3-(2-(Heteroaryl)-pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole derivatives as HDAC6 inhibitors

Abstract

The present invention relates to compounds as described herein for use as histone deacetylase 6 (HDAC6) inhibitors. The present invention also relates to pharmaceutical compositions comprising these compounds and their use in therapy.

Description

Technical Field

[0001] The present invention relates to 3-(2-(heteroaryl)-pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole derivatives which are useful as inhibitors of histone deacetylase 6. The invention also relates to pharmaceutical compositions comprising these compounds and their use in therapy.

[0002] background

[0003] Histone deacetylase (HDAC) is a component of a large family of enzymes that catalyze the removal of acetyl groups from histone and non-histone proteins. HDAC plays a vital role in many biological processes, mainly through their inhibitory effects on transcription. In humans, there are four classes of HDAC, including a total of 18 proteins: Class I HDAC is HDAC1, HDAC2, HDAC3 and HDAC8; Class II HDAC is HDAC4, HDAC5, HDAC6, HDAC7, HDAC9 and HDAC10; Class III HDAC is Sir2-like protein SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6 and SIRT7; and Class IV HDAC, which is HDAC11. Class II enzymes are further divided into two subclasses, Class IIa (HDAC4, HDAC5, HDAC7 and HDAC9) and Class IIb (HDAC6 and HDAC10).

[0004] Histone deacetylase 6 (HDAC6) primarily catalyzes the deacetylation of non-histone substrates, such as α-tubulin, heat shock protein (Hsp) 90, and cortical actin.

[0005] It is reported that HDAC6 activity is involved in a variety of pathological conditions, including cancer, neurological diseases, ciliopathies, cardiovascular diseases, infectious diseases and immune diseases and inflammatory diseases, as discussed in more detail below. Therefore, HDAC6 inhibitors have become an attractive method for treating a wide spectrum of diseases. It is still very desirable to provide HDAC6 inhibitors, particularly compounds that are effective and / or selective inhibitors of HDAC6 and exhibit properties suitable for drug development. The present invention addresses these and other needs. SUMMARY OF THE INVENTION

[0007] Provided herein are compounds and salts thereof that are inhibitors of HDAC, particularly HDAC6, and methods of using these compounds to treat diseases associated with HDAC6, including cancer, autoimmune or inflammatory diseases, transplant rejection, ciliopathy, neurological diseases, infectious diseases, cardiovascular diseases, muscle atrophy, and cachexia.

[0008] Therefore, the present invention provides a compound selected from the group consisting of:

[0009] (1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)(morpholino)methanone,

[0010] N-(3-(dimethylamino)propyl)-N,1-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide,

[0011] N-(2-hydroxyethyl)-N,1-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide,

[0012] N,1-dimethyl-N-((1-methylpiperidin-4-yl)methyl)-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide,

[0013] N,N-bis(2-hydroxyethyl)-1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide,

[0014] N-(cyclopropylmethyl)-N,1-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide,

[0015] N-(2-methoxyethyl)-N,1-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide,

[0016] (1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)(piperazin-1-yl)methanone,

[0017] N-ethyl-N,1-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide,

[0018] N,N-bis(2-methoxyethyl)-1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide,

[0019] (S)-(1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)(3-methylmorpholino)methanone,

[0020] (3-hydroxypyrrolidin-1-yl)(1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone,

[0021] 3-(2-(1-(3-methoxypropyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,

[0022] 3-(2-(1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,

[0023] 3-(2-(7-chloro-1-(2-methoxyethyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, and

[0024] 3-(2-(1-(2-methoxyethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole;

[0025] or a salt thereof.

[0026] The present invention also provides a pharmaceutical composition comprising a compound of the present invention (ie, the compound as described above) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0027] The present invention also provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use as a medicament.

[0028] The present invention also provides a compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, for use in treating diseases associated with HDAC6.

[0029] The present invention also provides use of the compound of the present invention or a pharmaceutically acceptable salt thereof in preparing a medicament for treating a disease associated with HDAC6.

[0030] The present invention also provides use of the compound of the present invention or a pharmaceutically acceptable salt thereof in treating diseases associated with HDAC6.

[0031] The present invention also provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use as an HDAC6 inhibitor.

[0032] The present invention also provides a method for treating a disease associated with HDAC6, comprising administering a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0033] The present invention also provides a method for inhibiting HDAC6 activity, comprising administering to a patient in need thereof an amount of a compound of the present invention or a pharmaceutically acceptable salt thereof sufficient to inhibit HDAC6 activity.

[0034] The present invention also provides a compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, for use in treating a disease selected from cancer, autoimmune or inflammatory diseases, transplant rejection, ciliopathies, nervous system diseases, mental or behavioral disorders, infectious diseases, cardiovascular diseases, muscle atrophy and cachexia.

[0035] The present invention also provides the use of the compound of the present invention or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease selected from cancer, autoimmune or inflammatory diseases, transplant rejection, ciliopathies, nervous system diseases, mental or behavioral disorders, infectious diseases, cardiovascular diseases, muscle atrophy and cachexia.

[0036] The present invention also provides the use of the compound of the present invention or a pharmaceutically acceptable salt thereof for treating a disease selected from cancer, autoimmune or inflammatory diseases, transplant rejection, ciliopathies, nervous system diseases, mental or behavioral disorders, infectious diseases, cardiovascular diseases, muscle atrophy and cachexia.

[0037] The present invention also provides a method for treating a disease selected from cancer, autoimmune or inflammatory diseases, transplant rejection, ciliopathies, neurological diseases, mental or behavioral disorders, infectious diseases, cardiovascular diseases, muscle atrophy and cachexia, comprising administering a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a patient in need thereof. DETAILED DESCRIPTION OF THE INVENTION

[0039] The present invention provides a compound selected from the group consisting of:

[0040] (1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)(morpholino)methanone,

[0041] N-(3-(dimethylamino)propyl)-N,1-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide,

[0042] N-(2-hydroxyethyl)-N,1-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide,

[0043] N,1-dimethyl-N-((1-methylpiperidin-4-yl)methyl)-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide,

[0044] N,N-bis(2-hydroxyethyl)-1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide,

[0045] N-(cyclopropylmethyl)-N,1-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide,

[0046] N-(2-methoxyethyl)-N,1-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide,

[0047] (1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)(piperazin-1-yl)methanone,

[0048] N-ethyl-N,1-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide,

[0049] N,N-bis(2-methoxyethyl)-1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide,

[0050] (S)-(1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)(3-methylmorpholino)methanone,

[0051] (3-hydroxypyrrolidin-1-yl)(1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone,

[0052] 3-(2-(1-(3-methoxypropyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,

[0053] 3-(2-(1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,

[0054] 3-(2-(7-chloro-1-(2-methoxyethyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, and

[0055] 3-(2-(1-(2-methoxyethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole;

[0056] or a salt thereof.

[0057] The chemical structures of the compounds of the present invention are shown in Table 1 below:

[0058]

[0059]

[0060] In the following paragraphs embodiments of the invention are summarized.Each embodiment described below can be combined with any other embodiment described herein without that embodiment being inconsistent with the embodiment with which it is combined.

[0061] In addition, each embodiment described herein includes within its scope salts (e.g., pharmaceutically acceptable salts) of the compounds described herein. Therefore, the phrase "or a salt thereof" (also including "or a pharmaceutically acceptable salt thereof") is implicit in the description of all compounds described herein. The present invention also specifically relates to all compounds described herein in non-salt form.

[0062] In certain embodiments, the present invention provides a compound selected from the group consisting of:

[0063] (1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)(morpholino)methanone,

[0064] N-(3-(dimethylamino)propyl)-N,1-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide,

[0065] N-(2-hydroxyethyl)-N,1-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide,

[0066] N,1-dimethyl-N-((1-methylpiperidin-4-yl)methyl)-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide,

[0067] N,N-bis(2-hydroxyethyl)-1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide,

[0068] N-(cyclopropylmethyl)-N,1-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide,

[0069] N-(2-methoxyethyl)-N,1-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide,

[0070] (1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)(piperazin-1-yl)methanone,

[0071] N-ethyl-N,1-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide,

[0072] N,N-bis(2-methoxyethyl)-1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide,

[0073] (S)-(1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)(3-methylmorpholino)methanone, and

[0074] (3-hydroxypyrrolidin-1-yl)(1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone;

[0075] or a salt thereof.

[0076] In certain embodiments, the present invention provides a compound selected from the group consisting of: 3-(2-(1-(3-methoxypropyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,

[0077] 3-(2-(1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,

[0078] 3-(2-(7-chloro-1-(2-methoxyethyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, and

[0079] 3-(2-(1-(2-methoxyethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole;

[0080] or a salt thereof.

[0081] In certain embodiments, the present invention provides a compound that is (1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)(morpholino)methanone or a salt thereof.

[0082] In certain embodiments, the present invention provides a compound that is N-(3-(dimethylamino)propyl)-N,1-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide or a salt thereof.

[0083] In certain embodiments, the present invention provides a compound that is N-(2-hydroxyethyl)-N,1-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide or a salt thereof.

[0084] In certain embodiments, the present invention provides a compound which is N,1-dimethyl-N-((1-methylpiperidin-4-yl)methyl)-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide or a salt thereof.

[0085] In certain embodiments, the present invention provides a compound which is N,N-bis(2-hydroxyethyl)-1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide or a salt thereof.

[0086] In certain embodiments, the present invention provides a compound that is N-(cyclopropylmethyl)-N,1-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide or a salt thereof.

[0087] In certain embodiments, the present invention provides a compound that is N-(2-methoxyethyl)-N,1-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide or a salt thereof.

[0088] In certain embodiments, the present invention provides a compound that is (1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)(piperazin-1-yl)methanone or a salt thereof.

[0089] In certain embodiments, the present invention provides a compound that is N-ethyl-N,1-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide or a salt thereof.

[0090] In certain embodiments, the present invention provides a compound which is N,N-bis(2-methoxyethyl)-1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide or a salt thereof.

[0091] In certain embodiments, the present invention provides a compound that is (S)-(1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)(3-methylmorpholino)methanone or a salt thereof.

[0092] In certain embodiments, the present invention provides a compound that is (3-hydroxypyrrolidin-1-yl)(1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone or a salt thereof. The present invention also relates to each enantiomer of the compound, namely (R)-(3-hydroxypyrrolidin-1-yl)(1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone and (S)-(3-hydroxypyrrolidin-1-yl)(1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone, as shown in the following examples:

[0093]

[0094] Thus, in certain embodiments, the present invention provides a compound that is (R)-(3-hydroxypyrrolidin-1-yl)(1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone or a salt thereof. In certain embodiments, the present invention provides a compound that is (S)-(3-hydroxypyrrolidin-1-yl)(1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone or a salt thereof.

[0095] In certain embodiments, the present invention provides a compound that is 3-(2-(1-(3-methoxypropyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole or a salt thereof.

[0096] In certain embodiments, the present invention provides a compound that is 3-(2-(1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole or a salt thereof.

[0097] In certain embodiments, the present invention provides a compound that is 3-(2-(7-chloro-1-(2-methoxyethyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole or a salt thereof.

[0098] In certain embodiments, the present invention provides a compound that is 3-(2-(1-(2-methoxyethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole or a salt thereof.

[0099] A particularly preferred compound of the present invention is (1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrazolo[2,3-c]pyridin-2-yl)(morpholino)methanone or a salt thereof. In certain embodiments, the compound is provided as a free base (i.e., in non-salt form). In certain embodiments, the compound is provided as a salt, preferably a pharmaceutically acceptable salt. In some embodiments, the salt is a hydrochloride salt. In some embodiments, the salt is a methanesulfonate salt.

[0100] Another particularly preferred compound of the present invention is (3-hydroxypyrrolidin-1-yl)(1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone or a salt thereof. In certain embodiments, the compound is provided as (S)-(3-hydroxypyrrolidin-1-yl)(1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone or a salt thereof. In certain embodiments, the compound is provided as (R)-(3-hydroxypyrrolidin-1-yl)(1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone or a salt thereof. In certain embodiments, the compound is provided as a free base (i.e., non-salt form). In certain embodiments, the compound is provided as a salt, preferably a pharmaceutically acceptable salt. In some embodiments, the salt is a hydrochloride salt. In some embodiments, the salt is a (+)-camphorsulfonate salt.

[0101] Another particularly preferred compound of the present invention is 3-(2-(1-(3-methoxypropyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole or a salt thereof. In certain embodiments, the compound is provided as a free base (ie, not in salt form).

[0102] Certain compounds of the present invention contain an asymmetric center and may give rise to stereoisomers. All stereoisomers such as enantiomers and mixtures thereof are intended to be included unless otherwise indicated. Thus, for example, in the case of the compound (3-hydroxypyrrolidin-1-yl)(1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone, which contains an asymmetric center, namely a ring carbon atom carrying a hydroxyl group at position 3 of the pyrrolidine ring, the present invention relates to each enantiomer, namely (R)-(3-hydroxypyrrolidin-1-yl)(1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone. (S)-(3-hydroxypyrrolidin-1-yl)(1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone and mixtures thereof. Compounds of the invention containing asymmetrically substituted carbon atoms can be isolated in optically active forms or as racemic mixtures. Methods for preparing optically active forms from optically inactive starting materials are known in the art and include, for example, by resolution of the racemic mixture or by stereoselective synthesis.

[0103] The compounds of the present invention include unlabeled forms of the compounds of the present invention and isotopically labeled forms thereof. Isotopically labeled forms of compounds are compounds that differ only in that one or more atoms are replaced by corresponding isotopically enriched atoms. Examples of isotopes that can be incorporated into the compounds of the present invention include, for example, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, and iodine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 15 N. 18 O. 17 O. 35 S. 18 F. 36 Cl and 125 I. Such isotopically labeled compounds are useful, for example, as probes in biological assays, analytical tools, or as therapeutic agents. In certain embodiments, the compounds of the invention are provided in unlabeled form.

[0104] "Polymorph" or "crystalline form" refers to a crystal structure in which a compound (or a salt or solvate thereof) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, Raman spectra, melting points, differential scanning calorimetry (DSC) spectra, crystal shapes, solubility and / or stability, etc. When a compound of the invention exists in different solid forms, all forms thereof, including amorphous forms and crystalline forms, are intended to be included within the scope of the invention.

[0105] The present invention also includes salts of the compounds of the present invention. Preferably, the salt is a pharmaceutically acceptable salt. As used herein, "pharmaceutically acceptable salt" means a salt that retains the biological effectiveness and properties of the parent compound and is not undesirable in biology or other aspects. Pharmaceutically acceptable salts include salts formed with inorganic or organic acids. Pharmaceutically acceptable salts are well known in the art. Exemplary pharmaceutically acceptable salts include those prepared by reacting the compounds of the present invention with inorganic or organic acids, such as hydrochlorides, hydrobromides, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, hydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, nitrates, acetates, haloacetates (e.g., trifluoroacetates), propionates, decanoates, octanoates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1 ,4-dioic acid salt, hexyne-1,6-dioic acid salt, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate, methanesulfonate (mesylate), ethanesulfonate, propanesulfonate, benzenesulfonate, toluenesulfonate, trifluorobenzenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, camphorsulfonate (camsylate (dextral camphorsulfonate)), mandelate, pyruvate, stearate, ascorbate or salicylate. Therefore, the present invention particularly relates to the salt of each compound provided herein, preferably a pharmaceutically acceptable salt (e.g., any of the above salts). The pharmaceutically acceptable salts of the present invention can be prepared from the parent compound by conventional chemical methods. For example, such salts can be prepared by reacting the free base form of these compounds with an appropriate amount of a suitable acid in a suitable solvent.

[0106] In addition, the compound of the present invention or its salt can exist in hydrated or non-hydrated (anhydrous) form or as a solvate with other solvent molecules. As used herein, "solvate" refers to a solvent addition form comprising a stoichiometric or non-stoichiometric solvent. Some compounds tend to capture a fixed molar ratio of solvent molecules in the crystalline solid state, thereby forming a solvate. If the solvent is water, the solvate formed is a hydrate. Non-limiting examples of solvates include hydrates and solvates with alcohols (also referred to as alcoholates), such as ethanol (ethanolate). When the compound of the present invention (or its salt) exists as a solvate, all of its solvates are intended to be included within the scope of the present invention, particularly pharmaceutically acceptable solvates. As used herein, "pharmaceutically acceptable solvates" are solvates formed with pharmaceutically acceptable solvents. Pharmaceutically acceptable solvents are well known in the art and include solvents such as water and ethanol.

[0107] The compounds of the present invention, including their salts, can be prepared using a number of synthetic routes, including the general synthetic routes described below and the methods disclosed in the examples, starting with commercially available starting materials, compounds known in the literature, or from readily available intermediates, by using standard synthetic methods and operations. Standard synthetic methods and operations for preparing organic compounds and functional group transformations and operations are known in the art and can be found in standard textbooks, such as Smith M.B., "March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 7th edition, Wiley, 2013; Greene TW and Wuts PGM "Greene's Protective Groups in Organic Synthesis", 4th edition, Wiley, 2006).

[0108] The reaction schemes described below are only used to illustrate the methods for obtaining the compounds of the present invention. Other routes and other reactants and intermediates known to those of ordinary skill in the art can also be used to obtain the compounds of the present invention.

[0109] In some of the methods described below, it may be necessary or advisable to protect reactive or unstable groups with conventional protecting groups. The nature of these protecting groups and the procedures for their introduction and removal are well known in the art (see, e.g., Greene TW and Wuts PGM, cited above). Whenever a protecting group is present, a subsequent deprotection step is required, which can be carried out under standard conditions well known in the art, such as those described in the above references.

[0110] Generally, the compounds of the present invention can be obtained according to the process shown in Scheme 1 below.

[0111]

[0112] Solution 1

[0113] Wherein in Scheme 1, the substituent "A" corresponds to a specific bicyclic heteroaryl group attached to the 2-position of the pyridine ring in the compound of the present invention, as shown in Table 1; the compound of formula (I) corresponds to the compound of the present invention (i.e., the compound as described in Table 1 and / or the claims); M and X have the meanings defined below.

[0114] In the first step, a compound of formula (IV) is obtained by cross-coupling reaction of an organometallic species (II) with a halide (III). Typically, this coupling is carried out using a Stille reaction, wherein M is a trialkylstannyl group and X is Cl, Br or I. The reaction can be carried out using a suitable Pd / ligand combination, such as Pd(PPh3)4, Pd(PPh3)Cl2 or Pd(dppb)Cl2 in the presence of a suitable Cu salt such as CuI or CuO, in the presence or absence of CsF, in a suitable solvent such as tetrahydrofuran, dioxane or dimethylformamide. The reaction temperature can typically be from room temperature to 120°C, and the reaction time is typically 1h-48h. The organotin used can be a trimethylstannyl derivative. Alternatively, an intermolecular Stille Kelly reaction can also be used, wherein reagents (II) and (III) are both halogen derivatives (i.e., M and X are halogens) and treated with (Bu3Sn)2, Et4N and a Pd / ligand combination.

[0115] The compound of the present invention is then obtained in two steps from the cyano derivative of formula (IV). In the first step, the cyano compound of formula (IV) is converted into an N'-hydroxyimide derivative of formula (V) by reaction with hydroxylamine, and then (V) is condensed with trifluoroacetic anhydride to obtain the compound of the present invention. Hydroxylamine is added to the cyano derivative (IV) in a suitable solvent such as EtOH or MeOH, and in the presence of a base when hydroxylamine hydrochloride is used. The reaction temperature can typically be from room temperature to 60°C, and the reaction time is typically 1h-48h. N'-hydroxyimide (V) is condensed with trifluoroacetic anhydride in a suitable solvent such as CH2Cl2 or THF to obtain the corresponding N'-trifluoroacetoxyimide, and the 1,2,4-oxadiazole of the present invention is obtained in the same reaction medium or after adding trifluoroacetic acid.

[0116] Compounds of formula (II) and (III) are commercially available or can be obtained by standard methods well known to those skilled in the art of organic chemistry. Organometallic derivatives of formula (II) can be obtained from the corresponding halogenated compounds by transmetallation according to standard methods well known to those skilled in the art of organic chemistry for the preparation of reagents for Stille coupling. For example, trimethyltin derivatives of formula (II) can be prepared by reacting the corresponding bromo derivative with hexamethylditin and (PPh3)4 in toluene at 110°C for 16h.

[0117] The salts of the compounds of the present invention can be obtained during the final isolation and purification of the compounds of the present invention or can be prepared by treating the compounds of the present invention with a sufficient amount of the desired acid in a conventional manner to give the corresponding salts.

[0118] In the case where the process for preparing the compounds of the invention produces a mixture of stereoisomers, the individual stereoisomers of the compounds of the invention can be obtained by resolution, for example, by starting from the compounds of the invention obtained as a mixture of stereoisomers, using well-known methods, such as forming diastereomeric pairs, by salification with an optically active acid, followed by fractional crystallization and regeneration of the free base, or by chiral preparative chromatography. Alternatively, any known chiral resolution method can be used to obtain an optically pure or enantiomerically enriched synthetic intermediate, which can then be used as is in the subsequent steps at various stages of the above-mentioned synthetic process. Alternatively, an optically pure or enantiomerically enriched final compound (or synthetic intermediate) can be obtained by using chiral chromatography.

[0119] The compounds of the present invention inhibit the activity of histone deacetylase. In particular, it has been found that the compounds of the present invention are effective inhibitors of HDAC6. The activity of the compounds of the present invention as HDAC6 inhibitors can be determined using, for example, an in vitro assay described in the Examples section. Specifically, Example 7 describes a method for determining HDAC6 inhibitory activity in vitro. Using the assay described in Example 7, it has been found that the compounds of the present invention are effective HDAC6 inhibitors. HDAC6 inhibitory activity can also be determined in cell assays, such as an assay for measuring HDAC6 specific substrates (such as α-tubulin) acetylation levels in cells, such as the assay described in Example 8. The compounds of the present invention have been shown to inhibit HDAC6 activity in cells, such as using the cell assay described in Example 8. Compared with other HDAC isoforms, the selectivity of HDAC6 can be determined using methods well known in the art, such as in vitro assays similar to those described in Example 7, using the corresponding HDAC isoforms of interest.

[0120] HDAC6 is a class IIb HDAC that can deacetylate substrates such as tubulin, heat shock protein (Hsp) 90, and cortical protein. HDAC6 is located in the cytosol and has two catalytic domains and a C-terminal zinc finger domain that can bind free ubiquitin as well as monoubiquitinated and polyubiquitinated proteins (Li et al., FEBS J. 2013 February; 280 (3): 775-93). The ubiquitin binding domain in HDAC6 is associated with several proteins that are involved in controlling ubiquitin, the proteasome system, aggregate formation, and autophagy. In addition, the ability of HDAC6 to deacetylate α-tubulin can affect microtubule-mediated processes such as cell migration, immune synapse formation, viral infection, misfolded proteins, and degradation of stress granules. It has also been demonstrated that HDAC6 can deacetylate Hsp90 and regulate its chaperone activity, thereby regulating various Hsp90-related cell signaling pathways, such as controlling stress-related responses.

[0121] Many studies have reported the role of HDAC6 in cancer. For example, in preclinical models, it has been shown that inhibition of HDAC6 can reduce the growth of multiple myeloma and enhance the effects of proteasome inhibitors and thalidomide-based immunomodulatory drugs used as standard of care (Santo et al., Blood. March 15, 2012; 119(11): 2579-89; North et al., PLoS One. March 6, 2017; 12(3): e0173507). It has also been shown that inhibition of HDAC6 can increase the effects of other standard of care drugs such as paclitaxel in ovarian, pancreatic and breast cancer cells (Huang et al., Oncotarget January 10, 2017; 8(2): 2694-2707). Antiproliferative activity of HDAC6 inhibitors has also been observed in prostate cancer and melanoma cells (Li et al., Eur J Med Chem. 2015 Jul 15; 100:270-6; Seidel et al., Biochem Pharmacol. 2016 Jan 1; 99:31-52). In addition, in vivo efficacy of HDAC6 inhibitors has been reported in colorectal cancer, inflammatory breast cancer, leukemia, lymphoma and ARID1A mutant ovarian xenograft models (Yang et al., J Med Chem. 2016 Feb 25; 59(4):1455-70; Putcha et al., Breast Cancer Res. 2015 Dec 8; 17(1):149; Bitler et al., Nat Cell Biol. 2017 Aug; 19(8):962-973). Similarly, HDAC6 knockout reduces proliferation of uterine leiomyoma and gastric cancer cells, whereas HDAC6 overexpression promotes proliferation and drug resistance of non-small cell lung cancer cells and glioblastoma cells (Wei et al. Reprod Sci. 2011 Aug;18(8):755-62; Park et al. Cancer Lett. 2014 Nov 1;354(1):97-106; Wang et al. Oncol Rep. 2016 Jul;36(1):589-97; Wang et al. Cancer Lett. 2016 Aug 28;379(1):134-42).In addition, HDAC6 inhibitors have shown anticancer activity in melanoma and non-small cell lung cancer models by stimulating an immune response to tumors when used alone or in combination with immune checkpoint inhibitors or epigenetic modulators (Knox et al., Abstract 4055, AACR Annual Meeting 2017; Apr 1-5, 2017; Washington, DC; Woan et al., Mol Oncol. 2015 Aug;9(7):1447-1457; Tavares et al., ACS Med Chem Lett. 2017 Sep 5;8(10):1031-1036; Adeegbe et al., Cancer Discov. 2017 Aug;7(8):852-867).

[0122] HDAC6 is also widely reported to play a role in inflammation and autoimmune diseases. The number of circulating regulatory T cells (Tregs) in mice knocking out HDAC6 increases, which is the key to maintaining immune homeostasis. Similarly, HDAC6 specific inhibitors promote Treg inhibitory activity in inflammatory bowel disease and graft-versus-host disease models (de Zoeten et al., Mol Cell Biol. May 2011; 31 (10): 2066-78). HDAC6 inhibitors show disease-improving activity in inflammation, rheumatoid arthritis and systemic lupus erythematosus models (Vishwakarma et al., Int Immunopharmacol. May 2013; 16 (1): 72-8; Regna et al., Clin Immunol. January 2016; 162: 58-73). Mice lacking HDAC6 show reduced autophagy, thereby improving chronic obstructive pulmonary disease (COPD)-associated ciliary dysfunction (Lam et al., J Clin Invest. 2013 Dec;123(12):5212-30).

[0123] It is also reported that HDAC6 inhibitors are effective in treating ciliopathies. Ciliopathy is a genetic disease associated with defects in ciliary structure or function, and includes polycystic kidney disease, polycystic liver disease, Bardet-Biedl syndrome, and retinal degeneration. In a polycystic kidney disease model, HDAC6 inhibitors prevent cyst formation and improve renal function (Cebotaru et al., Kidney Int. 2016 July; 90 (1): 90-9). Similarly, in a polycystic liver disease model, pharmacological inhibition of HDAC6 reduces the proliferation of cystic bile duct cells and reduces the development and fibrosis of liver cysts (Gradilone et al., Am J Pathol. 2014 March; 184 (3): 600-8).

[0124] HDAC6 has also been shown to play an important role in nervous system diseases. In particular, HDAC6 inhibitors show efficacy in peripheral neuropathy such as Charcot-Marie Tooth disease and chemotherapy-induced peripheral neuropathy models (Benoy et al., Neurotherapeutics. April 2017; 14 (2): 417-428; Krukowski et al., Pain. June 2017; 158 (6): 1126-1137). In addition, in neuronal cultures derived from patients with amyotrophic lateral sclerosis, treatment with HDAC6 inhibitors rescued their defective phenotypes (Guo et al., Nat Commun. October 11, 2017; 8 (1): 861).

[0125] It is also reported that HDAC6 inhibitors are effective in treating several other nervous system diseases. For example, in an Alzheimer's disease mouse model, the reduction or inhibition of HDAC6 has been shown to save memory and improve cognition (Govindarajan et al., EMBO Mol Med. January 2013; 5(1): 52-63). The absence or inhibition of HDAC6 inhibits the accumulation of neuritic tau, so inhibiting HDAC6 can be used not only to treat Alzheimer's disease, but also to treat other 4-repeat tau protein diseases (tauopathy), such as cortical basal degeneration and progressive supranuclear palsy (Tseng et al., Cell Rep. August 29, 2017; 20(9): 2169-2183). Furthermore, in a Huntington's disease (HD) model, HDAC6 inhibition reduced neuronal vulnerability to mutant huntingtin, suggesting that HDAC6 inhibitors are neuroprotective in HD (Guedes-Dias et al., Biochim Biophys Acta. 2015 Nov;1852(11):2484-93).

[0126] It has also been reported that HDAC6 plays a role in mental and behavioral disorders such as depression. For example, HDAC6 inhibitors can stimulate exploratory behavior in mice and play a positive role in anti-anxiety and social interaction tests (Jochems et al., Neuropsychopharmacology. 2014 January; 39(2): 389-400).

[0127] In addition, several publications have highlighted the important role of HDAC6 in infectious diseases. The use of HDAC6 inhibitors has been shown to reduce viral replication, such as Japanese encephalitis virus (JEV), hepatitis C virus (HCV) and rabies virus (Lu et al., Int J Mol Sci. 2017 May 1; 18 (5); Zan et al., Front Cell Infect Microbiol. 2017 April 26; 7: 146; Ai et al., J Med Chem. 2015 January 22; 58 (2): 785-800). HDAC6 has also been shown to promote influenza A virus entry into cells and control viral lysis-latency conversion of other viruses (Banerjee et al., Science 2014 October 24; 346 (6208): 473-7). For example, HDAC6 has been reported to be involved in maintaining HIV latency, and thus inhibition of HDAC6 can promote viral clearance in vivo (Huo et al., J Biol Chem. 2011 Mar 18; 286(11): 9280-6). In addition, selective HDAC6 inhibitors improved survival and bacterial clearance in a sepsis model (Zhao et al., J Trauma Acute Care Surg. 2016 Jan; 80(1): 34-40).

[0128] Several publications have also reported the role of HDAC6 in cardiovascular disease. HDAC6 knockout mice show improved heart conditions in heart failure mouse models. In addition, HDAC6-deficient mice are able to resist skeletal muscle atrophy, which is considered to be a life-threatening complication of congestive heart failure (Demos-Davies et al., Am J Physiol Heart CircPhysiol. 2014 Jul 15; 307 (2): H252-8). Pharmacological inhibition of HDAC6 has been shown to prevent atrial remodeling associated with atrial fibrillation (Zhang et al., Circulation. 2014 January 21; 129 (3): 346-58). HDAC6 activity continues to increase in stressed myocardium, thus revealing the role of HDAC6 inhibitors in cardiomyopathy (Lemon et al., J Mol Cell Cardiol. 2011 July; 51 (1): 41-50). It has also been reported that selective inhibition of HDAC6 can improve survival in a rodent hemorrhagic shock model (Chang et al., J Trauma Acute Care Surg. 2015 Dec; 79(6): 905-10). In addition, inhibition of HDAC6 can improve established pulmonary hypertension in experimental models and exert neuroprotective effects in a cerebral ischemia model (Boucherat et al., Sci Rep. 2017 Jul 3; 7(1): 4546; Liesz et al., J Neurosci. 2013 Oct 30; 33(44): 17350-62).

[0129] Therefore, it is expected that the compounds of the present invention can be used to treat diseases associated with HDAC, especially HDAC6. Diseases associated with HDAC6 treated with the compounds of the present invention include, but are not limited to, the diseases listed in the above paragraphs and the diseases listed below:

[0130] Cancers such as lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, brain cancer and other CNS tumors, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, pancreatic cancer, heart cancer, glioma, glioblastoma, esophageal cancer, hepatocellular carcinoma, bone and joint cancer, papillary renal cancer, head and neck squamous cell carcinoma, sarcoma, mesothelioma, leukemia, lymphoma and myeloma;

[0131] Autoimmune or inflammatory diseases, such as rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, psoriatic arthritis, infectious arthritis, progressive chronic arthritis, malformative arthritis, traumatic arthritis, gouty arthritis, Reiter's syndrome, polychondritis, acute synovitis and spondylitis, psoriasis, ischemia-reperfusion injury, inflammatory bowel disease (such as ulcerative colitis or Crohn's disease), eczema, ischemia / reperfusion injury, glomerulonephritis, hemolytic anemia, aplastic anemia anemia, idiopathic thrombocytopenia, neutropenia, chronic thyroiditis, Graves' disease, type I diabetes, scleroderma, diabetes, hepatitis, primary biliary cirrhosis, systemic inflammatory response syndrome, postoperative or posttraumatic inflammation, myasthenia gravis, pemphigus, alcoholic liver disease, cystic fibrosis, multiple sclerosis (MS), Addison's disease, Castleman's disease, polyarteritis nodosa, systemic lupus erythematosus, atopic dermatitis, contact dermatitis, chronic renal insufficiency, Stevens-Johnson syndrome, idiopathic sprue, sarcoidosis, Guillain-Barre syndrome, uveitis, conjunctivitis, keratoconjunctivitis, otitis media media), periodontal disease, pulmonary fibrosis, acute respiratory distress syndrome, asthma, bronchitis, rhinitis, sinusitis, pancreatitis, inflammatory bone disease, meningitis, cystitis, pharyngolaryngitis, pneumoconiosis, pulmonary insufficiency syndrome, pulmonary emphysema, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, silicosis, chronic inflammatory lung disease, or peritoneal fibrosis;

[0132] Transplant rejection, including host-versus-graft disease, graft-versus-host disease, and allograft rejection.

[0133] Infectious diseases, including influenza, viral encephalitis, HIV, viral hepatitis, pneumonia, and sepsis.

[0134] ciliary diseases, for example polycystic kidney disease, polycystic liver disease, Alstrom's syndrome, Bardet-Biedl syndrome, retinal degeneration, Joubert syndrome, Meckel-Gruber syndrome, nephronophthisis, orofaciodigital syndrome 1, Senior-Loken syndrome, primary ciliary dyskinesia (Kartagener Syndrome), orasphyxiating thoracic dysplasia (Jeune), Marden-Walker syndrome or isomerism;

[0135] Neurological disorders such as Wilson's disease, prion diseases, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, amyloidosis, Alzheimer's disease, Alexander's disease, Pick's disease, spinal muscular dystrophy, Lewy body dementia, chemotherapy-induced cognitive impairment, mitochondrial encephalomyopathies and enteric dysmotility syndromes, motor neurogenesis disease (MND), ataxia syndromes including Friedreich's ataxia and spinocerebellar ataxia (SCA), spinal cord injury, olivopontocerebellar atrophy, multiple system atrophy, progressive supranuclear palsy palsy, synucleinopathies, Down syndrome, corticodentatonigral degeneration, progressive familial myoclonic epilepsy, strionigral degeneration, torsion dystonia, familial tremor, Gilles de la Tourette syndrome, Shy-Drager syndrome and Hallervorden-Spatz disease, and peripheral neuropathies such as Charcot-Marie-Tooth disease, peripheral neuropathies induced by chemotherapeutic drugs (e.g., platinum-based chemotherapeutic agents, taxanes, vincristine, bortezomib, etc.), etc.;

[0136] Mental and behavioral disorders, including psychotic disorders and schizophrenia spectrum disorders, such as schizotypal (personality) disorder, delusional disorder, brief psychotic disorder, schizophreniform disorder, schizophrenia, schizoaffective disorder, substance / medication induced psychotic disorder, and psychotic disorder due to another medical condition; bipolar disorder, such as bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance / medication induced bipolar and related disorders; depression, such as disruptive mood dysregulation disorder, major depressive disorder, single and recurrent episodes, persistent depressive disorder (dysthymia), premenstrual dysphoric disorder, substance / medication induced depression, and depression due to another medical condition; anxiety disorders, such as separation anxiety disorder, selective mutism, specific phobias, phobia), social anxiety disorder (social phobia), panic disorder, agoraphobia, generalized anxiety disorder, etc.

[0137] Cardiovascular diseases, such as heart failure, cardiomyopathy, atrial fibrillation, pulmonary hypertension, hemorrhagic shock, stroke, ischemic heart disease, myocarditis, valvular heart disease;

[0138] Muscle wasting; and

[0139] Cachexia.

[0140] For the uses and methods of treatment described herein, any of the compounds of the invention, including any of the embodiments thereof, may be used.

[0141] Therefore, the present invention also provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use as a medicament.

[0142] The present invention also provides the compound of the present invention or a pharmaceutically acceptable salt thereof for use in treating diseases associated with HDAC6.

[0143] The present invention also provides use of the compound of the present invention or a pharmaceutically acceptable salt thereof in preparing a medicament for treating a disease associated with HDAC6.

[0144] The present invention also provides use of the compound of the present invention or a pharmaceutically acceptable salt thereof in treating diseases associated with HDAC6.

[0145] The present invention also provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use as an HDAC6 inhibitor.

[0146] The present invention also provides a method for treating a disease associated with HDAC6, comprising administering a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0147] The present invention also provides a method for inhibiting HDAC6 activity, comprising administering to a patient in need of such treatment an amount of a compound of the present invention or a pharmaceutically acceptable salt thereof sufficient to inhibit HDAC6 activity.

[0148] The present invention also provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use in treating a disease selected from cancer, autoimmune or inflammatory diseases, transplant rejection, ciliopathies, nervous system diseases, mental or behavioral disorders, infectious diseases, cardiovascular diseases, muscle atrophy and cachexia.

[0149] The present invention also provides the use of the compound of the present invention or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease selected from cancer, autoimmune or inflammatory diseases, transplant rejection, ciliopathies, nervous system diseases, mental or behavioral disorders, infectious diseases, cardiovascular diseases, muscle atrophy and cachexia.

[0150] The present invention also provides the use of the compound of the present invention or a pharmaceutically acceptable salt thereof in treating a disease selected from cancer, autoimmune or inflammatory diseases, transplant rejection, ciliopathies, nervous system diseases, mental or behavioral disorders, infectious diseases, cardiovascular diseases, muscle atrophy and cachexia.

[0151] The present invention also provides a method for treating a disease selected from cancer, autoimmune or inflammatory diseases, transplant rejection, ciliopathies, neurological diseases, mental or behavioral disorders, infectious diseases, cardiovascular diseases, muscle atrophy and cachexia, comprising administering a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0152] The present invention also provides a method for inhibiting HDAC6 activity in a sample (eg, a biological sample), comprising contacting the sample (eg, the biological sample) with a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0153] The present invention also provides the use of the compounds of the present invention or their pharmaceutically acceptable salts as HDAC6 inhibitors in research, particularly as research tool compounds for inhibiting HDAC6. Therefore, the present invention relates to the in vitro use of the compounds of the present invention or their salts (e.g., pharmaceutically acceptable salts thereof) as HDAC6 inhibitors, and particularly to the in vitro use of the compounds of the present invention or their salts (e.g., pharmaceutically acceptable salts thereof) as HDAC6 inhibitors. The present invention also relates to methods for inhibiting HDAC6, particularly in vitro methods, which include applying the compounds of the present invention or their salts (e.g., pharmaceutically acceptable salts thereof) to samples (e.g., biological samples). It should be understood that the term "in vitro" is used in this particular context with the meaning of "external to a living human or animal", which specifically includes experiments conducted with cells, cells or subcellular extracts and / or biomolecules in an artificial environment, such as aqueous solutions or culture media that can be provided in flasks, test tubes, culture dishes, microtiter plates, etc.

[0154] Unless otherwise indicated, any description of a method of treatment includes use of the compound to provide treatment as described herein, as well as use of the compound in the preparation of a medicament for treating such a condition.

[0155] Definitions of specific terms as used in the specification and claims are provided herein. All other technical and scientific terms used herein but not defined herein shall have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. In the event of a conflict, the present specification, including definitions, shall prevail.

[0156] In the event of a conflict between the chemical structure and the name of a compound disclosed herein, the chemical structure controls.

[0157] The term "disease associated with HDAC6" and the like refers to any disease or condition in which HDAC6 plays a role, and / or wherein the disease or condition is associated with the expression or activity of HDAC6, and / or a disease or condition whose course can be affected by regulating HDAC6. Diseases associated with HDAC6 include, but are not limited to, the diseases and conditions described herein. Preferably, the disease associated with HDAC is selected from cancer, autoimmune or inflammatory diseases, transplant rejection, ciliopathies, neurological diseases, mental or behavioral disorders, infectious diseases, cardiovascular diseases, muscle atrophy and cachexia.

[0158] As used herein, the term "subject" or "patient" or "individual" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and most preferably humans.

[0159] As used herein, the term "biological sample" includes, but is not limited to, cells, cell cultures, or extracts thereof; biopsy material obtained from an animal (e.g., a human) or extracts thereof; and blood, saliva, urine, feces, or any other body fluid, or extracts thereof.

[0160] As used herein, the term "therapeutically effective amount" refers to the amount of active compound that induces the biological or medical response being sought in a subject (preferably a human). Therefore, the therapeutically effective amount of a compound can be an amount that is sufficient to treat the disease or disorder, delay the onset or progression of the disease or disorder, and / or alleviate one or more symptoms of the disease or disorder when applied to a subject suffering from the disease or disorder. The precise effective amount for the subject will depend on a variety of factors, such as the subject's weight, size, and health, the nature and extent of the condition to be treated, and the therapeutic agent or therapeutic agent combination selected for administration. The therapeutically effective amount for a given situation can be determined by routine experiments within the skill and judgment of the clinician.

[0161] For any compound, the therapeutically effective amount can be initially estimated in in vitro tests, such as cell culture tests, or in animal models such as mice, rats or dogs. Animal models can also be used to determine suitable concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes for human administration. Therapeutic efficacy and toxicity can be determined by standard methods in cell culture or experimental animals, such as ED50 and LD50 values ​​can be determined, and the ratio of toxicity to therapeutic effect, also known as therapeutic index, can be calculated, and the suitable dose for use in humans can be determined.

[0162] As used herein, unless otherwise indicated, the term "treatment" in relation to a disease, disorder or condition refers to the treatment and care of a patient for the purpose of combating the disease, disorder or condition, such as reversing, alleviating, inhibiting the course of the disease, disorder or condition to which the term applies, or preventing the disease, disorder or condition to which the term applies, or one or more symptoms of such disease, disorder or condition, and includes the administration of a compound of the invention (or a pharmaceutically acceptable salt thereof) to prevent the onset of symptoms or complications, or to alleviate symptoms or complications, or to eliminate the disease, disorder or disorder. Preferably, the treatment is curative or ameliorative.

[0163] Although it is possible that the compound of the present invention can be directly administered as such for therapy, it is typically administered in the form of a pharmaceutical composition. These compositions include the compound of the present invention (or its pharmaceutically acceptable salt) as an active pharmaceutical ingredient and one or more pharmaceutically acceptable carriers. For the purposes of the present invention, the carrier is suitable for use in the pharmaceutical composition described herein, provided that it is compatible with the other ingredients of the composition and is harmless to the recipient of the composition. "Pharmaceutically acceptable carrier" includes non-API (API refers to active pharmaceutical ingredient) substances, such as disintegrants, binders, fillers, lubricants, etc., which are used to prepare drug products and are considered to be safe for subject (especially human) administration according to established government standards, including standards promulgated by the U.S. Food and Drug Administration and the European Medicines Agency. Pharmaceutically acceptable carriers are well known to those skilled in the art and are selected based on the selected formulation type and route of administration according to standard pharmaceutical practices described in the following documents: for example, Remington: The Science and Practice of Pharmacy, 22nd edition, edited by Loyd V Allen Jr, Pharmaceutical Press, Philadelphia, 2012.

[0164] Thus, provided herein are pharmaceutical compositions comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

[0165] Pharmaceutical compositions can be prepared in a manner well known in the pharmaceutical field and can be administered by a variety of routes, such as oral, parenteral, pulmonary or topical routes. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular. Parenteral administration can be in the form of a single bolus dose, or can be, for example, by a continuous infusion pump. Pulmonary administration includes, for example, by inhalation or insufflation of powders or aerosols, including by a nebulizer. Topical administration includes transdermal, epidermal, ocular and mucosal, including intranasal, vaginal and rectal delivery.

[0166] The compositions can be formulated so as to provide quick (immediate), sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.

[0167] Examples of pharmaceutically acceptable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, and methylcellulose. The pharmaceutical composition may additionally include other pharmaceutically acceptable excipients, including lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl hydroxybenzoate and propyl hydroxybenzoate; sweeteners; flavoring agents; and coloring agents.

[0168] Suitable oral dosage forms include, for example, tablets, pills, sachets or capsules of hard or soft gelatin or any other suitable materials. For example, the active compound can be incorporated into a preparation including a pharmaceutically acceptable carrier, such as a binder (e.g., gelatin, cellulose, tragacanth), an excipient (e.g., starch, lactose), a lubricant (e.g., magnesium stearate, silicon dioxide), a disintegrant (e.g., alginate, Primogel, corn starch) and a sweetener or flavoring agent (e.g., glucose, sucrose, saccharin, methyl salicylate and peppermint). Conventional techniques can then be used to press them into tablets or encapsulate them in a capsule. Capsules and tablets can also be coated with various coatings known in the art to change the flavor, taste, color and shape of capsules and tablets. In addition, liquid carriers such as fatty oils can also be included in capsules. Oral preparations can also be in the form of suspensions, solutions, syrups, etc. If desired, conventional agents for changing flavor, taste, color, etc. can be added.

[0169] Pharmaceutical compositions suitable for parenteral administration include sterile aqueous solutions or suspensions, or may be prepared in lyophilized form so that solutions or suspensions are prepared extemporaneously using sterile aqueous carriers before use. In such preparations, diluents or pharmaceutically acceptable carriers may be used, such as sterile water and physiological saline buffer. Other conventional solvents, pH buffers, stabilizers, antibacterial agents, surfactants and antioxidants may all be included. For example, useful ingredients include sodium chloride, acetate, citrate or phosphate buffer, glycerol, glucose, fixed oil, methyl paraben, polyethylene glycol, propylene glycol, sodium bisulfate, benzyl alcohol, ascorbic acid, etc. Parenteral preparations may be stored in any conventional container, such as vials and ampoules.

[0170] Compositions for administration by inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. Liquid or solid compositions may include suitable pharmaceutically acceptable excipients as described above. Such compositions may be administered by oral or nasal respiratory routes to obtain local or systemic effects. Compositions may be atomized by use of suitable gases. Atomized solutions may be breathed directly from an atomizing device, or an atomizing device may be connected to a mask or a breathing chamber. Solutions, suspensions, and powder compositions may be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0171] Pharmaceutical compositions for topical application may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Topical preparations may include one or more conventional carriers. For example, ointments may contain water and one or more hydrophobic carriers selected from liquid paraffin, polyoxyethylene alkyl ethers, propylene glycol, white vaseline, etc. The carrier composition of a cream may be based on a combination of water and glycerol and one or more other ingredients such as hexadecyl stearyl alcohol, glyceryl monostearate, etc. Gels may be prepared using isopropyl alcohol and water, suitably in combination with other excipients such as glycerol, cellulose, etc.

[0172] Pharmaceutical compositions, such as oral and parenteral compositions, can be formulated in unit dosage form for ease of administration and uniformity of dosage. As used herein, "unit dosage form" refers to physically discrete units suitable for administration as unit dosages to subjects, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, and one or more suitable pharmaceutical carriers.

[0173] In therapeutic applications, pharmaceutical composition will be used in a manner suitable for the disease to be treated, as determined by the medical field technician. Suitable dosage and suitable duration of application and frequency will be determined by factors such as the patient's condition, the type and severity of the disease, the concrete form of active ingredient, the method of application, etc. In general, suitable dosage and application regimen provide pharmaceutical composition with the amount of any other objectively identifiable improvement that is enough to provide the clinical outcome of treatment benefit such as improvement, such as more frequent complete or partial remission or longer disease-free and / or total survival period or alleviate the severity of symptoms or clinicians point out. Effective dose can be assessed or inferred using experimental models usually, such as deriving from the dose-response curve of in vitro or animal model test system.

[0174] The pharmaceutical compositions of the invention may be included in a container, pack, or dispenser together with instructions for administration.

[0175] The compounds of the present invention can be used as a single agent or can also be used or applied in combination with one or more additional therapeutic agents, such as drugs for treating diseases selected from cancer, autoimmune or inflammatory diseases, transplant rejection, ciliopathies, neurological diseases, mental or behavioral disorders, infectious diseases, cardiovascular diseases, muscle atrophy and cachexia. Combination therapy includes administering a single pharmaceutical dosage form comprising the compounds of the present invention and one or more additional therapeutic agents, and administering the compounds of the present invention and each other therapeutic agent for separate administration in their respective separate pharmaceutical dosage forms. If administered alone, administration can be performed simultaneously, sequentially or separately, and the compounds of the present invention and one or more other therapeutic agents can be administered by the same route of administration or using different routes of administration, such as a compound can be administered orally, and another by intravenous administration. In addition, as described above, the compounds of the present invention can also be used in monotherapy, particularly for monotherapy treatment methods for diseases selected from cancer, autoimmune or inflammatory diseases, transplant rejection, ciliopathies, neurological diseases, mental or behavioral disorders, infectious diseases, cardiovascular diseases, muscle atrophy and cachexia. Example

[0176] The following abbreviations are used in the examples:

[0177] AcN: acetonitrile

[0178] Boc: tert-Butyloxycarbonyl

[0179] DABAL-Me3: Bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]octane adduct

[0180] DCM: dichloromethane

[0181] DIPEA: N,N-diisopropylethylamine

[0182] DMF: N,N-dimethylformamide

[0183] EtOAc: ethyl acetate

[0184] EtOH: ethanol

[0185] HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0186] HPLC: High Performance Liquid Chromatography

[0187] LC-MS: Liquid chromatography-mass spectrometry

[0188] MeI: methyl iodide

[0189] MeOH: Methanol

[0190] PPh3: triphenylphosphine

[0191] Pd(PPh3)4:Tetrakis(triphenylphosphine)palladium(0)

[0192] Pet ether: petroleum ether

[0193] rt (or RT): room temperature

[0194] Rt: retention time

[0195] TBAB: Tetrabutylammonium bromide

[0196] TFA: trifluoroacetic acid

[0197] THF: Tetrahydrofuran

[0198] One of the following methods was used for LC-MS determination:

[0199] Method 1: Column: KINETEX-1.7μXB-C18 100A (50mm x 2.1mm, 1.7μm); Mobile phase: A: 0.05% formic acid in water B: 0.05% formic acid in acetonitrile; Gradient: time / % A: 0 / 97, 0.3 / 97, 3.2 / 2, 4.8 / 2, 5 / 97, 5.10 / 97; Column temperature: 35°C; Flow rate: 0.6mL / min

[0200] Method 2: Column: Aquity UPLC BEH C18 (50 mm x 2.1 mm, 1.7 μm); Mobile phase A: 0.01 M ammonium acetate in water; B: AcN; Gradient: Time / % A: 0 / 5, 0.1 / 5, 2.4 / 100, 3.8 / 100, 4.0 / 5, 4.8 / 5; Column temperature: 45 °C; Flow rate: 0.5 mL / min

[0201] Method 3: Column: Aquity UPLC BEH C18 (50 mm x 2.1 mm, 1.7 μm); Mobile phase: A: 0.1% formic acid in water, B: 0.1% formic acid in acetonitrile; Gradient: Time / %B: 0 / 5, 0.3 / 5, 2.5 / 95, 3.7 / 95, 4 / 5; Column temperature: 40°C; Flow rate: 0.6 mL / min

[0202] Method 4: Column-AQUITY UPLC BEH C18 (50mm x 2.1mm, 1.7μm); Mobile phase-A: 0.1% formic acid in water, B: 0.1% formic acid in acetonitrile T% A: 0 / 95, 0.3 / 95, 2.0 / 5, 3.5 / 5, 3.6 / 95, 4.4 / 95; Flow rate-0.6mL / min, Temperature: 40℃

[0203] Method 5: Column: Aquity UPLC BEH C18 (50 mm x 2.1 mm, 1.7 μm); Mobile phase A: 0.01 M ammonium acetate in water; B: AcN; Gradient: Time / % A: 0 / 5, 0.1 / 5, 2.4 / 100, 3.8 / 100, 4.0 / 5, 4.5 / 5; Column temperature: 50 °C; Flow rate: 0.5 mL / min

[0204] Method 6: Column: Aquity UPLC BEH C18 (50 mm x 2.1 mm, 1.7 μm); Mobile phase: A: 0.1% formic acid in water, B: 0.1% formic acid in acetonitrile; Gradient: Time / % A: 0 / 95, 0.3 / 95, 2.0 / 5, 3.1 / 5, 3.5 / 95, 4.3 / 95; Column temperature: 40°C; Flow rate: 0.6 mL / min

[0205] Method 7: Column: Luna Omega 3μm PS C18 100A; Mobile phase A: 0.01M ammonium formate in water: AcN (95:5); B: 0.01M ammonium formate in water: AcN (5:95); Gradient: Time / %B: 0 / 2, 1 / 2, 4 / 98, 4.5 / 98, 5.5 / 2, 6.5 / 2; Flow rate: 1.0 mL / min;

[0206] Method 8: Column-AQUITY UPLC BEH C18 (50mm x 2.1mm, 1.7μm); Mobile phase-A: 0.1% formic acid in water, B: 0.1% formic acid in acetonitrile T% A: 0 / 98, 0.3 / 98, 3.2 / 2, 4.4 / 2, 4.7 / 98; Flow rate-0.6mL / min, Temperature: 40℃

[0207] Method 9: Column: Aquity UPLC BEH C18 (50 mm x 2.1 mm, 1.7 μm); Mobile phase A: 0.01 M ammonium acetate in water; B: AcN; Gradient: Time / % A: 0 / 98, 0.3 / 98, 3.2 / 0, 4.5 / 0, 4.7 / 98; Column temperature: 45 °C; Flow rate: 0.5 mL / min

[0208] Method 10: Column: XBridge BEH C18 (50 mm x 2.1 mm, 2.5 μm); Mobile phase A: 0.01 M ammonium acetate in water; B: AcN; Gradient: time / %B: 0 / 5, 0.2 / 5, 7 / 100, 8 / 100, 8.5 / 5, 11 / 5; Column temperature: 50°C; Flow rate: 0.6 mL / min;

[0209] Method 11: Column: Phenomenex C18 (50 mm x 2.1 mm, 2.6 μm); Mobile phase: A: ACN + formic acid 0.1%, B% water 0.1% formic acid; Gradient: time / % B: 0 / 95, 0.3 / 95, 2.0 / 5, 3.1 / 5, 3.5 / 95, 4.3 / 95; Column temperature: 40 °C, Flow rate: 0.6 mL / min

[0210] Method 12: Column: Aquity UPLC BEH C18 (50 mm x 2.1 mm, 1.7 μm); Mobile phase: A: 0.1% formic acid in water, B: 0.1% formic acid in acetonitrile; Gradient: Time / %B: 0 / 5, 0.3 / 5, 2.5 / 95, 3.7 / 95, 4 / 5, 4.6 / 5; Column temperature: 40°C; Flow rate: 0.6 mL / min

[0211] Reference Example 1

[0212] 2-(Trimethylstannyl)isonicotinonitrile

[0213] To a stirred solution of 2-bromoisonicotinonitrile (2 g, 10.92 mmol) in toluene (20 mL) was added hexamethylditin (4.6 g, 14.20 mmol) and Pd(PPh3)4 (1.2 g, 1.09 mmol) at rt. The resulting solution was degassed with nitrogen for 10 min and heated to 110°C for 16 h. The reaction mixture was evaporated under reduced pressure and the crude compound was purified by neutral alumina flash column chromatography using 50% EtOAc in petroleum ether to give the title compound (1.5 g, 51.7%). LC-MS (Method 1): R t =1.93min; m / z=269.08 (M+H + ).

[0214] Reference Example 2

[0215] (5-Bromo-1-methyl-1H-pyrrolo[2,3-c]pyridin-2-yl)(morpholino)methanone

[0216] Step a. 5-bromo-1-methyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid methyl ester

[0217] To a stirred solution of 5-bromo-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (2 g, 8.3 mmol) in DMF (20 mL) was added Cs2CO3 (5.4 g, 16.6 mmol) and MeI (2.35 g, 16.6 mmol) at 0°C. The reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with ice-cold water and the resulting solid was filtered and washed with water and n-pentane to give 1.8 g (80.6%) of the title compound. LC-MS (Method 2): R t =2.67min; m / z=269.09 (M+H + ).

[0218] Step b. (5-Bromo-1-methyl-1H-pyrrolo[2,3-c]pyridin-2-yl)(morpholino)methanone

[0219] To a stirred solution of the compound obtained in step a (0.75 g, 2.8 mmol) in toluene were added triethylamine (0.84 g, 8.4 mmol), morpholine (0.26 g, 3.08 mmol) and DABAL-Me3 (1.07 g, 4.2 mmol) at 0°C. The reaction mixture was stirred at 100°C for 3 h. After completion of the reaction, it was filtered through a pad of celite and washed with ethyl acetate. The resulting solution was evaporated to give the crude compound which was purified by silica gel column chromatography using 3% MeOH in DCM to give 0.71 g (78.5%) of the title compound. LC-MS (Method 2): R t =2.26min; m / z=323.9 (M+H + ).

[0220] Reference Example 3

[0221] 5-Bromo-N-(3-(dimethylamino)propyl)-N,1-dimethyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide Step a. 5-Bromo-1-methyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid

[0222] To a stirred solution of the compound obtained in part a of reference example 2 (2.8 g, 10.4 mmol) in EtOH and water (35 mL. 1:0.1 volume ratio) was added NaOH (1.45 g, 3.5 eq). The reaction mixture was stirred at rt for 3 h. After the reaction was complete, acetic acid (1.5 mL) was added to neutralize the excess NaOH. The solvent was evaporated under reduced pressure and water was added. The pH was adjusted to 2-3 by adding 1 M HCl aqueous solution. The precipitated solid was filtered, washed with H2O and dried in vacuo to give 2.4 g (90.4%) of the title compound as a gray solid. LC-MS (Method 3): R t=1.36min; m / z=255.11 (M+H + ).

[0223] Step b. 5-Bromo-N-(3-(dimethylamino)propyl)-N,1-dimethyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

[0224] To a stirred solution of the compound obtained in step a (0.55 g, 2.2 mmol) in DMF (6 mL) at 0°C were added N 1 ,N 1 ,N 3 -trimethylpropane-1,3-diamine (0.51 g, 4.4 mmol), DIPEA (0.85 g, 6.6 mmol) and HATU (1.25 g, 3.3 mmol) were added and the reaction mixture was stirred at RT for 3 h. After completion of the reaction, it was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to give 0.60 g (78.7%) of the title compound as a dark brown liquid. LC-MS (Method 3): R t =1.05min; m / z=353.20 (M+H + ).

[0225] Following a procedure analogous to that described in Reference Example 3, but using in each case the corresponding starting materials, the following compounds were obtained:

[0226]

[0227]

[0228] Reference Example 4

[0229] 3-Bromo-1-(3-methoxypropyl)-1H-pyrazolo[4,3-b]pyridine

[0230] To a stirred solution of 3-bromo-1H-pyrazolo[4,3-b]pyridine (500 mg, 2.5 mmol) in DMF (2 mL) was added NaH (0.12 g, 5 mmol). The reaction mixture was stirred at 0 ° C for 15 min. Then 1-bromo-3-methoxypropane (0.57 g, 3.75 mmol) was added at 0 ° C and stirred overnight at rt. After the reaction was completed, it was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The crude compound was purified by silica gel column chromatography using 35-40% EtOAc in petroleum ether to give 0.30 g (43.9%) of the title compound. LC-MS (Method 4): R t =1.71min; m / z=270.04 (M+H+ ).

[0231] Following a procedure analogous to that described in Reference Example 4, but using in each case the corresponding starting materials, the following compounds were obtained:

[0232]

[0233] Reference Example 5

[0234] 3-Bromo-7-chloro-1H-pyrazolo[4,3-b]pyridine

[0235] To a stirred solution of 7-chloro-1H-pyrazolo[4,3-b]pyridine (400 mg, 2.6 mmol) in MeOH / H2O (1:1) (5 mL) at 0°C was added a solution of bromine (0.45 g, 2.86 mmol) in MeOH / H2O (1:1) (5 mL). The resulting solution was stirred at 0°C for 30 min. A solid precipitated from the reaction mixture, which was filtered and dried to give 500 mg (82.5%) of the title compound as a yellow solid. LC-MS (Method 4): R t =1.56min; m / z=232.01 (M+H + ).

[0236] Reference Example 6

[0237] 3-Bromo-7-chloro-1-(2-methoxyethyl)-1H-pyrazolo[4,3-b]pyridine

[0238] Following a procedure analogous to that described in Reference Example 4, but using Reference Example 5 instead of 3-bromo-1H-pyrazolo[4,3-b]pyridine, the desired compound was obtained. LC-MS (Method 3): R t =1.59min; m / z=290.14 (M+H + ).

[0239] Following a procedure analogous to that described in Reference Example 6, but using in each case the corresponding starting materials, the following compounds were obtained:

[0240]

[0241] Example 1

[0242] (1-Methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)(morpholino)methanone

[0243]

[0244] Step a. 2-(1-methyl-2-(morpholine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinonitrile

[0245] To a stirred solution of Reference Example 2 (700 mg, 2.2 mmol) in 1,4-dioxane (70 mL) was added Reference Example 1 (640 mg, 2.42 mmol), CsF (660 mg, 4.4 mmol) and CuI (83 mg, 0.44 mmol). The resulting solution was degassed with nitrogen for 5 minutes, and then Pd(PPh3)4 (250 mg, 0.22 equiv) was added. The reaction mixture was degassed for another 5 min and then heated at 110 °C for 16 h. The crude reaction system was filtered through a celite pad, washed with EtOAc (50 mL), and the filtered solution was evaporated to dryness. The crude compound was purified by preparative HPLC using ammonium bicarbonate buffer to give the title compound (185 mg, 24%) as an off-white solid. LC-MS (Method 2): R t =2.35min; m / z=348.1 (M+H + ).

[0246] Step b. (Z)-N'-Hydroxy-2-(1-methyl-2-(morpholine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinimidamide

[0247] To a stirred solution of the compound obtained in step a (165 mg, 0.5 mmol) in EtOH (16.5 mL) was added NH2OH.HCl (200 mg, 3 mmol), Na2CO3 (0.10 g, 1.0 mmol) and water (1.65 mL). The resulting solution was stirred at rt for 16 h. The reaction mixture was evaporated in vacuo, poured into ice water (20 mL) and extracted with 10% methanol in DCM. The organic layer was dried over anhydrous Na2SO4, filtered and the filtered solution was concentrated to give the title compound (0.18 g, 99%) as an off-white solid. LC-MS (Method 6): R t =0.83min; m / z=381.33 (M+H + ).

[0248] Step c. 1-Methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)(morpholino)methanone

[0249] To a stirred solution of the compound obtained in step b (180 mg, 0.50 mmol) in THF (1.8 mL) was added trifluoroacetic anhydride (310 mg, 1.5 mmol). The resulting solution was heated at 70 ° C for 3 h. The reaction mixture was evaporated in vacuo, poured into ice water (20 mL), and extracted with EtOAc (2X80 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the filtered solution was concentrated to obtain a crude residue, which was purified by preparative HPLC to obtain the title compound (93 mg, 42.8%) as an off-white solid. LC-MS (Method 6): R t =1.38; m / z = 459.33 (M+H + ).

[0250] Following a procedure analogous to that described in Example 1, but using in each case the corresponding starting materials, the following compounds were obtained:

[0251]

[0252]

[0253]

[0254]

[0255]

[0256] (*) After step c, 0.1% HCOOH in H2O was added for complete triflate deprotection.

[0257] (**) In step b, 1:0.2 EtOH:water was used as solvent

[0258] (***) In step b, 1:1:0.5 EtOH:MeOH:water was used as solvent

[0259] Example 2

[0260] N-(Cyclopropylmethyl)-N,1-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide hydrochloride

[0261] The hydrochloride salt of the compound of Example 1h was prepared by dissolving the compound from Example 1h (0.056 g, 0.1 mmol) in 1,4-dioxane (1 mL) at 0°C and then adding 4M HCl in dioxane (1 mL). The resulting mixture was stirred at RT for 20 min. Thereafter, the solvent was evaporated under reduced pressure followed by lyophilization to give 45 mg (75%) of the title compound. LC-MS (Method 3): Rt =1.72min; m / z=457.41 (M+H + ).

[0262] Following a procedure analogous to that described in Example 2, but using in each case the corresponding starting materials, the following compounds were obtained:

[0263]

[0264]

[0265] Example 3

[0266] (1-Methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)(morpholino)methanone methanesulfonate

[0267] The mesylate salt of Example 1 compound was prepared by dissolving the compound from Example 1 (0.011 g, 0.02 mmol) in acetonitrile (2 mL) at 0°C and then adding methanesulfonic acid (2.3 mg, 0.02 mmol). The resulting mixture was stirred at RT for 30 min. Thereafter, the solvent was evaporated under reduced pressure, followed by lyophilization, to give 0.013 g (quantitative yield) of the title compound. LC-MS (Method 10): R t =2.82min; m / z=459.0 (M+H + ).

[0268] Example 4

[0269] (1-Methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)(piperazin-1-yl)methanone

[0270]

[0271] Step a. tert-Butyl 4-(5-(4-cyanopyridin-2-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)piperazine-1-carboxylate

[0272] Following a procedure analogous to that described in Example 1 part a, but using Reference Example 3d instead of Reference Example 2, the desired compound was obtained. LC-MS (Method 4): R t =1.81min; m / z=447.99 (M+H +Step b. tert-Butyl 4-(5-(4-(N-hydroxycarbamimidoyl)pyridin-2-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)piperazine-1-carboxylate

[0273] Following a procedure analogous to that described in Example 1, part b, but using the compound obtained in step a instead of 2-(1-methyl-2-(morpholine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinonitrile, the desired compound was obtained. LC-MS (Method 3): R t =1.29min; m / z=480.37 (M+H + ).

[0274] Step c. tert-Butyl 4-(1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)piperazine-1-carboxylate

[0275] Following a procedure analogous to that described in Example 1, part c, but using the compound obtained in step b instead of (Z)-N'-hydroxy-2-(1-methyl-2-(morpholine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinimide, the desired compound was obtained. LC-MS (Method 3): R t =1.88min; m / z=558.36 (M+H + ).

[0276] Step d. (1-Methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)(piperazin-1-yl)methanone

[0277] To a stirred solution of the compound obtained in step c (0.1 g, 0.2 mmol) in 1,4-dioxane (3 mL) was added 4 M HCl in dioxane (1 mL) at 0°C. The reaction mixture was stirred at RT for 1 h. Thereafter, the solvent was evaporated under reduced pressure, triturated with ether and freeze-dried to give 28 mg (29.5%) of the title compound as the dihydrochloride salt. LC-MS (Method 10): R t =2.61min; m / z=458.0 (M+H + ).

[0278] Example 5

[0279] 3-(2-(7-chloro-1-(2-methoxyethyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole

[0280]

[0281] Step a. 2-(7-chloro-1-(2-methoxyethyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)isonicotinonitrile

[0282] Following a procedure analogous to that described in Example 1 part a, but using Reference Example 6 instead of Reference Example 2, toluene instead of dioxane as solvent, and without the addition of CsF and CuI, the title compound was obtained. LC-MS (Method 3): R t =1.65min; m / z=314.25 (M+H + ).

[0283] Step b. 2-(7-chloro-1-(2-methoxyethyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-N-hydroxyisonicotinimide

[0284] Following a procedure similar to that described in Example 1, part b, but using the compound obtained in step a instead of 2-(1-methyl-2-(morpholine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinonitrile and using EtOH:MeOH:H2O (1:1:0.5) instead of EtOH as solvent, the desired compound was obtained. LC-MS (Method 3): R t =1.17min; m / z=347.30 (M+H + ).

[0285] Step c. 3-(2-(7-chloro-1-(2-methoxyethyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole

[0286] Following a procedure similar to that described in Example 1, part c, but using the compound obtained in step b instead of (Z)-N'-hydroxy-2-(1-methyl-2-(morpholine-4-carbonyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinimide, POCl3 (2 equiv.) was added for cyclization completion to give the desired compound. LC-MS (Method 4): R t =2.35min; m / z=425.12 (M+H + ).

[0287] Example 6

[0288] (S)-(3-Hydroxypyrrolidin-1-yl)(1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone(+) ​​camphorsulfonate

[0289] The (+) camphorsulfonic acid salt of the compound of Example 1o was prepared by dissolving the compound from Example 1o (0.1 g, 0.21 mmol) in MeOH (2 mL) at 0°C and then adding (1S)-(+)-10-camphorsulfonic acid (0.05 g, 0.21 mmol). The reaction mixture was stirred at RT for 30 min. Thereafter, ether was added and the solid that immediately precipitated was filtered off, dried in vacuo, and HPLC afforded 0.1 g (69%) of the title compound as a light brown solid. LC-MS (Method 12): Rt=1.72 min; m / z=459.10 (M+H+).

[0290] Example 7

[0291] HDAC6 enzyme inhibition assay

[0292] method:

[0293] The biochemical activity of inhibitors on HDAC6 was determined in 96-well half-area black microplates (Corning #3686) + TopSeal-A Black Sealing Film (Perkin Elmer #6050173) using fluorescence determination. The test compound was dissolved in DMSO. A half-logarithmic serial dilution of the test compound was prepared with DMSO and then diluted 1:10 in assay buffer (BPS Bioscience #50031).

[0294] 2.5 μL of enzyme (BPS Bioscience #50006) was incubated with 2.5 μL of test compound in an assay buffer containing 0.1 mg / mL bovine serum albumin (Sigma-Aldrich #A7030) at 21°C in a total volume of 22.5 μL for 3 hours. The enzymatic reaction was initiated by adding 2.5 μL of fluorescent acetylated peptide substrate (BPS Bioscience #50037). The final concentrations of enzyme and substrate in the reaction system were 8.8 nM and 9 μM, respectively. After incubation at 37°C for 45 minutes, the addition of 25 μL of developer (BPS Bioscience #50030) released the fluorophore in an amount proportional to the amount of deacetylated product. After incubation at 21°C for 15 minutes, the fluorescence intensity was measured using a Tecan Infinite F200 microplate reader (excitation 360 nM-emission 460 nM).

[0295] Negative control (background) was represented by the reaction mixture in the absence of enzyme (containing 0.1% DMSO), while positive control of deacetylase activity was obtained in the absence of test compound (containing 0.1% DMSO) after background subtraction. Percent inhibition was calculated as a fraction of the positive control.

[0296] result:

[0297] The results obtained using the compounds of the present invention in the above test are shown in the following table:

[0298]

[0299] As is apparent from the above table, the compounds of the present invention exhibit potent HDAC6 inhibitory activity.

[0300] Example 8

[0301] In vitro HDAC6 cell-based assay

[0302] In order to determine the cell activity of HDAC6 after treatment with HDAC6 inhibitor, the acetylation level of α-tubulin (HDAC6-specific substrate) was measured by Western blotting.For this reason, MOLP8 cells were seeded in 6-well plates with a cell density of 500,000 cells / well, and in a humidified tissue incubator, at 37 ° C and 5% CO2, 5 and 1 μM of test compounds were used for 18h. Cell precipitation was continuously collected and the complete protein extract was prepared using RIPA buffer (SIGMA) supplemented with 1X protease inhibitor (cOmplete mini, Roche). According to the manufacturer's instructions, protein concentration was determined with Bradford reagent (Bio-Rad), and 7 μg of total protein was loaded into prefabricated 10% NuPAGE Novex gel (Life Technologies). Gel was run in MOPS-SDS buffer (Life Technologies), and iBlot2 dry blotting system (Life Technologies) was used to transfer protein. The blot was then rinsed in distilled water and stained with Ponceau S solution (SIGMA). The blots were then washed in distilled water to remove excess Ponceau and scanned using an Epson Perfection V600 Photo Professional Scanner. Afterwards, the blots were destained and blocked in 5% milk / PBS-Tween 0.1% for 1 h at room temperature and then incubated with primary antibodies anti-acetyl-α-tubulin (SIGMA catalog number 7451, 1:10.000 dilution) and anti-β-actin (SIGMA, catalog number A5316, 1:2.000 dilution) in 5% milk / PBS-T 0.1% at 4°C on a rocking platform overnight. After incubation, the blots were washed 3 times for 5 minutes in 0.5% PBS-Tween and incubated with anti-mouse HRP-conjugated secondary antibody (Jackson ImmunoResearch, catalog number 115-035-068) at 1:8.000 in 5% milk / PBS-Tween 0.1% for 1 h at room temperature on a rocking platform. After washing 3 times (5 minutes each) with PBS-Tween 0.5% and 1 time in PBS 1X, the blots were developed with ECL Plus (GE Healthcare) and the chemiluminescent reaction was imaged with a G:Box Chemi XRQ (Syngene) imaging system. WB and Ponceau images were analyzed with ImageJ software, and WB band intensities were calibrated by total protein or β-actin content and performed relative to ACY-1215 1 μM (equivalent to 100%).ACY-115 is an HDAC6 inhibitor and is also known as ricolinostat, which has the chemical name 2-(diphenylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]-5-pyrimidinecarboxamide.

[0303] Compounds of the invention were tested at 1 and 5 μM in this assay and were found to inhibit the cellular activity of HDAC6.

Claims

1. A compound selected from: (3-hydroxypyrrolidin-1-yl)(1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone, (1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)(morpholino)methanone, N-(3-(dimethylamino)propyl)-N,1-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide, N-(2-hydroxyethyl)-N,1-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide, N,1-dimethyl-N-((1-methylpiperidin-4-yl)methyl)-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide, N,N-bis(2-hydroxyethyl)-1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide, N-(cyclopropylmethyl)-N,1-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide, N-(2-methoxyethyl)-N,1-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide, (1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)(piperazin-1-yl)methanone, N-ethyl-N,1-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide, N,N-bis(2-methoxyethyl)-1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide, (S)-(1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)(3-methylmorpholino)methanone, 3-(2-(1-(3-methoxypropyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, 3-(2-(1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, 3-(2-(7-chloro-1-(2-methoxyethyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, and 3-(2-(1-(2-methoxyethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole; or a salt thereof.

2. The compound of claim 1, wherein the compound is (3-hydroxypyrrolidin-1-yl)(1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methanone or a salt thereof.

3. The compound or salt thereof according to claim 2, wherein the compound is in an optically active form.

4. The compound or salt thereof according to claim 2, wherein the compound is an enantiomer.

5. The compound of claim 1, wherein the compound is (1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)(morpholino)methanone or a salt thereof.

6. The compound of claim 1, wherein the compound is N-(3-(dimethylamino)propyl)-N,1-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide or a salt thereof.

7. The compound of claim 1, wherein the compound is N-(2-hydroxyethyl)-N,1-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide or a salt thereof.

8. The compound of claim 1, wherein the compound is N,1-dimethyl-N-((1-methylpiperidin-4-yl)methyl)-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide or a salt thereof.

9. The compound of claim 1, wherein the compound is N,N-bis(2-hydroxyethyl)-1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide or a salt thereof.

10. The compound of claim 1, wherein the compound is N-(cyclopropylmethyl)-N,1-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide or a salt thereof.

11. The compound of claim 1, wherein the compound is N-(2-methoxyethyl)-N,1-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide or a salt thereof.

12. The compound of claim 1, wherein the compound is (1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)(piperazin-1-yl)methanone or a salt thereof.

13. The compound of claim 1, wherein the compound is N-ethyl-N,1-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide or a salt thereof.

14. The compound of claim 1, wherein the compound is N,N-bis(2-methoxyethyl)-1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide or a salt thereof.

15. The compound of claim 1, wherein the compound is (S)-(1-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)(3-methylmorpholino)methanone or a salt thereof.

16. The compound of claim 1, wherein the compound is 3-(2-(1-(3-methoxypropyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole or a salt thereof.

17. The compound of claim 1, wherein the compound is 3-(2-(1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole or a salt thereof.

18. The compound of claim 1, wherein the compound is 3-(2-(7-chloro-1-(2-methoxyethyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole or a salt thereof.

19. The compound of claim 1, wherein the compound is 3-(2-(1-(2-methoxyethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole or a salt thereof.

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

21. Use of a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating amyotrophic lateral sclerosis.

22. Use of a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating peripheral neuropathy induced by chemotherapeutic drugs.

23. Use of the compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease associated with HDAC6.

24. The use of claim 23, wherein the disease is selected from the group consisting of cancer, autoimmune or inflammatory diseases, transplant rejection, ciliopathies, neurological diseases, mental or behavioral disorders, infectious diseases, cardiovascular diseases, muscle atrophy and cachexia.

25. The use according to claim 24, wherein the disease is a neurological disease.

26. The use according to claim 25, wherein the disease of the nervous system is peripheral neuropathy.

27. The use according to claim 25, wherein the disease of the nervous system is Charcot-Marie-Tooth disease.

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