidyl]acetic acid

[Image Omitted]

674.7
Intermediate D4

Example A4
2-[4-[[[4-[[3-[2,3- difluoro-4-(3-methyl- 1H-pyrazol-4- yl)phenyl]imidazo[1,2- a]pyrazin-8-yl]amino]-2- ethyl- benzoyl]amino]methyl]- 1-methyl-piperidin-1- ium-1-yl]acetic acid; formate

[Image Omitted]

643.5
Intermediate D4

Example A5
2-[1-(azetidin-3- ylmethyl)-4-[[[4-[[3- [2,3-difluoro-4-(3- methyl-1H-pyrazol-4- yl)phenyl]imidazo[1,2- a]pyrazin-8-yl]amino]-2- ethyl- benzoyl]amino]methyl] piperidin-1-ium-1- yl]acetic acid; formic acid; formate

[Image Omitted]

698.8
Intermediate D3; tert-butyl 2- bromoacetate

Example A6
4-[[3-[2,3-difluoro-4-(3- methyl-1H-pyrazol-4- yl)phenyl]imidazo[1,2- a]pyrazin-8-yl]amino]-2- ethyl-N-(4- piperidylmethyl) benzamide; formic acid

[Image Omitted]

571.5
Intermediate D5

Example A7
N-[[1-(2-amino-2-oxo- ethyl)-1-methyl- piperidin-1-ium-4- yl]methyl]-4-[[3-[2,3- difluoro-4-(3-methyl- 1H-pyrazol-4- yl)phenyl]imidazo[1,2- a]pyrazin-8-yl]amino]-2- ethyl-benzamide; formate

[Image Omitted]

642.5
Intermediate D2

Example A8
2-[1-(2-amino-2-oxo- ethyl)-4-[[[4-[[3-[2,3- difluoro-4-(3-methyl- 1H-pyrazol-4- yl)phenyl]imidazo[1,2- a]pyrazin-8-yl]amino]-2- ethyl- benzoyl]amino]methyl] piperidin-1-ium-1- yl]acetic acid; formate

[Image Omitted]

686.5
Intermediate D4

Example A9
2-[1-(carboxymethyl)-4- [[[4-[[3-[2,3-difluoro-4- (3-methyl-1H-pyrazol-4- yl)phenyl]imidazo[1,2- a]pyrazin-8-yl]amino]-2- ethyl- benzoyl]amino]methyl] piperidin-1-ium-1- yl]acetic acid; formate

[Image Omitted]

687.4
Intermediate D4; tert-butyl 2- bromoacetate

Example A10
N-[[1-(azetidin-3- ylmethyl)-4- piperidyl]methyl]-2- ethyl-4-[[3-[2-fluoro-6- (3-methyl-1H-pyrazol-4- yl)-3- pyridyl]imidazo[1,2- a]pyrazin-8- yl]amino]benzamide; formic acid

[Image Omitted]

623.5
Intermediate F1

Example A11
N-[[1-(azetidin-3- ylmethyl)-4- piperidyl]methyl]-4-[[3- [6-(3,5-dimethyl-1H- pyrazol-4-yl)-2-fluoro-3- pyridyl]imidazo[1,2- a]pyrazin-8-yl]amino]-2- ethyl-benzamide; formic acid

[Image Omitted]

637.6
Intermediate F4

Example A12
N-[[1-(azetidin-3- ylmethyl)-4- piperidyl]methyl]-4-[[3- [2,3-difluoro-4-[3- (trifluoromethyl)-1H- pyrazol-4- yl]phenyl]imidazo[1,2- a]pyrazin-8-yl]amino]-2- ethyl-benzamide; formic acid

[Image Omitted]

694.5
Intermediate D9

Example B1
N-[[1-(Azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]-2-ethyl-4-[[3-[2-fluoro-6-(3-methyl-1H-pyrazol-4-yl)-3-pyridyl]imidazo[1,2-a]pyrazin-8-yl]amino]benzamide; formic acid; formate

[Image Omitted]

Step 1: tert-butyl 4-(5-(8-((4-(((1-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)piperidin-4-yl)methyl)carbamoyl)-3-ethylphenyl)amino)imidazo[1,2-a]pyrazin-3-yl)-6-fluoropyridin-2-yl)-3-methyl-1H-pyrazole-1-carboxylate

In a 50 mL round-bottomed flask, Boc₂O (24.2 mg, 111 μmol), tert-butyl 3-((4-((2-ethyl-4-((3-(2-fluoro-6-(3-methyl-1H-pyrazol-4-yl)pyridin-3-yl)imidazo[1,2-a]pyrazin-8-yl)amino)benzamido)methyl)piperidin-1-yl)methyl)azetidine-1-carboxylate (40 mg, 55.3 μmol,), DMAP (2.03 mg, 16.6 μmol) and DIPEA (21.5 mg, 166 μmol) were combined with THF (3 mL) to give a light brown solution. The reaction mixture stirred at 50° C. for 2 hs. The crude reaction mixture was concentrated in vacuum to afford tert-butyl 4-(5-(8-((4-(((1-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)piperidin-4-yl)methyl)carbamoyl)-3-ethylphenyl)amino)imidazo[1,2-a]pyrazin-3-yl)-6-fluoropyridin-2-yl)-3-methyl-1H-pyrazole-1-carboxylate (45.5 mg, 55.3 μmol, 99.9% yield). MS: 823.7.

Step 2: tert-butyl 3-[[4-[[[4-[[3-[6-(1,3-dimethylpyrazol-4-yl)-2-fluoro-3-pyridyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]methyl]-1-methyl-piperidin-1-ium-1-yl]methyl]azetidine-1-carboxylate; iodide

In a 50 mL round-bottomed flask, tert-butyl 4-(5-(8-((4-(((1-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)piperidin-4-yl)methyl)carbamoyl)-3-ethylphenyl)amino)imidazo[1,2-a]pyrazin-3-yl)-6-fluoropyridin-2-yl)-3-methyl-1H-pyrazole-1-carboxylate (45 mg, 54.7 μmol), Mel (38.8 mg, 17.1 μl, 273 μmol) and DIPEA (35.3 mg, 47.8 μl, 273 μmol) were combined with MeCN (5 mL) to give a light red solution. The reaction mixture heated to 45° C. and stirred for 1 h. The crude reaction mixture concentrated in vacuum. the crude product was directly used to the next step, to afford tert-butyl 3-[[4-[[[4-[[3-[6-(1,3-dimethylpyrazol-4-yl)-2-fluoro-3-pyridyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzoyl]amino]methyl]-1-methyl-piperidin-1-ium-1-yl]methyl]azetidine-1-carboxylate; iodide (45.8 mg, 54.7 μmol, 100% yield). MS: 837.7.

Step 3: N-[[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]-2-ethyl-4-[[3-[2-fluoro-6-(3-methyl-1H-pyrazol-4-yl)-3-pyridyl]imidazo[1,2-a]pyrazin-8-yl]amino]benzamide; formic acid; formate

In a 50 mL round-bottomed flask, 4-((4-((3-(6-(1-(tert-butoxycarbonyl)-3-methyl-1H-pyrazol-4-yl)-2-fluoropyridin-3-yl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamido)methyl)-1-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)-1-methylpiperidin-1-ium (45 mg, 53.7 μmol) was combined with THE (2 mL) to give a light red solution. HCl (in water) (1.34 mL, 16.1 mmol) was added. The reaction stirred at room temperature for 1 h. The crude reaction mixture was concentrated in vacuum. The crude material was purified by preparative HPLC to afford N-[[1-(azetidin-3-ylmethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]-2-ethyl-4-[[3-[2-fluoro-6-(3-methyl-1H-pyrazol-4-yl)-3-pyridyl]imidazo[1,2-a]pyrazin-8-yl]amino]benzamide; formic acid; formate (6.6 mg, 8.87 μmol, 16.5% yield). MS: 637.

The following compounds were prepared in analogy:

MS
Starting

Int.
Name
Structure
ESI
Material

Example B2
N-[[1-(azetidin-3- ylmethyl)-1-methyl- piperidin-1-ium-4- yl]methyl]-2-ethyl-4- [[3-[4-methyl-6-(3- methyl-1H-pyrazol-4- yl)-3- pyridyl]imidazo[1,2- a]pyrazin-8- yl]amino]benzamide; formic acid; formate

[Image Omitted]

633.6
Intermediate F2

Example B3
N-[[1-(azetidin-3- ylmethyl)-1-methyl- piperidin-1-ium-4- yl]methyl]-2-ethyl-4- [[3-[5-fluoro-6-(3- methyl-1H-pyrazol-4- yl)-3- pyridyl]imidazo[1,2- a]pyrazin-8- yl]amino]benzamide; formic acid; formate

[Image Omitted]

637.5
Intermediate F3

Example B4
N-[[1-(azetidin-3- ylmethyl)-1-methyl- piperidin-1-ium-4- yl]methyl]-4-[[3-[6- (3,5-dimethyl-1H- pyrazol-4-yl)-2-fluoro- 3-pyridyl]imidazo[1,2- a]pyrazin-8-yl]amino]- 2-ethyl-benzamide; formic acid; formate

[Image Omitted]

651.5
Intermediate F4

Example B5
N-[[1-(azetidin-3- ylmethyl)-1-methyl- piperidin-1-ium-4- yl]methyl]-2-ethyl-4- [[3-[4-(3-methyl-1H- pyrazol-4- yl)phenyl]imidazo[1,2- a]pyrazin-8- yl]amino]benzamide; formic acid; formate

[Image Omitted]

618.6
Intermediate D8

Example B6
N-[[1-(azetidin-3- ylmethyl)-1-methyl- piperidin-1-ium-4- yl]methyl]-4-[[3-[2,3- difluoro-4-[3- (trifluoromethyl)-1H- pyrazol-4- yl]phenyl]imidazo[1,2- a]pyrazin-8-yl]amino]- 2-ethyl-benzamide; formic acid; formate

[Image Omitted]

708.5
Intermediate D9

Example C1
4-[[3-[2,3-Difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-N-[(1,1-dimethylpiperidin-1-ium-4-yl)methyl]-2-ethyl-benzamide; formate

[Image Omitted]

In a 50 mL round-bottomed flask, 4-((3-(2,3-difluoro-4-(1-(2-methoxyethyl)-3-methyl-1H-pyrazol-4-yl)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethyl-N-((1-methylpiperidin-4-yl)methyl)benzamide (60 mg, 93.3 μmol), Mel (66.2 mg, 29.2 μl, 467 μmol) and DIPEA (60.3 mg, 81.5 μl, 467 μmol) were combined with MeCN (5 mL) to give a light brown solution. The reaction stirred at room temperature for 15 h. The crude reaction mixture was concentrated in vacuum. The crude material was purified by preparative HPLC to afford 4-[[3-[2,3-difluoro-4-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-N-[(1,1-dimethylpiperidin-1-ium-4-yl)methyl]-2-ethyl-benzamide; formate (10.6 mg, 14.8 μmol, 15.8% yield). MS: 657.5.

The following compounds were prepared in analogy:

MS

ESI
Starting

Int.
Name
Structure
[M + H]⁺
Material

Example C2
N-[[1-(2-amino-2-oxo- ethyl)-1-methyl - piperidin-1-ium-4- yl]methyl]-4-[[3-[2,3- difluoro-4-[1-(2- methoxyethyl)-3- methyl-pyrazol-4- yl]phenyl]imidazo[1,2- a]pyrazin-8- yl]amino]-2-ethyl- benzamide; formate

[Image Omitted]

700.5
Intermediate G1; 2-iodoacetamide

Example C3
4-[[3-[2,3-difluoro-4- [1-(2-methoxyethyl)- 3-methyl-pyrazol-4- yl]phenyl]imidazo[1,2- a]pyrazin-8- yl]amino]-2-ethyl-N- [[1-(2-hydroxyethyl)- 1-methyl-piperidin-1- ium-4- yl]methyl]benzamide; formate

[Image Omitted]

687.5
Intermediate G1; 2-bromoethanol

Example C4
N-[[1-(azetidin-3- ylmethyl)-1-methyl- piperidin-1-ium-4- yl]methyl]-4-[[3-[2,3- difluoro-4-[1-(2- methoxyethyl)-3- methyl-pyrazol-4- yl]phenyl]imidazo[1,2- a]pyrazin-8- yl]amino]-2-ethyl- benzamide; formic acid; formate

[Image Omitted]

712.5
Intermediate G1; tert-butyl 3- (iodomethyl) azetidine-1- carboxylate

Example C5
N-[[1-(2-amino-2-oxo- ethyl)-1-methyl- piperidin-1-ium-4- yl]methyl]-4-[[3-[2,3- difluoro-4-[1-(2- methoxyethyl)-3,5- dimethyl-pyrazol-4- yl]phenyl]imidazo[1,2- a]pyrazin-8- yl]amino]-2-ethyl- benzamide; formate

[Image Omitted]

712.4
Intermediate G2; 2-iodoacetamide

Example C6
4-[[3-[2,3-difluoro-4- [1-(2-methoxyethyl)- 3,5-dimethyl-pyrazol- 4- yl]phenyl]imidazo[1,2- a]pyrazin-8- yl]amino]-2-ethyl-N- [[1-(2-hydroxyethyl)- 1-methyl-piperidin-1- ium-4- yl]methyl]benzamide; formate

[Image Omitted]

701.5
Intermediate G2; 2-iodoethan-1- ol

Example C7
N-[[1-(azetidin-3- ylmethyl)-1-methyl- piperidin-1-ium-4- yl]methyl]-4-[[3-[2,3- difluoro-4-[1-(2- methoxyethyl)-3,5- dimethyl-pyrazol-4- yl]phenyl]imidazo[1,2- a]pyrazin-8- yl]amino]-2-ethyl- benzamide; formic acid; formate

[Image Omitted]

712.4
Intermediate G2; tert-butyl 3- (iodomethyl) azetidine-1- carboxylate

Example D1
N-[[1-(2-Amino-2-oxo-ethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]-4-[[3-[4-[1-(cyanomethyl)-3-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide; formate

[Image Omitted]

Step 1: N-((1-(2-amino-2-oxoethyl)piperidin-4-yl)methyl)-4-((3-(2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamide

In a 50 mL round-bottomed flask, N-((1-(2-amino-2-oxoethyl)piperidin-4-yl)methyl)-4-((3-(2,3-difluoro-4-(3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamide (14 mg, 18.5 μmol) and HCl (462 μl, 5.54 mmol) were combined with THF (2 mL) to give a light brown solution. The reaction mixture heated to 45° C. and stirred for 15 h. The crude reaction mixture was concentrated in vacuum to afford N-((1-(2-amino-2-oxoethyl)piperidin-4-yl)methyl)-4-((3-(2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamide (11.6 mg, 18.5 μmol, 100% yield). MS[M+H]⁺: 628.5.

Step 2: N-((1-(2-amino-2-oxoethyl)piperidin-4-yl)methyl)-4-((3-(4-(1-(cyanomethyl)-3-methyl-1H-pyrazol-4-yl)-2,3-difluorophenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamide

In a 50 mL round-bottomed flask, N-((1-(2-amino-2-oxoethyl)piperidin-4-yl)methyl)-4-((3-(2,3-difluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamide (11.6 mg, 18.5 μmol), 3-bromoprop-1-yne (4.4 mg, 37 μmol) and DIPEA (7.17 mg, 9.68 μl, 55.4 μmol) were combined with DCM (2 mL) to give a light brown solution. The reaction stirred at room temperature for 1 h. The crude reaction mixture was concentrated in vacuum to afford N-((1-(2-amino-2-oxoethyl)piperidin-4-yl)methyl)-4-((3-(4-(1-(cyanomethyl)-3-methyl-1H-pyrazol-4-yl)-2,3-difluorophenyl)imidazo[1,2-a]pyrazin-8-yl)amino)-2-ethylbenzamide (12.3 mg, 18.4 μmol, 99.8% yield). MS[M+H]⁺: 667.8

Step 3: N-[[1-(2-amino-2-oxo-ethyl)-1-methyl-piperidin-1-ium-4-yl]methyl]-4-[[3-[4-[1-(cyanomethyl)-3-methyl-pyrazol-4-yl]-2,3-difluoro-phenyl]imidazo[1,2-a]pyrazin-8-yl]amino]-2-ethyl-benzamide; formate