The present invention relates to benzimidazole compounds and their pharmaceutically acceptable salts, that inhibit Janus kinase 1 (JAK1), pharmaceutical compositions comprising the compounds, methods of using the compounds to treat certain types of autoimmune diseases and cancer, and processes for preparing the compounds.

The family of Janus kinases (JAK1, JAK2, JAK3 and TYK2) are intracellular protein tyrosine kinases with essential roles in immune function, inflammation, and hematopoiesis through the Janus kinase-signal transducer and activator of transcription (the JAK-STAT) pathway. In response to extracellular polypeptides such as type 1 and type II cytokines, the Janus kinases regulate the tyrosine phosphorylation of various effectors and initiate activation of downstream signaling pathways inducing different physiological responses. Specifically the JAK1 isoform plays a key role in types I and II interferon signaling and elicits signals from the interleukin-2 (1L-2), interleukin-4 (IL-4), glycoprotein 130 (gp130) and class II receptor families. As such, small molecule inhibition of JAK1 may intervene in the signaling pathways involved in oncology, inflammation and autoimmune diseases. Ghoreschi K et al. Immunological Review 2009, 228, 273-287 and Zak M. et al. Med Chem. 2013, 56, 4764-4785.

Despite the recent successes of JAK inhibitor agents, there is still a need to discover and develop inhibitors, which selectively target a single JAK isoform. This can mitigate the risk of off target affects.

Janus kinase inhibitor compounds are known in the literature. For example, US 2015/0203455 discloses certain benzimidazole compounds that are JAK inhibitors and which are touted as being useful to treat autoimmune diseases, inflammatory diseases and proliferative diseases inter alia.

There remains a need to provide alternative JAK1 inhibitors for treatment of autoimmune diseases particularly for immunological diseases, such as arthritis, rheumatoid arthritis, and diabetic nephropathy. In addition, there remains a need to provide selective JAK1 inhibitors. The present invention provides certain inhibitors of JAK1, which can address one or more of these needs.

The present invention provides a compound of Formula 1, or a pharmaceutically acceptable salt thereof:

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where R is selected from: H, —C_1-3alkyl, —CH₂CH(OH)CH₃, or —C_2-3alkyl-O—CH₃,

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R1 is selected from: H, —CH₃and —OCH₃; R2 is —CHF₂or —CF₃; and R3 is H or —CH₃; provided that when R2 is —CF₃and R3 is H, either R or R1 can be —CH₃but not both. The bond illustrated as

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indicates the point of attachment of the tetrahydropyran ring or pyridine ring to the rest of the molecule.

The present invention provides a compound of Formula 2, or a pharmaceutically acceptable salt there, which is,

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where R is selected from: H, —C_1-3alkyl, —CH₂CH(OH)CH₃, or —C_2-3alkyl-O-CH₃,

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R1 is selected from: H, —CH₃and —OCH₃; R2 is —CHF₂or —CF₃; and R3 is H or —CH₃; provided that when R2 is —CF₃and R3 is CH₃, either R or R1 can be —CH₃but not both.

In one form, the present invention provides a compound according to Formula 1 or 2 where R is selected from: —CH₃, —CH₂CH₃, and

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or a pharmaceutically acceptable salt thereof. In certain embodiments, R is —CH₃, or —CH₂CH₃. In other embodiments, R is

[Image Omitted]

In another form the present invention provides a compound according to Formula 1 or 2 where R is

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where the bond illustrated as

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indicates the point of attachment to the rest of the molecule. In another form, the present invention provides a compound according to Formula 1 or 2 where R is

[Image Omitted]

In another form, the present invention provides a compound according to Formula 1 or 2 where R1 is selected from: H, —CH₃, and —OCH₃. In certain embodiments R1 is H or —CH₃. In other embodiments, R1 is —OCH₃.

In another form, the present invention provides a compound according to Formula 1 or 2 where R2 is —CF₃. In certain embodiments of this form, R is —CH₃, or —CH₂CH₃and R1 is —CH₃, or —OCH₃. In other embodiments of this form, R is

[Image Omitted]

and R1 is H.

In another form, the present invention provides a compound according to Formula 1 or 2 wherein R3 is —CH₃. In certain embodiments R is H, R1 is H, and R2 is CH₃.

In one embodiment, the present invention provides a compound of Formula 3 which is

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