BR102018004862A2 - compound, crystalline form, pharmaceutical composition, and methods for inhibiting ask1 and treating a condition - Google Patents

Abstract

compound, crystalline form, pharmaceutical composition, and methods for inhibiting ask1 and for treating a condition. a compound of formula (i) is provided; or a pharmaceutically acceptable salt thereof thereof for use in the treatment of nonalcoholic steatohepatitis, alcoholic hepatitis, pulmonary arterial hypertension, preserved ejection fraction heart failure, and diabetic kidney disease. Amorphous and crystalline forms of the compound of formula (I) and salts, cocrystals, solvates, and hydrates thereof are also provided.

Description

“COMPOUND, CRYSTALLINE FORM, PHARMACEUTICAL COMPOSITION, AND, METHODS TO INHIBIT ASK1 AND TO TREAT A CONDITION” [001] This claim claims the benefit according to 35 U.S.C. §

119e) of North American Provisional Order No. 62 / 471,300, filed on March 14, 2017, which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION [002] The present description relates to new compounds that are ASK1 inhibitors and that can be used in the treatment of ASK1-mediated diseases. The description also relates to methods of preparing the compounds of formula (I) and methods of treating the disease by administering the compounds of formula (I), a salt, cocrystalline, solvate or hydrate thereof.

BACKGROUND [003] The kinase regulating the apoptosis signal 1 ASK1) is a member of the family of the protein kinase activated by mitogen “MAP3K”) that activates the N-terminal protein kinase c-Jun “JNK”) and the p38 MAP kinase Ichijo , H., Nishida, E., Irie, K., Dijke, PT, Saitoh, M., Moriguchi, T., Matsumoto, K., Miyazono, K., and Gotoh, Y. 1997) Science, 275, 90 -94). ASK1 is activated by a variety of stimuli, including oxidative stress, reactive oxygen species (ROS), LPS, TNF-α, FasL, ER stress and increased intracellular calcium concentrations Hattori, K., Naguro, I., Runchel , C. and Ichijo, H. 2009) Cell Comm. Signal. 7: 1-10; Takeda, K., Noguchi, T., Naguro, I., and Ichijo, H. 2007) Annu. Rev. Pharmacol. Toxicol. 48: 1-8.27; Nagai, H., Noguchi, T., Takeda, K., and Ichijo, I. 2007) J. Biochem. Mol. Biol. 40: 1-6). Activation and signaling of ASK1 has been reported to play an important role in a wide range of diseases, including liver diseases such as non-alcoholic steatohepatitis,

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2/85 non-alcoholic fatty liver, alcoholic hepatitis), cardiovascular diseases such as pulmonary arterial hypertension and heart failure), kidney disease such as chronic kidney disease) and also neurodegenerative, inflammatory, autoimmune and metabolic disorders. Thereby, therapeutic agents that act as ASK1 signaling inhibitors have the potential to remedy or improve the lives of patients who need treatment for various diseases.

[004] U.S. Patent No. 8,378,108, U.S. Patent No. 8,552,196, to

US Patent No. 8,598,360, US Patent No. 8,742,126, US Patent No. 9,067,933, US Patent No. 9,254,284, US Patent No. 9,333,197, US Patent No. 9,586 .932, US Patent Publication No. 2015/0342943 and US Patent Publication No. 2016/0166556 describe compounds useful as ASK1 inhibitors and methods of treating disease with an ASK1 inhibitor. Surprisingly, depositors found a new compound exhibiting good potency and pharmacokinetic and / or pharmacodynamic parameters.

SUMMARY [005] A compound and pharmaceutical compositions useful as an ASK1 inhibitor are provided in the present invention. The compound described in the present invention can be used in pharmaceutical compositions, together with at least one pharmaceutically acceptable excipient, to treat an individual who needs it. The compound of the present description was found to inhibit ASK1. The description also provides compositions, including pharmaceutical compositions, kits that include the compound of formula (I) and methods of preparing and using the compounds of formula (I). Salts, co-crystals, hydrates and solvates of the compounds of formula (I) are also provided.

[006] In one embodiment of the description, a compound of formula (I),

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F (I) or a pharmaceutically acceptable salt, cocrystal, solvate or hydrate thereof.

[007] In one embodiment, the compound of formula (I) is a free base. In another embodiment of the description, the compound of formula (I) is a salt. In one embodiment, the compound of formula (I) is a salt selected from succinate, hydrochloride, phosphate, malate, sulfate, citrate, glutarate and methanesulfonate.

[008] In one embodiment of the description, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is amorphous.

[009] In one embodiment of the description, the free base compound of formula (I) is the crystalline form I. In one embodiment, the compound of formula I of the free base of form I is distinguished by a powder X-ray diffractogram with peaks at 8.7, 10.2 and 18.1 ° 2Θ ± 0.2 ° 2Θ. In one embodiment, the compound of formula (I) of the free base of form I is distinguished by a powder X-ray diffractogram with peaks at 15.8, 17.3 and 23.5 ° 2Θ ± 0.2 ° 2Θ . In one embodiment, the compound of formula (I) of the free base of form I is distinguished by a powder X-ray diffractogram with peaks at 15.2, 18.5 and

24.9 ° 2 Θ ± 0.2 ° 2Θ.

[0010] In one embodiment, the compound of formula (I) of the free base of form I is distinguished by a powder X-ray diffractogram which is substantially as shown in figure 1.

[0011] In one embodiment, the compound of formula (I) of the free base of form I is distinguished by a differential scanning calorimetry curve (DSC) substantially as shown in figure 2.

[0012] In another embodiment, the description provides a compound of formula (I) of free base of form II. In one embodiment, the compound is distinguished by a powder X-ray diffractogram with peaks at 8.7, 10.0 and

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17.0 ° 2 θ ± 0.2 ° 2Θ. In another modality, ο compound is distinguished by a powder X-ray diffractogram with peaks at 13.9, 21.3 and 22.8 ° 2 Θ ± 0.2 ° 2Θ. In one embodiment, the compound is distinguished by a powder X-ray diffractogram with peaks at 24.0, 28.0 and 29.1 ° 2 Θ ± 0.2 ° 2Θ.

[0013] In one embodiment of the description, a compound of formula (I) of free base of the form Π is distinguished by a powder X-ray diffractogram substantially as shown in figure 4.

[0014] In one embodiment of the description, a compound of formula (I) of the free base of the form Π is distinguished by a DSC scanning differential calorimetry curve substantially as shown in figure 5.

[0015] In another embodiment, the description provides a crystalline succinate form I of the compound of formula (I). In one embodiment, the succinate form I of the compound of formula (I) is distinguished by a powder X-ray diffractogram with peaks at 7.5, 20.9 and 24.9 ° 2 Θ ± 0.2 ° 2Θ . In one embodiment, form I of succinate is distinguished by a powder X-ray diffractogram with peaks at 15.4, 22.4 and 31.1 ° 2 Θ ± 0.2 ° 2Θ. In yet another embodiment, form I of succinate is distinguished by a powder X-ray diffractogram with peaks at 14.9, 23.2 and 25.4 ° 2 Θ ± 0.2 ° 2Θ.

[0016] In one embodiment of the description, a crystalline compound of formula (I) of form I of succinate is distinguished by a powder X-ray diffractogram substantially as shown in figure 7.

[0017] In one embodiment of the description, a crystalline compound of formula (I) of form I of succinate is substantially distinguished by a differential scanning calorimetry curve (DSC) substantially as shown in figure 8.

[0018] In one embodiment, the description provides a crystalline compound of formula (I) of the Π form of succinate. In one embodiment, the crystalline compound of formula (I) of form II of succinate is distinguished by

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5/85 a powder X-ray diffractogram with peaks at 9.8, 11.7 and 23.3 ° 2 Θ ± 0.2 ° 2Θ. In another embodiment, the compound of formula (I) of the Π form of succinate is distinguished by a powder X-ray diffractogram with peaks in

15.9, 21.5 and 32.0 ° 2 Θ ± 0.2 ° 2Θ. In another embodiment, the compound of formula (I) of the Π form of succinate is distinguished by a powder X-ray diffractogram with peaks at 16.3, 20.8 and 24.8 ° 2 Θ ± 0.2 ° 2Θ.

[0019] In one embodiment of the description, the compound of formula (I) of form II of succinate is distinguished by a powder X-ray diffractogram substantially as shown in figure 10.

[0020] In one embodiment of the description, the crystalline compound of formula (I) of form II of succinate is substantially distinguished by a differential scanning calorimetry curve (DSC) substantially as shown in figure 11.

[0021] In another embodiment, the description provides a crystalline compound of formula (I) of form I of hydrochloride. In one embodiment, the crystalline compound of formula (I) of hydrochloride form I is distinguished by a powder X-ray diffractogram with peaks at 9.3, 21.2 and 26.2 ° 2 Θ ± 0.2 ° 2Θ. In one embodiment, the crystalline compound of the formula (I) of hydrochloride form I is distinguished by a powder X-ray diffractogram with peaks in

20.9, 24.7 and 27.6 ° 2 Θ ± 0.2 ° 2Θ. In one embodiment, the crystalline compound of formula (I) of hydrochloride form I is distinguished by a powder X-ray diffractogram with peaks at 23.8, 24.3 and 26.6 ° 2 Θ ± 0.2 ° 2Θ.

[0022] In one embodiment of the description, a crystalline compound of formula (I) of hydrochloride form I is substantially distinguished by a powder X-ray diffractogram as shown in figure 13.

[0023] In one embodiment of the description, the crystalline compound of formula (I) of hydrochloride form I is distinguished substantially by a differential scanning calorimetry curve (DSC) substantially as shown in figure 14.

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6/85 [0024] In another embodiment, the description provides a crystalline compound of formula (I) of the Π form of hydrochloride. In one embodiment, the crystalline compound of formula (I) of the Π hydrochloride form is distinguished by a powder X-ray diffractogram with peaks at 8.3, 12.0 and 26.0 ° 2 Θ ± 0.2 ° 2Θ. In one embodiment, the crystalline compound of formula (I) of the Π form of hydrochloride is distinguished by a powder X-ray diffractogram with peaks at 19.3, 21.7 and 24.0 ° 2 Θ ± 0.2 ° 2Θ. In one embodiment, the powder X-ray diffractogram of the crystalline compound of formula (I) of the Π form of hydrochloride has peaks at 9.8, 15.4 and 28.9 ° 2 Θ ± 0.2 ° 2Θ.

[0025] In one embodiment of the description, the compound of formula (I) of hydrochloride form II is substantially distinguished by a powder X-ray diffractogram as shown in figure 16.

[0026] In one embodiment of the description, the crystalline compound of formula (I) of hydrochloride form II is substantially distinguished by a DSC scanning differential calorimetry curve substantially as shown in figure 33.

[0027] In another embodiment, the description provides a crystalline compound of formula (I) of the ΠΙ form of hydrochloride. In one embodiment, the crystalline compound of formula (I) of the ΙΠ form of hydrochloride is distinguished by a powder X-ray diffractogram with peaks of 6.6, 12.9 and 19.7 ° 2 Θ ± 0.2 ° 2Θ. In one embodiment, the crystalline compound of formula (I) of the ΠΙ form of hydrochloride is distinguished by a powder X-ray diffractogram with peaks at 20.4, 23.4 and 24.8 ° 2 Θ ± 0.2 ° 2Θ. In one embodiment, the crystalline compound of formula (I) of the ΠΙ form of hydrochloride presents a powder X-ray diffractogram with peaks at 18.1, 25.4 and 26.7 ° 2 Θ ± 0.2 ° 2Θ.

[0028] In one embodiment of the description, the crystalline compound of formula (I) of the ΠΙ form of hydrochloride is distinguished by a powder X-ray diffractogram, substantially as shown in figure 17.

[0029] In a description mode, the crystalline compound of

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7/85 formula (I) of the ΙΠ form of hydrochloride is distinguished by a differential scanning calorimetry curve (DSC) substantially as shown in figure 18.

[0030] In one embodiment, the description provides a crystalline compound of formula (I) of L-malate. In one embodiment, the crystalline compound of the formula (I) of L-malate is distinguished by a powder X-ray diffractogram with peaks at 7.2, 21.9 and 24.5 ^Ο 2Θ ± ^Ο 2Θ. In another embodiment, the compound of the formula (I) of L-malate is distinguished by a powder X-ray diffractogram with peaks at 10.9, 16.6 and 19.7 ^Ο 2Θ ± ^Ο 2Θ. In another embodiment, the compound of the formula (I) of L-malate is distinguished by a powder X-ray diffractogram with peaks at 8.2, 22.8 and 27.3 ^Ο 2Θ ± ^Ο 2Θ.

[0031] In one embodiment of the description of the crystalline compound of the formula (I) of L-malate it is distinguished by a powder X-ray diffractogram substantially as shown in figure 19.

[0032] In one embodiment of the description, the crystalline compound of formula (I) of L-malate is distinguished by a DSC scanning differential calorimetry curve substantially as shown in figure 20. [0033] In one embodiment, the description provides a crystalline compound of formula (I) of phosphate material A. In one embodiment, the crystalline compound of the formula (I) of phosphate material A is distinguished by a powder X-ray diffractogram with peaks at 6.9, 8.0 and 21.2 ^Ο 2Θ ± ^Ο 2Θ. In another embodiment, the compound of formula (I) of phosphate material A is distinguished by a powder X-ray diffractogram with peaks at 22.8, 25.3 and 26.0 ^Ο 2Θ ± ^Ο 2Θ. In another embodiment, the compound of formula (I) of phosphate material A is distinguished by a powder X-ray diffractogram with peaks at 19.8, 20.6, 23.2 ^Ο 2Θ ± ^Ο 2Θ.

[0034] In one embodiment of the description, the compound of formula (I) of phosphate material A is distinguished by a powder X-ray diffractogram substantially as shown in figure 22.

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8/85 [0035] In one embodiment, the description provides a crystalline compound of formula (I) of phosphate material B. In one embodiment, the crystalline compound of formula (I) of phosphate material B is distinguished by a powder X-ray diffractogram with peaks at 13.4, 23.5 and 24.3 ^Ο 2Θ ± ^Ο 2Θ. In another embodiment, the compound of formula (I) of phosphate material B is distinguished by a powder X-ray diffractogram with peaks at 21.7, 25.1 and 25.8 ^Ο 2Θ ± ^Ο 2Θ. In another embodiment, the compound of formula (I) of phosphate material B is distinguished by a powder X-ray diffractogram with peaks at 17.0, 18.6 and 22.5 ^Ο 2Θ ± ^Ο 2Θ.

[0036] In one embodiment of the description, the compound of formula (I) of phosphate material B is distinguished by a powder X-ray diffractogram substantially as shown in figure 23.

[0037] In one embodiment, the description provides a crystalline compound of formula (I) of sulfate. In one embodiment, the crystalline compound of the formula (I) of sulfate is distinguished by a powder X-ray diffractogram with peaks at 7.2, 13.5 and 21.5 ^Ο 2Θ ± ^Ο 2Θ. In another embodiment, the sulfate compound of formula (I) is distinguished by a powder X-ray diffractogram with peaks at 16.9, 20.5 and 25.3 ^Ο 2Θ ± ^Ο 2Θ. In another embodiment, the compound of the formula (I) of sulfate is distinguished by a powder X-ray diffractogram with peaks at 18.2, 20.6 and 27.2 ^Ο 2Θ ± ^Ο 2Θ.

[0038] In one embodiment of the description, the crystalline compound of the formula (I) of sulfate is distinguished by a powder X-ray diffractogram substantially as shown in figure 24.

[0039] In one embodiment of the description, the crystalline compound of formula (I) of sulfate is substantially distinguished by a differential scanning calorimetry curve (DSC) substantially as shown in figure 25.

[0040] In one embodiment, the description provides a crystalline compound of formula (I) of material A of citrate. In one embodiment, the crystalline compound of the formula (I) of citrate material A is distinguished by

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9/85 a powder X-ray diffractogram with peaks at 5.6, 9.1, 16.7 ^Ο 2Θ ± ^Ο 2Θ. In one embodiment, the compound of formula (I) of citrate material A is distinguished by a powder X-ray diffractogram with peaks at 12.2, 21.0, 23.0 ^Ο 2Θ ± ^Ο 2Θ. In another embodiment, the compound of the formula (I) of citrate material A is distinguished by a powder X-ray diffractogram with peaks at 18.7, 24.9, 25.8 ^Ο 2Θ ± ^Ο 2Θ.

[0041] In one embodiment of the description, the crystalline compound of formula (I) of material A of citrate is distinguished by a powder X-ray diffractogram substantially as shown in figure 27.

[0042] In one embodiment, the description provides a crystalline compound of formula (I) of material B of citrate. In one embodiment, the crystalline compound of formula (I) of citrate material B is distinguished by a powder X-ray diffractogram with peaks at 5.6, 8.6 and 9.1 ^Ο 2Θ ± ^Ο 2Θ. In one embodiment, the compound of formula (I) of citrate material B is distinguished by a powder X-ray diffractogram with peaks at 12.2, 23.2 and

23.9 ^Ο 2Θ ± ^Ο 2Θ. In another embodiment, the compound of formula (I) of material B of citrate is distinguished by a powder X-ray diffractogram with peaks at 16.8, 18.5 and 21.1 ^Ο 2Θ ± ^Ο 2Θ.

[0043] In one embodiment of the description, the crystalline compound of formula (I) of material citrate B is distinguished by a powder X-ray diffractogram substantially as shown in figure 28.

[0044] In one embodiment of the description, the crystalline compound of formula (I) of citrate material B is distinguished by a DSC scanning differential calorimetry curve substantially as shown in figure 29.

[0045] In one embodiment, the description provides a crystalline compound of formula (I) of glutarate. In one embodiment, the crystalline compound of formula (I) of glutarate is distinguished by a powder X-ray diffractogram with peaks at 6.7, 8.0 and 12.1 ^Ο 2Θ ± ΠΠΠ ^Ο 2Θ. In another

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10/85 modality, the crystalline compound of formula (I) of glutarate is distinguished by a powder X-ray diffractogram with peaks at 14.6, 20.9 and 21.8 ^Ο 2Θ ± ^Ο 2Θ. In another embodiment, the compound of formula (I) of glutarate is distinguished by a powder X-ray diffractogram with peaks at 17.9, 19.3 and

26.2 ^Ο 2Θ ± ^Ο 2Θ.

[0046] In one embodiment of the description, the crystalline compound of the formula (I) of glutarate is distinguished by a powder X-ray diffractogram substantially as shown in figure 30.

[0047] In one embodiment of the description, the crystalline compound of formula (I) of glutarate is distinguished by a differential scanning calorimetry curve (DSC) substantially as shown in figure 31. [0048] In one embodiment, the description provides a compound crystalline formula (I) of methanesulfonate. In one embodiment, the crystalline compound of formula (I) of methanesulfonate is distinguished by a powder X-ray diffractogram with peaks at 8.4, 19.1 and 21.2 ° 2Θ ± Π □ Π ° 2Θ. In one embodiment, the compound of formula (I) of methanesulfonate is distinguished by a powder X-ray diffractogram with peaks at 17.2, 19.7 and

20.2 ^Ο 2Θ ± ^Ο 2Θ. In one embodiment, the compound of formula (I) of methanesulfonate is distinguished by a powder X-ray diffractogram with peaks at 12.8, 21.8 and 25.2 ^Ο 2Θ ± ^Ο 2Θ.

[0049] In one embodiment of the description, the crystalline compound of the methanesulfonate formula (I) is substantially distinguished by a powder X-ray diffractogram substantially as shown in figure 32.

[0050] In one embodiment, the description provides a therapeutically effective amount of a compound of formula (I), a salt, a cocrystalline, a solvate or a hydrate thereof with a pharmaceutically acceptable excipient.

[0051] In one embodiment, the description provides a composition that comprises a compound of formula (I), a salt, a cocrystal, a solvate or

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11/85 a hydrate thereof with a pharmaceutically acceptable excipient and one, two or three additional agents.

[0052] In one embodiment, the description provides a composition comprising a compound of formula (I), a salt, a cocrystal, a solvate or a hydrate thereof with a pharmaceutically acceptable excipient and an additional agent which is an FXR agonist. The FXR agonist can be a compound of formula (ΙΠ) or a compound of formula (IV), as defined in this document.

[0053] In one embodiment, the description provides a composition comprising a compound of formula (I), a salt, a cocrystal, a solvate or a hydrate thereof with a pharmaceutically acceptable excipient and an additional agent that is an ACC inhibitor . The ACC inhibitor can be a compound of formula (V), as defined in this document.

[0054] The description provides methods for inhibiting ASK1 with a compound of formula (I), or a salt, cocrystalline, solvate or hydrate thereof.

[0055] In another embodiment, the description provides a method of treating a selected condition of non-alcoholic steatohepatitis, alcoholic hepatitis, pulmonary arterial hypertension, heart failure with preserved ejection fraction and diabetic kidney disease by administering a therapeutically amount effect of a compound of formula (I), or a salt, cocrystal, solvate or hydrate thereof.

[0056] In one embodiment, the description provides a method of treating fibrosis with a therapeutically effective amount of a compound of formula (I), a salt, a cosolvate or a hydrate thereof.

[0057] In one embodiment, the description provides a compound of formula Ia):

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DESCRIPTION OF THE DRAWINGS [0058] Figure 1 is an XRPD standard for a compound of formula (I) of form I of free base.

[0059] Figure 2 is a DSC thermogram for a compound of formula (I) of form I of free base.

[0060] Figure 3 is a TGA thermogram for a compound of formula (I) of form I of free base.

[0061] Figure 4 is an XRPD standard for a compound of formula (I) of form II of free base.

[0062] Figure 5 is a DSC thermogram for a compound of formula (I) of form II of free base.

[0063] Figure 6 is a TGA thermogram for a compound of formula (I) of form II of free base.

[0064] Figure 7 is an XRPD standard for a compound of formula (I) of form I succinate.

[0065] Figure 8 is a DSC thermogram for a compound of formula (I) of form I succinate.

[0066] Figure 9 is a TGA thermogram for a compound of formula (I) of form I succinate.

[0067] Figure 10 is an XRPD standard for a compound of formula (I) of form II of succinate.

[0068] Figure 11 is a DSC thermogram for a compound of formula (I) of form II of succinate.

[0069] Figure 12 is a TGA thermogram for a compound of formula (I) of form II of succinate.

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13/85 [0070] Figure 13 is an XRPD standard for a compound of formula (I) of form I of HCl.

[0071] Figure 14 is a DSC thermogram for a compound of formula (I) of form I of HCl.

[0072] Figure 15 is a TGA thermogram for a compound of formula (I) of form I of HCl.

[0073] Figure 16 is an XRPD standard for a compound of formula (I) of form II of HCl.

[0074] Figure 17 is an XRPD standard for a compound of formula (I) of the ΙΠ form of HCl.

[0075] Figure 18 is a DSC thermogram for a compound of formula (I) of the ΙΠ form of HCl.

[0076] Figure 19 is an XRPD standard for a compound of formula (I) of L-malate.

[0077] Figure 20 is a DSC thermogram for a compound of formula (I) of L-malate.

[0078] Figure 21 is a TGA thermogram for a compound of formula (I) of L-malate.

[0079] Figure 22 is an XRPD standard for a compound of formula (I) of phosphate material A.

[0080] Figure 23 is an XRPD standard for a compound of formula (I) of phosphate material B.

[0081] Figure 24 is an XRPD standard for a compound of formula (I) of sulfate.

[0082] Figure 25 is a DSC thermogram for a compound of formula (I) of sulfate.

[0083] Figure 26 is a TGA thermogram for a compound of formula (I) of sulfate.

[0084] Figure 27 is an XRPD standard for a compound of formula

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14/85 (I) of citrate material A.

[0085] Figure 28 is an XRPD standard for a compound of formula (I) of citrate material B.

[0086] Figure 29 is a DSC thermogram for a compound of formula (I) of material B of citrate.

[0087] Figure 30 is an XRPD standard for a compound of formula (I) of glutarate.

[0088] Figure 31 is a DSC thermogram for a compound of formula (I) of glutarate.

[0089] Figure 32 is an XRPD standard for a compound of formula (I) of methanesulfonate.

[0090] Figure 33 is a DSC thermogram for a compound of formula (I) of form II of HCl.

[0091] Figures 34 and 35 show profiles of solubility kinetics of various salts of the compound of formula (I) 50 mM acetate, pH = 5.5.1 = 150 mM, FaSSIF).

DETAILED DESCRIPTION

Definitions [0092] The following description establishes exemplary methods, parameters and the like. It must be recognized, however, that such a description is not intended to be a limitation on the scope of the present description, but rather it is provided as a description of exemplary modalities.

[0093] A dash “-”) that is not between two letters or symbols, is used to indicate a point of attachment for a substituent. For example, CO) NH ₂ is bonded via the carbon atom. A dash in front or at the end of a chemical group is a matter of convenience; chemical groups can be depicted with or without one or more strokes, without losing their common meaning. A wavy line across a line in a structure indicates a fixation point for a group. Unless it is

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15/85 chemically or structurally required, no directionality is indicated or implied in the order in which a chemical group is written or named.

[0094] Reference to "about" a value or parameter of the present invention includes and describes) modalities that are directed to that value or parameter alone. In certain embodiments, the term “about” includes the indicated amount ± 10%. In other modalities, the term “about” includes the indicated amount ± 5%. In certain other modalities, the term “about” includes the indicated amount ± 1%. Likewise, the term "about X" includes the description of "X". Likewise, the singular forms "one", "one" and "o / a" include references in the plural, unless the context clearly specifies otherwise. Thus, for example, the reference to the "compound" includes a plurality of such compounds, and reference to the "test" includes reference to one or more tests and equivalents thereof known to those skilled in the art.

[0095] Any formula or structure presented here is also intended to represent both unmarked and isotopically marked forms of the compounds. Unveiling labeled compounds have structures depicted by the formulas given in this document, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the description include the isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to, ² H deuterium, D), ³ H tritium), ⁿ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ F, ³¹ P, ³² P, ³⁶ C1 and ¹²³ I, respectively. Various isotopically labeled compounds of the present description, for example, those in which radioactive isotopes, such as ³ H, ¹³ C and ¹⁴ C, are incorporated. These isotopically labeled compounds can be useful in metabolic studies, reaction kinetics studies, detection or image capture techniques, such as emission tomography.

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16/85 positron PET) or computed tomography by emission of single photon SPECT), including assays of distribution in drug tissue or substrate, or in the radioactive treatment of patients.

[0096] The description also includes "deuterated analogs" of compounds of formula I, where 1 to n hydrogens attached to a carbon atom is / are replaced by deuterium, where n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and, therefore, are useful for increasing the half-life of any compound of Formula I when administered to a mammal, and particularly, to a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Know. 512): 524-527 1984). Such compounds are synthesized by means well known in the art, for example, using raw materials in which one or more hydrogens have been replaced by deuterium.

[0097] The deuterium-labeled or substituted compounds of the description may have enhanced DMPK properties (drug metabolism and pharmacokinetics), relative to ADME distribution, metabolism and excretion). Substitution with heavier isotopes, such as deuterium, can yield certain therapeutic advantages resulting from greater metabolic stability, for example, longer half-life in vivo, reduced dosage requirements and / or improved therapeutic index. An ¹⁸ F labeled compound can be useful for PET or SPECT studies. The isotopically identified compounds of that description and their prodrugs can generally be prepared by performing the procedures described in the schemes or in the examples and preparations described below, by replacing a readily available isotopically labeled reagent with a non-isotopically reagent. marked. It is understood that deuterium, in this context, is considered as a substituent in the compound of formula (I).

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17/85 [0098] The concentration of such a heavier isotope, specifically deuterium, can be defined by an isotopic enrichment factor. In the compounds of that description, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen", it is understood that the position has hydrogen in its naturally abundant isotopic composition. Therefore, in the compounds of this description, any atom specifically designated as a deuterium D) must represent deuterium.

[0099] The compound of Formula (I) is capable of forming salts, as described in the present invention. Pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs and prominences of the compounds described in the present invention are provided. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms and other materials that are useful in the preparation of a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.

[00100] The salt can be any acid or base capable of forming a salt with the compound of formula (I). It can, for example, be selected from a pharmaceutically acceptable salt or a synthetically useful salt. The term "pharmaceutically acceptable salt" of a given compound refers to salts that retain the biological efficacy and properties of the given compound, and which are not biologically or otherwise undesirable. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts with inorganic acids and salts with organic acids. In addition, if the compounds described in that document are obtained as an acid addition salt, the free base can be obtained by alkalinizing a solution of the acid salt. On the other hand, if the product is a free base, a salt

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18/85 addition, particularly a pharmaceutically acceptable addition salt, it can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, according to conventional procedures for the preparation of addition salts of acid from the base compounds. Those skilled in the art will recognize a number of synthetic methodologies that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from organic and inorganic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic bases and organic bases. Salts derived from inorganic bases include, for example, the sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, primary, secondary and tertiary amine salts, such as alkylamines ie NH ₂ (alkyl), dialkylamines (ie HN (alkyl) 2), trialkylamines (ie , N (alkyl) 3), substituted alkylamines (i.e., NH ₂ (substituted alkyl)), di (substituted alkyl) amines (i.e., HN (substituted alkyl) ₂ ), tri (substituted alkyl) amines (i.e., N (substituted alkyl ^), alkenylamines (i.e., NH ₂ (alkenyl)), dialkylenylamines (i.e., HN (alkenyl) ₂ ), trialkylenamines (i.e., Nalkenyl) ₃ ), substituted alkenylamines (ie, NH ₂ ( substituted alkenyl)), di (substituted alkenyl) amines (i.e. HN (substituted alkenyl) ₂ ), tri amines (alkenyl

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Substituted 19/85) (ie N (substituted alkenyl ^, mono, di or tricycloalkyl amines (i.e. NH ₂ (cycloalkyl), HN (cycloalkyl) 2, N (cycloalkyl) 3), mono, di or triaryl amines (i.e. NH ₂ (aryl), HN (aryl) ₂ , N (aryl) 3), or mixed amines, etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri amine - (isopropyl), tri (n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine and the like.

[00101] As used in the present invention, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonics and absorption retarding agents, and the like. The use of such means and agents for pharmaceutically active substances is well known in the art. Except since any conventional medium or agent is incompatible with the active ingredient, its use in therapeutic compositions is contemplated. Additional active ingredients can also be incorporated into the compositions.

[00102] The term "therapeutically effective amount" refers to an amount of the compound of Formula (I) that is sufficient to effect the treatment, as defined below, when administered to a patient, particularly a human) in need of such treatment in one or more doses. The therapeutically effective amount will vary, depending on the patient, the disease being treated, the patient's weight and / or age, the severity of the disease or the mode of administration, as determined by a qualified prescriber or caregiver.

[00103] The term "treatment" or "treating" means administering a compound or a pharmaceutically acceptable salt of formula (I) for the purpose of: (I) delaying the onset of a disease, that is, causing the clinical symptoms disease do not develop or delay the

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20/85 development thereof; ii) inhibiting the disease, that is, preventing the development of clinical symptoms; and / or (ΙΠ) alleviate the disease, that is, cause the regression of clinical symptoms or the severity of the same.

Methods [00104] A method of treating and / or preventing liver disease in a patient in need thereof is described in the present invention, comprising administering to the patient a therapeutically effective amount of a compound of formula (I). The presence of active liver disease can be detected by the presence of high levels of enzymes in the blood. Specifically, blood levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) above the clinically accepted normal ranges are known to be indicative of ongoing liver damage. Routine monitoring of patients with liver disease for blood levels of ALT and AST is used clinically to measure the progress of liver disease during medical treatment. The reduction in elevated ALT and AST within the accepted normal range is considered clinical evidence that reflects a reduction in the severity of ongoing liver damage in the patient.

[00105] In certain modalities, liver disease is a chronic liver disease. Chronic liver diseases involve the progressive destruction and regeneration of the liver parenchyma, leading to fibrosis and cirrhosis. In general, chronic liver disease can be caused by viruses such as hepatitis B, hepatitis C, cytomegalovirus CMV) or Epstein-Barr EBV virus), toxic agents or drugs such as alcohol, methotrexate or nitrofurantoin), a metabolic disease such as liver disease non-alcoholic fatty NAFLD), non-alcoholic steatohepatitis NASH), hemochromatosis or Wilson's disease), an autoimmune disease such as chronic autoimmune hepatitis, primary biliary cholangitis previously known as primary biliary cirrhosis) or primary sclerosing cholangitis) or other causes such as heart failure right).

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21/85 [00106] In one embodiment, a method for reducing the level of cirrhosis is provided in the present invention. In one embodiment, cirrhosis is pathologically distinguished by the loss of normal microscopic lobular architecture, with fibrosis and nodular regeneration. Methods for measuring the extent of cirrhosis are well known in the art. In one embodiment, the level of cirrhosis is reduced by about 5% to about 100%. In one embodiment, the level of cirrhosis is reduced by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95% or about 100% in the individual.

[00107] In certain embodiments, liver disease is a metabolic liver disease. In one embodiment, liver disease is a non-alcoholic fatty liver disease (NAFLD). NAFLD is associated with insulin resistance and the metabolic syndrome, obesity, combined hyperlipidemia, diabetes mellitus type Π) and arterial hypertension). NAFLD is considered to encompass a spectrum of disease activity and begins as the accumulation of fat in the liver (fatty liver).

[00108] It has been shown that both obesity and insulin resistance are likely to play an important role in the NAFLD disease process. In addition to a poor diet, NAFLD has several other known causes. For example, NAFLD can be caused by certain medications, such as amiodarone, antiviral drugs for example, nucleoside analogs), aspirin rarely as part of Reye's syndrome in children), corticosteroids, methotrexate, tamoxifen or tetracycline. NAFLD has also been linked to the consumption of soft drinks through the

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22/85 presence of corn syrup rich in fructose, which can cause increased deposition of fat in the abdomen, although the consumption of sucrose shows a similar effect probably due to its breakdown in fructose). Genetics is also known to play a role, as two genetic mutations for this susceptibility have been identified.

[00109] If left untreated, NAFLD can progress to non-alcoholic steatohepatitis (NASH), which is the most extreme form of NAFLD, a state in which steatosis is combined with inflammation and fibrosis. NASH is considered to be a major cause of liver cirrhosis. Accordingly, a method of treating and / or preventing non-alcoholic steatohepatitis (NASH) is described in the present invention in a patient in need of this, comprising administering to the patient a therapeutically effective amount of a compound of formula (I).

[00110] Also provided in the present invention is a method of treating and / or preventing liver disease in a patient who needs it, comprising administering to the patient a therapeutically effective amount of a compound of formula (I). Liver fibrosis is the excessive accumulation of extracellular matrix proteins, including collagen, which occurs in most types of chronic liver disease. In certain modalities, advanced liver fibrosis results in cirrhosis and liver failure. Methods for measuring liver histologies, such as changes in the extent of fibrosis, lobular hepatitis, and periportal bridging necrosis, are well known in the art. In one embodiment, treatment, as described in the present invention, can improve a patient's fibrosis from the initial assessment, for example, improving from F4 to F3, from F3 to F2, or from F2 to Fl. In one embodiment, a patient's fibrosis score is improved by one or more after 24 weeks of daily treatment. In one embodiment, a method is provided to treat liver fibrosis in a patient who needs it,

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The patient's liver fibrosis is F3, comprising administering to the patient a therapeutically effective amount of an ASK1 inhibitor. In one embodiment, a method is provided for treating liver fibrosis in a patient who needs it, where the patient's liver fibrosis stage is F3, comprising administering to the patient a therapeutically effective amount of an ASK1 inhibitor together with a therapeutically amount. effectiveness of an ACC inhibitor. In one embodiment, a method is provided for treating liver fibrosis in a patient who needs it, where the patient's liver fibrosis stage is F4, comprising administering to the patient a therapeutically effective amount of an ASK1 inhibitor. In another embodiment, a method is provided for treating liver fibrosis in a patient who needs it, wherein the patient's liver fibrosis stage is F4, comprising administering to the patient a therapeutically effective amount of an ASK1 inhibitor together with a therapeutically amount. effectiveness of an ACC inhibitor.

[00111] In still other embodiments, a method is provided to treat NASH in a patient who needs it, in which the patient's liver fibrosis stage is F3, comprising administering to the patient a therapeutically effective amount of an ASK1 inhibitor. In still other embodiments, a method is provided for treating NASH in a patient who needs it, where the patient's stage of liver fibrosis is F4, comprising administering to the patient a therapeutically effective amount of an ASK1 inhibitor.

[00112] Liver disease can be classified into 4 stages: F0 indicates absence of fibrosis; F1 indicates mild fibrosis; F2 indicates moderate fibrosis; F3 indicates severe fibrosis; and F4 indicates cirrhosis. As used in the present invention, "fibrosis scoring" refers to a scoring system for fibrosis as described by Kleiner et al. Hepatology, Design and validation of

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24/85 a histological scoring system for nonalcoholic fatty liver disease 2005), 41: 1313-1321).

[00113] In one embodiment, the level of hepatic fibrosis, which is the formation of fibrous tissue, fibroid or fibrous degeneration, is reduced by more than about 90%. In one embodiment, the level of fibrosis, which is the formation of fibrous tissue, fibroid or fibrous degeneration, is reduced by at least about 90%, at least about 80%, at least about 70%, at least about 60%, less than 50%, at least about 40%, at least about 30%, at least about 20%, at least about 10%, at least about 5% or at least about 2% .

[00114] In one embodiment, the compounds provided here reduce the level of fibrogenesis in the liver. Hepatic fibrogenesis is the process that leads to the deposition of an excess of extracellular matrix components in the liver, known as fibrosis. It is observed in several conditions, such as chronic viral hepatitis B and C, alcoholic liver disease, drug-induced liver disease, hemochromatosis, autoimmune hepatitis, Wilson's disease, primary biliary cholangitis formerly known as primary biliary cirrhosis), sclerosing cholangitis, liver schistosomiasis and others. In another modality, the level of fibrogenesis is reduced by more than about 90%. In one embodiment, the level of fibrogenesis is reduced by at least about 90%, at least about 80%, at least about 70%, at least about 60%, at least about 50%, at least 40% at least about 30%, at least about 20%, at least about 10%, at least about 5% or at least about 2%.

[00115] In still other embodiments, a method of treating and / or preventing primary sclerosing cholangitis PSC) is provided in a patient in need of this, comprising administering to the patient a therapeutically effective amount of a compound of formula (I) .

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A method for treating or preventing cardiovascular disorder in a patient in need of such treatment is also described in the present invention, comprising administering a therapeutically effective amount of a compound of formula (I). Cardiovascular diseases refer to any one or more of, for example, heart failure including congestive heart failure, diastolic heart failure, systolic heart failure, heart failure with preserved ejection fraction), acute heart failure, ischemia, recurrent ischemia, infarction myocardial infarction, arrhythmias, angina including exercise-induced angina, variant angina, stable angina, unstable angina), acute coronary syndrome, diabetes, intermittent claudication and idiopathic pulmonary fibrosis.

[00117] Also provided in the present invention is a method of treatment and / or prevention of pulmonary vascular disease in a patient who needs it, comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a salt, cocrystalline, solvate or hydrate thereof. In certain embodiments, pulmonary vascular disease is pulmonary arterial hypertension (PAH). In some modalities, the patient is diagnosed with group 1, Γ, 1 ”, 2, 3, 4 or 5 pulmonary hypertension.

[00118] A method of treatment and / or prevention of right ventricular dysfunction is also provided in a patient who needs it, comprising administering to the patient a therapeutically effective amount of an ASK1 inhibitor.

[00119] A method of treatment, prevention and / or reversal of narrowing or narrowing of the pulmonary arteries is also provided in a patient who needs it, comprising administering to the patient a therapeutically effective amount of an ASK1 inhibitor. Additionally, a method of reducing or normalizing the

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26/85 high mean pulmonary arterial pressure (mPAP) and / or high pulmonary vascular resistance in a patient who needs it, comprising administering to the patient a therapeutically effective amount of an ASK1 inhibitor. In one embodiment, the high level of mPAP> 25 mmHg at rest can be reduced to levels within the normal range at rest by the methods described in the present invention. In some embodiments, the high level of mPAP> 25 mmHg at rest can be reduced to about 22 mmHg, 20 mmHg, 18 mmHg, 16 mmHg or 14 mmHg at rest by the methods described in the present invention. In certain modalities, mPAP is determined by catheterization of the RHC right heart).

[00120] A method is provided in the present invention to improve or reduce the symptoms of PAH in a patient who needs it, comprising administering a therapeutically effective amount of ASK1 inhibitor. In some modalities, symptoms of PAH include and are not limited to shortness of breath or difficulty breathing (dyspnea), fatigue, dizziness, fainting syncope), swollen ankles and legs (edema), chest pain, right heart failure and / or dysfunction . In certain modalities, improvement can be determined by a change in the baseline level in pulmonary vascular resistance (PVR), a change in the baseline level in the cardiac index (IC), such as mean pulmonary arterial pressure (mPAP), mean right atrial pressure (mRAP), mixed venous oxygen saturation (SvO2) and right ventricular cardiac power, a change in baseline level in the initial measures of symptoms and function, including but not limited to submaximal exercise 6 min walk test 6MWT)), HRR recovery) after the 6MWT, the Borg dyspnea index, the WHO functional class, the N-terminal cerebral natriuretic pro-peptide and / or the quality of life by the SF-36® Health Survey. In other modalities, PVR is determined by catheterization of the right heart. In modalities

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27/85, cardiac function is determined by echocardiography or cardiac hemodynamic data.

[00121] Additionally, a method is provided in the present invention to reduce remodeling of the pulmonary vasculature or arteries in a patient who needs it, comprising administering to the patient a therapeutically effective amount of an ASK1 inhibitor.

[00122] A method of treatment and / or prevention of right ventricular failure or right ventricular dysfunction is also additionally provided in a patient who needs it, comprising administering to the patient a therapeutically effective amount of an ASK1 inhibitor. In one embodiment, the failure or dysfunction of the right ventricle can be detected or monitored by cardiac imaging, such as echocardiography and cardiac magnetic resonance imaging.

[00123] A method is provided in the present invention to improve and / or reduce PVR, pulmonary pressure, pulmonary vascular remodeling, vascular function, maladaptive RV hypertrophy and / or VR function in a patient who needs in addition, comprising administering to the patient a therapeutically effective amount of an ASK1 inhibitor.

[00124] The present application provides therapy or treatment to a patient in need of this, in which the patient has or is suspected to have pulmonary vascular disease, such as pulmonary hypertension or pulmonary arterial hypertension. In one embodiment, patients experience one or more selected symptoms of shortness of breath or difficulty breathing (dyspnea), fatigue, dizziness, fainting (syncope), swollen ankles and legs (edema) or chest pain (eg angina). Patients may be in various clinical or treatment stages, including patients who have not received prior treatment for pulmonary hypertension or pulmonary arterial hypertension, patients who have received previous therapies or medications for pulmonary hypertension or pulmonary arterial hypertension and

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28/85 remain symptomatic, and patients who currently receive other therapies or drugs for pulmonary hypertension or pulmonary arterial hypertension. For example, the patient may have received the therapy of the present application (e.g., the ASK1 inhibitor or a pharmaceutical composition thereof) and other PAH drugs concomitantly.

[00125] In any of the previous cases, treatment, prevention, reduction, reversal and / or improvement by the method described here can be determined by a change in the baseline level in pulmonary vascular resistance PVR), a change in the baseline level in the cardiac index IC). such as pulmonary arterial pressure mPAP), right atrial pressure mean mRAP), mixed venous oxygen saturation Sv02) and right ventricular cardiac power, a change from the baseline level in clinical measures of symptoms and function, including, but not limited to, submaximal exercise 6-minute walk test 6MWT)), HRR recovery) after 6MWT, Borg's dyspnea index, WHO functional class, N-terminal cerebral natriuretic pro-peptide and / or quality of life by SF36® Health Survey. In other modalities, PVR is determined by catheterization of the right heart. In additional modalities, cardiac function is determined by echocardiography or cardiac hemodynamic data. The baseline level refers to a value, number or reading that is determined or measured by the individual before any treatment. For example, the baseline level is a value, number or reading of a patient before being treated with the methods described here, from a healthy individual, from a group of individuals or from appropriate guidelines. In one embodiment, the basilar level is a value, number or reading from a patient before being treated with the methods described in the present invention. The baseline value or number can be determined or measured by any suitable methods.

[00126] As used in the present invention, the terms "right ventricular (VR) dysfunction", "right ventricular dysfunction",

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29/85 “right heart failure”, or variants thereof, refer to the failure of the right ventricle or the right heart that makes you unable to perform the normal function, for example, to pump blood out of the heart into the lungs to be replenished with oxygen and / or maintain sufficient blood flow to meet the needs of the body). RV dysfunction can be determined or detected by cardiac images, including echocardiography and cardiac magnetic resonance imaging that characterize structural changes in myocardial hypertrophy followed by progressive contractile dysfunction and chamber dilation) and / or functional changes reduction of fractional shortening, increased pressures filling, reduced right ventricular ejection fraction and decreased cardiac output). Other commonly used methods can also be used to determine or detect RV dysfunction. In addition, "promoting" or "stimulating" refers to one or more factors that may cause or contribute to the progress of the activity, disease, disorder or condition. For example, the promotion or contribution to PAH is used to describe one or more factors that can cause or contribute to the progress or development of PAH.

[00127] Also described in the present invention is a method of treating or preventing kidney disorders, such as chronic kidney disease or diabetic kidney disease. The term "chronic kidney disease", as used in the present invention, refers to the progressive loss of kidney function over time, typically months or even years. Chronic kidney disease is diagnosed by a competent caregiver using appropriate information, tests or markers known to a person skilled in the art. Chronic kidney disease includes, by implication, kidney disease. The term "diabetic kidney disease", as used in the present invention, refers to kidney disease caused by diabetes, exacerbated by diabetes, or co-presenting with diabetes. It is a form of chronic kidney disease that

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30/85 occurs in approximately 30% of patients with diabetes. It is defined as diabetes with the presence of albuminuria and / or renal failure, that is, decreased glomerular filtration rate see from B, I, et al. Temporal trends in the prevalence of diabetic kidney disease in the United States. JAMA June 22, 2011; 305 24): 2532-2539).

[00128] In alternative modalities, a compound of formula (I), or a salt thereof, can be used to prevent or decrease the likelihood of transplant rejection.

[00129] In still other modalities, an inflammatory disease, such as rheumatoid arthritis, is treated by the administration of a compound of formula (I), or a salt thereof.

[00130] In certain embodiments, systemic lupus erythematosus is treated by administering a compound of formula (I), or a salt thereof.

[00131] In still other modalities, neuropathy, such as HIV-associated neuropathy, is treated by the administration of a compound of formula (I), or a salt thereof.

[00132] Also provided in the present invention is a method of improving the consequence or pathological outcome associated with oxidative stress in a patient who needs it, comprising administering to the patient a therapeutically effective amount of an ASK1 inhibitor.

Combinations [00133] In one embodiment, the compound of formula (I) is combined with an additional active agent selected from an ACE inhibitor, acetyl-CoA carboxylase inhibitor, A3 adenosine receptor agonist, adiponectin receptor agonist, inhibitor of protein kinase activated by AMP inhibitor of protein kinase AMPK), amylin receptor agonist, angiotensin Π AT-1 receptor antagonist, autotaxin inhibitors,

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31/85 bioactive lipid, calcitonin agonist, caspase inhibitor, caspase-3 stimulator, cathepsin B inhibitor, cathepsin K inhibitor, cathepsin S inhibitor, caveolin 1 inhibitor, CCR2 chemokine antagonist, CCR3 chemokine antagonist, CCR5 chemokine antagonist, chloride channel stimulator, CNR1 inhibitor, cyclin Dl inhibitor, cytochrome P450 7A1 inhibitor, DGAT2 gene inhibitor, dipeptidyl peptidase IV inhibitor, eotaxin ligand inhibitor, extracellular matrix protein modulator, Farsenoid X receptor agonist, FGF1 receptor agonist, FGF-19 ligand, galectin-3 inhibitor, glucagon receptor agonist, glucagon-like peptide 1 agonist, G protein-coupled bile acid receptor 1 agonist, protein modulators Hedgehog Hh), hepatitis C virus NS3 protease inhibitor, HMG CoA reductase inhibitor, IL-10 agonist, IL-17 antagonist, ilea sodium bile acid cotransporter inhibitor l, insulin sensitizer, β3 or βΐ integrins, interleukin-1 receptor kinase 4 IRAK4), Jak2 tyrosine kinase inhibitor, Klotho beta stimulator, 5-lipoxygenase inhibitor, lipoprotein lipase inhibitor, LPL gene stimulator, lysophosphatidate-1 receptor antagonist, MMPs matrix metalloproteinases), protein kinase inhibitor MEKK-5, copper membrane amine oxidase inhibitor VAP-1), methionine aminopeptidase-2 inhibitor, methyl CpG 2 binding protein modulator, mitochondrial uncouplers, myelin basic protein stimulator, NACHT LRR PYD NLRP3 domain 3 protein) NAD-dependent sirtuin deacetylase inhibitor, NADPH oxidase 1 inhibitor, NADPH oxidase 4 inhibitor, nicotinic acid receptor 1 agonist, stimulator of nicotinic acid purinoceptor P2Y13, PDE 3 inhibitor, PDE 4 inhibitor, PDE 5 inhibitor, PDGF beta-receptor modulator, phospholipase C inhibitor, PPAR alpha agonist, PPA agonist R delta, PPAR gamma agonist, PPAR gamma modulator, protease activated receptor 2 antagonist, protein kinase modulator, protein kinase 2 inhibitor associated with

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32/85

Rho, sodium glucose transporter 2 inhibitor, SREBP transcription factor inhibitor, STAT-1 inhibitor, stearoyl CoA desaturase 1 inhibitor, cytokine-1 signaling stimulation suppressant, cytokine-3 signaling stimulation suppressor , transforming growth factor βΐ TGF-βΙ), beta thyroid hormone receptor agonist, TLR-4 antagonist, transglutaminase inhibitor, tyrosine kinase receptor modulator, unspecified GPCR modulator, unspecified nuclear hormone receptor modulator , WNT modulators and YAP / TAZ modulators. Specific examples include A-4250, AC-3174, acetylsalicylic acid, AK-20, tiparvovec alipogene, aramcol, ARI-3037MO, atorvastatin, AZ NASH / NAFLD compound), bertilimumab, anhydrous betaine, BI-1467335, BMS-986036, BMT -053011, BOT-191, CAT-2003, cenicriviroc, CER-209, CF-102, CNX-014, CNX-023, CNX-024, CNX-025, cobiprostone, colesevelam, dapagliflozin, 2,4-enantiomer deuterated pioglitazone dinitrophenyl, DRX-065, DS-102, glucagon-like peptide receptor 1 / double-acting glucagon receptor coagonist, DUR-928, EDP305, elafibranor, emricasan, enalapril, ertugliflozin, GKT-831, GNF-5120 , GR-MD-02, GS-4997, GS-9674, hydrochlorothiazide, icosapent ethyl ester, IMM-124-E, INT-767, IONIS-DGAT2Rx, ipragliflozin, irbesarta + propagermanio, IVA-337, JKB-121, KB-GE-001, KBP-042, KD-025, leucine + metformin + sildenafil, linagliptin, liraglutide, LJN-452, MBX-8025, MDV-4463, mercaptamine, MGL-3196, MGL-3745, MSDC-0602K, namacizumab, NC-101, NDI-010976, ND-L02-s0201, NG M-282, NGM313, NGM-386, NGM-395, norursodeoxycholic acid, 0-304, obeticolic acid, PAT-505, PAT-048, peg-ilodecaquine, pioglitazone, Px-102, PXS-4728A, PZ-235, RDX-009 program, remogliflozin etabonate, RG125, saroglitazar, semagglutide, simtuzumab, solithromycin, sotagliflozin, TCM-606F, IEV-45478, tipelukast MN-001), TRX-318, UD-009, ursodeoxycholic acid VBY-825, VK-2809, potassium ethanolate of

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33/85 hydrated volixibate SHP-626), VVP-100X, WAV-301 and ZGN-83.

[00134] In certain embodiments of the pharmaceutical methods and compositions described in the present invention, an FXR agonist is administered or formulated with the compound of formula (I) or salts and / or forms thereof. In one embodiment, the FXR agonist is a compound with the structure of formula (III):

ci

III) or a pharmaceutically acceptable salt, cocrystal, solvate or hydrate thereof.

[00135] In other modalities, the FXR agonist is a compound with the structure of formula (IV):

IV) or a pharmaceutically acceptable salt, cocrystal, solvate or hydrate thereof.

[00136] The compounds of formula (III) and formula (IV) can be synthesized and distinguished using methods known to those skilled in the art, such as those described in US Publication No. 9,139,539.

[00137] In another embodiment, the compound of formula (I) or a salt, cocrystalline, solvate or hydrate thereof is combined with an ACC inhibitor. In one embodiment, the ACC inhibitor is a compound of formula (V):

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34/85

pharmaceutically acceptable product.

[00138] Diseases or related cardiovascular conditions that may benefit from a combined treatment of ASK1 inhibitors with other therapeutic agents include, without limitation, angina, including stable angina, unstable angina AU), exercise-induced angina, variant angina, arrhythmias, intermittent claudication, myocardial infarction, including non-STE NSTEMI myocardial infarction), heart failure including congestive or chronic heart failure), acute heart failure or recurrent ischemia.

[00139] Therapeutic agents suitable for the treatment of cardiovascular diseases or conditions include antianginal agents, heart failure agents, antithrombotic agents, antiarrhythmic agents, antihypertensive agents and hypolipidemic agents.

[00140] Co-administration of ASK1 inhibitors with appropriate therapeutic agents for the treatment of related cardiovascular conditions allows for an improvement in the standard of care therapy that the patient is currently receiving.

[00141] Antiangines include beta-blockers, calcium channel blockers and nitrates. Beta-blockers reduce the heart's need for oxygen, reducing its workload, resulting in decreased heart rate and less vigorous heart contraction. Examples of beta-blockers include acebutolol Sectral), atenolol Tenormin), betaxolol Kerlone), bisoprolol / hydrochlorothiazide Ziac), bisoprolol

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35/85

Zebeta), Cartrol cardolol), Brevibloc esmolol), Normodyne labetalol, Trandato), Lopressor metoprolol, Toprol XL), Corgard nadolol), Inderal propranolol), Betapace sotalol) and Blocadren timolol).

[00142] Nitrates dilate arteries and veins, thus increasing coronary blood flow and decreasing blood pressure. Examples of nitrates include nitroglycerin, nitrate adhesives, isosorbide dinitrate and isosorbide-5 mononitrate.

[00143] Calcium channel blockers prevent the normal flow of calcium into the cells of the heart and blood vessels, causing the blood vessels to relax, thereby increasing the supply of blood and oxygen to the heart. Examples of calcium channel blockers include amlodipine Norvasc, Lotrel), bepridil Vascor), diltiazem Cardizem, Tiazac), felodipine Plendil), nifedipine Adalat, Procardia), nimodipine Nimotop), nisoldipine Sular), verapamil Calan, Verapamil Calan nicardipine.

[00144] The agents used to treat heart failure include diuretics, ACE inhibitors, vasodilators and cardiac glycosides. Diuretics eliminate excess fluids in tissues and circulation, thus relieving many of the symptoms of heart failure. Examples of diuretics include [00145] hydrochlorothiazide, metolazone Zaroxolyn), furosemide Lasix), bumetanide Bumex), spironolactone Aldactone) and eplerenone Inspra).

[00146] Inhibitors of the angiotensin-converting enzyme (ACE) reduce the workload in the heart, expanding blood vessels and decreasing resistance to blood flow. Examples of ACE inhibitors include benazepril Lotensin), captopril Capoten), enalapril Vasotec), fosinopril Monopril), lisinopril Prinivil, Zestril), moexipril Univasc), perindopril Aceon), quinapril Accupril), ramipril Altace) and trandolapril).

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36/85 [00147] Vasodilators reduce pressure in blood vessels, causing them to relax and expand. Examples of vasodilators include hydralazine, diazoxide, prazosin, clonidine and methyldopa. ACE inhibitors, nitrates, potassium channel activators and calcium channel blockers also act as vasodilators.

[00148] Cardiac glycosides are compounds that increase the strength of the heart's contractions. These compounds strengthen the heart's pumping capacity and improve irregular heartbeat activity. Examples of cardiac glycosides include digitalis, digoxin and digitoxin.

[00149] Antithrombotics inhibit the blood's clotting ability. There are three main types of antithrombotics - platelet inhibitors, anticoagulants and thrombolytic agents. Platelet inhibitors inhibit platelet clotting activity, thereby reducing clotting in the arteries. Examples of platelet inhibitors include acetylsalicylic acid (aspirin), ticlopidine, clopidogrel plavix), dipyridamole, cilostazol, persinine sulfinpyrazone, dipyridamole, indomethacin and glycoprotein llb / llla inhibitors, such as abciximab, tirofiban eelinif and ept. Beta blockers and calcium channel blockers also have a platelet-inhibiting effect.

[00150] Anticoagulants prevent blood clots from growing and prevent the formation of new clots. Examples of anticoagulants include bivalirudin (Angiomax), warfarin Coumadin), unfractionated heparin, low molecular weight heparin, danaparoid, lepirudin and argatroban.

[00151] Thrombolytic agents act to break an existing blood clot. Examples of thrombolytic agents include streptokinase, urokinase and tenecteplase (TNK) and tissue plasminogen activator t-PA).

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37/85 [00152] Antiarrhythmic agents are used to treat disorders of heart rate and rhythm. Examples of antiarrhythmic agents include amiodarone, quinidine, procainamide, lidocaine and propafenone. Cardiac glycosides and beta-blockers are also used as antiarrhythmic agents.

[00153] Antihypertensive agents are used to treat hypertension, a condition in which blood pressure is consistently higher than normal. Hypertension is associated with many aspects of cardiovascular disease, including congestive heart failure, atherosclerosis and clot formation.

[00154] Examples of antihypertensive agents include alpha-1-adrenergic antagonists, such as prazosin Minipress), doxazosin mesylate Cardura), prazosin hydrochloride Minipress), prazosin, polythiazide Minizide) and terazosin hydrochloride Hytrin); beta-adrenergic antagonists, such as propranolol Inderal), nadolol Corgard), timolol Blocadren), metoprolol Lopressor) and pindolol Visken); central alpha-adrenoceptor agonists, such as clonidine hydrochloride (Catapres), clonidine hydrochloride and Chlortalidone chloride, Combipres), guanabenz acetate Wytensin), guanfacine hydrochloride Tenex), methyldopa Aldomet), methyldopa and chlorothiazide Aldoclor) Aldoril); combined alpha / beta-adrenergic antagonists, such as labetalol Normodyne, Trandate), Carvedilol Coreg); adrenergic neuron blocking agents, such as guanetidine Ismelin), reserpine Serpasil); antihypertensives of action in the central nervous system, such as clonidine Catapres), methyldopa Aldomet), guanabenz Wytensin); anti-angiotensin agents Π; ACE inhibitors, such as perindopril Aceon), captopril Capoten), enapril Vasotec), lisinopril Prinivil, Zestril); angiotensin-receptor receptor antagonists, such as Candesartan Atacand), Eprosartan Teveten), Irbesartan Avapro), Losartan Cozaar), Telmisartan Micardis), Valsartan Diovan); calcium channel blockers such as

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38/85 verapamil Calan, Isoptin), diltiazem Cardizem), nifedipine Adalat, Procardia); diuretics; and direct vasodilators, such as Nipride nitroprusside) and diazoxide. Hyperstat (IV), hydralazine Apresoline), minoxidil Loniten), verapamil; and potassium channel activators, such as apricalim, bimacalim, cromacalim, emacalim, nicorandil and pinacidil.

[00155] Agents that reduce the concentration of lipids are used to decrease the amounts of cholesterol or fatty sugars present in the blood. Examples of lipid-lowering agents include bezafibrate Bezalip), ciprofibrate Modalim) and statins, such as atorvastatin Lipitor), fluvastatin Lescol), lovastatin Mevacor, Altocor), mevastatin, pitavastatin Livalo, Pitava), pravastatin Lipostat) and rosuvastatin Crestor) simvastatin Zocor).

[00156] In this description, an individual who needs the ASK1 inhibitor often suffers from secondary medical conditions, such as one or more metabolic disorders, pulmonary disorders, peripheral vascular disorders or gastrointestinal disorders. Such patients can benefit from the treatment of a combination therapy comprising administering to the patient the compounds of the invention in combination with at least one therapeutic agent.

[00157] Lung disorder refers to any disease or condition related to the lungs. Examples of lung disorders include, without limitation, asthma, chronic obstructive pulmonary disease (COPD), bronchitis and emphysema.

[00158] Examples of therapeutic agents used to treat lung disorders include bronchodilators including beta-2 agonists and anticholinergics, corticosteroids and electrolyte supplements. Specific examples of therapeutic agents used to treat lung disorders include epinephrine, terbutaline Brethaire, Bricanyl), albuterol Proventil), salmeterol Serevent, Serevent Diskus), theophylline, ipratropium bromide

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Atrovent), tiotropium Spiriva), methylprednisolone Solu- Medrol, Medrol), magnesium and potassium.

[00159] Examples of metabolic disorders include, without limitation, diabetes, including type I and type diabetes diabetes, metabolic syndrome, dyslipidemia, obesity, glucose intolerance, hypertension, high serum cholesterol and elevated triglycerides.

[00160] Examples of therapeutic agents used to treat metabolic disorders include antihypertensive agents and lipid-lowering agents. Additional therapeutic agents used to treat metabolic disorders include insulin, sulfonylureas, biguanides, alpha-glucosidase inhibitors and incretin mimetics.

[00161] Peripheral vascular disorders are disorders related to blood vessels (arteries and veins) located outside the heart and brain, including, for example, peripheral arterial disease (PAD), a condition that develops when arteries supply blood to internal organs , arms and legs are completely or partially blocked as a result of atheriosclerosis.

[00162] Gastrointestinal disorders refer to diseases and conditions associated with the gastrointestinal tract. Examples of gastrointestinal disorders include gastroesophageal reflux disease (GERD), inflammatory bowel disease (IBD), gastroenteritis, gastritis and peptic ulcer disease and pancreatitis.

[00163] Examples of therapeutic agents used to treat gastrointestinal disorders include proton pump inhibitors, such as pantoprazole Protonix), lansoprazole Prevacid), esomeprazole Nexium), omeprazole Prilosec), rabeprazole; H2 blockers, such as cimetidine Tagamet), ranitidine Zantac), famotidine Pepcid), nizatidine Axid); prostaglandins, such as misoprostol (Cytotec); sucralfate; and antacids.

[00164] In one embodiment, a compound of formula (I) or a salt,

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40/85 cocrystal, solvate or hydrate thereof, as described herein, can be used together with one or more additional therapeutic agents that are being used and / or developed to treat gastrointestinal disorders. In one embodiment, a compound of formula (I) or a salt, cocrystalline, solvate or hydrate thereof, as described herein, can be used together with one or more additional therapeutic agents that are being used and / or developed to treat inflammatory disorders for example, IBD). In such embodiments the one or more additional therapeutic agent) may be an α4β7 inhibitor, a steroid, an MMP-9 antibody, an S1P1 agonist, a TNF biological or any combination thereof.

[00165] In some embodiments, the one or more additional therapeutic agent may be an α4β7 integrin inhibitor, or an agent that inhibits α4β7 integrin expression and / or activity. The inhibitor can be small molecule or biological. For example, the α4β7 integrin inhibitor may be natalizumab or vedolizumab.

[00166] In some embodiments, the one or more additional therapeutic agents may be a steroid, including, but not limited to, corticosteroids. Corticosteroids can be administered by several routes, including intravenously (eg, methylprednisolone, hydrocortisone), orally ie prednisone, prednisolone, budesonide, dexamethasone) or topically ie enema preparations, suppository or foam) .

[00167] In some embodiments, the one or more additional therapeutic agent may be an MMP9 inhibitor, or an agent that inhibits MMP9 expression and / or activity. A representative protein sequence for MMP9 is GenBank adhesion No. NP_004985. The inhibitor can be small molecule or biological. For example, Gu et al., The Joumal of Neuroscience, 25 27): 6401-6408 2005) describes a specific MMP9 inhibitor, SB-3CT CAS 292605-14-2). In addition, siRNA, antisense RNA and antibodies

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41/85 also demonstrated that they inhibit MMP9 expression or activity and are within the scope of the present description. In one embodiment, an MMP9 inhibitor is an anti-MMP9 monoclonal antibody. In some embodiments, the one or more additional therapeutic agent includes an MMP9 inhibitor and a nucleoside analog, such as gemcitabine.

[00168] In some embodiments, the one or more additional therapeutic agent may be an inhibitor of the sphingosine 1-phosphate S1P1 receptor), or an agent that inhibits S1P1 expression and / or activity. The inhibitor can be small molecule or biological. For example, the S1P1 inhibitor can be RPC1063.

[00169] In some embodiments, the one or more additional therapeutic agent may be a TNF inhibitor, or an agent that inhibits TNF expression and / or activity. The inhibitor can be small molecule or biological. For example, the TNF inhibitor may be golimumab.

[00170] In some embodiments, the one or more additional therapeutic agent is being used and / or developed to treat ulcerative colitis (UC) and / or Crohn's disease CD). The agent can be a biological or small molecule. In some embodiments, the agent is a modulator (eg, agonist or antagonist) of S1P1, IL-6, CX3CL1, DHODH, <χ4, β7, JAK, TNF, CB, IL-12 / IL-23, CCL20, TLR9, MAdCAM, CCR9, CXCL10, Smad7, PDE4, MC, VLA-1, GC, GATA-3, eotaxin, FFA2, LIGHT, FMS, MMP9, CD40, steroid, 5-ASA, Immunomod, STAT3 and / or EP4. In some embodiments, the JAK inhibitor is filgotinib.

[00171] Non-limiting examples of agents being used and / or developed to treat ulcerative colitis UC) include GSK3050002 CCL20 modulator, from GSK), GS-5745 MMP9 modulator, from Gilead), AVX-470 TNF modulator, from Avaxia), Bertilimumab eotaxin modulator, from Immune Pharma), Simponi TNF modulator, from Johnson & Johnson and Merck), RX-10001 from Resolvyx), IBD-98 5-ASA modulator, from

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Holy Stone), SP-333 GC Modulator, from Synergy), KAG-308 EP4 modulator, from Kaken), SB012 GATA-3 modulator from Stema), AJM300 modulator <x4, from Ajinomoto), BL-7040 modulator TLR9, from BiolineRx), TAK-114 modulator from SAT3, from Takeda), CyCol from Sigmoid), GWP-42003 from CB, from GW Pharma), ASP3291 from MC, from Drais), GLPG0974 from FFA2, from Galapagos), Ozanimode S1P1 modulator, from Receptos), ASP015K modulator from JAK, from Astellas), Apremilast modulator from PDE4, from Celgene), Zoenasa from Altheus), Kappaproct from TLR, from InDex), phosphatidylcholine from Falk / Lipid Tx), tofacitinib modulator by JAk, by Pfizer), Cortment steroid modulator, by Ferring), Uceris steroid modulator, by Salix) and 5ASA modulators such as Delzicol by Actavis), Canasa by Aptalis), Asacol by Actavis), Pentasa by Shire / Ferring), Lialda by Shire), Mezavant by Shire), Apriso by Salix), Colazal by Salix), Giazo by Salix) and Salofalk by Dr Falk). Non-limiting examples of agents used and / or developed to treat Crohn's disease CD) include FFP102 modulator CD40, from Fast Forward), E6011 modulator CX3CL1, from Eisai), PF-06480605 from Pfizer), QBECO SSI immunomodic modulator, from Qu Biologies), PDA-001 from Celgene), BI 655066 IL-12 / IL-23 modulator, from Boehringer), TNFa TNF modulator cinoid, from Neovacs), AMG 139 / MEDI-2070 modulator from IL-12 / IL-23, from AstraZeneca), PF-04236921 IL-6 modulator, from Pfizer), Tysabri β7 modulator, sold by Biogen Idee, in the USA), Cimzia sold by UCB in the USA), JNJ-40346527 FMS modulator, (JandJ), SGX-203 steroid modulator, from Solgenix), CyCron from Sigmoid), CCX507 from CCR9, from ChemoCentryx), MT1303 from S1P1, from Mitsubishi), 6-MP from Teva), ABT-494 from JAk, from Abbvie), Tofacitinib modulator from JAk, from Pfizer), TRK-170 modulator from β7, from Toray), Mongersen modulator from Smad7, from Celgene), RHB-104 from Redhill), Rifaxmin EIR from S alix), Dr. Falk's Budenofalk) and Entocort of

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AstraZeneca).

[00172] Non-limiting examples of the agents being used and / or developed to treat ulcerative colitis UC) and Crohn's disease CD) include PF-06410293 from Pfizer), SAN-300 VLA-1 modulator from Salix), SAR252067 modulator LIGHT, from Sanofi), PF-00547659 modulator MAdCAM, from Pfizer), Eldelumabe modulator Smad7, from BMS), AMG 181 / MEDI-7183 modulator β7, from Amgen / AstraZeneca), etrolizumab modulator β7, from Roche), ustecinumabe modulator IL-12 / IL-23, from J&J), TNF modulator remedy, from J&J and Merck), Entyvio modulator β7, from Takeda), Humira TNF modulator, from Abbvie), infliximab from Celtrion), PF-06651600 from Pfizer ), GSK2982772 from GSK), GLPG1205 FFA2 modulator, from Galapagos), AG014 from Intrexon) and Vidofludimus modulator from DHODH, da4SC).

[00173] In some embodiments, the one or more additional therapeutic agent may be a JAK inhibitor, particularly a selective JAK-1 inhibitor. The inhibitor can be small molecule or biological. For example, the JAK inhibitor can be filgotinib, GLPG0634 modulator from JAK, from Galapagos).

[00174] Patients who have an acute coronary disease event may have conditions that benefit from the administration of therapeutic agents or antibiotic agents, analgesics, antidepressants and anxiolytic agents together with ranolazine.

[00175] Antibiotics are therapeutic agents that kill or prevent the growth of microorganisms, including bacteria and fungi. Examples of antibiotics include β-lactam antibiotics, including penicillins (amoxicillin), cephalosporins, such as cefazolin, cefuroxime, cefadroxil Duricef), cephalexin Keflex), cefradine Velosef), cefaclor Ceclor), cefuroxime cefinacid, lefefab), cefproz) cefixime Suprax), cefpodoxime proxetil Vantin), ceftibuten Cedax), cefdinir Omnicef),

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44/85 ceftriaxone Rocephin), carbapenemas and monobactams; tetracyclines, such as tetracycline; macrolide antibiotics, such as erythromycin; aminoglycosides, such as gentamicin, tobramycin, amikacin; quinolones such as ciprofloxacin; cyclic peptides, such as vancomycin, streptogramins, polymyxins; lincosamides, such as clindamycin; oxazolidinoes, such as linezolid; and sulfa-antibiotics, such as sulfisoxazole. [00176] Analgesics are therapeutic agents used to relieve pain. Examples of painkillers include opiates and morphomimetics, such as fentanyl and morphine; paracetamol; NSAIDs and COX-2 inhibitors.

[00177] Antidepressant and anxiolytic agents include those agents used to treat anxiety disorders, depression and those used as sedatives and tranquilizers. Examples of antidepressant and anxiolotic agents include benzodiazepines, such as diazepam, lorazepam and midazolam; enzodiazepines; barbiturates; glutetimide; chloral hydrate; meprobamate; sertraline Zoloft, Lustrai, Apo-Sertral, Asentra, Gladem, Serlift, Stimuloton); escitaloprame Lexapro, Cipralex); fluoxetine Prozac, Sarafem, Fluctina, Fontex, Prodep, Fludep, Lovan); venlafaxine Effexor XR, Efexor); citaloprame Celexa, Cipramil, talohexane); paroxetine Paxil, Seroxat, Aropax); trazodone Desyrel); amitriptyline Elavil); and bupropion Wellbutrin, Zyban).

[00178] Patients undergoing treatment for cardiorenal diseases, such as chronic kidney disease, can benefit from combined drug treatment. For example, the compound of the present invention can be combined with one or more inhibitors of the angiotensin-converting enzyme (ACE), such as enalapril, captopril, ramipril, lisinopril and quinapril; or angiontesin receptor blockers (ARBs) such as losartan, olmesartan and irbesartan; or antihypertensive agents such as amlodipine, nifedipine and felodipine. The benefit of the combination may be increased effectiveness and / or reduced side effects for a component, since

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45/85 that the dose of this component can be adjusted to reduce its side effects while benefiting from its increased effectiveness by the effectiveness of formula (I) or a salt, cocrystal, solvate or hydrate of the same.

[00179] Patients who have chronic kidney disease treatable with ASK1 inhibitors, such as a compound of formula (I), may also have conditions that benefit from co-administration as indicated by a qualified caregiver) of a therapeutic agent or antibiotic, analgesic and antidepressants and / or anxiolytic agents in combination with a compound of formula (I). Combination treatments can be administered simultaneously or one after the other at intervals, as indicated by a qualified caregiver or through a fixed dose presentation all active ingredients are combined in a single dosage form, for example, tablet). two or more active agents.

[00180] Coronary patients being treated for an acute cardiovascular disease event by administering ASK1 inhibitors often exhibit diseases or conditions that benefit from treatment with other therapeutic agents. These diseases or conditions may be of a cardiovascular nature or may be related to lung disorders, metabolic disorders, gastrointestinal disorders and the like. In addition, some coronary patients who are being treated for an acute cardiovascular disease event by administering an ASK1 inhibitor exhibit conditions that may benefit from treatment with therapeutic agents that are antibiotics, analgesics and / or antidepressants and anxiolytic agents.

Pharmaceutical Compositions [00181] Although it is possible for the active ingredients to be administered alone, it may be preferable to present them as pharmaceutical formulations (compositions). The formulations of the invention, both for use

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46/85 veterinary as human, comprise at least one active ingredient, as described above, together with one or more acceptable carriers thereof and, optionally, therapeutic ingredients. The) vehicles) must) be acceptable / acceptable in the sense of being compatible with the other ingredients of the composition and must be physiologically harmless to their receptors.

[00182] The formulations include those suitable for the previous routes of administration. The formulations can conveniently be presented in unit dosage form and can be prepared by any of the methods well known in the pharmaceutical art. Techniques and formulations are generally found in Rcmington’s Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of associating the active ingredient with inactive ingredients (for example, a carrier, pharmaceutical excipient, etc.) that constitutes one or more supporting ingredients. In general, formulations are prepared by uniformly and deeply associating the active ingredient with liquid vehicles, or finely divided solid vehicles, or both, and then, if necessary, product modeling.

[00183] In certain embodiments, formulations suitable for oral administration are presented as discrete units, such as capsules, wafers or tablets, each containing a predetermined amount of the active ingredient.

[00184] In certain embodiments, pharmaceutical formulations include one or more compounds of the invention together with one or pharmaceutically acceptable vehicles or excipients and, optionally, other therapeutic agents. Pharmaceutical formulations containing the active ingredient can be in any form suitable for the intended method of administration. When used for oral use, for example, tablets, troches, lozenges, aqueous or oily suspensions, powders or granules

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47/85 dispersables, emulsions, hard or soft capsules, syrups or elixirs can be prepared. Compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents, including sweetening agents, flavoring agents, coloring agents and preserving agents, to provide a palatable preparation. Tablets containing the active ingredient mixed with non-toxic pharmaceutically acceptable excipients that are suitable for making tablets are acceptable. Such excipients can be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscamellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binding agents, such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets can be uncoated or coated by known techniques, including microencapsulation, to delay disintegration and absorption in the gastrointestinal tract and thus provide a sustained action for a longer period. For example, a time-delaying material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax, can be used.

[00185] The amount of active ingredient that is combined with the inactive ingredients to produce a dosage form will vary depending on the treated host and the particular mode of administration. For example, in some embodiments, a dosage form for oral administration in humans contains approximately 1 to 1000 mg of active material formulated with a suitable and convenient amount of carrier material (eg, inactive ingredient or excipient material). In certain embodiments, the carrier material ranges from about 5 to about 95% of the total weight: weight compositions). In some modalities,

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48/85 the pharmaceutical compositions described in the present invention contain about 1 to 800 mg, about 1 to 600 mg, about 1 to 400 mg, about 1 to 200 mg, about 1 to 100 mg, or about 1 to 50 mg of the compound of formula I, or a pharmaceutically acceptable salt, cocrystalline, solvate or hydrate thereof. In some embodiments, the pharmaceutical compositions described herein contain no more than about 400 mg of the compound of formula (I). In some embodiments, the pharmaceutical compositions described in the present invention contain about 100 mg of the compound of formula (I), or a salt, cocrystalline, solvate or hydrate thereof.

[00186] It should be understood that in addition to the ingredients particularly mentioned above, the formulations described in the present invention may include other agents conventional in the art in relation to the type of formulation in question, for example, those suitable for oral administration may include flavoring agents.

[00187] Veterinary compositions comprising at least one active ingredient, as defined above, together with a veterinary vehicle, are additionally provided.

[00188] Veterinary vehicles are useful materials for the purpose of administering the composition and can be solid, liquid or gaseous materials, which are otherwise inert or acceptable in the veterinary technique and are compatible with the active ingredient. These veterinary compositions can be administered orally, parenterally or by any other route.

[00189] The effective dose of the active ingredient depends on at least the nature of the condition being treated, the toxicity, whether the compound is being used prophylactically (lower doses), the method of administration and the pharmaceutical formulation, and will be determined by the doctor using conventional dose escalation studies.

Routes of administration

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49/85 [00190] One or more compounds of formula I referred to herein as the active ingredients), or a pharmaceutically acceptable salt, cocrystalline, solvate or hydrate thereof, are administered by any route suitable for the condition being treated. Suitable routes include oral, rectal, nasal, topical including buccal and sublingual), vaginal and parenteral including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It will be estimated that the preferred route may vary according to, for example, the condition of the recipient.

[00191] An advantage of the compounds of the present invention is that they are orally bioavailable and can be dosed orally. Accordingly, in one embodiment, the pharmaceutical compositions described herein are oral dosage forms. In certain embodiments, the pharmaceutical compositions described in the present invention are solid dosage forms.

[00192] In one embodiment, the daily oral dosage of formula (I) as a free base) is between about 0.5 mg and about 100 mg as a daily dose. In preferred embodiments, the dose is about 1 mg a day, about 2 mg a day, about 3 mg a day, about 4 mg a day, about 5 mg a day, about 6 mg a day, about 7 mg a day, about 8 mg a day, about 9 mg a day, about 10 mg a day, about 11 mg a day, about 12 mg a day, about 13 mg a day, about about 14 mg a day, about 15 mg a day, about 16 mg a day, about 17 mg a day, about 18 mg a day, about 19 mg a day, about 20 mg a day, about 25 mg a day, about 30 mg a day, or about 35 mg a day. In another embodiment, the daily dose of the free base of formula (I) is less than about 18 mg per day.

EXAMPLES [00193] The following examples are included to demonstrate specific modalities of the description. Must be understood by people

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50/85 skilled in the art that the techniques described in the examples below are techniques to work well in the practice of the invention and, therefore, they can be considered as constituting preferred modes for their practice. However, people skilled in the art should, in the light of the present description, note that many changes can be made in the specific modalities that are described and still obtain an equal or similar result without departing from the spirit and scope of the description.

[00194] The crystalline forms and their salts were analyzed by XRPD, DSC and TGA. The XRPD patterns were collected by a PANalytical X'Pert RO MPD diffractometer usually with the following parameters: 5kB, 40mA, Καί = 1.5406 A, scanning range 2-40 ° 2O, step size 0.0167 ° 2. All ° 2 Θ values are ± 0.2 ° 2 Θ. DSC thermograms were collected on a TA Instruments Q2000 system equipped with a 50-position auto-sampler. The energy and temperature calibration was performed using certified Indian. Typically, 1 to 5 mg of each sample, in an aluminum pan with pin holes, was heated to 10 ° C / min from 25 ° C to 250 ° C, or above. A dry nitrogen purge at 50 mL / min was maintained over the sample during measurement. TGA thermograms were collected on a TA Instruments Q5000 or Q500. Typically, 1 to 5 mg of each sample, in an open aluminum pan, was heated to 10 ° C / min from 25 ° C to 250 ° C, or above. DSC values can vary up to about 3%, or about 2% or about 1%.

List of abbreviations and acronyms

Abbreviation Meaning ° C Celsius degree B.C Acetyl aq. Aqueous ATP Adenosine triphosphate br Wide BSA Bovine serum albumin d Stunt DCM Dichloromethane dd Stunt doubles ddd Doublet of stunt doubles DMA Dimethylacetamide

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DME 1,2-dimethoxyethane DMF Dimethylformamide DMSO Dimethylsulfoxide dt Double-triplet DTT Cleland Reagent Dithiothreitol) EDTA Ethylenediaminetetraacetic acid Equiv. Equivalents ES / MS Electrospray mass spectrometry Et It's yours EtOAc Ethyl acetate EtOH Ethanol (ethyl alcohol) FBS Fetal bovine serum g Grams HEPES 2- [4-2-hydroxyethyl) piperazin-1-yl] ethanesulfonic acid HC1 Hydrochloric acid HPLC High pressure liquid chromatography H Hours Hz hertz IBD Inflammatory bowel disease IC50 Half of the maximum inhibitory concentration z-pr Isopropyl J Coupling constant Hz) LPS Lipopolysaccharide M Molar m Multiplete M + Mass peak M + H + Peak mass plus hydrogen Me Methyl MeCN Acetonitrile MeOH Methanol (methyl alcohol) MeLi Methyl lithium MeMgX Methylmagnesium halide (Grignard reagent), where X is fluorine, chlorine, bromine or iodine MeeSn ₂ Hexamethyldiestanane (hexamethylditine) mg Milligram MgSÜ4 Magnesium sulfate MHz Megahertz min Minute ml / ml Milliliter mM Millimolar mmol Millimol NBS N-Bromosuccinimide n- Normal nBu / Bu n-butyl butyl normal) n-BuLi n-butyl lithium NaH Sodium hydride NaHCO ₃ Sodium bicarbonate nL Nanoliter NMR Nuclear magnetic resonance NP-40 N onylphenoxypolyethoxyethanol Ph Phenyl q Quartet q.s. Enough quantity to achieve a specific function RP Reverse phase RRT Relative retention time s Singlet Sat Saturated t Triplet THF T etrahydrofuran TFA Trifluoroacetic acid

General Scheme 1:

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suitable reagent

[00195] A compound of Formula (I) can be prepared by reacting compound 6) with a suitable chlorination reagent, including, but not limited to, oxalyl chloride or thionyl chloride, to produce the corresponding acid chloride. Suitable reagents are known to those of ordinary skill in the art. The subsequent formation of the amide bond between the acid chloride and compound 12) produces a compound of formula (I). Suitable reagents to facilitate the formation of the amide bond are known to those skilled in the art.

Reaction Scheme I: Preparation of 5-4-cyclopropyl-1Himidazol-1-yl) -2-fluoro-4-methylbenzoic acid hydrochloride 6)

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Step 1 Preparation of 5-amino-2-fluorine-4-methylbenzonitrile - Compound

2) [00196] 5-bromo-4-fluor-2-methylaniline 1) 20 g, 98 mmol) was dissolved in 1-methyl-2-pyrrolidinone anhydrous 10 mL), and copper (I) cyanide 17.6 g, 196 mmol) was added. The reaction was heated to about 180 ° C for about 3 hours, cooled to room temperature and water (300 ml) and concentrated ammonium hydroxide (300 ml) were added. The mixture was stirred for about 30 minutes and then extracted with ethyl acetate 3 x 200 ml). The combined extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure. The oily residue was washed with 2 x 100 ml hexanes) and the solid was dissolved in dichloromethane and loaded onto a silica gel column. Eluting with a gradient of 0 to 25% ethyl acetate in hexanes, 5-amino-2-fluoro-4-methylbenzonitrile was obtained. LC / MSm / z: 151 M ^{+ I} ).

Step 2 - Preparation of 5-2-cyclopropyl-2-oxoethylamino) -2-fluor-4methylbenzonitrile - Compound 3) [00197] 5-amino-2-fluor-4-methylbenzonitrile 80 mmol) was dissolved in Ν, Ν-dimethylformamide anhydrous 160 mL) under nitrogen, and potassium carbonate 96 mmol) and potassium iodide 88 mmol) were added as stirring solids. The reaction was stirred for 5 minutes at room temperature and then bromomethyl cyclopropyl ketone (180 mmol) was added. The reaction mixture was heated at 60 ° C for 3 hours and then the solvents were removed under reduced pressure. O

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The residue was dissolved in ethyl acetate (400 ml) and washed with 400 ml of water. The organic layer was dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was redissolved in a minimum amount of ethyl acetate, and hexanes were added to swell the solution to 3: 1 hexanes: ethyl acetate. The product precipitated out of solution and was collected by filtration to produce 5-2-cyclopropyl-2oxoethylamino) -2-fluoro-4-methylbenzonitrile. LC / MS m / z: 233, M ⁺¹ )

Step 3 - Preparation of 5-4-cyclopropyl-2-mercapto-1H-imidazol-l-yl) -2fluor-4-methylbenzonitrile - Compound 4) [00198] 5-2-cyclopropyl-2-oxoethylamino) - 2-fluor-4methylbenzonitrile (14.19 g, 61.2 mmol) in glacial acetic acid 300 mL). Potassium thiocyanate 11.9 g, 122.4 mmol) was then added as a solid with stirring, and the reaction was heated to about 110 ° C for about 4 hours, when the solvent was removed under reduced pressure . The residue was resuspended in 200 ml of dichloromethane) and washed with 200 ml of water. The aqueous extract was extracted with 2 x 200 mL) of additional dichloromethane, the organic extracts were combined and dried over magnesium sulfate. The solvent was removed under reduced pressure, the oily residue was redissolved in ethyl acetate (50 ml) and 150 ml of hexanes were added. A dark layer formed and a stir bar was added to the flask. The vigorous stirring caused the product to be eliminated as a peach-colored solid. The product was collected by filtration to produce 5-4-cyclopropyl-2-mercapto-1H-imidazol-1-yl) -2-fluoro4-methylbenzonitrile. Anal. LC / MS m / z: 274, M ⁺¹ ).

[00199] Step 3 - Preparation of 5-4-cyclopropyl-1H-imidazol-l-yl) 2-fluoro-4-methylbenzonitrile - Compound 5) [00200] In a round-bottomed flask with three 500 mL necks acetic acid 96 mL), water 19 mL) and then 30% hydrogen peroxide, 7.47 mL, 65.88 mmol). The mixture was heated to about

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55/85 of 45 ° C with stirring under nitrogen, with concomitant monitoring of the internal temperature. 5-4-cyclopropyl-2-mercapto-1Himidazol-1-yl) -2-fluor-4-methylbenzonitrile (6.00 g, 21.96 mmol) was then added as a solid in small portions over about 30 minutes while maintained an internal temperature below 55 ° C. When the addition of thioimidazole was complete, the reaction was stirred for about 30 minutes at a temperature of about 45 ° C, then cooled to room temperature and a 20% by weight solution of sodium sulfite in water was slowly added 6 mL). The mixture was stirred for 30 minutes and then the solvents were removed under reduced pressure. The residue was suspended in 250 ml of water and 4 N aqueous ammonium hydroxide was added to adjust the pH to ~ 10. The mixture was extracted with 3 x 200 ml dichloromethane), the organics were combined, dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was dissolved in 20 ml of ethyl acetate and 80 ml of hexanes were added with stirring. The solvents were removed by decanting and an oily residue was formed. This process was repeated and the product, 5-4-cyclopropyl-1H-imidazol-1-yl) -2fluor-4-methylbenzonitrile was obtained as a viscous oil. Anal. LC / MS m / z: 242, M ⁺¹ ).

Step 5 - Preparation of 5-4-cyclopropyl-1H-imidazoll-yl) -2-fluoro-4-methylbenzoic acid hydrochloride 6) [00201] 5-4-cyclopropyl-1H-imidazol-l-yl) - 2-fluorine-4methylbenzonitrile 11.21 g, 46.50 mmol) in a round-bottom flask fitted with a reflux condenser, and suspended in 38% hydrochloric acid (200 mL). The mixture was heated to about 100 ° C for about

4.5 hours and then it was cooled to room temperature. The solvent was removed under reduced pressure to produce a pink solid, to which 100 ml of ethyl acetate was added. The solid product was collected by filtration and washed with 3 x 100 ml of ethyl acetate. To

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56/85 solid product 100 ml of 10% methanol in dichloromethane was added, the mixture was stirred and the filtrate collected. This was repeated with 2 more 100 ml portions of 10% methanol in dichloromethane. The filtrates were combined and the solvent was removed under reduced pressure to produce 5-4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoic acid hydrochloride. No further purification was performed. Anal. LC / MS m / z: 261, M ⁺¹ ).

Reaction Scheme II:

Step 1 Preparation of methyl 6-benzyloxy) carbonyl) amino) picolinate 8) [00202] To a solution of methyl 6-aminopicolinate 70 g, 460.53 mmol, 1.0 equiv.) And 96.71 g NaHCO3, 1151.32 mmol, 2.5 equiv.) In acetone / H ₂ O 500 mL / 250 mL) CbzCl 98.54 mL, 690.79 mmol,

1.5 equiv.) By dripping at about 0 ° C. The mixture was warmed to room temperature and was stirred at room temperature overnight. CCF indicated that the reaction was complete. Water (1500 ml) was added and the mixture was stirred for about 20 minutes. Then, it was filtered to produce the desired product. 400 MHz ^NMR ', CDCl3) δ 8,208.22 1H, m), 7.75-7.84 3H, m), 7.34-7.39 5H, m), 5.23 2H, s), 3 , 98 3H, s).

Step 2 - Preparation of benzyl 6-hydrazinocarbonyl) pyridin-2-yl) carbamate 9) [00203] To a solution of benzyl 6-hydrazinocarbonyl) pyridin-2-yl) carbamate 121 g, 423.08 mmol, 1, 0 equiv.) In MeOH 500 ml) Η2ΝΝΗ2Ή2Ο 31.73 g, 634.62 mmol, 1.5 equiv.) Was added. The mixture was refluxed overnight. CCF indicated that the reaction was complete.

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After cooling to room temperature, the solid precipitated. The mixture was stirred for about 0.5 h in ice water and was filtered to produce the desired product as a white solid. 400 MHz ^NMR ', CDCl3) δ 8.66 1H, s), 8.13-8.16 1H, m), 7.84-7.86 2H, m), 7.36-7.43 6H, m), 5.24 2H, s), 4.04 2H, d, 7 = 4.4 Hz).

Step 3 - Preparation of E) -6-2-dimethylamino) methylene) hydrazino-lcarbonyl) benzyl pyridin-2-yl) benzamate 10) [00204] A mixture of 6-hydrazinocarbonyl) pyridin-2-yl) benzyl carbamate 170.2 g, 595.10 mmol, 1.0 equiv.) In DMF-DMA 350 mL) was refluxed under argon for 45 min. CCF indicated that the reaction was complete. The mixture was cooled to room temperature and concentrated to obtain a solid. It was washed with ethyl acetate to obtain 184.2 g of the desired compound as a light yellow solid. [M + H] = 342.

Step 4 - Preparation of S) -6-4-1-fluoropropan-2-yl) -4H-1,2,4-triazol-3-yl) pyridin-2-yl) benzyl carbamate 11) [00205] A a solution of E) -6-2-dimethylamino) methylene) hydrazino-lcarbonyl) pyridin-2-yl) benzyl carbamate 160 g, 469.21 mmol, 1.0 equiv.) in MeCN / AcOH 800 mL / 200 mL ) S) -fluorpropan-2-amine hydrochloride (106.04 g, 938.42 mmol, 2.0 equiv.) was added. The mixture was refluxed under argon overnight. CCF and LCMS showed that the reaction was complete. The mixture was concentrated and adjusted to pH = 8 by the addition of NaHCCU solution. The mixture was filtered to produce the crude product as a solid. Ethyl acetate (400 ml) was added and stirring took place under reflux for 1 h. After cooling to room temperature, it was filtered to produce the pure product. The filtrate was then concentrated to form the crude product. Ethyl acetate (100 ml) was added and stirred at room temperature for 10 minutes. The solid was precipitated and refluxed for about 0.5 h. The mixture

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58/85 was filtered to produce the product. [M + H] = 356.

Step 5 - Preparation of S) -6-4-1-fluoropropan-2-yl) -4H-1,2,4-triazol-3-yl) pyridin-2-amine 12) [00206] To a solution of S ) -6-4-1-fluoropropan-2-yl) -4H-1,2,4triazol-3-yl) pyridin-2-yl) benzyl carbamate 46.2 g, 130.14 mmol, 1.0 equiv .) in MeOH 450 ml) Pd / C 3.17 g, 10%) was added. The mixture was stirred at room temperature under H ₂ overnight. CCF showed that the reaction was complete, and it was filtered. The filtrate was concentrated and purified by MeOH: DCM column = 1: 100-1: 70) to obtain a white solid. The solid was washed by PE and EA EA: PE = 1:50) to produce the desired product. [M + H] = 222, NMR Ή 400 MHz, CDC13) δ 8.39 1H, s), 7.66 1H, d, J = 7.6 Hz), 7.59 1H, t, J = 7, 8 Hz), 6.57 1H, d, J = 8.0 Hz), 5,835.91 1H, m), 4.74 1H, d, J = 3.8 Hz), 4.63 1H, d, J = 3 Hz), 4.46 1H, s), 1.64 3H, d, J = 7.2 Hz).

Reaction Scheme III:

Preparation of S) -5-4-cyclopropyl-1H-imidazol-1-yl) -2-fluorine-N-6-4-1fluorpropan-2-yl) -4H-1,2,4-triazol-3-yl ) pyridin-2-yl) -4-methylbenzamide Formula (I) [00207] 5-4-cyclopropyl-1H-imidazol-l-yl) -2-fluoro4-methylbenzoic acid 1.0 eq) was suspended in dichloromethane at room temperature and DMF 0.1 eq) was added. Oxalyl chloride 1.1 eq) was then slowly added with stirring under nitrogen. The mixture was stirred for about 5 hours at room temperature, and the solvent was concentrated under reduced pressure to approximately half the volume, and dichloromethane was added (2090 ml). The solution was cooled to about

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59/85 ° C and diisopropylethylamine was added slowly. The mixture was heated to 15 ° C and S) -6-4-1-fluoropropan-2-yl) -4H-1,2,4-triazol-3-yl) pyridin2-amine 1.1 eq) was added. The mixture was stirred at room temperature for 17 hours and a 1 eq) dehydrated tribasic sodium citrate solution was added. IN NaOH was added and the mixture was stirred for about 10 min. The layers were separated, and the organic layer was washed with water and concentrated under reduced pressure. The solids were suspended in EtOH (1000 mL) and heated to reflux. The mixture was cooled, stirred at room temperature for about 3.5 hours and filtered. The solids were washed with EtOH to produce S) -5-4cyclopropyl-1H-imidazol-1-yl) -2-fluorine-N- 6-4-1-fluoropropan-2-yl) -4H-1,2,4 triazole -3-yl) pyridin-2-yl) -4-methylbenzamide. H ^NMR 400 MHz, DMSO-I / O) δ 10.93, 1H), 8.88 s, 1H), 8.17 dd, J = 8.3, 0.9 Hz, 1H), 8, 04 t, J = 8.0 Hz, 1H), 7.93 dd, J = 7.6, 0.9 Hz, 1H), 7.70 d, J = 1.4 Hz, 1H), 7.65 d, J = 6.5 Hz, 1H), 7.50 d, J = 10.7 Hz, 1H), 7.18 d, J = 1.4 Hz, 1H), 6.04-5.89 m , 1H), 4.78-4.71 m, 1H), 4.67-4.59 m, 1H), 2.25 s, 3H), 1.88-1.81 m, 1H), 1, 51 d, J = 6.9 Hz, 3H), 0.82-0.78 m, 2H), 0.71-0.68 m, 2H). LCMS-ESI ⁺ m / z): [M + H] ⁺ calc. 464.20; found 464.21.

Preparation of S) -5-4-cyclopropyl-1H-imidazol-1-yl) -2-fluorine-N-6-4-1fluorpropan-2-yl) -4H-1,2,4-triazol-3-yl ) pyridin-2-yl) -4-methylbenzamide Formula (I) [00208] 5-4-cyclopropyl-1H-imidazol-l-yl) -2-fluoro-4methylbenzoic acid 1.0 equiv) was combined with dichloromethane 10 L / Kg) and N, Ndimethylformamide 0.1 equiv). The resulting mixture was added oxalyl chloride (1.1 equiv) at a rate to control the evolution of the gas. The reaction mixture was heated to about 35 ° C until the reaction was complete. The reaction mixture was concentrated to 5 L / kg and then dichloromethane (10 L / Kg) was added. The reaction mixture was cooled to about 0 ° C and then 0.6 equiv. Diisopropylethylamine was added, followed by S) -6-4-l

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60/85 fluorpropan-2-yl) -4H-1,2,4-triazol-3-yl) pyridin-2-amine 12) 1.1 equiv) which was slowly added. The reaction mixture was heated to about 22 ° C and was maintained until the reaction was complete. The reaction was concentrated to 5 L / kg and then 1-methyl-2-pyrrolidinone was added (10 L / Kg). The reaction was concentrated to 10 L / Kg, followed by a temperature adjustment to about 65 ° C. A solution of citric acid 0.5 equiv) and water 10 L / kg) was added, maintaining a temperature above about 55 ° C. The pH was adjusted to about 6, using 50% by weight aqueous sodium hydroxide solution. The contents were heated to about 65 ° C for about 1 h, and then the reaction mixture was cooled to about 20 ° C. The product was isolated by filtration, washed with water 2x5 L / Kg) and dried to produce the compound of formula (I).

Preparation of S) -5-4-cyclopropyl-1H-imidazol-1-yl) -2-fluorine-N-6-4-1fluorpropan-2-yl) -4H-1,2,4-triazol-3-yl ) pyridin-2-yl) -4-methylbenzamide Formula (I) [00209] A mixture of 5-4-cyclopropyl-1Himidazol-1-yl) -2-fluoro-4-methylbenzoic acid 1,0 equiv.) in 1-methyl-2-pyrrolidinone 10 L / kg) was cooled to about 5 ° C. To this was added thionyl chloride 1.1 equiv) followed by S) -6-4-1-fluoropropan-2-yl) -4H-1,2,4-triazol-3yl) pyridin-2-amine 12) 1 , 0 equiv). This reaction mixture was maintained at about 25 ° C until the reaction was complete and then heated to about 70 ° C. In a separate reaction vessel, sodium hydroxide 3.5 equiv), sodium citrate 0.5 equiv) and water 10 L / kg) were combined. The resulting solution was then added to the reaction mixture. The pH was adjusted to about 6, using 50% by weight aqueous sodium hydroxide solution. The resulting mixture was heated to about 70 ° C and then cooled to about 5 ° C. The product was isolated by filtration, washed with water 2x5 L / Kg) and dried to produce the compound of formula (I).

Preparation of the compound of formula (I) Form I free base

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61/85 [00210] Formula (I) of free base form I was crystallized from the reaction mixture using the following procedure: 1.0 equivalent of oxalyl chloride was added to compound 6) and the mixture was stirred at about 35 ° C. The solution was then distilled to dryness and 15 volumes of DCM were added. 0.7 equivalent of DIPEA, followed by 1.1 equivalent of compound 12), were then added. The mixture was stirred at about 22 ° C. 10 volumes of NMP were then placed in the reactor and the DCM was distilled to a level of 15% by weight. An equivalent of sodium citrate dissolved in 2 volumes of water was then added to the reactor, at about 22 ° C. Three volumes of an IN NaOH solution and 5 volumes of water were then added. The solution was then aged overnight. The resulting slurry was then filtered and washed with 5 volumes of water and 2 volumes of methanol. The resulting solid was then dried at about 50 ° C. The XRPD pattern of formula (I) of free base form I is shown in figure 1. The pattern contains the following characteristic peaks: 1) 8.7, 10.2 and 18.1 ^Ο 2Θ ± ^Ο 2Θ; 2) 15.8, 17.3 and

23.5 ^Ο 2Θ ± ^Ο 2Θ; 3) 15.2, 18.5 and 24.9 ^Ο 2Θ ± ^Ο 2Θ. Figure 2 is the DSC thermogram of formula (I) of free base form I. There is a melting transition with an onset of about 223 ° C. Figure 3 is the TGA thermogram of the compound of formula (I) of the free base form I. There is a weight loss of 0.9% between 25 and 220 ° C.

Table 1: XRPD peak table of Formula (I) of free base Form I

At the. Pos. [° 2Th.] King. Int. [%] 1 8.7 100 2 10.2 13 3 15.2 22 4 15.8 19 5 17.3 22 6 18.1 25, 7 18.5 14 8 21.2 6 9 22.3 5 10 23.0 11 11 23.2 15 12 23.5 16 13 23.9 4 14 24.9 13

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At the. Pos. [° 2Th.] King. Int. [%] 15 26.0 9 16 26.1 8 17 26.6 5 18 26.9 4 19 27.8 3 20 28.3 7 21 28.6 11 22 29.2 5 23 31.4 3 24 31.9 2 25, 37.2 4

Preparation of the compound of formula (I) Form II free base [00211] Formula (I) of form II free base was crystallized from the reaction mixture using the following procedure: 1.0 equivalent of oxalyl chloride was added to the compound 6) and the mixture was stirred at about 35 ° C. The solution was then distilled to 5 volumes and 10 volumes of DCM were added. 0.6 equivalent of DIPEA was added, followed by 1.1 equivalent of compound 12). The mixture was stirred at about 22 ° C and the DCM was distilled to dryness. 10 volumes of NMP were then added. The reactor contents were then heated to about 70 ° C, and a solution of 0.5 equiv. of sodium citrate, 1.5 equivalent of NaOH and water was added at a rate that would allow the internal temperature of the solution to remain above about 58 ° C. The mixture was then maintained at about 65 ° C for about 1 h and was cooled to about 20 ° C for 3 h. The resulting slurry was then filtered and washed with 5 volumes of water 2 times. The solid was then dried.

[00212] Formula (I) of free base form II can also be obtained by fluidizing Formula (I) of free base form I in a variety of solvents, including ethanol.

[00213] Figure 4 shows the XRPD pattern of formula (I) of free base form II. It contains the following characteristic peaks: 1) 8.7, 10.0, and 17.0 ^Ο 2Θ ± ^Ο 2Θ; 2) 13.9, 21.3 and 22.8 ^Ο 2Θ ± ^Ο 2Θ; 3) 24.0, 28.0 and 29.1 ^Ο 2Θ ± ^Ο 2Θ. Figure 5 is the DSC thermogram of formula (I) of free base form II. It shows a fusion endotherm that starts at about 208 ° C. THE

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63/85 figure 6 is the TGA thermogram of formula (I) of free base form II. The solid loses about 1% by weight when heating to 200 ° C.

Table 2: XRPD peak table of Formula (I) of Form Π free base

At the. Pos. [° 2Th.] King. Int. [%] 1 8.5 8 2 8.7 18 3 10.0 23 4 10.4 6 5 13.0 13 6 13.9 35 7 14.5 7 8 15.2 10 9 16.4 20 10 17.0 55 11 17.9 19 12 18.6 22 13 18.9 14 14 19.4 6 15 20.0 10 16 20.5 11 17 21.3 72 18 22.1 9 19 22.5 27 20 22.8 100 21 23.1 14 22 23.5 5 23 24.0 28 24 25.1 6 25, 25.5 10 26 26.1 8 27 26.5 11 28 27.2 6 29 28.0 31 30 28.6 7 31 29.1 49 32 29.5 17 33 31.4 6 34 32.2 5

Reaction Scheme IV:

Preparation of S) -5-4-cyclopropyl-1H-imidazol-1-yl) -2-fluoroN-6-4-1-fluorpropan-2-yl) -4H-1,2,4-triazole-3 succinate -yl) pyridin-2-yl) -4methylbenzamide

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64/85 [00214] A solution of succinic acid 1.0 equiv), methanol 1.1 L / kg) and acetonitrile 9.9 L / Kg) was combined with S) -5-4-cyclopropyl-1H-imidazole- 1-yl) -2-fluoro-N-64-1-fluorpropan-2-yl) -4H-1,2,4-triazol-3-yl) pyridin-2-yl) -4-methylbenzamide 1.0 equiv ). The resulting mixture was heated to about 80 ° C, and then it was cooled to about 5 ° C. The product was isolated by filtration, washed with acetonitrile 2x3 L / Kg) and dried to produce the compound of formula (I) as succinate.

Preparation of Formula (I) Form I of Succinate [00215] Formula (I) Form I of succinate was first obtained by suspending about 40 mg of formula (I) form Π of free base in 0.2 ml of acetonitrile with an equivalent of succinic acid, which is about 11 mg. The slurry was stirred with a stir bar at about 22 ° C for about 16 hours. A small amount of slurry was then centrifuged, and the XRPD pattern of the solid was obtained after being dried in the vacuum oven at about 50 ° C. The XRPD pattern of form I of succinate is shown in figure 7. The pattern contains the following characteristic peaks:

1) 7.5, 20.9 and 24.9 ^Ο 2Θ ± ^Ο 2Θ; 2) 15.4, 22.4 and 31.1 ^Ο 2Θ ± ^Ο 2Θ; 3) 14.9, 23.2 and

25.4 ^Ο 2Θ ± ^Ο 2Θ. Figure 8 shows the DSC thermogram of formula (I) of form I succinate. The solid has an onset of melting at approximately 159 ° C. Figure 9 shows the TGA thermogram of formula (I) of form I succinate. The solid loses about 0.6% of the weight between room temperature and approximately 160 ° C.

[00216] Table 3: XRPD peak table of formula I of form I of succinate

At the. Pos. [° 2Th.] King. Int. [%] 1 7.5 67 2 12.4 5 3 13.0 4 4 14.9 12 5 15.4 26 6 16.8 2 7 18.7 2 8 18.9 3 9 19.3 15 10 19.9 5 11 20.2 8 12 20.9 100

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At the. Pos. [° 2Th.] King. Int. [%] 13 21.8 3 14 22.4 17 15 23.2 11 16 23.4 9 17 24.3 3 18 24.9 79 19 25.4 10 20 25.7 5 21 25.9 3 22 26.4 4 23 27.0 4 24 27.7 2 25, 28.2 2 26 28.9 9 27 29.2 3 28 30.0 9 29 30.3 4 30 31.1 18 31 32.2 2 32 32.7 3 33 33.9 2 34 35.9 3 35 37.9 4

Preparation of Formula (I) Form II Succinate [00217] Formula (I) form Π succinate is a methanol solvate. It was first obtained by fluidizing the formula (I) form I of succinate in pure methanol at about 22 ° C for approximately 16 hours. The slurry was then centrifuged, and the XRPD pattern of the dry solid at about 50 ° C was obtained. Formula (I) form Π of succinate is a methanol solvate.

[00218] It was also obtained by fluidizing the formula (I) form I of succinate in a solvent mixture composed of 4.7% water and 95.3% methanol, as well as by fluidizing the formula (I) form I of succinate in a solvent mixture composed of 20% acetonitrile and 80% methanol.

[00219] Figure 10 shows the XRPD pattern of formula (I) of form II of succinate. The following peaks are characteristic of this pattern: 1) 9.8, 11.7,

23.3 2) 15.9, 21.5, 32.0 3) 16.3, 20.8, 24.8 ° 2 θ. Figure 11 shows the DSC thermogram of formula (I) of form II of succinate. It shows an endothermic event with an onset at about 100 ⁰ C, followed by two consecutive endothermic events starting at about 159 and about

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162 ° C. Figure 12 is the TGA thermogram of formula (I) of form II of succinate. There are two weight losses of 4.6 and 9.2% by weight, at about 100 and 200 ° C, respectively.

[00220] Table 4: XRPD peak table of Formula (I) of Form II succinate

At the. Pos. [° 2Th.] King. Int. [%] 1 8.3 5 2 9.8 43 3 10.7 4 4 11.7 26 5 12.3 3 6 13.1 3 7 13.7 9 8 14.9 9 9 15.4 8 10 15.9 24 11 16.1 14 12 16.3 22 13 16.6 9 14 16.9 4 15 17.3 8 16 18.6 5 17 18.8 9 18 19.2 3 19 19.6 5 20 20.2 8 21 20.8 15 22 21.5 12 23 22.8 5 24 23.3 100 25, 23.4 68 26 23.9 12 27 24.2 28 28 24.5 10 29 24.8 23 30 25.7 7 31 26.1 4 32 26.5 6 33 27.0 12 34 27.6 5 35 27.9 6 36 28.4 4 37 29.0 4 38 29.8 5 39 30.1 7 40 31.5 6 41 32.0 26 42 32.1 22 43 32.5 4 44 33.1 4 45 34.0 2 46 34.3 3 47 34.9 4 48 35.4 3

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At the. Pos. [° 2Th.] King. Int. [%] 49 36.5 3

Preparation of Formula (I) Hydrochloride Form I [00221] Formula (I) of hydrochloride form I was first prepared by adding an equivalent of concentrated HCl to 47 mg of formula (I) form Π of free base suspended in acetonitrile. The resulting solution was stirred at approximately 22 ° C for about 16 h.

[00222] The XRPD standard of Formula (I) of HCl form I is shown in figure 13. It contains the following representative peaks 1) 9.3, 21.2, 26.2 2) 20.9, 24.7 , 27.6 3) 23.8, 24.3, 26.6 ° 2 θ Figure 14 is the DSC thermogram of formula (I) of form I of HCl. Fusion / dehydration occurs at about 152 ° C. Figure 15 is the TGA thermogram of formula (I) of HCl form I. There are two weight losses, the first is about 4.2% by weight and occurs between about 30 ° C and 140 ° C. The second is about 1.7% by weight and occurs between about 140 and 200 ° C.

Table 5: Table of XRPD peaks of Formula (I) of Form I HCl

At the. Pos. [° 2Th.] King. Int. [%] 1 9.3 100 2 10.3 3 3 13.9 6 4 14.8 6 5 14.9 4 6 16.1 5 7 17.1 8 8 17.3 6 9 19.8 7 10 19.9 8 11 20.9 18 12 21.2 24 13 22.5 3 14 22.7 2 15 23.8 14 16 24.3 14 17 24.7 16 18 25.7 5 19 26.2 28 20 26.6 14 21 27.6 16 22 27.8 8

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At the. Pos. [° 2Th.] King. Int. [%] 23 28.0 6 24 28.8 10 25, 29.1 10 26 29.4 6 27 29.8 7 28 30.2 4 29 31.1 2 30 33.1 2 31 35.9 2

Preparation of Formula (I) HCl Form II [00223] Formula (I) of HCl form II was prepared first by suspending a mixture of formula (I) of HCl form I and material A about 1: 1 p / p) in 10:90 of water: acetonitrile v / v) for 16 h at approximately 22 ° C. After 16 h, the XRPD of the centrifuged and air-dried solid was collected. Formula (I) of form Π of HCl was also prepared by fluidizing formula (I) of form I of HCl in 10:90 of water: v / v acetonitrile), centrifuging and drying in a vacuum oven at about 50 ° C. Figure 16 shows the XRPD pattern of formula (I) of HCl form II. It contains the following characteristic peaks: 1) 8.3, 12.0 and 26.0 ^Ο 2Θ ± ^Ο 2Θ; 2) 19.3, 21.7 and 24.0 ^Ο 2Θ ± ^Ο 2Θ; 3) 9.8, 15.4 and 28.9. Figure 33 is the DSC thermogram of formula (I) of form II HCl, in which there are two endothermic events starting at about 135 and about 205 ° C.

Table 6: XRPD peak table of Formula (I) of Form Π of HCl

At the. Pos. [° 2Th.] King. Int. [%] 1 8.3 100 2 9.8 6 3 12.0 16 4 14.2 9 5 14.6 10 6 15.4 8 7 17.0 7 8 18.4 7 9 19.3 30 10 19.7 17 11 19.9 9 12 21.1 7 13 21.7 24 14 23.0 8 15 23.4 10 16 23.7 8 17 24.0 26 18 24.5 8

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At the. Pos. [° 2Th.] King. Int. [%] 19 25.6 6 20 26.0 58 21 26.4 22 22 26.6 12 23 27.6 9 24 28.4 8 25, 28.9 19 26 29.6 6 27 30.0 8 28 30.7 8 29 30.8 9 30 32.0 5 31 33.5 12

Preparation of Formula (I) of HCl Form III [00224] Formula (I) of HCl material A was first prepared by adding an equivalent of 1 M HCl / dioxane to formula (I) of suspended form II free base in acetonitrile. The resulting solution was stirred at approximately 22 ° C for about 16 h and the XRPD of the centrifuged and dried solid was collected. Figure 17 shows the XRPD pattern of formula (I) of HCl form III. It contains the following characteristic peaks: 1) 6.6, 12.9 and 19.7 ^Ο 2Θ ± ^Ο 2Θ; 2) 20.4, 23.4 and 24.8 ^Ο 2Θ ± ^Ο 2Θ; 3) 18.1, 25.4 and 26.7 ^Ο 2Θ ± ^Ο 2Θ. Figure 18 is the DSC thermogram of formula (I) of HCl form III. No clear thermal event can be observed.

[00225] Table 7: Table of XRPD peaks of Formula (I) of Form III HCl

At the. Pos. [° 2Th.] King. Int. [%] 1 6.6 26 2 10.2 11 3 12.9 38 4 14.0 34 5 16.1 11 6 18.1 37 7 19.0 28 8 19.7 59 9 20.4 100 10 21.7 33 11 23.4 99 12 24.8 49 13 25.4 49 14 25.9 40 15 26.7 55 16 27.5 34 17 29.4 33 18 30.9 13 19 33.4 10 20 34.0 9

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Preparation of L-malate Formula (I) [00226] L-malate formula (I) was first obtained by fluidizing about 40 mg of formula Π) of free base form II in 0.2 ml of acetonitrile with an equivalent of L-malic acid, about 12 mg, for approximately 16 h at about 22 ° C. The slurry was then centrifuged, and an XRPD pattern of the dry solid was collected.

[00227] Figure 19 shows the XRPD pattern of the formula (I) of Lmalate. It contains the following characteristic peaks: 1) 7.2, 21.9 and 24.5 ^Ο 2Θ ± ^Ο 2Θ; 2) 10.9, 16.6 and 19.7 ^Ο 2Θ ± ^Ο 2Θ; 3) 8.2, 22.8 and 27.3 ^Ο 2Θ ± ^Ο 2Θ. Figure 20 shows the DSC thermogram of the formula (I) of L-malate. There are two endothermic events, the first around 23 ° C and the second, the melting endotherm, at approximately 110 ° C. Figure 21 shows the TGA thermogram of the formula (I) of L-malate. The solid loses about 2.5% of its weight when it is heated to about 150 ° C.

[00228] Table 8: XRPD peak table of Lmalate formula (I)

At the. Pos. [° 2Th.] King. Int. [%] 1 7.2 39 2 8.2 14 3 9.0 5 4 10.0 4 5 10.9 25, 6 12.7 5 7 14.5 6 8 15.1 7 9 16.6 20 10 16.8 23 11 17.4 7 12 17.9 11 13 19.7 25, 14 21.1 28 15 21.4 25, 16 21.9 38 17 22.8 16 18 24.5 100 19 25.5 18 20 27.3 29 21 29.1 12 22 30.3 7 23 32.1 3 24 33.6 7

Preparation of formula (I) of phosphate material A

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71/85 [00229] The formula (I) of phosphate material A was obtained by fluidizing about 37 mg of formula (I) of free base form II in 0.2 ml of acetonitrile and adding an equivalent of phosphoric acid 14, 8 M. After stirring for 16 h at approximately 22 ° C, the solution was evaporated and 0.2 ml of IPA was added. This solution was stirred for 10 days. A slurry was obtained and the XRPD of the centrifuged and dry solid was collected.

[00230] The XRPD standard of formula (I) of phosphate material A is shown in figure 22, it has the following characteristic peaks: 1) 6.9, 8.0 and 21.2 ^Ο 2Θ ± ^Ο 2Θ; 2) 22.8, 25.3 and 26.0 ^Ο 2Θ ± ^Ο 2Θ; 3) 19.8, 20.6, 23.2 ^Ο 2Θ ± ^Ο 2Θ. Table 9: XRPD peak table of Formula (I) of phosphate material A

At the. Pos. [° 2Th.J King. Int. [%] 1 6.9 15 2 8.0 16 3 8.7 4 4 10.1 20 5 10.8 13 6 11.0 12 7 11.3 20 8 12.0 8 9 12.9 5 10 13.9 4 11 15.3 15 12 15.7 42 13 16.4 7 14 16.9 27 15 17.5 17 16 17.9 15 17 18.6 31 18 18.8 25, 19 19.1 43 20 19.8 46 21 20.6 45 22 21.2 47 23 21.4 40 24 21.8 26 25, 22.1 23 26 22.8 63 27 23.2 45 28 23.7 33 29 24.3 31 30 25.3 100 31 25.8 42 32 26.0 46 33 26.4 29 34 26.9 28 35 27.7 26 36 28.0 15

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At the. Pos. [° 2Th.] King. Int. [%] 37 28.7 11 38 29.1 24 39 30.6 5 40 31.7 5 41 32.5 6 42 35.0 3 43 38.4 3

[00231] The formula (I) of phosphate material B was obtained by placing about 1 mg of formula (I) of phosphate material A in an aluminum pan and subjecting it to the following relative humidity conditions inside the instrument. dynamic vapor sorption (DVS): equilibrate at 25 ° C and 10% relative humidity for 20 min, increase to 90% relative humidity and maintain for 30 min. The XRPD pattern of the solid was collected after the DVS cycle. Figure 23 shows the XRPD pattern of formula (I) of phosphate material B. It contains the following characteristic peaks: 1) 13.4,

23.5 and 24.3 ^Ο 2Θ ± ^Ο 2Θ; 2) 21.7, 25.1 and 25.8 ^Ο 2Θ ± ^Ο 2Θ; 3) 17.0, 18.6 and 22.5 ^Ο 2Θ ± ^Ο 2Θ.

Table 10: XRPD peak table of Formula (I) of phosphate material B

At the. Pos. [° 2Th.] King. Int. [%] 1 5.7 3 2 7.3 18 3 9.0 25, 4 9.5 25, 5 11.7 16 6 12.2 16 7 13.1 39 8 13.4 84 9 15.0 17 10 15.3 16 11 15.9 8 12 17.0 49 13 17.3 52 14 18.0 25, 15 18.6 40 16 19.7 15 17 20.2 26 18 20.8 33 19 21.4 38 20 21.7 55 21 22.0 26 22 22.5 53 23 23.5 84 24 24.3 100 25, 24.7 26 26 25.1 61 27 25.8 66 28 26.3 25,

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At the. Pos. [° 2Th.] King. Int. [%] 29 27.5 24 30 28.0 17 31 28.5 10 32 31.4 10 33 35.9 5

Preparation of sulfate formula (I) [00232] Sulphate formula (I) was first obtained by adding 1 equivalent of 98% sulfuric acid to 38 mg of formula (I) of free base form II in 0.2 ml of acetonitrile. The solution was stirred for about 16 hours at approximately 22 ° C, and then it was evaporated. 0.2 ml of IPA was added and the solution was stirred for about 16 h. The slurry was then centrifuged and the XRPD of the dry solid in the vacuum oven at about 50 ° C was obtained.

[00233] The XRPD standard of Formula (I) of sulfate is shown in figure 24. It has the following characteristic peaks: 1) 7.2, 13.5 and 21.5 ^Ο 2Θ ± ^Ο 2Θ; 2) 16.9, 20.5 and 25.3 ^Ο 2Θ ± ^Ο 2Θ; 3) 18.2, 20.6 and 27.2 ^Ο 2Θ ± ^Ο 2Θ. Figure 25 shows the DSC thermogram of the sulfate formula (I). The solid melts at approximately 210 ° C. Figure 26 is the TGA thermogram of the formula (I) of sulfate. It shows a weight loss of about 1.8% at approximately 225 ° C.

Table 11: Sulfate Formula (I) Peak Table

At the. Pos. [° 2Th.] King. Int. [%] 1 7.2 34 2 9.1 9 3 10.7 6 4 12.4 26 5 13.1 12 6 13.5 100 7 15.7 13 8 16.9 41 9 17.1 19 10 18.2 38 11 18.5 16 12 18.9 17 13 19.5 19 14 20.1 31 15 20.5 54 16 20.6 41

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At the. Pos. [° 2Th.] King. Int. [%] 17 21.2 18 18 21.5 69 19 22.7 8 20 23.2 17 21 23.9 6 22 24.4 22 23 25.3 86 24 26.0 26 25, 26.3 22 26 26.6 19 27 27.2 53 28 27.8 15 29 28.7 11 30 29.0 14 31 30.5 9 32 31.5 7 33 32.5 7 34 35.5 5

Preparation of Formula (I) material A and citrate material B [00234] Formula (I) of citrate was obtained by fluidizing about 42 mg of formula (I) of the Π form of free base and an equivalent of citric acid, about 18 mg in 0.2 ml of acetonitrile at about 22 ° C for approximately 16 h. The centrifuged wet solid XRPD standard was obtained.

[00235] Figure 27 shows the XRPD pattern of formula (I) of citrate material A. The pattern has the following characteristic peaks: 1) 5.6, 9.1, 16.7 ^Ο 2Θ ± ^Ο 2Θ; 2) 12.2, 21.0, 23.0 ^Ο 2Θ ± ^Ο 2Θ; 2) 18.7, 24.9, 25.8 ^Ο 2Θ ± ^Ο 2Θ. Formula (I) of citrate material B was obtained by drying formula (I) of citrate material A in a vacuum oven at about 50 ° C. The XRPD pattern of formula (I) of citrate material B is shown in figure 28. It has the following characteristic peaks: 1) 5.6, 8.6 and 9.1 ^Ο 2Θ ± ^Ο 2Θ; 2) 12.2, 23.2 and 23.9 ^Ο 2Θ ± ^Ο 2Θ; 3) 16.8, 18.5 and 21.1 ^Ο 2Θ ± ^Ο 2Θ. Figure 29 shows the DSC thermogram of formula (I) of citrate material B. There are two thermal events, starting at about 54 and about 122 ° C.

Table 12a: Table of peaks of Formula (I) of material A of citrate | No. | Pos. [° 2Th,] | King. Int. [%] |

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At the. Pos. [° 2Th.] King. Int. [%] 1 5.6 57 2 8.5 9 3 9.1 42 4 9.6 11 5 10.7 10 6 12.2 46 7 12.6 33 8 14.4 3 9 14.9 14 10 15.9 16 11 16.4 13 12 16.7 65 13 17.1 10 14 18.3 28 15 18.7 35 16 19.5 13 17 20.1 23 18 20.3 27 19 21.0 81 20 21.4 30 21 21.6 34 22 22.4 16 23 23.0 100 24 23.7 31 25, 24.9 52 26 25.5 17 27 25.8 37 28 26.4 18 29 26.9 21 30 27.3 17 31 27.9 21 32 28.9 22 33 29.9 18 34 31.3 16 35 31.9 10 36 32.5 11 37 34.4 6 38 34.9 5 39 35.9 6 40 37.2 4 41 38.0 7 42 38.7 9 43 39.3 5

Table 12b: Table of XRPD peaks of Formula (I) of citrate material B

At the. Pos. [° 2Th.] King. Int. [%] 1 5.6 57 2 6.9 6 3 8.6 11 4 9.1 33 5 9.6 25, 6 10.7 8 7 12.2 48 8 12.5 45 9 13.3 7 10 15.0 32 11 16.1 21 12 16.8 48

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At the. Pos. [° 2Th.] King. Int. [%] 13 18.3 57 14 18.5 59 15 20.3 40 16 21.1 76 17 21.6 63 18 23.2 96 19 23.9 100 20 25.1 45 21 26.1 43 22 27.2 31 23 28.2 21 24 28.9 20 25, 29.9 17 26 32.3 2

Preparation of Glutarate Formula (I) [00236] Glutarate Formula (I) was first prepared by stirring together 55.1 mg of formula (I) of free base form II and an equivalent of glutaric acid, approximately 17 mg, in 0.2 ml of acetonitrile for about 16 hours at about 22 ° C.

[00237] Figure 30 is the XRPD standard of formula (I) of glutarate. It contains the following characteristic peaks: 1) 6.7, 8.0 and 12.1 ^Ο 2Θ ± ^Ο 2Θ; 2) 14.6,

20.9 and 21.8 ^Ο 2Θ ± ^Ο 2Θ; 3) 17.9, 19.3 and 26.2 ^Ο 2Θ ± ^Ο 2Θ. Figure 31 is the DSC thermogram of formula (I) of glutarate. The start of fusion is about 150 ° C.

Table 13: Glutarate formula (I) peak table

At the. Pos. [° 2Th.] King. Int. [%] 1 6.7 74 2 8.0 42 3 9.8 3 4 12.1 100 5 12.8 3 6 13.3 3 7 14.6 58 8 14.9 5 9 15.2 11 10 16.0 4 11 16.6 6 12 17.2 4 13 17.9 62 14 18.7 8 15 19.3 57 16 19.7 14 17 20.1 16 18 20.9 65 19 21.8 30 20 22.1 10 21 22.5 15

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At the. Pos. [° 2Th.] King. Int. [%] 22 22.9 6 23 23.9 11 24 24.2 27 25, 24.4 29 26 24.6 52 27 24.7 81 28 24.9 55 29 25.1 44 30 25.7 5 31 26.2 22 32 26.6 8 33 26.8 15 34 27.3 16 35 27.6 14 36 28.4 5 37 28.9 7 38 29.8 13 39 30.1 22 40 30.8 6 41 31.6 10 42 32.4 6 43 33.1 6 44 34.4 5 45 34.8 4 46 35.5 2 47 36.3 13 48 37.0 4 49 37.7 4 50 39.2 5

[00238] Preparation of methanesulfonate form (I) [00239] Methanesulfonate formula (I) was first prepared by adding an equivalent of methanesulfonic acid to 53.5 mg of formula (I) of free-form fluidized base II 0.2 ml of acetone at about 22 ° C. The slurry was centrifuged and the solid was dried in a vacuum oven at about 50 ° C.

[00240] Figure 32 is the XRPD standard of the methanesulfonate formula (I). It contains the following characteristic peaks: 1) 8.4, 19.1 and 21.2 ^Ο 2Θ ± ^Ο 2Θ; 2) 17.2, 19.7 and 20.2 ^Ο 2Θ ± ^Ο 2Θ; 3) 12.8, 21.8 and 25.2 ^Ο 2Θ ± ^Ο 2Θ. Table 14: Peak Table: Form (I) of methanesulfonate

At the. Pos. [° 2Th.] King. Int. [%] 1 6.4 11 2 7.3 7 3 8.4 42 4 10.2 4 5 12.8 23 6 13.3 16 7 13.6 21 8 14.4 19

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At the. Pos. [° 2Th.] King. Int. [%] 9 16.2 18 10 17.2 43 11 18.3 26 12 18.8 34 13 19.1 64 14 19.5 53 15 19.7 57 16 20.2 78 17 21.2 100 18 21.8 49 19 22.6 49 20 23.7 30 21 24.0 42 22 24.3 58 23 25.2 48 24 26.4 38 25, 26.9 28 26 28.0 19 27 28.4 20 28 29.0 20 29 29.5 17 30 34.4 11 31 38.3 10

Example 1: AS-K1 TR-FRET assay for apoptosis signal regulatory kinase) Biochemical IC50) [00241] HTRF detection was used to measure the phosphorylation level of a biotinylated peptide substrate by the ASK1 kinase. This is a time resolved and competitive fluorescence resonance energy transfer immunoassay (TR-FRET) based on Cisbio's HTRF® KinEASE ™ -STK manual. The compound of Formula (I), 1 μΜ of STK3 peptide substrate, 4 nM of ASK1 kinase are incubated with 10 mM MOP buffer, at pH 7.0 containing 10 mM Mg acetate, 0.025% NP-40, DTT 1 mM, 0.05% BS and 1.5% glycerol for about 30 minutes and 100 M ATP were added to initiate the kinase reaction, and it was incubated for 3 h. Peptide antibody labeled with IX Eu3 buffer + cryptate containing 10 mM EDTA and 125 nM streptavidin XL665 was added to stop the reaction and the phosphorylated peptide substrate was detected using the PerkinElmer Multilabeled Envision 2103 reader. Fluorescence was measured at 615 nm (Cryptate) and 665 nm (XL665) and a ratio of 665 nm / 615 nm is calculated for each well. The resulting TR-FRET level a ratio of 665

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79/85 nm / 615 nm) is proportional to the level of phosphorylation. In these test conditions, the degree of phosphorylation of the peptide substrate was linear with time and concentration for the enzyme. The assay system produced consistent results in relation to K _m and specific activities for the enzyme. For the IC50 inhibition experiments), the activities were carried out with constant concentrations of ATP, peptide and various fixed concentrations of inhibitors. Staurosporine, the non-selective kinase inhibitor, was used as a positive control. All enzyme activity data are reported as a quadruplicate determination average. The compound of Formula (I) inhibited ASK1 with an IC 50 of 2.4 nM.

Example 2: ASK1 Whole and Cellular Blood Potency [00242] To further characterize the cellular potency of the compound of Formula (I), the activation of ASK1 induced by auranofin autophosphorylation Thr845) and the downstream activation of p38 and JNK MAP kinases were evaluated in human proximal tubular epithelial cells HK-2 and in neonatal rat ventricular myocytes (NRVMs). In resting cells, ASK1 is bound and repressed by the reduced form of the antioxidant protein thioredoxin. Auranofin agonizes the ASK1 pathway causing oxidation of the thioredoxin, the dissociation of the thioredoxin / ASKl complex and the autophosphorylation and activation of ASK1. Activated ASK1 phosphorylates and activates MAPKKs downstream, including MAPKK3, 4, 6 and 7, which in turn phosphorylate p38 and JNK. This is followed by an increased phosphorylation of the substrates of p38 and JNK ATF2 and c-Jun, respectively; and by enhanced expression of a variety of known ATF2 / cJun / APl target genes including the CXCL1 / KC chemokines. All of these signaling events induced by auranofin are blocked by ASK1 inhibitors, demonstrating that ASK1 drives the chain of signaling events after auranofin stimulation. Using phosphorylated p38 as a substitute marker for ASK1 activity in the serum-free environment, the EC50 of the

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80/85 formula (I) was determined in HK-2 to be 9.2 nM. In NRVMs, the compound of formula (I) inhibited the phosphorylated p38 induced by auranofin with the mean EC50 of 6.4 nM.

[00243] The CXCL1 assay is performed on human whole blood and measures the ability of a test compound to inhibit the production of the cytokine CXCL1 after stimulation of auranofin from the ASK1 pathway. The compound of formula (I) inhibited auranofin-induced CXCL1 production in whole blood with an average EC50 of 80.8 nM.

[00244] In conclusion, the compound of formula (I) inhibits ASK1 activity in multiple cell assays with or without human whole blood in the medium. The compound of formula (I) inhibits endogenous downstream targets of ASK1, such as fos-p38 and the production of CXCL-1.

Example 3: Kd determination

Kinase assays [00245] Kinase-labeled T7 phage strains were prepared in an E. coli host derived from the BL21 strain. E. coli were cultured to the log stage and infected with the T7 phage and incubated with shaking at 32 ° C until lysis. The lysates were centrifuged and filtered to remove cell fragments. The remaining kinases were produced in HEK-293 cells and subsequently labeled with DNA for detection by qPCR. Streptavidin-coated magnetic beads were treated with biotinylated small molecule binders for about 30 minutes at room temperature to generate affinity resins for the kinase assays.

[00246] Beads were blocked with excess biotin and washed with SeaBlock Pierce blocking buffer), 1% bovine serum albumin), 0.05% Tween 20, 1 mM DTT dithiothreitol) to remove unbound ligand and to reduce non-specific binding. Binding reactions were assembled by combining kinases, bound affinity beads and

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81/85 test compounds in 1 x 20% SeaBlock binding buffer, 0.17 x PBS, 0.05% Tween 20, 6 mM DTT). All reactions were performed on 96-well polystyrene plates in a final volume of 0.135 mL. The assay plates were incubated at room temperature with shaking for 1 hour and the affinity beads were washed with washing buffer (1x PBS, 0.05% Tween 20). The beads were then resuspended in 1 x PBS elution buffer, 0.05% Tween 20, 0.5 M non-biotinylated affinity binder) and incubated at room temperature with shaking for about 30 minutes. The kinase concentration in the eluates was measured by qPCR.

[00247] Binding constants (Kds) were calculated using a standard dose-response curve using Hill's equation.

Result [00248] The compound of Formula (I) exhibited a Kj of 0.17 nM. These data suggest that the compound of Formula (I) potentially binds to the ASK1 receptor in the absence of ATP.

Example 4: CYP-mediated metabolism in cryopreserved human microsomes [00249] To study the mechanism of CYP-mediated metabolism, compounds 1 μΜ) were incubated with human liver microsomes in 2, 12, 25, 45 and 65 minutes with the cofactors of NADPH. The samples were collected at various time points and the reactions were stopped by adding 10% MeOH, 90% acetonitrile, 0.1% formic acid and 50 nM internal standard. The concentration of the compound in each sample was analyzed using LC / MS / MS. The disappearance half-life of the compound in the hepatocyte suspension was determined by adjusting the concentration-time data with a monophasic exponential equation. The data has also been expanded to represent intrinsic liver clearance and / or total liver clearance.

[00250] The recognizable metabolism of the compound of formula (I) does not

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82/85 was observed, while considerable loss of the original compound through N-dealkylation was observed for N-6-4-tert-butyl) -4H-1,2,4triazol-3-yl) pyridin-2-yl ) -5-4-cyclopropyl-1 H-imidazol-1-yl) -2-fluoro-4methylbenzamide; 5-4-cyclopropyl-1 H-imidazol-1-yl) -N-6-4-cyclopropylmethyl) 4H-1,2,4-triazol-3-yl) pyridin-2-yl) -2-fluoro-4 -methylbenzamide; and N-6-4-benzyl4H-1,2,4-triazol-3-yl) pyridin-2-yl) -5-4-cyclopropyl-1 H-imidazol-1-yl) -2-fluoro4-methylbenzamide.

Example 5: Pharmacokinetics of Formula (I) in a cynomologist monkey Cynomologist monkeys [00251] The compound of formula (I) was formulated in 5% dextrose at 0.50 mg / ml for IV infusion. Each dosing group consisted of 3 male cynomologist monkeys. At the time of dosing, the animals weighed ~ 4.4 kg. The animals were fasted overnight before administration of the dose and up to 4 hours after dosing. For the IV infusion group, the test article was administered by intravenous infusion over 30 min. The infusion rate was adjusted according to the body weight of each animal to administer a dose of 1 mg / kg. Serial venous blood samples were collected approximately 0.3 ml each) at specified time points after dosing each animal (see Appendix I for time points). Blood samples were collected in Vacutainer ™ tubes containing EDTA-K2 as an anticoagulant and were immediately placed under centrifugation on wet ice to obtain plasma. An LC / MS / MS method was used to measure the concentration of the compound of formula (I) in plasma. The terminal ti / ₂ was ~ 9.8 and the average residence time (MRT) was ~ 9.4 h. The ti / ₂ terminal for 5-4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-N-6-4isopropyl-4H-1,2,4-triazol-3-yl) pyridin-2-yl ) -4-methylbenzamide is ~ 3.16 h.

Example 6: Kinetic Solubility Studies [00252] The required amount of solid compound of formula (I) free base or salt form) was added to a reaction vessel equipped

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83/85 with a stir bar. The buffer solution was then added to the stirring vessel and the reaction timer was started. Samples of the solution were collected at different time points (5, 10, 20, 30, 60 and 120 minutes) and filtered through an acrodisc GHP 0.45 um filter). The resulting filtrate was diluted 1: 1 with 65/35 v / v diluent H ₂ O 0.1% TFA / ACN and the amount of the compound of Formula (I) was quantified by UPLC compared to a reference standard. After 20 hours of stirring, a final sample was taken to analyze the equilibrium concentration of each salt form. The remaining solids from the reaction vessel were collected and analyzed by X-ray powder diffraction to determine the final solid form.

[00253] The data in figure 34 and figure 35 show that the salts of the compound of formula (I) improved the kinetic solubility over in relation to the free base.

Example 7: Stability Studies [00254] Crystalline batches were prepared from three salts of formula (I) form I of succinate, form I of HCl and form I of malate) and each was placed in a stability chamber at 40 ° C / 75% RH for one month in an open container. After one month, the samples were tested for appearance, assay and impurities by HPLC, water content and XRPD x-ray powder diffraction) Table 15). Form I of HCl was chemically and physically stable, but it absorbed a lot of water. The malate salt was less stable and dissociated back into the free base after one month of storage at 40 ° C / 75% RH. Form I succinate was physically and chemically stable under open conditions and was not hygroscopic.

Table 15.

test Succinate form I HC1 Form I Malate Initial 1 month Initial 1 month Initial 1 month Appearance White powder Off-white powder 0 Off-white powder 0 Off-white powder White powder Off-white sticky powder) Test 100.6 100.3 96.4 98.0 100.4 102.1 Water 0.0 0.1 2.7 3.8 1.3 5.8

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test Succinate form I HC1 Form I Malate Initial 1 month Initial 1 month Initial 1 month Total impurities * 0.05 0.06 0.05 0.06 0.12 0.22 RRT 0.55 ND ND 0.03 0.04 ND 0.06 RRT 0.67 ND ND 0.03 0.03 ND ND RRT 0.79 ND ND ND ND ND 0.10 RRT 0.82 ND ND ND ND 0.03 ND RRT 0.85 ND ND 0.03 0.03 ND ND RRT 0.97 0.05 0.06 0.05 0.06 0.06 0.06 RRT 0.98 0.04 0.04 0.04 0.03 0.04 0.03 RRT 1.21 ND ND ND ND 0.06 ND XRPD Crystalline No changes to the XRD in relation to initial Crystalline No change in XRD in relation to the initial Crystalline Free base form II * Includes individual impurities> 0.05%

[00255] The crystalline form I was also stable under mechanical stress. The crystal has the morphology of the plate and, therefore, presents less risk of fluidity compared to the needles. The powder was then milled for one minute and five minutes with a mortar and pestle, and was analyzed by XRPD X-ray powder diffraction. Compression was performed at 2000 psi on a Carver press. The morphology was then distinguished by optical microscopy (Table 16).

Table 16.

API MP (° C) Physical stability, grinding, compression) Morphology Formula (I) of succinate form I 159 No changes to the XRPD standard Plate type Formula (I) of HCl form I 136 No changes to the XRPD standard Needles

Example 8: Drug interaction [00256] The following data shows that the salts of formula (I) reduce the acid suppressive effect that is observed with the free base. Table 17 compares formula (I) formulated as a free base, form Π, in a tablet, and the salts of formula (I) formulated as a powder in a PIC capsule) in a 1: 2 ratio of formula (I ): PGS pregelatinized starch). The tablets were administered at a fixed dose of 6 mg to male dogs pretreated with pentagastrin or famotidine. The free base formula (I)

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85/85 shows a ~ 12x decrease in plasma exposure when dosed in dogs pretreated with famotidine, suggesting that the free base of formula (I) will have a significant drug interaction when used to treat patients using acid suppressing agents, like famotidine or omeprazole. However, the salts of formula (I) counteract this effect and show a ~ 2x difference between pretagastrin and famotidine pretreatment.

Table 17.

API Formulation Dose AUCiast nM «h) Pentagastrina Famotidine Reason Formula (I) Π free base shape API tablet 6 mg 8437 ± 2658 700 ± 175 12 Formula (I) of succinate form I API: PGS 1: 2) PIC 6 mg 7250 ± 859 3050 ± 1100 2.4 Formula (I) of HCl form I API: PGS 1: 2) PIC 6 mg AT 2840 ± 1530 2.6 Malate Formula (I) API: PGS 1: 2) PIC 6 mg AT 3760 ± 1620 1.9

Petition 870180029644, of 12/04/2018, p. 91/138

Claims (59)

1. Compound, characterized by the fact that it is of Formula (I): f (I) or a pharmaceutically acceptable salt thereof, cocrystal, solvate, or hydrate thereof. 2. Compound according to claim 1, characterized by the fact that the compound is a free base. 3. A compound according to claim 1, characterized by the fact that the compound is a salt selected from succinate, hydrochloric acid, phosphate, malate, sulfate, citrate, glutarate, and methane sulfonate. 4. Compound, the compound characterized by the fact that it is (S) -5 (4-cyclopropyl-1 H-imidazol-1-yl) -2-fluoro-N- (6- (4- (1-fluoropropan-2- il) -4H- Amorphous 1,2,4-triazol-3-yl) pyridin-2-yl) -4-methylbenzamide. 5. Crystalline I form of a compound, characterized by the fact that the compound is (S) -5- (4-cyclopropyl-1 H-imidazol-1-yl) -2-fluoro-N- (6- (4 ( 1-fluoropropan-2-yl) -4H-1,2,4-triazol-3-yl) pyridin-2-yl) -4-methylbenzamide. 6. Crystalline form I according to claim 5, characterized by the fact that the compound is distinguished by an X-ray powder diffractogram having peaks at 8.7, 10.2, and 18.1 ^Ο 2θ ± 0, 2 ° 2θ. Crystalline form I according to claim 5 or 6, characterized in that (S) -5- (4-cyclopropyl-1H-imidazol-l-yl) -2fluoro-N- (6- (4 - (1-fluoropropan-2-yl) -4H-1,2,4-triazol-3-i 1) pyridin-2-i 1) -4methylbenzamide is distinguished by a powder X-ray diffractogram having peaks at 15 , 8, 17.3, and 23.5 ^Ο 2θ ± 0.2 ° 2Θ. Crystalline form I according to any one of claims 5 to 7, characterized by the fact that (S) -5- (4-cyclopropyl-1HPtion 870180019765, dated 12/03/2018, page 213/259 2/11 imidazol-1-yl) -2-fluoro-N- (6- (4- (1-fluoropropan-2-yl) -4H-1,2,4-triazol-3yl) pyridin-2-yl) -4-methylbenzamide is distinguished by an X-ray powder diffractogram having peaks at 15.2, 18.5, and 24.9 ^Ο 2θ ± 0.2 ° 2θ. Crystalline form I of a compound according to any one of claims 5 to 8, characterized in that the (S) -5- (4cyclopropyl-1 H-imidazol-1-yl) -2-fluoro-N - (6- (4- (1-fluoropropan-2-yl) -4H- 1,2,4-triazol-3-yl) pyridin-2-yl) -4-methylbenzamide is distinguished by an X-ray diffractogram of powder which is substantially as shown in FIG. 1. Crystalline form I of a compound according to any one of claims 5 to 9, characterized in that the (S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro- N- (6- (4- (l-fluoropropan-2yl) -4H-1,2,4-triazol-3-yl) pyridin-2-yl) -4-methylbenzamide is distinguished by a differential scanning calorimetry curve (DSC) substantially as shown in FIG. 2. 11. Crystalline form II of a compound, characterized by the fact that the compound is (S) -5- (4-cyclopropyl-1H-imidazol-l-yl) -2-fluoro-N (6- (4- (1 -fluoropropan-2-yl) -4H-1,2,4-triazol-3-yl) pyridin-2-yl) -4methylbenzamide. Crystalline form II according to claim 11, characterized in that (S) -5- (4-cyclopropyl-1H-imidazol-l-yl) -2fluoro-N- (6- (4- (1 -fluoropropan-2-yl) -4H-1,2,4-triazol-3-yl) pyridin-2-yl) -4methylbenzamide is distinguished by a powder X-ray diffractogram having peaks at 8.7, 10, 0, and 17.0 ^Ο 2θ ± 0.2 ° 2θ. Crystalline form II according to claim 11 or 12, characterized in that (S) -5- (4-cyclopropyl-1H-imidazol-l-yl) -2fluoro-N- (6- (4- (1-fluoropropan-2-yl) -4H-1,2,4-triazol-3-yl) pyridin-2-yl) -4methylbenzamide is distinguished by an X-ray powder diffractogram having peaks at 13.9, 21.3, and 22.8 ^Ο 2θ ± 0.2 ° 2θ. Petition 870180019765, of 12/03/2018, p. 214/259 3/11 Crystalline form II according to any of claims 11 to 13, characterized in that the (S) -5- (4-cyclopropillH-imidazol-1-yl) -2-fluoro-N- (6- ( 4- (l-fluoropropan-2-yl) -4H-1,2,4-triazol-3yl) pyridin-2-yl) -4-methylbenzamide is distinguished by an X-ray powder diffractogram having peaks at 24.0, 28.0, and 29.1 ° 20 ± 0.2 ° 20. Christian form II according to any one of claims 11 to 14, characterized in that (S) -5- (4-cyclopropillH-imidazol-1-yl) -2-fluoro-N- (6- ( 4- (1-fluoropropan-2-yl) -4H-1,2,4-triazol-3yl) pyridin-2-yl) -4-methylbenzamide is distinguished by a powder X-ray diffractogram substantially as shown in FIG. 4. Christian form II according to any one of claims 11 to 15, characterized in that (S) -5- (4-cyclopropillH-imidazol-1-yl) -2-fluoro-N- (6- ( 4- (l-fluoropropan-2-yl) -4H-1,2,4-triazol-3yl) pyridin-2-yl) -4-methylbenzamide is distinguished by a differential scanning calorimetry (DSC) curve substantially as shown in FIG. 5. 17. Christian form I of a compound, characterized by the fact that the compound is (S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-N- (6- (4 (1 -fluoropropan-2-yl) -4H-1,2,4-triazol-3-yl) pyridin-2-yl) -4-methylbenzamide succinate. Crystalline form I of succinate according to claim 17, characterized in that the succinate of (S) -5- (4cyclopropyl-1 H-imidazol-1 -yl) -2-fluoro-N- (6- (4- (1-fluoropropan-2-yl) -4H- 1,2,4-triazol-3-yl) pyridin-2-yl) -4-methylbenzamide is distinguished by an X-ray powder diffractogram having peaks in 7.5, 20.9, and 24.9 ^Ο 2θ ± 0.2 ° 2θ. Crystalline form I of succinate according to claim 17 or 18, characterized in that the (S) -5- (4cyclopropyl-1 H-imidazol-1-yl) -2-fluoro-N- ( 6- (4- (1-fluoropropan-2-yl) -4H- 1,2,4-triazol-3-yl) pyridin-2-yl) -4-methylbenzamide is distinguished by a powder X-ray diffractogram having peaks at 15.4, 22.4, and 31.1 ^Ο 2θ ± 0.2 ° 2θ. Petition 870180019765, of 12/03/2018, p. 215/259 4/11 Crystalline form I of succinate according to any one of claims 17 to 19, characterized in that the succinate of (S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro- N- (6- (4- (1-fluoropropan-2yl) -4H-1,2,4-triazol-3-yl) pyridin-2-yl) -4-methylbenzamide is distinguished by an X-ray diffractogram of powder having peaks at 14.9, 23.2, and 25.4 ^Ο 2θ ± 0.2 ° 2θ. 21. The crystalline form I of succinate according to any one of claims 17 to 20, characterized in that the succinate of (S) -5- (4-cyclopropyl-1H-imidazol-l-yl) -2-fluoro- N- (6- (4- (1-fluoropropan-2yl) -4H-1,2,4-triazol-3-yl) pyridin-2-yl) -4-methylbenzamide is distinguished by an X-ray diffractogram of powder substantially as shown in FIG. 7. 22. Crystalline form I of succinate according to any one of claims 17 to 21, characterized in that the succinate of (S) -5- (4-cyclopropyl-1H-imidazol-l-yl) -2-fluoro- N- (6- (4- (l-fluoropropan-2yl) -4H-1,2,4-triazol-3-yl) pyridin-2-yl) -4-methylbenzamide is distinguished by a differential scanning calorimetry curve (DSC) substantially as shown in FIG. 8. 23. Crystalline form II of a compound, the compound characterized by the fact that it is (S) -5- (4-cyclopropyl-1Himidazol-1-yl) -2-fluoro-N- (6- (4- ( 1-fluoropropan-2-yl) -4H-1,2,4-triazol-3yl) pyridin-2-yl) -4-methylbenzamide. 24. Crystalline form II of succinate according to claim 23, characterized in that the succinate of (S) -5- (4cyclopropyl-1 H-imidazol-1-yl) -2-fluoro-N- (6- (4- (1-fluoropropan-2-yl) -4H- 1,2,4-triazol-3-yl) pyridin-2-yl) -4-methylbenzamide is distinguished by an X-ray powder diffractogram having peaks in 9.8, 11.7, and 23.3 ^Ο 2θ ± 0.2 ° 2θ. 25. Crystalline form II of succinate according to claim 23 or 24, characterized in that the (S) -5- (4cyclopropyl-1 H-imidazol-1-yl) -2-fluoro-N- ( 6- (4- (1-fluoropropan-2-yl) -4H- 1,2,4-triazol-3-yl) pyridin-2-yl) -4-methylbenzamide is distinguished by a Petition 870180019765, of 12/03/2018, p. 216/259 5/11 X-ray powder diffractogram having peaks at 15.9, 21.5, and 32.0 ^Ο 2θ ± 0.2 ° 2θ. 26. Crystalline form II of succinate according to any one of claims 23 to 25, characterized in that the succinate of (S) -5- (4-cyclopropyl-1H-imidazol-l-yl) -2-fluoro- N- (6- (4- (1-fluoropropan-2yl) -4H-1,2,4-triazol-3-yl) pyridin-2-yl) -4-methylbenzamide is distinguished by an X-ray diffractogram of powder having peaks at 16.3, 20.8, and 24.8 ^Ο 2θ ± 0.2 ° 2θ. 27. Crystalline form II of succinate according to any one of claims 23 to 26, characterized in that the (S) -5- (4-cyclopropyl-1H-imidazol-l-yl) -2-fluoro- N- (6- (4- (1-fluoropropan-2yl) -4H-1,2,4-triazol-3-yl) pyridin-2-yl) -4-methylbenzamide is distinguished by an X-ray diffractogram of powder substantially as shown in FIG. 10. 28. Crystalline form of succinate according to any one of claims 23 to 27, characterized in that the (S) -5- (4-cyclopropyl-1H-imidazol-l-yl) -2-fluoro- N- (6- (4- (l-fluoropropan-2yl) -4H-1,2,4-triazol-3-yl) pyridin-2-yl) -4-methylbenzamide is distinguished by a differential scanning calorimetry curve (DSC) substantially as shown in FIG. 11. 29. Crystalline form I of a compound, characterized by the fact that the compound is (S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoroN- (6- (4- ( 1-fluoropropan-2-yl) -4H-1,2,4-triazol-3-yl) pyridin-2-yl) -4methylbenzamide. 30. Crystalline form I of HCl according to claim 29, characterized in that the HCl of (S) -5- (4-cyclopropyl-1H-imidazol1 -yl) -2-fluoro-N- (6- ( 4- (1-fluoropropan-2-yl) -4H-1,2,4-triazol-3-yl) pyridin-2-yl) 4-methylbenzamide is distinguished by an X-ray powder diffractogram having peaks at 9 , 3, 21.2, and 26.2 ^Ο 2θ ± 0.2 ° 2θ. 31. Crystalline form I of HCl according to claim 29 or 30, characterized in that the HCl of (S) -5- (4-cyclopropyl-1Himidazol-1-yl) -2-fluoro-N- (6 - (4- (1-fluoropropan-2-yl) -4H-1,2,4-triazole-3 Petition 870180019765, of 12/03/2018, p. 217/259 6/11 il) pyridin-2-yl) -4-methylbenzamide is distinguished by an X-ray powder diffractogram having peaks at 20.9, 24.7, and 27.6 ° 20 ± 0.2 ° 20. 32. Crystalline form I of HCl according to any one of claims 29 to 31, characterized in that the HCl of (S) -5- (4cyclopropyl-1 H-imidazol-1-yl) -2-fluoro-N - (6- (4- (1-fluoropropan-2-yl) -4H- 1,2,4-triazol-3-yl) pyridin-2-yl) -4-methylbenzamide is distinguished by an X-ray diffractogram of dust having peaks at 23.8, 24.3, and 26.6 ° 20 ± 0.2 ° 20. 33. Crystalline form I of HCl according to any one of claims 29 to 32, characterized in that the HCl of (S) -5- (4cyclopropyl-1 H-imidazol-1-yl) -2-fluoro-N - (6- (4- (1-fluoropropan-2-yl) -4H- 1,2,4-triazol-3-yl) pyridin-2-yl) -4-methylbenzamide is distinguished by an X-ray diffractogram of powder substantially as shown in FIG. 13. 34. Crystalline form I of HCl according to any one of claims 29 to 33, characterized in that the HCl of (S) -5- (4cyclopropyl-1 H-imidazol-1-yl) -2-fluoro-N - (6- (4- (1-fluoropropan-2-yl) -4H- 1,2,4-triazol-3-yl) pyridin-2-yl) -4-methylbenzamide is distinguished by a scanning calorimetry curve differential (DSC) substantially as shown in FIG. 14. 35. Crystalline form II of a compound, characterized by the fact that the compound is (S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2fluoro-N- (6- (4- ( 1-fluoropropan-2-yl) -4H-1,2,4-triazol-3-yl) pyridin-2-yl) -4methylbenzamide. 36. Crystalline form II of HCl according to claim 35, characterized in that the HCl of (S) -5- (4-cyclopropyl-1H-imidazol1 -yl) -2-fluoro-N- (6- ( 4- (1-fluoropropan-2-yl) -4H-1,2,4-triazol-3-yl) pyridin-2-yl) 4-methylbenzamide is distinguished by an X-ray powder diffractogram having peaks at 8 , 3, 12.0, and 26.0 ^Ο 2θ ± 0.2 ° 2θ. 37. Crystalline form II of HCl according to claim 35 or 36, characterized in that the HCl of (S) -5- (4-cyclopropyl-1H Petition 870180019765, of 12/03/2018, p. 218/259 7/11 imidazol-1-yl) -2-fluoro-N- (6- (4- (1-fluoropropan-2-yl) -4H-1,2,4-triazol-3yl) pyridin-2-yl) -4-methylbenzamide is distinguished by an X-ray powder diffractogram having peaks at 19.3, 21.7, and 24.0 ^Ο 2θ ± 0.2 ° 2θ. 38. Crystalline form II of HCl according to any one of claims 35 to 37, characterized in that the HCl of (S) -5- (4cyclopropyl-1 H-imidazol-1-yl) -2-fluoro-N - (6- (4- (1-fluoropropan-2-yl) -4H- 1,2,4-triazol-3-yl) pyridin-2-yl) -4-methylbenzamide is distinguished by an X-ray diffractogram of dust having peaks at 9.8, 15.4, and 28.9 ^Ο 2θ ± 0.2 ° 2θ. 39. Crystalline form II of HCl according to any one of claims 35 to 38, characterized in that the HCl of (S) -5- (4cyclopropyl-1 H-imidazol-1-yl) -2-fluoro-N - (6- (4- (1-fluoropropan-2-yl) -4H- 1,2,4-triazol-3-yl) pyridin-2-yl) -4-methylbenzamide is distinguished by an X-ray diffractogram of powder substantially as shown in FIG. 16. 40. Crystalline form II of HCl according to any one of claims 35 to 39, characterized in that the HCl of (S) -5- (4cyclopropyl-1 H-imidazol-1-yl) -2-fluoro-N - (6- (4- (1-fluoropropan-2-yl) -4H- 1,2,4-triazol-3-yl) pyridin-2-yl) -4-methylbenzamide is distinguished by a scanning calorimetry curve differential (DSC) substantially as shown in FIG. 33. 41. Crystalline form III of a compound, characterized by the fact that the compound is (S) -5- (4-cyclopropyl-1H-imidazol-l-yl) -2fluoro-N- (6- (4- ( 1-fluoropropan-2-yl) -4H-1,2,4-triazol-3-yl) pyridin-2-yl) -4methylbenzamide. 42. HCl crystalline form III according to claim 41, characterized in that the HCl of (S) -5- (4-cyclopropyl-1H-imidazol1 -yl) -2-fluoro-N- (6- ( 4- (1-fluoropropan-2-yl) -4H-1,2,4-triazol-3-yl) pyridin-2-yl) 4-methylbenzamide is distinguished by an X-ray powder diffractogram having peaks at 6 , 6, 12.9, and 19.7 ^Ο 2θ ± 0.2 ° 2θ. 43. Crystalline form III of HCl according to claim Petition 870180019765, of 12/03/2018, p. 219/259 11/11 41 or 42, characterized by the fact that (S) -5- (4-cyclopropyl-1Himidazol-1-yl) -2-fluoro-N- (6- (4- (1-fluoropropan-2-yl) HCl ) -4H-1,2,4-triazol-3yl) pyridin-2-yl) -4-methylbenzamide is distinguished by an X-ray powder diffractogram having peaks at 20.4, 23.4, and 24.8 ° 20 ± 0.2 ° 20. 44. Crystalline form III of HCl according to any one of claims 41 to 43, characterized in that the HCl of (S) -5- (4cyclopropyl-1 H-imidazol-1-yl) -2-fluoro-N - (6- (4- (1-fluoropropan-2-yl) -4H- 1,2,4-triazol-3-yl) pyridin-2-yl) -4-methylbenzamide is distinguished by an X-ray diffractogram of dust having peaks at 18.1, 25.4, and 26.7 ° 20 ± 0.2 ° 20. 45. Crystalline form III of HCl according to any one of claims 41 to 44, characterized in that the HCl of (S) -5- (4cyclopropyl-1 H-imidazol-1-yl) -2-fluoro-N - (6- (4- (1-fluoropropan-2-yl) -4H- 1,2,4-triazol-3-yl) pyridin-2-yl) -4-methylbenzamide is distinguished by an X-ray diffractogram of powder substantially as shown in FIG. 17. 46. Crystalline form III of HCl according to any one of claims 41 to 45, characterized in that the HCl of (S) -5- (4cyclopropyl-1 H-imidazol-1-yl) -2-fluoro-N - (6- (4- (1-fluoropropan-2-yl) -4H- 1,2,4-triazol-3-yl) pyridin-2-yl) -4-methylbenzamide is distinguished by a scanning calorimetry curve differential (DSC) substantially as shown in FIG. 18. 47. Pharmaceutical composition, characterized by the fact that it comprises a therapeutically effective amount of (S) -5- (4-cyclopropillH-imidazol-1-yl) -2-fluoro-N- (6- (4- (l-fluoropropan -2-yl) -4H-1,2,4-triazol-3yl) pyridin-2-yl) -4-methylbenzamide as defined in any one of claims 1 to 45 and a pharmaceutically acceptable excipient. 48. Pharmaceutical composition according to claim 47, characterized by the fact that it additionally comprises one, two, or three additional therapeutic agents. 49. Pharmaceutical composition according to claim Petition 870180019765, of 12/03/2018, p. 220/259 9/11 48, characterized by the fact that the pharmaceutical composition comprises an additional therapeutic agent which is an FXR agonist. 50. Pharmaceutical composition according to claim 49, characterized by the fact that the FXR agonist is a compound of Formula (III): (III), or a pharmaceutical, cocrystalline, solvate, or hydrate salt thereof. 51. Pharmaceutical composition according to claim 49, characterized by the fact that the FXR agonist is a compound of Formula (IV): (IV), or a pharmaceutically acceptable salt thereof, cocrystal, solvate, or hydrate thereof. 52. Pharmaceutical composition according to the claim 49, characterized by the fact that the pharmaceutical composition comprises an additional therapeutic agent that is an ACC inhibitor. 53. Composition according to claim 52, characterized in that the ACC inhibitor is a compound of Formula (V): Petition 870180019765, of 12/03/2018, p. 221/259 10/11 (V), or a pharmaceutically acceptable salt thereof, cocrystal, solvate, or hydrate thereof. 54. Method for inhibiting ASK1, characterized in that it is with a compound or pharmaceutical composition as defined (a) in any one of claims 1 to 53. 55. Method for treating an ASK1-mediated condition, characterized in that it comprises administering a compound or pharmaceutical composition as defined (a) in any of claims 1 to 53 to a patient in need thereof. 56. Method for treating a condition, the condition being selected from non-alcoholic steatohepatitis, alcoholic hepatitis, pulmonary arterial hypertension, heart failure with preserved ejection fraction, and diabetic kidney disease, the method being characterized by the fact that it comprises administering a therapeutically effective amount of a compound or pharmaceutical composition as defined (a) in any one of claims 1 to 53 to a patient in need thereof. 57. Method for treating a condition, the condition being non-alcoholic steatohepatitis, characterized by the fact that it comprises administering therapeutically effective amounts of a compound or pharmaceutical composition as defined (a) in any of claims 1 to 53 to a patient in need for it. 58. Method for treating a condition, the condition being fibrosis, characterized by the fact that it comprises administering quantities Petition 870180019765, of 12/03/2018, p. 222/259 11/11 a therapeutically effective compound or composition as defined (a) in any one of claims 1 to 53 to a patient in need thereof. 59. A compound according to claim 1, the compound being characterized by the fact that it is of Formula (Ia): (Ia).