Salts and solid forms of compounds that regulate IRAK4

Abstract

This disclosure relates to salts and solid forms of compounds that are inhibitors of the kinase IRAK4, and their use as therapeutic agents for treating diseases, disorders, or conditions regulated by IRAK4, such as inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), psoriasis, or rheumatoid arthritis. Salts and solid forms of compounds useful as IRAK4 inhibitors are provided herein. Also disclosed herein are pharmaceutical compositions comprising salts and solid forms of compound I, and methods of using them in the treatment of diseases, disorders, or conditions regulated by IRAK4.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application asserts the interests under Section 119(e) of U.S. Provisional Application No. 63 / 511,597, filed on 30 June 2023, which is incorporated herein by reference in its entirety.

[0002] This disclosure relates, in general, to salts and solid forms of compounds that are inhibitors of the kinase IRAK4. This disclosure also relates to pharmaceutical compositions comprising such salts and solid forms, and methods of using them. [Background technology]

[0003] Interleukin-1 receptor-associated kinase-4 (IRAK4) is a serine-threonine kinase that acts as a mediator in the interleukin-1 / Toll-like receptor (IL-1 / TLR) signaling cascade. More specifically, IRAK4 is involved in the activation of the adapter protein myeloid differentiation primary response gene 88 (MyD88) signaling cascade and is hypothesized to play a role in inflammatory and fibrotic disorders such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), gout, Lyme disease, arthritis, psoriasis, pelvic inflammatory disease, systemic lupus erythematosus (SLE), Sjögren's syndrome, viral myocarditis, acute and chronic tissue injury, non-alcoholic steatohepatitis (NASH), alcoholic hepatitis, and renal diseases including chronic kidney disease and diabetic nephropathy. Furthermore, IRAK4 is hypothesized to play a role in certain cancers and in inflammation associated with gastrointestinal infections, including Clostridioides difficile (C. difficile). IL-1R / TLR-mediated signaling activates MyD88, recruiting IRAK4 and IRAK1 to form a signaling complex. This complex then interacts with a series of kinases, adapter proteins, and ligases, ultimately activating nuclear factor-κ light chain enhancer (NF-κB), activator protein-1 (API), cyclic AMP response element-binding protein (CREB), and interferon regulators (IRFs), including IRF5 and IRF7, in activated B cells, inducing the production of pro-inflammatory cytokines and type I interferons.

[0004] Therefore, IRAK4 inhibitors may be useful in treating inflammatory and fibrotic disorders such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), gout, Lyme disease, arthritis, psoriasis, pelvic inflammatory disease, systemic lupus erythematosus (SLE), Sjögren's syndrome, inflammation associated with gastrointestinal infections including Clostridioides difficile, viral myocarditis, acute and chronic tissue injury, non-alcoholic steatohepatitis (NASH), alcoholic hepatitis, and renal diseases including chronic kidney disease and diabetic nephropathy. [Overview of the project] **Means for Solving the Problems**

[0005] Salts and solid forms of compounds useful as inhibitors of IRAK4 are provided herein. Also disclosed herein are pharmaceutical compositions comprising salts and solid forms of Compound I, and methods of using them in the treatment of diseases, disorders, or conditions modulated by IRAK4.

[0006] Some embodiments are crystalline forms of Compound I: **[Chemical Formula]** (Compound I Form I), which provides a crystalline form characterized by an X-ray powder diffraction pattern comprising peaks (±0.2°) at 7.5, 12.3, and 7.2° 2θ measured with a diffractometer using Cu-Kα radiation.

[0007] s Some embodiments are crystalline forms of Compound I (Compound I Form II), which provides a crystalline form characterized by an X-ray powder diffraction pattern comprising peaks (±0.2°) at 7.5, 14.6, and 17.8° 2θ measured with a diffractometer using Cu-Kα radiation.

[0008] Some embodiments are crystalline forms of Compound I (Compound I Form IV), which provides a crystalline form characterized by an X-ray powder diffraction pattern comprising peaks (±0.2°) at 10.1, 10.7, and 17.9° 2θ measured with a diffractometer using Cu-Kα radiation.

[0009] Some embodiments are crystalline forms of Compound I (Compound I Form V), which is a monohydrate and provides a crystalline form characterized by an X-ray powder diffraction pattern comprising peaks (±0.2°) at 11.8, 25.9, and 20.7° 2θ measured with a diffractometer using Cu-Kα radiation.

[0010] Some embodiments provide a crystalline form of Compound I (Compound I Form VI), which is a monohydrate and is characterized by an X-ray powder diffraction pattern comprising peaks (±0.2°) at 4.9, 5.6, and 7.4° 2θ measured with a diffractometer using Cu-Kα radiation.

[0011] Some embodiments provide a crystalline form of the monocitrate of Compound I (Compound I Monocitrate Form I), which is characterized by an X-ray powder diffraction pattern comprising peaks (±0.2°) at 5.7, 7.0, and 22.7° 2θ measured with a diffractometer using Cu-Kα radiation.

[0012] Some embodiments provide a crystalline form of Compound I (Compound I Form III), which is characterized by an X-ray powder diffraction pattern comprising peaks (±0.2°) at 21.2, 12.3, and 10.7° 2θ measured with a diffractometer using Cu-Kα radiation; or a crystalline form of Compound I (Compound I Form VII), which is a water:tetrahydrofuran (THF) solvate and is characterized by an X-ray powder diffraction pattern comprising peaks (±0.2°) at 4.0, 25.8, and 6.9° 2θ measured with a diffractometer using Cu-Kα radiation; or a crystalline form of Compound I (Compound I Form VIII), which is a water:acetonitrile (ACN) solvate and is characterized by an X-ray powder diffraction pattern comprising peaks (±0.2°) at 8.0, 25.8, and 6.1° 2θ measured with a diffractometer using Cu-Kα radiation; or a crystalline form of Compound I (Compound I Form IX), which is a water:2-methyltetrahydrofuran (Me-THF) solvate and is characterized by an X-ray powder diffraction pattern comprising peaks (±0.2°) at 9.4, 4.5, and 18.3° 2θ measured with a diffractometer using Cu-Kα radiation; or a crystalline form of Compound I (Compound I Form X), which is an isopropyl alcohol (IPA) solvate and is characterized by an X-ray powder diffraction pattern comprising peaks (±0.2°) at 4.0, 7.0, and 8.2° 2θ measured with a diffractometer using Cu-Kα radiation; or A crystalline form of compound I (compound I form XI), which is a methyl isobutyl ketone (MIBK) solvate, characterized by an X-ray powder diffraction pattern containing peaks (±0.2°) at 4.0, 6.9, and 14.5°²θ as measured with a Cu-Kα diffractometer; or A crystalline form of compound I (compound I form XII) characterized by an X-ray powder diffraction pattern that includes peaks (±0.2°) at 7.7, 11.7, and 26.1°²θ measured with a Cu-Kα diffractometer; or A crystalline form of compound I (compound I form XIII) characterized by an X-ray powder diffraction pattern that includes peaks (±0.2°) at 7.6, 14.6, and 17.9°²θ measured with a Cu-Kα diffractometer; or A crystalline form of compound I (compound I monocitrate form II), which is a monocitrate, characterized by an X-ray powder diffraction pattern showing peaks (±0.2°) at 5.6, 7.0, and 24.2°²θ as measured with a Cu-Kα diffractometer; or A crystalline form of compound I (compound I monocitrate form III), which is a monocitrate, and is characterized by an X-ray powder diffraction pattern that includes peaks (±0.2°) at 6.3, 18.8, and 7.7°²θ as measured with a Cu-Kα diffractometer; or A crystalline form of compound I (compound I monocitrate form IV), which is a monocitrate and is characterized by an X-ray powder diffraction pattern that includes peaks (±0.2°) at 26.8, 25.7, and 25.1°²θ as measured with a Cu-Kα diffractometer; or A crystalline form of compound I (compound I hemicitrate form I), which is a hemicitrate and is characterized by an X-ray powder diffraction pattern measured with a Cu-Kα diffractometer, which includes peaks at 6.1, 7.4, and 17.1°²θ (±0.2°); or A crystalline form of compound I (compound I monoHCl form I), which is a monohydrochloric acid (HCl) salt, characterized by an X-ray powder diffraction pattern containing peaks (±0.2°) at 6.9, 20.7, and 16.9°²θ as measured with a Cu-Kα diffractometer; or A crystalline form of compound I (compound I monomaleate form I), which is a monomaleate, and is characterized by an X-ray powder diffraction pattern that includes peaks (±0.2°) at 7.4, 6.1, and 23.2°2θ measured with a Cu-Kα diffractometer; or A crystalline form of compound I (compound I hemi-fumarate form I), which is a hemi-fumarate, and is characterized by an X-ray powder diffraction pattern that includes peaks (±0.2°) at 7.7, 6.8, and 13.0°²θ measured with a Cu-Kα diffractometer; or A crystalline form of compound I (compound I monofumarate form I), which is a monofumarate, and is characterized by an X-ray powder diffraction pattern that includes peaks (±0.2°) at 6.1, 7.8, and 18.7°2θ measured with a Cu-Kα diffractometer; or A crystalline form of compound I (compound I hemi-L-tartrate form I), which is a hemi-L-tartrate, and is characterized by an X-ray powder diffraction pattern that includes peaks (±0.2°) at 8.5, 5.2 and 18.6°2θ measured with a Cu-Kα diffractometer; or A crystalline form of compound I (compound I monoESA form I), which is a monoethanesulfonic acid (ESA) salt, characterized by an X-ray powder diffraction pattern containing peaks (±0.2°) at 6.4, 10.9, and 19.0°²θ as measured with a Cu-Kα diffractometer; or A crystalline form of compound I (compound I hemiglycolate form I), which is a hemiglycolate, and is characterized by an X-ray powder diffraction pattern that includes peaks (±0.2°) at 6.2, 8.0, and 22.9°2θ as measured with a Cu-Kα diffractometer; or A crystalline form of compound I (sulfate form I of compound I), which is a sulfate, and is characterized by an X-ray powder diffraction pattern that includes peaks (±0.2°) at 5.5, 4.9, and 11.1°²θ as measured with a Cu-Kα diffractometer; or A crystalline form of compound I (compound I phosphate form I), which is a phosphate, and is characterized by an X-ray powder diffraction pattern that includes peaks (±0.2°) at 4.8, 9.7, and 16.9°²θ as measured with a Cu-Kα diffractometer; or A crystalline form of compound I (compound I hemiHCl form I), which is a hemihydrochloride (HCl) salt, characterized by an X-ray powder diffraction pattern measured with a Cu-Kα diffractometer, including peaks (±0.2°) at 5.6, 9.2, and 11.2°²θ; or The present invention provides a crystalline form of compound I (compound I cocrystal form I), which is a cocrystal of compound I and 4-(((S)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide, characterized by an X-ray powder diffraction pattern that includes peaks (±0.2°) at 19.1, 10.3, and 9.4°2θ measured with a Cu-Kα diffractometer.

[0013] Several embodiments provide pharmaceutical compositions comprising the crystalline form described herein and a pharmaceutically acceptable carrier. [Brief explanation of the drawing]

[0014] [Figure 1] The X-ray powder diffraction (XRPD) pattern of compound I form I is shown.

[0015] [Figure 2] The differential scanning calorimetry (DSC) curve for compound I form I is shown.

[0016] [Figure 3] The thermogravimetric analysis (TGA) of compound I form I is shown.

[0017] [Figure 4] The X-ray powder diffraction (XRPD) pattern of compound form I II is shown.

[0018] [Figure 5] The differential scanning calorimetry (DSC) curves for compound I and form II are shown.

[0019] [Figure 6] The thermogravimetric analysis (TGA) of compound I form II is shown.

[0020] [Figure 7] The X-ray powder diffraction (XRPD) pattern of compound form I III is shown.

[0021] [Figure 8] The X-ray powder diffraction (XRPD) pattern of compound I form IV is shown.

[0022] [Figure 9] The differential scanning calorimetry (DSC) curves for compound I form IV are shown.

[0023] [Figure 10] The thermogravimetric analysis (TGA) results for compound I form IV are shown.

[0024] [Figure 11] The dynamic water vapor adsorption (DVS) curves for compound form I and form IV are shown.

[0025] [Figure 12] The X-ray powder diffraction (XRPD) pattern of compound form I V is shown.

[0026] [Figure 13] The differential scanning calorimetry (DSC) curve for compound form I V is shown.

[0027] [Figure 14] The thermogravimetric analysis (TGA) of compound form I V is shown.

[0028] [Figure 15] The dynamic water vapor adsorption (DVS) curves for compound form I and form V are shown.

[0029] [Figure 16] The X-ray powder diffraction (XRPD) pattern of compound form I VI is shown.

[0030] [Figure 17] The differential scanning calorimetry (DSC) curve for compound I form VI is shown.

[0031] [Figure 18] The thermogravimetric analysis (TGA) results for compound I form VI are shown.

[0032] [Figure 19] The dynamic water vapor adsorption (DVS) curve for compound form VI is shown.

[0033] [Figure 20] The X-ray powder diffraction (XRPD) pattern of compound form I VII is shown.

[0034] [Figure 21] The differential scanning calorimetry (DSC) curve for compound I form VII is shown.

[0035] [Figure 22] The thermogravimetric analysis (TGA) results for compound I form VII are shown.

[0036] [Figure 23] The dynamic water vapor adsorption (DVS) curve for compound form I VII is shown.

[0037] [Figure 24] The X-ray powder diffraction (XRPD) pattern of compound form I VIII is shown.

[0038] [Figure 25] The differential scanning calorimetry (DSC) curve for compound form I VIII is shown.

[0039] [Figure 26] The thermogravimetric analysis (TGA) results for compound form I, type VIII are shown.

[0040] [Figure 27] The dynamic water vapor adsorption (DVS) curve for compound form I and form VIII is shown.

[0041] [Figure 28] The X-ray powder diffraction (XRPD) pattern of compound form I IX is shown.

[0042] [Figure 29] The differential scanning calorimetry (DSC) curve for compound form I IX is shown.

[0043] [Figure 30] The thermogravimetric analysis (TGA) of compound form I IX is shown.

[0044] [Figure 31] The dynamic water vapor adsorption (DVS) curve for compound form I IX is shown.

[0045] [Figure 32] The X-ray powder diffraction (XRPD) pattern of compound form I X is shown.

[0046] [Figure 33] The differential scanning calorimetry (DSC) curve of compound form I X is shown.

[0047] [Figure 34] The thermogravimetric analysis (TGA) of compound form I X is shown.

[0048] [Figure 35] The X-ray powder diffraction (XRPD) pattern of compound form I XI is shown.

[0049] [Figure 36] The X-ray powder diffraction (XRPD) pattern of compound form I-XII is shown.

[0050] [Figure 37]The X-ray powder diffraction (XRPD) pattern of compound form I-XIII is shown.

[0051] [Figure 38] This shows the X-ray powder diffraction (XRPD) of compound I in its amorphous form.

[0052] [Figure 39] The X-ray powder diffraction (XRPD) pattern of compound I monocitrate form I is shown.

[0053] [Figure 40] The differential scanning calorimetry (DSC) curve for compound I monocitrate form I is shown.

[0054] [Figure 41] The thermogravimetric analysis (TGA) of compound I monocitrate form I is shown.

[0055] [Figure 42] The dynamic water vapor adsorption (DVS) curve for compound I monocitrate form I is shown.

[0056] [Figure 43] The proton nuclear magnetic resonance (1H NMR) of compound I monocitrate form I is shown.

[0057] [Figure 44] The X-ray powder diffraction (XRPD) pattern of compound I monocitrate form II is shown.

[0058] [Figure 45] The X-ray powder diffraction (XRPD) pattern of compound I monocitrate form III is shown.

[0059] [Figure 46] The differential scanning calorimetry (DSC) curve for compound I monocitrate form III is shown.

[0060] [Figure 47]The thermogravimetric analysis (TGA) of compound I monocitrate form III is shown.

[0061] [Figure 48] The dynamic water vapor adsorption (DVS) curve of compound I monocitrate form III is shown.

[0062] [Figure 49] The X-ray powder diffraction (XRPD) pattern of compound I monocitrate form IV is shown.

[0063] [Figure 50] The differential scanning calorimetry (DSC) curve for compound I monocitrate form IV is shown.

[0064] [Figure 51] The thermogravimetric analysis (TGA) of compound I monocitrate form IV is shown.

[0065] [Figure 52] The dynamic water vapor adsorption (DVS) curve for compound I monocitrate form IV is shown.

[0066] [Figure 53] The X-ray powder diffraction (XRPD) pattern of compound I hemicitrate form I is shown.

[0067] [Figure 54] The differential scanning calorimetry (DSC) curve for compound I hemicitrate form I is shown.

[0068] [Figure 55] The thermogravimetric analysis (TGA) of compound I hemicitrate form I is shown.

[0069] [Figure 56] The dynamic water vapor adsorption (DVS) curve for compound I hemicitrate form I is shown.

[0070] [Figure 57]The proton nuclear magnetic resonance (1H NMR) of compound I hemicitrate form I is shown.

[0071] [Figure 58] The X-ray powder diffraction (XRPD) pattern of compound I monoHCl form I is shown.

[0072] [Figure 59] The differential scanning calorimetry (DSC) curve of compound I monoHCl form I is shown.

[0073] [Figure 60] The thermogravimetric analysis (TGA) of compound I monoHCl form I is shown.

[0074] [Figure 61] The dynamic water vapor adsorption (DVS) curve for compound I in monoHCl form I is shown.

[0075] [Figure 62] The X-ray powder diffraction (XRPD) pattern of compound I monomaleate form I is shown.

[0076] [Figure 63] The differential scanning calorimetry (DSC) curve for compound I monomaleate form I is shown.

[0077] [Figure 64] The thermogravimetric analysis (TGA) of compound I monomaleate form I is shown.

[0078] [Figure 65] The dynamic water vapor adsorption (DVS) curve for compound I monomaleate form I is shown.

[0079] [Figure 66] This shows the proton nuclear magnetic resonance (1H NMR) of compound I monomaleate form I.

[0080] [Figure 67]The X-ray powder diffraction (XRPD) pattern of compound I hemi fumarate form I is shown.

[0081] [Figure 68] The differential scanning calorimetry (DSC) curve for compound I hemi-fumarate form I is shown.

[0082] [Figure 69] The thermogravimetric analysis (TGA) of compound I hemi fumarate form I is shown.

[0083] [Figure 70] The dynamic water vapor adsorption (DVS) curve for compound I hemi-fumarate form I is shown.

[0084] [Figure 71] The proton nuclear magnetic resonance (1H NMR) of compound I hemi fumarate form I is shown.

[0085] [Figure 72] The X-ray powder diffraction (XRPD) pattern of compound I monofumarate form I is shown.

[0086] [Figure 73] The differential scanning calorimetry (DSC) curve for compound I monofumarate form I is shown.

[0087] [Figure 74] The thermogravimetric analysis (TGA) of compound I monofumarate form I is shown.

[0088] [Figure 75] The dynamic water vapor adsorption (DVS) curve for compound I monofumarate form I is shown.

[0089] [Figure 76] This shows the proton nuclear magnetic resonance (1H NMR) of compound I monofumarate form I.

[0090] [Figure 77]The X-ray powder diffraction (XRPD) pattern of compound I hemi-L-tartrate form I is shown.

[0091] [Figure 78] The differential scanning calorimetry (DSC) curve for compound I hemi-L-tartrate form I is shown.

[0092] [Figure 79] The thermogravimetric analysis (TGA) of compound I hemi-L-tartrate form I is shown.

[0093] [Figure 80] The dynamic water vapor adsorption (DVS) curve for compound I hemi-L-tartrate form I is shown.

[0094] [Figure 81] The proton nuclear magnetic resonance (1H NMR) of compound I hemi-L-tartrate form I is shown.

[0095] [Figure 82] The X-ray powder diffraction (XRPD) pattern of compound I mono-ESA form I is shown.

[0096] [Figure 83] The differential scanning calorimetry (DSC) curve of compound I mono-ESA form I is shown.

[0097] [Figure 84] The thermogravimetric analysis (TGA) of compound I mono-ESA form I is shown.

[0098] [Figure 85] The dynamic water vapor adsorption (DVS) curve for compound I mono-ESA form I is shown.

[0099] [Figure 86] This shows the proton nuclear magnetic resonance (1H NMR) of compound I mono-ESA form I.

[0100] [Figure 87]The X-ray powder diffraction (XRPD) pattern of compound I hemiglycolate form I is shown.

[0101] [Figure 88] The differential scanning calorimetry (DSC) curve for compound I hemiglycolate form I is shown.

[0102] [Figure 89] The thermogravimetric analysis (TGA) of compound I hemiglycolate form I is shown.

[0103] [Figure 90] The dynamic water vapor adsorption (DVS) curve for compound I hemiglycolate form I is shown.

[0104] [Figure 91] This shows the proton nuclear magnetic resonance (1H NMR) of compound I hemiglycolate form I.

[0105] [Figure 92] The X-ray powder diffraction (XRPD) pattern of compound I sulfate form I is shown.

[0106] [Figure 93] The differential scanning calorimetry (DSC) curve for compound I sulfate form I is shown.

[0107] [Figure 94] The thermogravimetric analysis (TGA) of compound I sulfate form I is shown.

[0108] [Figure 95] The X-ray powder diffraction (XRPD) pattern of compound I phosphate form I is shown.

[0109] [Figure 96] The differential scanning calorimetry (DSC) curve for compound I phosphate form I is shown.

[0110] [Figure 97]The thermogravimetric analysis (TGA) of compound I phosphate form I is shown.

[0111] [Figure 98] The X-ray powder diffraction (XRPD) pattern of compound I hemiHCl form I is shown.

[0112] [Figure 99] The differential scanning calorimetry (DSC) curve of compound I hemiHCl form I is shown.

[0113] [Figure 100] The thermogravimetric analysis (TGA) of compound I hemiHCl form I is shown.

[0114] [Figure 101] The dynamic water vapor adsorption (DVS) curve for compound I hemiHCl form I is shown.

[0115] [Figure 102] This shows the X-ray powder diffraction (XRPD) pattern of compound I in cocrystal form I.

[0116] [Figure 103] The differential scanning calorimetry (DSC) curve of compound I cocrystal morphology I is shown.

[0117] [Figure 104] The thermogravimetric analysis (TGA) of compound I in cocrystal form I is shown. [Modes for carrying out the invention]

[0118] The compound referred to herein as Compound I, 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide, has the following formula: [ka]

[0119] Compound I is an inhibitor of IRAK4. Its synthesis and use are described in International Publication 2020 / 014468, U.S. Patent No. 10,875,866, U.S. Patent Application No. 63 / 511,558 (filed June 30, 2023, title “Processes for Making IRAK4 Inhibitors”), and International Application PCT Publication / US2024 / 036103 (claiming priority to U.S. Patent Application No. 63 / 511,558, filed on the same date as this application, title “Processes for Making IRAK4 Inhibitors”), each incorporated herein by reference in its entirety. Unless otherwise specified, references to Compound I are intended to include the compound itself or its salts, e.g., pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, solid forms, cocrystals, solvates, and / or hydrates. definition

[0120] When used herein, the following words and phrases are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0121] The term "comprise" and its variations, such as "comprises" and "comprising," should be interpreted in an open and comprehensive sense, meaning "including, but not limited to." Furthermore, the singular forms "a," "an," and "the" include multiple references unless otherwise clearly indicated in the context. Thus, a reference to "compound" includes multiple such compounds, and a reference to "assay" includes one or more assays and their equivalents known to those skilled in the art.

[0122] References to values ​​or parameters of “approximately” in this specification include (and are described) embodiments relating to the value or parameter itself. In certain embodiments, the term “approximately” includes the indicated amount ± 10%. In other embodiments, the term “approximately” includes the indicated amount ± 5%. In certain other embodiments, the term “approximately” includes the indicated amount ± 2.5%. In certain other embodiments, the term “approximately” includes the indicated amount ± 1%. Furthermore, “approximately X” in relation to that term includes a description of “X”.

[0123] The numerical ranges described throughout the disclosure are intended to serve as abbreviated notation for each distinct value within the range, including the value defining the range, and each distinct value is incorporated into the specification as it is individually described herein.

[0124] Forms of Compound I or its salts, cocrystals, solvates, or hydrates are provided herein. In one embodiment, reference to Compound I or its salts, cocrystals, solvates, or hydrates means that at least 50% to 99% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of Compound I or its salts, cocrystals, solvates, or hydrates are present in the composition in the specified form. For example, in one embodiment, reference to Compound I Form I means that at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of Compound I are present in the composition as Form I.

[0125] The term "solid state" refers to types of solid-state materials, including amorphous and crystalline states. The term "crystalline state" refers to polymorphs, solvates, hydrates, etc. The term "polymorph" refers to a specific crystalline structure that has certain physical properties such as X-ray diffraction and melting point.

[0126] As used herein, the term “salt” refers to a compound formed by the reaction of an acid and a base, resulting in the formation of a positively charged cation and a negatively charged anion. Generally, a salt is defined as a compound formed by a combination of positively and negatively charged ions, the charge of which determines the neutral compound produced. A salt may be either an inorganic or organic salt. As used herein, the term “salt” includes partially or completely ionized salt forms. In some embodiments, the salt is completely ionized.

[0127] The term "cocrystal" refers to a molecular complex of a compound disclosed herein and one or more non-ionized cocrystal-forming agents bonded via non-covalent interactions. In some embodiments, the cocrystals disclosed herein may comprise a non-ionized form of compound I (e.g., a free form of compound I) and one or more non-ionized cocrystal-forming agents, wherein the non-ionized compound I and the cocrystal-forming agents are bonded via non-covalent interactions. In some embodiments, the cocrystals disclosed herein may comprise an ionized form of compound I (e.g., a salt of compound I) and one or more non-ionized cocrystal-forming agents, wherein the ionized compound I and the cocrystal-forming agents are bonded via non-covalent interactions. The cocrystals may further exist in anhydrous, solvated, or hydrated forms. In certain cases, the cocrystals may have improved properties compared to the parent form (i.e., a free molecule, a zwitterion, etc.) or a salt of the parent compound. Improved properties may include enhanced solubility, improved bioavailability, improved dose response, reduced hygroscopicity, improved stability, crystalline form of normally amorphous compounds, crystalline form of compounds that are difficult or impossible to salt, reduced morphological diversity, and more desirable morphologies. Methods for preparing and characterizing cocrystals are known to those skilled in the art.

[0128] The terms “cocrystal-forming agent” or “co-forming agent” refer to one or more pharmaceutically acceptable bases or acids disclosed herein in connection with Compound I or any other compound disclosed herein. Examples of such bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, and N-methylglucamine. Examples of such acids include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid; or organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, maleic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, gluconic acid, glutamic acid, salicylic acid, and stearic acid.

[0129] The term “solvate” refers to a complex formed by a combination of solvent molecules and solute molecules or ions. The solvent may be an organic compound, an inorganic compound, or a mixture of both. As used herein, the term “solvate” includes “hydrates” (i.e., complexes formed by a combination of water molecules and solute molecules or ions), hemihydrates, channel hydrates, and the like. Some examples of solvents include, but are not limited to, acetonitrile, methanol, N,N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfoxide, and water. Generally, solvated forms are equivalent to non-solvated forms and are encompassed within the scope of this disclosure.

[0130] The term "desolvated" refers to a solvate as described herein, in compound I form, from which solvent molecules have been partially or completely removed. Desolvation techniques for producing a desolvated form include, but are not limited to, exposure of compound I form (solvate) to a vacuum, exposure of the solvate to a high temperature, exposure of the solvate to a stream of gas such as air or nitrogen, or any combination thereof. Thus, a desolvated or "non-solvated" compound I form may be "anhydrous," i.e., completely free of solvent molecules, or partially solvated, in which case solvent molecules may be present in stoichiometric or non-stoichiometric amounts.

[0131] The term "amorphous" refers to a state in which a material lacks long-range order at the molecular level and can exhibit the physical properties of a solid or a liquid depending on temperature. Typically, such materials yield a characteristic X-ray diffraction pattern and exhibit the properties of a solid, but are more formally described as liquids. Heating causes a change from solid to liquid properties, typically characterized by a secondary state change (glass transition).

[0132] "Stereoisomers" are isomers that differ only in the arrangement of atoms in space.

[0133] Any formula or structure given herein that includes Compound I is also intended to represent both the unlabeled form and the isotopically labeled form of the compound. For any given atom, the isotopes can be present in their natural abundance ratios essentially, or, using synthetic methods known to those skilled in the art, one or more specific atoms can be enhanced with respect to one or more isotopes. Thus, for hydrogen, for example, 1 H, 2 H, 3 H are included, and for carbon, for example, 11 C, 12 C, 13 C, 14 C are included, and for oxygen, for example, 16 O, 17 O, 18 O are included, and for nitrogen, for example, 13 N, 14 N, 15 N are included, and for sulfur, for example, 32 S, 33 S, 34 S, 35 S, 36 S, 37 S, 38 S are included, and for fluorine, for example, 17 F, 18 F, 19 F are included, and for chlorine, for example, 35 Cl, 36 Cl, 37 Cl, 38 Cl, 39 Cl and the like are included.

[0134] As used herein, the terms “treat,” “treating,” “therapy,” “therapies,” and similar terms mean administering a material of Compound I as described herein, for example, any one or more solids, crystals, or polymorphs thereof, in an amount effective to prevent, alleviate, or improve one or more symptoms of a disease or condition, i.e., an indication, and / or to prolong the survival of the subject being treated.

[0135] The term "administering" refers to oral administration, suppository administration, topical contact, intravenous administration, intraperitoneal administration, intramuscular administration, intrafocal administration, intranasal administration, or subcutaneous administration to a subject, or implantation of a sustained-release device, such as a mini osmotic pump. Administration is carried out via any route, including parenteral and transmucosal (e.g., oral, sublingual, palate, gingival, nasal cavity, vagina, rectum, or percutaneous). Parenteral administration includes, for example, intravenous, intramuscular, intraarteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous injection, and transdermal patch.

[0136] As used herein, the terms “modulate” or “regulate” refer to the effect of altering biological activity, particularly the biological activity associated with a specific biomolecule, such as IRAK4 activity. For example, an agonist or antagonist of a particular biomolecule modulates IRAK4 activity by either increasing (e.g., an agonist, an activator) or decreasing (e.g., an antagonist, an inhibitor) the activity of the biomolecule. Such activity is typically measured by the inhibitory concentration (IC) of the compound in the case of an inhibitor. 50 ), or, in the case of an activator, the excitation concentration (EC) of the compound. 50 These are shown in the respective sections. In some embodiments, the term “modulate” or “to regulate” refers, for example, to inhibit IRAK4 or to inhibit it.

[0137] As used herein, in some embodiments, the term “composition” refers to a pharmaceutical formulation suitable for administration to a target intended for therapeutic purposes, comprising at least one pharmaceutically active compound (including any solid form thereof). The composition may also include at least one pharmaceutically acceptable component, such as a suitable carrier or excipient, to provide an improved formulation of the compound.

[0138] As used herein, the terms “subject” or “patient” refer to a living organism treated with any of the compounds described herein, including, but not limited to, any mammal, such as humans, other primates, sports animals, animals of commercial value, such as cattle, livestock, such as horses, or pets, such as dogs and cats.

[0139] The term "pharmaceutically acceptable" indicates that the material being described does not possess properties that would cause a reasonably prudent physician to avoid administering the material to a patient, taking into account the disease or condition being treated and the respective route of administration. For example, such materials are generally required to be essentially sterile for injectable substances. The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological efficacy and properties of the given compound and is not biologically or otherwise undesirable. pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Examples of salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Examples of salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines. Specific examples of suitable amines include isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, lysine, arginine, histidine, caffeine, procaine, hydravamin, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamine, theobromine, purine, piperazine, piperidine, morpholine, and N-ethylpiperidine. Medicinally acceptable acid addition salts can be prepared from inorganic and organic acids. Examples of salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of 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 acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.

[0140] In this context, the terms “therapeutic effective” or “effective dose” indicate that a material or quantity of material is effective in preventing, alleviating, or improving one or more symptoms of a disease or condition, and / or extending the survival of the subject being treated. The therapeutic effective dose varies depending on the compound, the disorder or condition and its severity, and the age and weight of the mammal being treated. For example, the effective dose is the amount sufficient to achieve a beneficial or desired clinical outcome. The effective dose may be provided in a single dose or in divided doses that provide the effective dose over multiple doses. Determining the amount considered effective may be based on individual factors for each subject, such as the size, age, injury, and / or the disease or injury being treated, the time elapsed since the injury occurred, or the onset of the disease. A person skilled in the art will be able to determine the effective dose for a given subject based on these considerations routinely practiced in the art.

[0141] In some embodiments, the phrase "substantially shown in the figure" or "as substantially shown in the figure" means, when applied to an X-ray powder diffraction pattern, to include variations of ±0.2°²θ or ±0.1°²θ; when applied to a DSC thermogram, to include variations of ±3°C; and when applied to thermogravimetric analysis (TGA), to include variations of ±2% of the weight loss. In some embodiments, the phrase "substantially shown in the figure" or "as substantially shown in the figure" means, when applied to a DVS curve, to include variations of ±5%.

[0142] "Substantially pure form (polymorphic)" means, in some embodiments, that in the referenced material, at least 99.9% of the material is the referenced polymorph. "Substantially pure form (polymorphic)" means, in some embodiments, that in the referenced material, at least 99.5% of the material is the referenced polymorph. "Substantially pure form (polymorphic)" means, in some embodiments, that in the referenced material, at least 99% of the material is the referenced polymorph. "Substantially pure form (polymorphic)" means, in some embodiments, that in the referenced material, at least 98% of the material is the referenced polymorph. "Substantially pure form (polymorphic)" means, in some embodiments, that in the referenced material, at least 97% of the material is the referenced polymorph. "Substantially pure form (polymorphic)" means, in some embodiments, that in the referenced material, at least 96% of the material is the referenced polymorph. "Substantially pure form (polymorphic)" means, in some embodiments, that in the referenced material, at least 95% of the material is the referenced polymorph. Salts and forms of compound I

[0143] As outlined above, this disclosure provides salts and solid forms, such as crystalline form, of compound 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (hereinafter, "Compound I"), as well as salts, cocrystals, solvates, or hydrates thereof. The crystalline form of Compound I, and its salts, cocrystals, solvates, and hydrates, as well as other forms of Compound I (e.g., amorphous form), and its salts, cocrystals, solvates, or hydrates, are collectively referred to herein as "forms of Compound I".

[0144] In some embodiments, compound I is in a free form, for example, a free base. In some embodiments, compound I is a salt. In some embodiments, compound I is a pharmaceutically acceptable salt. In some embodiments, compound I is a solvate. In some embodiments, compound I is a hydrate. In some embodiments, compound I is non-solvated. In some embodiments, compound I is an anhydride. In some embodiments, a substantially pure solid form of compound I described herein is provided. In some embodiments, a substantially pure crystalline form of compound I described herein is provided.

[0145] While not intended to be bound by any particular theory, certain solid forms are characterized by physical properties suitable for pharmaceutical and therapeutic dosage forms, such as stability, solubility, and dissolution rate. Furthermore, while not bound by any particular theory, certain solid forms are characterized by physical properties (e.g., density, compressibility, hardness, morphology, cleavage, tackiness, solubility, water uptake, electrical properties, thermal behavior, solid-state reactivity, physical stability, and chemical stability) that influence certain processes (e.g., yield, filtration, washing, drying, grinding, mixing, tableting, flowability, dissolution, formulation, and freeze-drying) that make a particular solid form suitable for the manufacture of a solid dosage form. Such properties can be determined using certain analytical chemistry techniques, including solid-state analysis techniques (e.g., X-ray diffraction, microscopy, spectroscopy, and thermal analysis), as described herein.

[0146] The identification and selection of the solid form of a pharmaceutical compound is complex, considering that changes in solid form can affect a variety of physical and chemical properties, which may offer advantages or disadvantages in processing, formulation, stability, bioavailability, storage, and handling (e.g., shipping), among other important pharmaceutical characteristics. Useful pharmaceutical solids include crystalline and amorphous solids, depending on the product and its mode of administration. Amorphous solids are characterized by the lack of long-range structural order, while crystalline solids are characterized by structural periodicity. The desired class of pharmaceutical solid depends on the specific application; amorphous solids may be selected based, for example, on an enhanced solubility profile, while crystalline solids may be desirable for properties such as physical or chemical stability.

[0147] Whether crystalline or amorphous, medicinal compounds can take the form of single-component solids and multi-component solids. Single-component solids consist essentially of the medicinal compound or active ingredient in the absence of other compounds. Diversity within single-component crystalline materials can potentially arise from polymorphism, with multiple three-dimensional configurations existing for a given medicinal compound.

[0148] In particular, it is impossible to predict a priori whether a crystalline form of a compound exists, much less how to successfully prepare them (e.g., Braga and Grepioni, 2005, "Making crystals from crystals: a green route to crystal engineering and polymorphism," Chem.Commun.:3635-3645 (with regard to crystal engineering, if the instructions are not very precise and / or if other external factors affect the process, the results may be unpredictable), Jones et al., 2006, "Pharmaceutical Cocrystals: An Emerging Approach to Physical Property Enhancement," MRS Bulletin 31:875-879 (currently, even for the simplest molecules, it is generally impossible to computationally predict the number of observable polymorphs), Price, 2004, "The computational prediction of pharmaceutical crystal structures and polymorphism," Advanced Drug Delivery Reviews 56:301-319 ("Price"), and Bernstein, 2004, "Crystal Structure Prediction and See "Polymorphism," ACA Transactions 39:14-23 (before we can state with any degree of confidence that we have the ability to predict crystal structures, much more must be learned and done, and polymorphism even more so).

[0149] The diversity of possible solid forms brings potential diversity to the physical and chemical properties of a given pharmaceutical compound. The discovery and selection of solid forms are crucial in the development of effective, stable, and marketable pharmaceutical products. Form of compound I Compound I Form I

[0150] In one embodiment, a crystalline 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide form I (compound I form I) is provided, characterized by an X-ray powder diffraction pattern including peaks (±0.2°) at 7.5, 12.3, and 7.2°2θ as measured with a Cu-Kα diffractometer.

[0151] In some embodiments, Compound I form I is i) One or more peaks at 19.1°2θ±0.2°, 22.7±0.2°, or 15.1±0.2°; ii) Diffraction diagrams substantially as shown in Figure 1; iii) Differential scanning calorimetry (DSC) curves including endothermic heating at approximately 155.3°C (start temperature) and approximately 174.7°C (start temperature); iv) Differential scanning calorimetry (DSC) curves, substantially as shown in Figure 2; v) Thermogravimetric analysis (TGA) showing a weight loss of approximately 1.0% by weight up to approximately 150°C; or vi) Further characterized by thermogravimetric analysis (TGA) including a thermogram, as substantially shown in Figure 3.

[0152] In some embodiments, Compound I Form I is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 19.1, 22.7, or 15.1°²θ. In some embodiments, Compound I Form I is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 28.4, 26.4, or 16.5°²θ. In some embodiments, Compound I Form I is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 1.

[0153] In some embodiments, Compound I Form I is further characterized by a DSC curve that includes endothermic activity at approximately 155.3°C (start temperature) and approximately 174.7°C (start temperature). In some embodiments, Compound I Form I is further characterized by a DSC curve that includes endothermic activity at approximately 161.6°C (peak) and approximately 182.9°C (peak). In some embodiments, Compound I Form I is further characterized by a DSC curve substantially as shown in Figure 2.

[0154] In some embodiments, Compound I Form I further features a TGA that exhibits a weight loss of about 1.0% by weight from room temperature to about 150°C. In some embodiments, Compound I Form I further features a TGA including a thermogram substantially as shown in Figure 3.

[0155] In some embodiments, compound form I is non-solvable. Compound I Form II

[0156] In one embodiment, a crystalline 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide form II (compound I form II) is provided, characterized by an X-ray powder diffraction pattern including peaks (±0.2°) at 7.5, 14.6, and 17.8°2θ as measured with a Cu-Kα diffractometer.

[0157] In some embodiments, compound form I II is i) One or more peaks at 22.8°2θ±0.2°, 26.7±0.2°, or 22.0±0.2°; ii) Diffraction diagrams substantially as shown in Figure 4; iii) Differential scanning calorimetry (DSC) curve including endothermic heating at approximately 190.7°C (start temperature); iv) Differential scanning calorimetry (DSC) curves substantially as shown in Figure 5; v) Thermogravimetric analysis (TGA) showing a weight loss of approximately 1.0% by weight up to approximately 200°C; or vi) Further characterized by thermogravimetric analysis (TGA) including a thermogram, as substantially shown in Figure 6.

[0158] In some embodiments, Compound I Form II is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 22.8, 26.7, or 22.0°²θ. In some embodiments, Compound I Form II is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 15.2, 21.6, or 20.1°²θ. In some embodiments, Compound I Form II is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 4.

[0159] In some embodiments, Compound I Form II is further characterized by a DSC curve that includes endothermic activity at approximately 190.7°C (start temperature). In some embodiments, Compound I Form II is further characterized by a DSC curve that includes endothermic activity at approximately 191.2°C (peak). In some embodiments, Compound I Form II is further characterized by a DSC curve substantially as shown in Figure 5.

[0160] In some embodiments, Compound I Form II further features a TGA that exhibits a weight loss of about 1.0% by weight from room temperature to about 200°C. In some embodiments, Compound I Form II further features a TGA including a thermogram substantially as shown in Figure 6.

[0161] In some embodiments, compound form I II is non-solvable. Compound I Form III

[0162] In one embodiment, a crystalline 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide form III (compound I form III) is provided, characterized by an X-ray powder diffraction pattern including peaks (±0.2°) at 21.2, 12.3, and 10.7°2θ as measured with a Cu-Kα diffractometer.

[0163] In some embodiments, Compound I Form III is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 23.8, 11.7, or 21.5°²θ. In some embodiments, Compound I Form III is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 25.1, 16.9, or 20.0°²θ. In some embodiments, Compound I Form III is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 7.

[0164] In some embodiments, compound form I III is non-solvable. Compound I Form IV

[0165] In one embodiment, a crystalline 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide form IV (compound I form IV) is provided, characterized by an X-ray powder diffraction pattern including peaks (±0.2°) at 10.1, 10.7, and 17.9°2θ as measured with a Cu-Kα diffractometer.

[0166] In some embodiments, Compound I Form IV is i) One or more peaks at 17.3°2θ±0.2°, 11.7±0.2°, or 21.7±0.2°; ii) Diffraction diagrams substantially as shown in Figure 8; iii) Differential scanning calorimetry (DSC) curve including endothermic heating at approximately 192.0°C (start temperature); iv) Differential scanning calorimetry (DSC) curves substantially as shown in Figure 9; v) Thermogravimetric analysis (TGA) showing a weight loss of approximately 0.8% by weight up to approximately 200°C; vi) Thermogravimetric analysis (TGA) including a thermogram as substantially shown in Figure 10; or vii) It is further characterized by a dynamic water vapor adsorption (DVS) curve, as substantially shown in Figure 11.

[0167] In some embodiments, Compound I Form IV is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 17.3, 11.7, or 21.7°²θ. In some embodiments, Compound I Form IV is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 18.2, 23.3, or 15.9°²θ. In some embodiments, Compound I Form IV is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 8.

[0168] In some embodiments, compound I form IV is further characterized by a DSC curve that includes endothermic heating at approximately 192.0°C (start temperature). In some embodiments, compound I form IV is further characterized by a DSC curve that includes endothermic heating at approximately 194.2°C (peak). In some embodiments, compound I form IV is further characterized by a DSC curve substantially as shown in Figure 9.

[0169] In some embodiments, Compound I Form IV further features a TGA that exhibits a weight loss of about 0.8% by weight up to about 200°C. In some embodiments, Compound I Form IV further features a TGA including a thermogram substantially as shown in Figure 10.

[0170] In some embodiments, compound form I IV is further characterized by a DVS curve substantially as shown in Figure 11.

[0171] In some embodiments, compound form I IV is non-solvable. Compound I Form V

[0172] In one embodiment, a crystalline 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide form V (compound I form V) is provided, characterized by an X-ray powder diffraction pattern including peaks (±0.2°) at 11.8, 25.9, and 20.7°2θ as measured with a Cu-Kα diffractometer.

[0173] In some embodiments, compound form I V is i) One or more peaks at 16.8°2θ±0.2°, 23.1±0.2°, or 18.5±0.2°; ii) Diffraction diagrams substantially as shown in Figure 12; iii) Differential scanning calorimetry (DSC) curves including endothermic reactions at approximately 70.5°C (start temperature), approximately 151.6°C (start temperature), and approximately 189.1°C (start temperature); iv) Differential scanning calorimetry (DSC) curves substantially as shown in Figure 13; v) Thermogravimetric analysis (TGA) showing a weight loss of approximately 3.6% by weight up to approximately 100°C; vi) Thermogravimetric analysis (TGA) including a thermogram as substantially shown in Figure 14; or vii) It is further characterized by a dynamic water vapor adsorption (DVS) curve, as substantially shown in Figure 15.

[0174] In some embodiments, compound I form V is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 16.8, 23.1, or 18.5°²θ. In some embodiments, compound I form V is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 10.2, 20.4, or 15.7°²θ. In some embodiments, compound I form V is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 12.

[0175] In some embodiments, compound I form V further features a DSC curve including endothermic events at approximately 70.5°C (start temperature), approximately 151.6°C (start temperature), and approximately 189.1°C (start temperature). In some embodiments, compound I form V further features a DSC curve including exothermic events at approximately 171°C (start temperature). In some embodiments, compound I form V further features a DSC curve including endothermic events at approximately 97.6°C (peak), approximately 155.6°C (peak), and approximately 190.5°C (peak). In some embodiments, compound I form V further features a DSC curve substantially as shown in Figure 13.

[0176] In some embodiments, compound I form V further features a TGA that exhibits a weight loss of about 3.6% by weight up to about 100°C. In some embodiments, compound I form V further features a TGA including a thermogram substantially as shown in Figure 14.

[0177] In some embodiments, compound form I V is further characterized by a DVS curve substantially as shown in Figure 15.

[0178] In some embodiments, compound I form V is a monohydrate. In some embodiments, compound I form V contains about 1 molar equivalent of water. Compound I Form VI

[0179] In one embodiment, a crystalline 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide form VI (compound I form VI) is provided, characterized by an X-ray powder diffraction pattern including peaks (±0.2°) at 4.9, 5.6, and 7.4°2θ as measured with a Cu-Kα diffractometer.

[0180] In some embodiments, compound form I VI is i) One or more peaks at 8.4°2θ±0.2°, 12.3±0.2°, or 27.2±0.2°; ii) Diffraction diagrams substantially as shown in Figure 16; iii) Differential scanning calorimetry (DSC) curves including endothermic reactions at approximately 47.0°C (start temperature), approximately 111.1°C (start temperature), and approximately 122.9°C (start temperature); iii) Differential scanning calorimetry (DSC) curves, substantially as shown in Figure 17; v) Thermogravimetric analysis (TGA) showing a weight loss of approximately 5.2% by weight up to approximately 140°C; vi) Thermogravimetric analysis (TGA) including a thermogram as substantially shown in Figure 18; or vii) It is further characterized by a dynamic water vapor adsorption (DVS) curve, as substantially shown in Figure 19.

[0181] In some embodiments, Compound I Form VI is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, which includes one or more additional peaks (±0.2°) at 8.4, 12.3, or 27.2°2θ. In some embodiments, Compound I Form VI is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 16.

[0182] In some embodiments, Form VI of Compound I is further characterized by a DSC curve including an endotherm at about 47.0 °C (starting temperature), an endotherm at about 111.1 °C (starting temperature), and an endotherm at about 122.9 °C (starting temperature). In some embodiments, Form VI of Compound I is further characterized by a DSC curve including an endotherm at about 75.6 °C (peak), an endotherm at 115.4 °C (peak), and an endotherm at 125.7 °C (peak). In some embodiments, Form VI of Compound I is further characterized by a DSC curve substantially as shown in FIG. 17.

[0183] In some embodiments, Form VI of Compound I is further characterized by a TGA showing a weight loss of about 5.2 wt% from room temperature to about 140 °C. In some embodiments, Form VI of Compound I is further characterized by a TGA including a thermogram substantially as shown in FIG. 18.

[0184] In some embodiments, Form VI of Compound I is further characterized by a DVS curve substantially as shown in FIG. 19.

[0185] In some embodiments, Form VI of Compound I is a hydrate. In some embodiments, Form VI of Compound I contains about 1.25 molar equivalents of water. Crystalline 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide Form VII (Compound I Form VII) is provided, which is characterized by an X-ray powder diffraction pattern including peaks (±0.2°) at 4.0, 25.8, and 6.9 °2θ measured with a diffractometer using Cu-Kα radiation in one embodiment.

[0186]

[0187] In some embodiments, Compound I Form VII is further characterized by an X-ray powder diffraction pattern that includes one or more additional peaks (±0.2°) at 8.2, 14.7, or 18.1° 2θ measured with a diffractometer using Cu-Kα radiation. In some embodiments, Compound I Form VII is further characterized by an X-ray powder diffraction pattern that includes one or more additional peaks (±0.2°) at 18.9, 11.4, or 9.1° 2θ measured with a diffractometer using Cu-Kα radiation. In some embodiments, Compound I Form VII is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 20.

[0188] In some embodiments, Compound I Form VII is further characterized by a DSC curve that includes endotherms at about 17 °C (onset temperature), about 53.8 °C (onset temperature), about 138.2 °C (onset temperature), and about 187.1 °C (onset temperature). In some embodiments, Compound I Form VII is further characterized by a DSC curve that includes endotherms at about 28.7 °C (peak), about 70.5 °C (peak), about 147.4 °C (peak), and about 189.0 °C (peak). In some embodiments, Compound I Form VII is further characterized by a DSC curve substantially as shown in Figure 21.

[0189] In some embodiments, Compound I Form VII is further characterized by a TGA that shows a weight loss of about 7.9 wt% from room temperature to about 160 °C. In some embodiments, Compound I Form VII is further characterized by a TGA that includes a thermogram substantially as shown in Figure 22.

[0190] In some embodiments, Compound I Form VII is further characterized by a DVS curve substantially as shown in Figure 23.

[0191] In some embodiments, Compound I Form VII is a water:THF solvate. Compound I Form VIII

[0192] In one embodiment, a crystalline 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide form VIII (compound I form VIII) is provided, characterized by an X-ray powder diffraction pattern including peaks (±0.2°) at 8.0, 25.8, and 6.1°2θ as measured with a Cu-Kα diffractometer.

[0193] In some embodiments, Compound I Form VIII is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 19.7, 23.2, or 15.5°²θ. In some embodiments, Compound I Form VIII is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 16.9, 20.4, or 12.3°²θ. In some embodiments, Compound I Form VIII is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 24.

[0194] In some embodiments, Compound I Form VIII is further characterized by a DSC curve including endothermic events at approximately 17.2°C (start temperature), approximately 99.2°C (start temperature), approximately 124.3°C (start temperature), and approximately 183.3°C (start temperature). In some embodiments, Compound I Form VIII is further characterized by a DSC curve including endothermic events at approximately 34.0°C (peak), approximately 115.8°C (peak), approximately 128.3°C (peak), and approximately 186.3°C (peak). In some embodiments, Compound I Form VIII is further characterized by a DSC curve substantially as shown in Figure 25.

[0195] In some embodiments, Compound I Form VIII further features a TGA that exhibits a weight loss of about 1.4% by weight from room temperature to about 52°C and a weight loss of about 6.6% by weight from about 52°C to about 160°C. In some embodiments, Compound I Form VIII further features a TGA that includes a thermogram substantially as shown in Figure 26.

[0196] In some embodiments, compound form I VIII is further characterized by a DVS curve substantially as shown in Figure 27.

[0197] In some embodiments, compound form I VIII is a water:ACN solvate. Compound I Form IX

[0198] In one embodiment, a crystalline 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide form IX (compound I form IX) is provided, characterized by an X-ray powder diffraction pattern including peaks (±0.2°) at 9.4, 4.5, and 18.3°2θ as measured with a Cu-Kα diffractometer.

[0199] In some embodiments, compound I form IX is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 23.0, 22.6, or 25.8°²θ. In some embodiments, compound I form IX is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 17.9, 24.9, or 20.7°²θ. In some embodiments, compound I form IX is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 28.

[0200] In some embodiments, compound I form IX is further characterized by a DSC curve including endothermic events at approximately 19.7°C (start temperature), approximately 78.9°C (start temperature), approximately 124.9°C (start temperature), and approximately 139.3°C (start temperature). In some embodiments, compound I form IX is further characterized by a DSC curve including endothermic events at approximately 42.4°C (peak), approximately 92.0°C (peak), approximately 129.1°C (peak), and approximately 146.0°C (peak). In some embodiments, compound I form IX is further characterized by a DSC curve substantially as shown in Figure 29.

[0201] In some embodiments, Compound I Form IX further features a TGA that exhibits a weight loss of about 2.7% by weight from room temperature to about 50°C and a weight loss of about 15.5% by weight from about 50°C to about 114°C. In some embodiments, Compound I Form IX further features a TGA that includes a thermogram substantially as shown in Figure 30.

[0202] In some embodiments, compound form I IX is further characterized by a DVS curve substantially as shown in Figure 31.

[0203] In some embodiments, compound form I IX is a water:2-MeTHF solvate. Compound I Form X

[0204] In one embodiment, a crystalline 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide form X (compound I form X) is provided, characterized by an X-ray powder diffraction pattern including peaks (±0.2°) at 4.0, 7.0, and 8.2°2θ as measured with a Cu-Kα diffractometer.

[0205] In some embodiments, Form X of Compound I is further characterized by an X-ray powder diffraction pattern that includes one or more additional peaks (±0.2°) at 5.9, 14.7, or 11.5° 2θ measured with a diffractometer using Cu-Kα radiation. In some embodiments, Form X of Compound I is further characterized by an X-ray powder diffraction pattern that includes one or more additional peaks (±0.2°) at 16.8, 18.3, or 9.1° 2θ measured with a diffractometer using Cu-Kα radiation. In some embodiments, Form X of Compound I is further characterized by an X-ray powder diffraction pattern substantially as shown in FIG. 32.

[0206] In some embodiments, Form X of Compound I is further characterized by a DSC curve that includes an endotherm at about 43.2 °C (onset temperature), an endotherm at about 149.1 °C (onset temperature), and an endotherm at about 188.0 °C (onset temperature). In some embodiments, Form X of Compound I is further characterized by a DSC curve that includes an endotherm at about 66.6 °C (peak), an endotherm at about 152.6 °C (peak), and an endotherm at about 189.5 °C (peak). In some embodiments, Form X of Compound I is further characterized by a DSC curve substantially as shown in FIG. 33.

[0207] In some embodiments, Form X of Compound I is further characterized by a TGA that shows a weight loss of about 5.1 wt% from room temperature to about 150 °C. In some embodiments, Form X of Compound I is further characterized by a TGA that includes a thermogram substantially as shown in FIG. 34.

[0208] In some embodiments, Form X of Compound I is solvated. In some embodiments, Form X of Compound I is an isostructural solvate. In some embodiments, Form X of Compound I is an IPA, acetone, or MTBE solvate. In some embodiments, Form X of Compound I is an IPA solvate. In some embodiments, Form X of Compound I is an acetone solvate. In some embodiments, Form X of Compound I is an MTBE solvate. Form XI of Compound I

[0209] In one embodiment, a crystalline 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide form XI (compound I form XI) is provided, characterized by an X-ray powder diffraction pattern including peaks (±0.2°) at 4.0, 6.9, and 14.5°2θ as measured with a Cu-Kα diffractometer.

[0210] In some embodiments, Compound I Form XI is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 18.0, 11.4, or 8.0°²θ. In some embodiments, Compound I Form XI is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 12.0, 15.1, or 18.9°²θ. In some embodiments, Compound I Form XI is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 35.

[0211] In some embodiments, compound I form XI is solvated. In some embodiments, compound I form XI is a structural solvate. In some embodiments, compound I form XI is a MIBK or THF solvate. In some embodiments, compound I form XI is a MIBK solvate. In some embodiments, compound I form XI is a THF solvate. Compound I Form XII

[0212] In one embodiment, a crystalline 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide form XII (compound I form XII) is provided, characterized by an X-ray powder diffraction pattern including peaks (±0.2°) at 7.7, 11.7, and 26.1°2θ as measured with a Cu-Kα diffractometer.

[0213] In some embodiments, Compound I Form XII is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 18.3, 16.7, or 20.6°²θ. In some embodiments, Compound I Form XII is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 21.1, 20.0, or 23.1°²θ. In some embodiments, Compound I Form XII is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 36. Compound I Form XIII

[0214] In one embodiment, a crystalline 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide form XIII (compound I form XIII) is provided, characterized by an X-ray powder diffraction pattern including peaks (±0.2°) at 7.6, 14.6, and 17.9°2θ as measured with a Cu-Kα diffractometer.

[0215] In some embodiments, Compound I Form XIII is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 22.8, 15.2, or 22.1°²θ. In some embodiments, Compound I Form XIII is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 21.1, 20.1, or 24.8°²θ. In some embodiments, Compound I Form XIII is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 37.

[0216] In some embodiments, compound form I-XIII is non-solvable. Compound I, amorphous form

[0217] In one embodiment, amorphous 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (amorphous form of Compound I) is provided.

[0218] In some embodiments, the amorphous form of compound I is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 38. Compound I monocitrate form I

[0219] In one embodiment, a crystalline 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide monocitrate form I (compound I monocitrate form I) is provided, characterized by an X-ray powder diffraction pattern including peaks (±0.2°) at 5.7, 7.0, and 22.7°2θ as measured with a Cu-Kα diffractometer.

[0220] In some embodiments, compound I monocitrate form I is i) One or more peaks at 19.6°2θ±0.2°, 15.6±0.2°, or 8.1±0.2°; ii) Diffraction diagrams substantially as shown in Figure 39; iii) Differential scanning calorimetry (DSC) curves including endothermic heating at approximately 145.2°C (start temperature) and approximately 186.6°C (start temperature); iv) Differential scanning calorimetry (DSC) curves substantially as shown in Figure 40; v) Thermogravimetric analysis (TGA) showing a weight loss of approximately 0.6% by weight up to approximately 150°C; vi) Thermogravimetric analysis (TGA) including a thermogram as substantially shown in Figure 41; vii) It is further characterized by a dynamic water vapor adsorption (DVS) curve, as substantially shown in Figure 42.

[0221] In some embodiments, compound I monocitrate form I is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 19.6, 15.6, or 8.1°²θ. In some embodiments, compound I monocitrate form I is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 16.3, 11.3, or 18.5°²θ. In some embodiments, compound I monocitrate form I is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 39.

[0222] In some embodiments, compound I monocitrate form I is further characterized by a DSC curve that includes endothermic activity at approximately 145.2°C (start temperature) and approximately 186.6°C (start temperature). In some embodiments, compound I monocitrate form I is further characterized by a DSC curve that includes endothermic activity at approximately 146.9°C (peak) and approximately 189.2°C (peak). In some embodiments, compound I monocitrate form I is further characterized by a DSC curve substantially as shown in Figure 40.

[0223] In some embodiments, compound I monocitrate form I further features a TGA that exhibits a weight loss of about 0.6% by weight from room temperature to about 150°C. In some embodiments, compound I monocitrate form I further features a TGA including a thermogram substantially as shown in Figure 41.

[0224] In some embodiments, compound I monocitrate form I is further characterized by a DVS curve substantially as shown in Figure 42.

[0225] In some embodiments, compound I monocitrate form I is substantially as shown in Figure 43. 1 Further features include the 1H NMR spectrum.

[0226] In some embodiments, Compound I monocitrate form I contains about 1 molar equivalent of citric acid. In some embodiments, Compound I monocitrate form I is non-solvable. Compound I monocitrate form II

[0227] In one embodiment, a crystalline 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide monocitrate form II (compound I monocitrate form II) is provided, characterized by an X-ray powder diffraction pattern including peaks (±0.2°) at 5.6, 7.0, and 24.2°2θ as measured with a Cu-Kα diffractometer.

[0228] In some embodiments, compound I monocitrate form II is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 19.5, 15.7, or 12.5°²θ. In some embodiments, compound I monocitrate form II is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 25.1, 14.0, or 18.0°²θ. In some embodiments, compound I monocitrate form II is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 44.

[0229] In some embodiments, compound I monocitrate form II is nonsolvable. Compound I monocitrate form III

[0230] In one embodiment, a crystalline 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide monocitrate form III (compound I monocitrate form III) is provided, characterized by an X-ray powder diffraction pattern including peaks (±0.2°) at 6.3, 18.8, and 7.7°2θ as measured with a Cu-Kα diffractometer.

[0231] In some embodiments, compound I monocitrate form III is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 22.9, 19.1, or 22.4°²θ. In some embodiments, compound I monocitrate form III is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 21.4, 18.1, or 25.1°²θ. In some embodiments, compound I monocitrate form III is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 45.

[0232] In some embodiments, compound I monocitrate form III is further characterized by a DSC curve including endothermic reactions at approximately 25.4°C (start temperature), approximately 123.0°C (start temperature), and approximately 159.0°C (start temperature). In some embodiments, compound I monocitrate form III is further characterized by a DSC curve including endothermic reactions at approximately 49.8°C (peak), approximately 130.1°C (peak), and approximately 172.9°C (peak). In some embodiments, compound I monocitrate form III is further characterized by a DSC curve substantially as shown in Figure 46.

[0233] In some embodiments, compound I monocitrate form III further features a TGA showing a weight loss of about 4.5% by weight. In some embodiments, compound I monocitrate form III further features a TGA including a thermogram substantially as shown in Figure 47.

[0234] In some embodiments, compound I monocitrate form III is further characterized by a DVS curve substantially as shown in Figure 48.

[0235] In some embodiments, compound I monocitrate form III is a hydrate. In some embodiments, compound I monocitrate form III contains about 1.5 molar equivalents of water. Compound I monocitrate form IV

[0236] In one embodiment, a crystalline 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide monocitrate form IV (compound I monocitrate form IV) is provided, characterized by an X-ray powder diffraction pattern including peaks (±0.2°) at 26.8, 25.7, and 25.1°2θ as measured with a Cu-Kα diffractometer.

[0237] In some embodiments, compound I monocitrate form IV is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 17.1, 20.5, or 21.9°²θ. In some embodiments, compound I monocitrate form IV is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 16.3, 13.0, or 7.4°²θ. In some embodiments, compound I monocitrate form IV is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 49.

[0238] In some embodiments, compound I monocitrate form IV is further characterized by a DSC curve including endothermic activity at approximately 75.2°C (start temperature), approximately 139.1°C (start temperature), and approximately 182.6°C (start temperature). In some embodiments, compound I monocitrate form IV is further characterized by a DSC curve including endothermic activity at approximately 91.3°C (peak) and approximately 190.0°C (peak). In some embodiments, compound I monocitrate form IV is further characterized by a DSC curve substantially as shown in Figure 50.

[0239] In some embodiments, compound I monocitrate form IV further features a TGA that exhibits a weight loss of about 22.5% by weight from room temperature to about 140°C. In some embodiments, compound I monocitrate form IV further features a TGA including a thermogram substantially as shown in Figure 51.

[0240] In some embodiments, compound I monocitrate form IV is further characterized by a DVS curve substantially as shown in Figure 52.

[0241] In some embodiments, compound I monocitrate form IV is a solvate. In some embodiments, compound I monocitrate form IV is a monohexafluoro-2-propanol solvate. Compound I hemicitrate form I

[0242] In one embodiment, a crystalline 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide hemicitrate form I (compound I hemicitrate form I) is provided, characterized by an X-ray powder diffraction pattern including peaks (±0.2°) at 6.1, 7.4, and 17.1°2θ as measured with a Cu-Kα diffractometer.

[0243] In some embodiments, compound I hemicitrate form I is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 11.2, 5.7, or 18.0°²θ. In some embodiments, compound I hemicitrate form I is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 14.9, 3.7, or 23.2°²θ. In some embodiments, compound I hemicitrate form I is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 53.

[0244] In some embodiments, the hemicitrate form I of compound I is further characterized by a DSC curve that includes endothermic reactions at approximately 69.6°C (start temperature), approximately 133.3°C (start temperature), and approximately 153.5°C (start temperature). In some embodiments, the hemicitrate form I of compound I is further characterized by a DSC curve that includes endothermic reactions at approximately 82.3°C (peak), approximately 140.5°C (peak), and approximately 175.1°C (peak). In some embodiments, the hemicitrate form I of compound I is further characterized by a DSC curve substantially as shown in Figure 54.

[0245] In some embodiments, the hemicitrate form I of compound I is further characterized by a TGA that shows a weight loss of about 2.8% by weight from room temperature to about 100°C. In some embodiments, the hemicitrate form I of compound I is further characterized by a TGA including a thermogram substantially as shown in Figure 55.

[0246] In some embodiments, compound I hemicitrate form I is further characterized by a DVS curve substantially as shown in Figure 56.

[0247] In some embodiments, the hemicitrate form I of compound I is substantially as shown in Figure 57. 1 Further features include the 1H NMR spectrum.

[0248] In some embodiments, compound I hemicitrate form I is a monohydrate. In some embodiments, compound I hemicitrate form I contains about 1 molar equivalent of water. Compound I monoHCl form I

[0249] In one embodiment, a crystalline 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide monohydrochloride form I (compound I monoHCl form I) is provided, characterized by an X-ray powder diffraction pattern including peaks (±0.2°) at 6.9, 20.7, and 16.9°2θ as measured with a Cu-Kα diffractometer.

[0250] In some embodiments, compound I monoHCl form I is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 18.2, 12.8, or 21.8°²θ. In some embodiments, compound I monoHCl form I is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 24.4, 15.3, or 21.2°²θ. In some embodiments, compound I monoHCl form I is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 58.

[0251] In some embodiments, compound I monoHCl form I is further characterized by a DSC curve substantially as shown in Figure 59.

[0252] In some embodiments, compound I monoHCl form I further features a TGA that exhibits a weight loss of about 0.2% by weight from room temperature to about 100°C. In some embodiments, compound I monoHCl form I further features a TGA including a thermogram substantially as shown in Figure 60.

[0253] In some embodiments, compound I monoHCl form I is further characterized by a DVS curve substantially as shown in Figure 61.

[0254] In some embodiments, compound I monoHCl form I is nonsolvable. Compound I monomaleate form I

[0255] In one embodiment, a crystalline 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide monomaleate form I (compound I monomaleate form I) is provided, characterized by an X-ray powder diffraction pattern including peaks (±0.2°) at 7.4, 6.1, and 23.2°2θ as measured with a Cu-Kα diffractometer.

[0256] In some embodiments, compound I monomaleate form I is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 18.0, 19.0, or 12.2°²θ. In some embodiments, compound I monomaleate form I is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 25.2, 22.7, or 20.6°²θ. In some embodiments, compound I monomaleate form I is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 62.

[0257] In some embodiments, compound I monomaleate form I is further characterized by a DSC curve that includes endothermic activity at approximately 188.0°C (start temperature). In some embodiments, compound I monomaleate form I is further characterized by a DSC curve that includes endothermic activity at approximately 189.5°C (peak). In some embodiments, compound I monomaleate form I is further characterized by a DSC curve substantially as shown in Figure 63.

[0258] In some embodiments, compound I monomaleate form I further features a TGA that exhibits a weight loss of about 0.1% by weight from room temperature to about 100°C. In some embodiments, compound I monomaleate form I further features a TGA including a thermogram substantially as shown in Figure 64.

[0259] In some embodiments, compound I monomaleate form I is further characterized by a DVS curve substantially as shown in Figure 65.

[0260] In some embodiments, compound I monomaleate form I is substantially as shown in Figure 66. 1 Further features include the 1H NMR spectrum.

[0261] In some embodiments, compound I monomaleate form I is non-solvable. In some embodiments, compound I monomaleate form I contains about 1 molar equivalent of maleic acid. Compound I hemifumarate form I

[0262] In one embodiment, a crystalline 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide hemifumarate form I (compound I hemifumarate form I) is provided, characterized by an X-ray powder diffraction pattern including peaks (±0.2°) at 7.7, 6.8, and 13.0°2θ as measured with a Cu-Kα diffractometer.

[0263] In some embodiments, compound I hemi-fumarate form I is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 5.5, 19.4, or 20.3°²θ. In some embodiments, compound I hemi-fumarate form I is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 17.1, 13.5, or 23.7°²θ. In some embodiments, compound I hemi-fumarate form I is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 67.

[0264] In some embodiments, compound I hemi-fumarate form I is further characterized by a DSC curve that includes endothermic activity at approximately 151.4°C (start temperature). In some embodiments, compound I hemi-fumarate form I is further characterized by a DSC curve that includes endothermic activity at approximately 155.2°C (peak). In some embodiments, compound I hemi-fumarate form I is further characterized by a DSC curve substantially as shown in Figure 68.

[0265] In some embodiments, compound I hemi-fumarate form I further features a TGA that exhibits a weight loss of about 0.8% by weight from room temperature to about 100°C. In some embodiments, compound I hemi-fumarate form I further features a TGA including a thermogram substantially as shown in Figure 69.

[0266] In some embodiments, compound I hemifumarate form I is further characterized by a DVS curve substantially as shown in Figure 70.

[0267] In some embodiments, compound I hemifumarate form I is substantially as shown in Figure 71. 1 Further features include the 1H NMR spectrum.

[0268] In some embodiments, compound I hemi-fumarate form I is non-solvable. In some embodiments, compound I hemi-fumarate form I contains about 0.5 molar equivalents of fumaric acid. Compound I monofumarate form I

[0269] In one embodiment, a crystalline 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide monofumarate form I (compound I monofumarate form I) is provided, characterized by an X-ray powder diffraction pattern including peaks (±0.2°) at 6.1, 7.8, and 18.7°2θ as measured with a Cu-Kα diffractometer.

[0270] In some embodiments, compound I monofumarate form I is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 23.9, 14.5, or 21.0°²θ. In some embodiments, compound I monofumarate form I is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 24.5, 22.2, or 16.5°²θ. In some embodiments, compound I monofumarate form I is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 72.

[0271] In some embodiments, compound I monofumarate form I is further characterized by a DSC curve substantially as shown in Figure 73.

[0272] In some embodiments, compound I monofumarate form I further features a TGA that exhibits a weight loss of about 0.4% by weight from room temperature to about 100°C. In some embodiments, compound I monofumarate form I further features a TGA including a thermogram substantially as shown in Figure 74.

[0273] In some embodiments, compound I monofumarate form I is further characterized by a DVS curve substantially as shown in Figure 75.

[0274] In some embodiments, compound I monofumarate form I is substantially as shown in Figure 76. 1 Further features include the 1H NMR spectrum.

[0275] In some embodiments, compound I monofumarate form I is non-solvable. In some embodiments, compound I monofumarate form I contains about 1.0 molar equivalent of fumaric acid. Compound I hemi-L-tartrate form I

[0276] In one embodiment, a crystalline 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide hemi-L-tartrate form I (compound I hemi-L-tartrate form I) is provided, characterized by an X-ray powder diffraction pattern including peaks (±0.2°) at 8.5, 5.2, and 18.6°2θ as measured with a Cu-Kα diffractometer.

[0277] In some embodiments, compound I hemi-L-tartrate form I is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 17.0, 10.5, or 14.3°²θ. In some embodiments, compound I hemi-L-tartrate form I is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 24.6, 21.3, or 9.3°²θ. In some embodiments, compound I hemi-L-tartrate form I is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 77.

[0278] In some embodiments, compound I hemi-L-tartrate form I is further characterized by a DSC curve that includes endothermic reactions at approximately 64.6°C (start temperature) and approximately 126.9°C (start temperature). In some embodiments, compound I hemi-L-tartrate form I is further characterized by a DSC curve that includes endothermic reactions at approximately 91.0°C (peak) and approximately 133.3°C (peak). In some embodiments, compound I hemi-L-tartrate form I is further characterized by a DSC curve substantially as shown in Figure 78.

[0279] In some embodiments, compound I hemi-L-tartrate form I further features a TGA that exhibits a weight loss of about 4.8% by weight from room temperature to about 65°C. In some embodiments, compound I hemi-L-tartrate form I further features a TGA including a thermogram substantially as shown in Figure 79.

[0280] In some embodiments, compound I hemi-L-tartrate form I is further characterized by a DVS curve substantially as shown in Figure 80.

[0281] In some embodiments, compound I hemi-L-tartrate form I is substantially as shown in Figure 81. 1 Further features include the 1H NMR spectrum.

[0282] In some embodiments, compound I hemi-L-tartrate form I is a hydrate. In some embodiments, compound I hemi-L-tartrate form I contains about 0.5 molar equivalents of L-tartaric acid. Compound I Mono-ESA Form I

[0283] In one embodiment, a crystalline 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide monoethanesulfonate (ESA) salt form I (compound I monoESA form I) is provided, characterized by an X-ray powder diffraction pattern including peaks (±0.2°) at 6.4, 10.9, and 19.0°2θ as measured with a Cu-Kα diffractometer.

[0284] In some embodiments, compound I mono-ESA form I is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 21.0, 16.8, or 15.6°²θ. In some embodiments, compound I mono-ESA form I is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 24.6, 22.0, or 23.0°²θ. In some embodiments, compound I mono-ESA form I is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 82.

[0285] In some embodiments, compound I mono-ESA form I is further characterized by a DSC curve that includes endothermic reactions at approximately 86.3°C (start temperature) and approximately 123.0°C (start temperature). In some embodiments, compound I mono-ESA form I is further characterized by a DSC curve that includes endothermic reactions at approximately 104.9°C (peak) and approximately 128.2°C. In some embodiments, compound I mono-ESA form I is further characterized by a DSC curve substantially as shown in Figure 83.

[0286] In some embodiments, compound I mono-ESA form I further features a TGA that exhibits a weight loss of about 3.5% by weight from room temperature to about 86°C. In some embodiments, compound I mono-ESA form I further features a TGA including a thermogram substantially as shown in Figure 84.

[0287] In some embodiments, compound I monoESA form I is further characterized by a DVS curve substantially as shown in Figure 85.

[0288] In some embodiments, compound I monoESA form I is substantially as shown in Figure 86. 1 Further features include the 1H NMR spectrum.

[0289] In some embodiments, compound I mono-ESA form I is a hydrate. In some embodiments, compound I mono-ESA form I contains about 1.0 molar equivalent of ethylsulfonic acid. Compound I hemiglycolate form I

[0290] In one embodiment, a crystalline 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide hemiglycolate form I (compound I hemiglycolate form I) is provided, characterized by an X-ray powder diffraction pattern including peaks (±0.2°) at 6.2, 8.0, and 22.9°2θ as measured with a Cu-Kα diffractometer.

[0291] In some embodiments, compound I hemiglycolate form I is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 19.6, 2.3, or 25.6°²θ. In some embodiments, compound I hemiglycolate form I is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 24.2, 22.4, or 16.7°²θ. In some embodiments, compound I hemiglycolate form I is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 87.

[0292] In some embodiments, compound I hemiglycolate form I is further characterized by a DSC curve that includes endothermic heating at approximately 107.0°C (start temperature). In some embodiments, compound I hemiglycolate form I is further characterized by a DSC curve that includes endothermic heating at approximately 109.5°C (peak). In some embodiments, compound I hemiglycolate form I is further characterized by a DSC curve substantially as shown in Figure 88.

[0293] In some embodiments, compound I hemiglycolate form I further features a TGA that exhibits a weight loss of about 0.4% by weight from room temperature to about 100°C. In some embodiments, compound I hemiglycolate form I further features a TGA including a thermogram substantially as shown in Figure 89.

[0294] In some embodiments, compound I hemiglycolate form I is further characterized by a DVS curve substantially as shown in Figure 90.

[0295] In some embodiments, compound I hemiglycolate form I is substantially as shown in Figure 91. 1 Further features include the 1H NMR spectrum.

[0296] In some embodiments, compound I hemiglycolate form I is non-solvable. In some embodiments, compound I hemiglycolate form I contains about 0.5 molar equivalents of glycolic acid. Compound I sulfate form I

[0297] In one embodiment, a crystalline 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide sulfate form I (compound I sulfate form I) is provided, characterized by an X-ray powder diffraction pattern including peaks (±0.2°) at 5.5, 4.9, and 11.1°2θ as measured with a Cu-Kα diffractometer.

[0298] In some embodiments, compound I sulfate form I is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 19.2, 9.9, or 16.8°²θ. In some embodiments, compound I sulfate form I is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 17.4, 22.1, or 5.5°²θ. In some embodiments, compound I sulfate form I is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 92.

[0299] In some embodiments, compound I sulfate form I is further characterized by a DSC curve including endothermic reactions at approximately 44.2°C (start temperature), approximately 125.8°C (start temperature), and approximately 164.4°C (start temperature). In some embodiments, compound I sulfate form I is further characterized by a DSC curve including endothermic reactions at approximately 64.2°C (peak), approximately 133.5°C (peak), and approximately 177.8°C (peak). In some embodiments, compound I sulfate form I is further characterized by a DSC curve substantially as shown in Figure 93.

[0300] In some embodiments, compound I sulfate form I further features a TGA that exhibits a weight loss of about 2.1% by weight from room temperature to about 100°C. In some embodiments, compound I sulfate form I further features a TGA including a thermogram substantially as shown in Figure 94.

[0301] In some embodiments, compound I sulfate form I is solvated. In some embodiments, compound I sulfate form I is a hydrate. In some embodiments, compound I sulfate form I is an ethanol solvate. Compound I phosphate form I

[0302] In one embodiment, a crystalline 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide phosphate form I (compound I phosphate form I) is provided, characterized by an X-ray powder diffraction pattern including peaks (±0.2°) at 4.8, 9.7, and 16.9°2θ as measured with a Cu-Kα diffractometer.

[0303] In some embodiments, compound I phosphate form I is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 17.9, 10.3, or 22.0°²θ. In some embodiments, compound I phosphate form I is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 19.2, 23.6, or 25.9°²θ. In some embodiments, compound I phosphate form I is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 95.

[0304] In some embodiments, compound I phosphate form I is further characterized by a DSC curve including endothermic reactions at approximately 46.1°C (start temperature), approximately 146.3°C (start temperature), and approximately 178.8°C (start temperature). In some embodiments, compound I phosphate form I is further characterized by a DSC curve including endothermic reactions at approximately 75.1°C (peak), approximately 152.2°C (peak), and approximately 185.1°C (peak). In some embodiments, compound I phosphate form I is further characterized by a DSC curve substantially as shown in Figure 96.

[0305] In some embodiments, compound I phosphate form I further features a TGA that exhibits a weight loss of about 4.2% by weight from room temperature to about 120°C. In some embodiments, compound I phosphate form I further features a TGA including a thermogram substantially as shown in Figure 97.

[0306] In some embodiments, compound I phosphate form I is non-solvable. Compound I hemi-HCl form I

[0307] In one embodiment, a crystalline 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide hemiHCl salt form I (compound I hemiHCl form I) is provided, characterized by an X-ray powder diffraction pattern including peaks (±0.2°) at 5.6, 9.2, and 11.2°2θ as measured with a Cu-Kα diffractometer.

[0308] In some embodiments, compound I hemiHCl form I is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 4.7, 17.2, or 6.8°²θ. In some embodiments, compound I hemiHCl form I is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 11.8, 15.9, or 19.0°²θ. In some embodiments, compound I hemiHCl form I is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 98.

[0309] In some embodiments, compound I hemiHCl form I is further characterized by a DSC curve that includes endothermic activity at approximately 79.9°C (start temperature) and approximately 136.7°C (start temperature). In some embodiments, compound I hemiHCl form I is further characterized by a DSC curve that includes endothermic activity at approximately 112.3°C (peak) and approximately 140.4°C (peak). In some embodiments, compound I hemiHCl form I is further characterized by a DSC curve substantially as shown in Figure 99.

[0310] In some embodiments, compound I hemiHCl form I further features a TGA that exhibits a weight loss of about 5.5% by weight from room temperature to about 130°C. In some embodiments, compound I hemiHCl form I further features a TGA including a thermogram substantially as shown in Figure 100.

[0311] In some embodiments, compound I hemiHCl form I is further characterized by a DVS curve substantially as shown in Figure 101.

[0312] In some embodiments, compound I hemiHCl form I is a hydrate. Compound I Cocrystal Form I

[0313] In one embodiment, a crystalline cocrystal (compound I cocrystal form I) of compound I and 4-(((S)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide is provided, characterized by an X-ray powder diffraction pattern including peaks (±0.2°) at 19.1, 10.3, and 9.4°2θ, as measured with a Cu-Kα diffractometer.

[0314] In some embodiments, compound I cocrystal form I is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 16.6, 17.1, and 14.0°²θ. In some embodiments, compound I cocrystal form I is further characterized by an X-ray powder diffraction pattern, measured with a Cu-Kα diffractometer, containing one or more additional peaks (±0.2°) at 4.7, 14.9, and 20.6°²θ. In some embodiments, compound I cocrystal form I is further characterized by an X-ray powder diffraction pattern substantially as shown in Figure 102.

[0315] In some embodiments, compound I cocrystal form I is further characterized by a DSC curve that includes endothermic activity at approximately 42.6°C (start temperature) and approximately 238.6°C (start temperature). In some embodiments, compound I cocrystal form I is further characterized by a DSC curve that includes endothermic activity at approximately 53.9°C (peak) and approximately 241.0°C (peak). In some embodiments, compound I cocrystal form I is further characterized by a DSC curve substantially as shown in Figure 103.

[0316] In some embodiments, compound I cocrystal form I further features a TGA that exhibits a weight loss of about 1.6% by weight from room temperature to about 65°C and a weight loss of about 6.6% by weight from about 65°C to about 200°C. In some embodiments, compound I cocrystal form I further features a TGA that includes a thermogram substantially as shown in Figure 104.

[0317] In some embodiments, compound I cocrystal form I is solvated. In some embodiments, compound I cocrystal form I is the 2-MeTHF solvate. composition

[0318] In some embodiments, compositions are provided herein that include a salt or solid form of 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (Compound I) as described herein.

[0319] In one embodiment, a composition is provided comprising a salt or solid form of 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (compound I), or a salt or solvate thereof, wherein at least 50% to 99% (for example, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of compound I present in the composition is in the form of a specified salt, solid form, crystalline form, or crystalline salt form.

[0320] In one embodiment, a composition is provided comprising 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide form I (compound I form I), or a solvate thereof, wherein at least 50% to 99% (for example, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of compound I present in the composition is compound I form I.

[0321] In one embodiment, a composition is provided comprising 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide form II (compound I form II), or a solvate thereof, wherein at least 50% to 99% (for example, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of compound I present in the composition is compound I form II.

[0322] In one embodiment, a composition is provided comprising 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide form III (compound I form III), or a solvate thereof, wherein at least 50% to 99% (for example, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of compound I present in the composition is compound I form III.

[0323] In one embodiment, a composition is provided comprising 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide form IV (compound I form IV), or a solvate thereof, wherein at least 50% to 99% (for example, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of compound I present in the composition is compound I form IV.

[0324] In one embodiment, a composition is provided comprising 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide form V (compound I form V), or a solvate thereof, wherein at least 50% to 99% (for example, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of compound I present in the composition is compound I form V.

[0325] In one embodiment, a composition is provided comprising 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide form VI (compound I form VI), or a solvate thereof, wherein at least 50% to 99% (for example, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of compound I present in the composition is compound I form VI.

[0326] In one embodiment, a composition is provided comprising 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide form VII (compound I form VII), or a solvate thereof, wherein at least 50% to 99% (for example, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of compound I present in the composition is compound I form VII.

[0327] In one embodiment, a composition is provided comprising 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide form VIII (compound I form VIII), or a solvate thereof, wherein at least 50% to 99% (for example, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of compound I present in the composition is compound I form VIII.

[0328] In one embodiment, a composition is provided comprising 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide form IX (compound I form IX), or a solvate thereof, wherein at least 50% to 99% (for example, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of compound I present in the composition is compound I form IX.

[0329] In one embodiment, a composition is provided comprising 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide form X (compound I form X), or a solvate thereof, wherein at least 50% to 99% (for example, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of compound I present in the composition is compound I form X.

[0330] In one embodiment, a composition is provided comprising 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide form XI (compound I form XI), or a solvate thereof, wherein at least 50% to 99% (for example, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of compound I present in the composition is compound I form XI.

[0331] In one embodiment, a composition is provided comprising 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide form XII (compound I form XII), or a solvate thereof, wherein at least 50% to 99% (for example, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of compound I present in the composition is compound I form XII.

[0332] In one embodiment, a composition is provided comprising 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide form XIII (compound I form XIII), or a solvate thereof, wherein at least 50% to 99% (for example, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of compound I present in the composition is compound I form XIII.

[0333] In one embodiment, a composition is provided comprising 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide amorphous form I (amorphous form of compound I), or a solvate thereof, wherein at least 50% to 99% (for example, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of compound I present in the composition is the amorphous form of compound I.

[0334] In one embodiment, a composition is provided comprising 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide monocitrate form I (compound I monocitrate form I), or a solvate thereof, wherein at least 50% to 99% (for example, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of compound I present in the composition is compound I monocitrate form I.

[0335] In one embodiment, a composition is provided comprising 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide monocitrate form II (compound I monocitrate form II), or a solvate thereof, wherein at least 50% to 99% (for example, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of compound I present in the composition is compound I monocitrate form II.

[0336] In one embodiment, a composition is provided comprising 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide monocitrate form III (compound I monocitrate form III), or a solvate thereof, wherein at least 50% to 99% (for example, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of compound I present in the composition is compound I monocitrate form III.

[0337] In one embodiment, a composition is provided comprising 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide monocitrate form IV (compound I monocitrate form IV), or a solvate thereof, wherein at least 50% to 99% (for example, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of compound I present in the composition is compound I monocitrate form IV.

[0338] In one embodiment, a composition is provided comprising 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide hemicitrate form I (compound I hemicitrate form I), or a solvate thereof, wherein at least 50% to 99% (for example, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of compound I present in the composition is compound I hemicitrate form I.

[0339] In one embodiment, a composition is provided comprising 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide monoHCl form I (compound I monoHCl salt form I), or a solvate thereof, wherein at least 50% to 99% (for example, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of compound I present in the composition is compound I monoHCl form I.

[0340] In one embodiment, a composition is provided comprising 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide monomaleate form I (compound I monomaleate form I), or a solvate thereof, wherein at least 50% to 99% (for example, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of compound I present in the composition is compound I monomaleate form I.

[0341] In one embodiment, a composition is provided comprising 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide hemi-fumarate form I (compound I hemi-fumarate form I), or a solvate thereof, wherein at least 50% to 99% (for example, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of compound I present in the composition is compound I hemi-fumarate form I.

[0342] In one embodiment, a composition is provided comprising 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide monofumarate form I (compound I monofumarate form I), or a solvate thereof, wherein at least 50% to 99% (for example, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of compound I present in the composition is compound I monofumarate form I.

[0343] In one embodiment, a composition is provided comprising 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide hemi-L-tartrate form I (compound I hemi-L-tartrate form I), or a solvate thereof, wherein at least 50% to 99% (for example, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of compound I present in the composition is compound I hemi-L-tartrate form I.

[0344] In one embodiment, a composition is provided comprising 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide monoESA salt form I (compound I monoESA form I), or a solvate thereof, wherein at least 50% to 99% (for example, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of compound I present in the composition is compound I monoESA form I.

[0345] In one embodiment, a composition is provided comprising 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide hemiglycolate form I (compound I hemiglycolate form I), or a solvate thereof, wherein at least 50% to 99% (for example, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of compound I present in the composition is compound I hemiglycolate form I.

[0346] In one embodiment, a composition is provided comprising 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide sulfate form I (compound I sulfate form I), or a solvate thereof, wherein at least 50% to 99% (for example, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of compound I present in the composition is compound I sulfate form I.

[0347] In one embodiment, a composition is provided comprising 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide phosphate form I (compound I phosphate form I), or a solvate thereof, wherein at least 50% to 99% (for example, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of compound I present in the composition is compound I phosphate form I.

[0348] In one embodiment, a composition is provided comprising 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide hemiHCl salt form I (compound I hemiHCl form I), or a solvate thereof, wherein at least 50% to 99% (for example, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of compound I present in the composition is compound I hemiHCl form I.

[0349] In one embodiment, a composition is provided comprising a crystalline cocrystal (compound I cocrystal form I) of compound I and 4-(((S)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide, or a solvate thereof, wherein at least 50% to 99% (for example, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of compound I present in the composition is compound I cocrystal form I.

[0350] In some embodiments, the composition is a pharmaceutical composition further comprising pharmaceutically acceptable excipients. Pharmaceutical composition and administration

[0351] In some embodiments, a chemical substance that inhibits kinase IRAK4 (e.g., a salt or solid form of compound I described herein, and its salts, cocrystals, solvates, or hydrates) is administered as a pharmaceutical composition comprising the chemical substance, one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents described herein. Some embodiments provide a pharmaceutical composition comprising the crystalline form described herein and a pharmaceutically acceptable carrier.

[0352] In some embodiments, the chemical substance may be administered in combination with one or more conventional pharmaceutical excipients. pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS), e.g., d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms, e.g., Tween®, poloxamer, or other similar polymer delivery matrices, serum proteins, e.g., human serum albumin, buffers, e.g., phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and lanolin. Cyclodextrins such as α-, β-, and γ-cyclodextrins, or chemically modified derivatives such as hydroxyalkylcyclodextrins including 2- and 3-hydroxypropyl-β-cyclodextrin, or other solubilizing derivatives may also be used to enhance the delivery of the chemicals described herein. Dosage forms or compositions can be prepared containing the chemicals described herein in an amount ranging from 0.005% to 100%, with the remainder consisting of non-toxic excipients. The compositions intended may contain 0.001% to 100%, 0.1% to 95% in one embodiment, 75% to 85% in another embodiment, and 20% to 80% in a further embodiment, of the chemicals provided herein. Practical methods for preparing such dosage forms are known or obvious to those skilled in the art. See, for example, Remington: The Science and Practice of Pharmacy, 22nd Edition (Pharmaceutical Press, London, UK, 2012). Route of administration and compositional components

[0353] In some embodiments, the chemical substances or pharmaceutical compositions thereof described herein can be administered to the target subject as required by any acceptable route of administration. Acceptable routes of administration include, but are not limited to, oral, skin, cervix, paranasal sinuses, trachea, enteral, epidural, interstitial, abdominal, arterial, bronchial, bursa, brain, cisternal, coronary artery, intradermal, intratubular, duodenal, intradural, intraepidermal, esophageal, gastric, gingival, ileum, lymphatic vessel, intramedullary, intrameningeal, intramuscular, ovarian, abdominal, prostate, lung, paranasal sinuses, spinal cord, synovial, testis, intramedullary cavity, renal tubule, tumor, uterus, intravascular, intravenous, nasal cavity, nasogastric tube, oral, parenteral, percutaneous, peridural, rectal, respiratory tract (inhalation), subcutaneous, sublingual, submucosal, local, percutaneous, transmucosal, tracheal, ureter, urethra, and vagina.

[0354] The composition can be formulated for parenteral administration, for example, for injection via intravenous, intramuscular, subcutaneous, or even intraperitoneal routes. Typically, such compositions can be prepared for injection as either a liquid solution or a suspension. Solid forms suitable for preparing a solution or suspension by adding liquid before injection can also be prepared, and the formulation can also be emulsified. The preparation of such formulations is known to those skilled in the art in light of this disclosure.

[0355] Suitable pharmaceutical formulations for injection include sterile aqueous solutions or dispersions; formulations containing sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the immediate preparation of sterile injectable solutions or dispersions. Generally, formulations need to be sterile and fluid enough to be easily injected. They also need to be stable under manufacturing and storage conditions and protected from contamination by microorganisms such as bacteria and fungi.

[0356] The carrier may be a solvent or dispersion medium, for example, containing water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. Appropriate fluidity can be maintained, for example, by the use of coatings such as lecithin, maintaining the required particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial action can be achieved by various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and thimerosal. In many cases, isotonic agents, such as sugars or sodium chloride, may be included. Sustained absorption of the injectable composition can be achieved by using absorption retarders, such as aluminum monostearate and gelatin, in the composition.

[0357] Sterile injectable solutions are prepared by incorporating the required amount of the active compound (i.e., the chemicals listed herein) into a suitable solvent, along with various other components listed above as needed, and then sterilizing by filtration. Generally, dispersions are prepared by incorporating various sterilized active ingredients into a sterile vehicle containing a basic dispersion medium and other necessary components from those listed above. For sterile powders used to prepare sterile injectable solutions, examples of preparation methods include vacuum drying and freeze-drying, which yield the active ingredient powder and any additional desired components from its pre-sterilized filtered solution.

[0358] Pharmacologically acceptable excipients usable in rectal compositions as gels, creams, enemas, or rectal suppositories include, but are not limited to, any one or more cocoa butter glycerides, synthetic polymers, e.g., polyvinylpyrrolidone, PEG (PEG ointment, etc.), glycerin, glycerinated gelatin, hydrogenated vegetable oil, poloxamer, mixtures of polyethylene glycol and fatty acid esters of polyethylene glycol of various molecular weights, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxide SBN (anoxide Examples of ingredients include SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodium propyl p-oxybenzoate, diethylamine, carbomer, carbopole, methyl oxybenzoic acid, macrogol cetostearyl ether, cocoyl caprylate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-methabites, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins such as vitamins A and E, and potassium acetate.

[0359] In certain embodiments, suppositories can be prepared by mixing the chemicals described herein with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or suppository wax, which is solid at room temperature but becomes liquid at body temperature and melts in the rectum to release the active compound. In other embodiments, the composition for rectal administration is in the form of an enema.

[0360] In other embodiments, the chemical substances or pharmaceutical compositions thereof described herein are suitable for local delivery to the gastrointestinal tract or GI tract by oral administration (e.g., in solid or liquid dosage forms).

[0361] Examples of solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the chemical is mixed with one or more pharmaceutically acceptable excipients such as sodium citrate or dicalcium phosphate, and / or a) fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) dissolution retarders such as paraffin; f) absorption enhancers such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also include a buffer. Similar types of solid compositions can also be used as fillers for soft and rigid gelatin capsules, using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycol, etc.

[0362] In one embodiment, the composition may take the form of a unit dosage form such as a pill or tablet, and therefore the composition may contain, along with the chemicals provided herein, diluents such as lactose, sucrose, and dicalcium phosphate; lubricants such as magnesium stearate; and binders such as starch, acacia gum, polyvinylpyrrolidone, gelatin, cellulose, and cellulose derivatives. Another solid dosage form involves encapsulating a powder, marme, solution, or suspension (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglycerides) in a capsule (gelatin or cellulose-based capsule). Unit dosage forms in which one or more chemicals or additional active ingredients provided herein are physically separated are also conceivable, such as capsules containing granules (or tablets within a capsule) of each drug; two-layer tablets; and two-chambered Zel capsules. Enteric-coated or delayed-release oral dosage forms are also conceivable.

[0363] Other physiologically acceptable compounds include wetting agents, emulsifiers, dispersants, or preservatives that are particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known, such as phenol and ascorbic acid.

[0364] In certain embodiments, the excipients are sterilized and generally free of undesirable substances. These compositions can be sterilized by conventional, well-known sterilization techniques. Sterility is not required for excipients in various oral dosage forms, such as tablets and capsules. USP / NF standards are usually sufficient.

[0365] Ophthalmic compositions may contain, but are not limited to, one or more of the following: thickeners (e.g., carboxymethylcellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol); stabilizers (e.g., Pluronic® (triblock copolymer), cyclodextrin); and preservatives (e.g., benzalkonium chloride, EDTA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)).

[0366] Topical compositions may include ointments and creams. Ointments are typically semi-solid formulations based on petrolatum or other petroleum derivatives. Creams containing the selected active ingredient are typically viscous liquids or semi-solid emulsions, often either oil-in-water or water-in-oil. Cream bases are typically washable and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase, sometimes referred to as the “internal” phase, generally consists of petrolatum and fatty alcohols such as cetyl alcohol or stearyl alcohol. The aqueous phase is usually not essential but exceeds the volume of the oil phase and generally contains a humectant. Emulsifiers in cream formulations are generally nonionic, anionic, cationic, or amphoteric surfactants. Like other carriers or vehicles, ointment bases need to be inert, stable, non-irritating, and non-sensitizing.

[0367] In any of the embodiments described above, the pharmaceutical composition described herein may comprise one or more of the following: lipids, interlayer crosslinked multilayer vehicles, biodegradable poly(D,L-lactic acid-co-glycolic acid) [PLGA]-based or polyanhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers. Dosage

[0368] The dosage may be adjusted depending on the patient's needs, the severity of the condition being treated, and the specific compound used. The appropriate dosage for a particular situation may be determined by those skilled in the medical field. In some cases, the total daily dose may be divided and administered in multiple doses throughout the day, or by means of continuous delivery.

[0369] In some embodiments, the chemicals described herein are present in concentrations of approximately 0.001 mg / kg to approximately 500 mg / kg (for example, approximately 0.001 mg / kg to approximately 200 mg / kg; approximately 0.01 mg / kg to approximately 200 mg / kg; approximately 0.01 mg / kg to approximately 150 mg / kg; approximately 0.01 mg / kg to approximately 100 mg / kg; approximately 0.01 mg / kg to approximately 50 mg / kg; approximately 0.01 mg / kg to approximately 10 mg / kg; approximately 0.01 mg / kg to approximately 5 mg / kg; approximately 0.01 mg / kg to approximately 1 mg / kg; The drug is administered in doses of approximately 0.01 mg / kg to 0.5 mg / kg; approximately 0.01 mg / kg to 0.1 mg / kg; approximately 0.1 mg / kg to 200 mg / kg; approximately 0.1 mg / kg to 150 mg / kg; approximately 0.1 mg / kg to 100 mg / kg; approximately 0.1 mg / kg to 50 mg / kg; approximately 0.1 mg / kg to 10 mg / kg; approximately 0.1 mg / kg to 5 mg / kg; approximately 0.1 mg / kg to 1 mg / kg; approximately 0.1 mg / kg to 0.5 mg / kg), where kg refers to the patient's body weight. regimen

[0370] The aforementioned dosage can be administered daily (for example, as a single dose or in two or more divided doses) or on days other than daily (for example, every other day, every two days, every three days, once a week, twice a week, once every two weeks, or once a month).

[0371] In some embodiments, the duration of administration of the chemicals described herein is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In further embodiments, the period of administration cessation is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In one embodiment, the chemical substance described herein is administered to an individual for a certain period, and then administered for a separate period. In another embodiment, the chemical substance described herein is administered for a first period and a second period following the first period, with administration being suspended during the second period, followed by a third period in which administration of the chemical substance described herein is initiated, and then a fourth period following the third period in which administration is suspended. In one embodiment of this specification, the administration period of the chemical substance described herein and the subsequent administration discontinuation period are repeated over a predetermined or indefinite period. In a further embodiment, the administration period is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In further embodiments, the period for discontinuing administration is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. Treatment methods

[0372] This disclosure features a method for treating a subject (e.g., a human) having a disease, disorder, or condition regulated by interleukin-1 receptor-related kinase-4 (IRAK4).

[0373] In some embodiments, the diseases, disorders, or conditions regulated by IRAK4 include inflammatory or fibrotic disorders, rheumatoid arthritis (RA), inflammatory bowel disease (IBD), gout, Lyme disease, arthritis, psoriasis, pelvic inflammatory disease, systemic lupus erythematosus (SLE), Sjögren's syndrome, inflammation associated with gastrointestinal infections including Clostridioides difficile, viral myocarditis, acute and chronic tissue injury, non-alcoholic steatohepatitis (NASH), alcoholic hepatitis, and renal diseases including chronic kidney disease and diabetic kidney disease.

[0374] In some embodiments, the disease, disorder, or condition regulated by IRAK4 is cancer, such as lymphoma.

[0375] In some embodiments, the diseases, disorders, or conditions regulated by IRAK4 are metabolic disorders such as diabetes mellitus, including type 1 and type 2 diabetes mellitus, metabolic syndrome, dyslipidemia, obesity, impaired glucose tolerance, hypertension, elevated serum cholesterol, and elevated triglycerides.

[0376] Furthermore, this specification also provides a method for treating an inflammatory condition, comprising administering to a patient who needs treatment for an inflammatory condition a salt or solid form of compound I, or a pharmaceutical composition comprising a salt or solid form of compound I and a pharmaceutically acceptable carrier. Some embodiments provide a method for treating an inflammatory condition, comprising administering to a patient who needs treatment for an inflammatory condition the crystalline form or pharmaceutical composition described herein. Some embodiments provide a method for treating an inflammatory condition, comprising administering to a patient who needs treatment for an inflammatory condition a therapeutically effective amount of the crystalline form or pharmaceutical composition described herein.

[0377] In some embodiments, the inflammatory condition is selected from inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), psoriasis, and rheumatoid arthritis.

[0378] In some embodiments, the inflammatory condition is inflammatory bowel disease (IBD).

[0379] In some embodiments, the inflammatory condition is rheumatoid arthritis. Combination therapy

[0380] This disclosure envisions both monotherapy regimens and combination therapy regimens.

[0381] In some embodiments, the methods described herein may further include administering one or more additional therapies (e.g., one or more additional therapeutic agents and / or one or more therapeutic regimens) in combination with the administration of the chemicals described herein.

[0382] In some embodiments, the chemicals described herein can be administered in combination with one or more additional therapeutic agents.

[0383] Patients treated with the IRAK4 inhibitors of this disclosure often exhibit diseases or conditions that would benefit from treatment with other therapeutic agents. These diseases or conditions may be inflammatory or associated with cancer, metabolic disorders, gastrointestinal disorders, etc. Accordingly, one aspect of this disclosure is a method for treating an inflammation-related disease or condition, or metabolic disorder, gastrointestinal disorder, or cancer, etc., comprising administering the chemicals described herein in combination with one or more compounds useful for treating such diseases to a subject in need, particularly a human subject.

[0384] In some embodiments, the chemicals described herein are co-formulated with one or more additional active ingredients. In some embodiments, the other active ingredients are administered in separate dosage forms at approximately the same time. In some embodiments, the other active ingredients may be administered sequentially and at different times in relation to the chemicals described herein. Combinations for inflammatory diseases and conditions

[0385] For example, the chemicals of this disclosure include one or more 5-lipoxygenase inhibitors, acetylcholinesterase inhibitors, acetyl-CoA carboxylase (ACC) inhibitors, ACTH receptor agonists, activin receptor antagonists, acyltransferase inhibitors, adrenocorticotropic hormone ligands, AKT1 gene inhibitors, alkaline phosphatase modulators, alkaline phosphatase stimulants, androgen receptor agonists, apolipoprotein C3 antagonists, ASK1 kinase inhibitors, bactericidal permeable protein stimulants, β-adrenergic receptor antagonists, β-glucuronidase inhibitors, B lymphocyte antigen CD20 inhibitors, bradykinin receptor modulators, BTK kinase inhibitors, calcineurin inhibitors, calcium channel inhibitors, cannabinoid CB1 receptor modulators, and cannabinoid CB2 receptor modulators. Cannabinoid receptor antagonists, cannabinoid receptor modulators, caspase inhibitors, cathepsin S inhibitors, CCN protein stimulants, CCR3 chemokine antagonists, CCR5 chemokine antagonists, CCR9 chemokine antagonists, CD3 modulators, CD40 ligand inhibitors, CD40 ligand receptor antagonists, CD49b antagonists, CD49d antagonists, CD89 agonists, cell adhesion molecule inhibitors, chemokine CXC ligand inhibitors, CHST15 gene inhibitors, collagen modulators, CSF-1 agonists, CSF-1 antagonists, CXC10 chemokine ligand inhibitors, CXCR2 chemokine antagonists, cyclic GMP phosphodiesterase inhibitors, cyclooxygenase 2 inhibitors, cyclooxygenase inhibitors, cyclooxygenase stimulants, cytochrome P450 3A4 inhibitors, cytotoxic T lymphocyte protein-4 stimulants, dihydroceramide Δ4 desaturates inhibitors, dihydroorotate dehydrogenase inhibitors, DNA polymerase inhibitors, DPP-4 inhibitors, EGFR family tyrosine kinase receptor modulators, eosinophil peroxidase inhibitors, eotaxin ligand inhibitors, EP4 prostanoid receptor agonists, epidermal growth factor agonists, epidermal growth factor ligands, estrogen receptor β agonists, factor XIII agonists, FGF-10 ligands, FGF2 receptor agonists,Fractalkine ligand inhibitors, free fatty acid receptor 2 antagonists, FXR agonists, GATA3 transcription factor inhibitors, glucagon-like peptide 1 agonists, glucagon-like peptide 2 agonists, glucocorticoid agonists, GM-CSF receptor agonists, G protein-coupled receptor 84 antagonists, guanylate cyclase receptor agonists, histamine H2 receptor antagonists, histone acetyltransferase inhibitors, histone deacetylase inhibitors Agents, HLA class II antigen modulators, hydrolase inhibitors, HSD17β13 inhibitors, ICAM1 gene inhibitors, ICAM-1 inhibitors, IL1 gene inhibitors, IL-10 agonists, IL10 gene stimulants, IL-11 agonists, IL-12 antagonists, IL12 gene inhibitors, IL-13 antagonists, IL-17 antagonists, IL-2 antagonists, IL-2 receptor α subunit inhibitors, IL-21 antagonists, IL-23 antagonists IL-6 antagonist, IL-6 gene inhibitor, IL-6 receptor modulator, IL-7 antagonist, IL-8 antagonist, immunoglobulin G1 agonist, immunoglobulin G2 modulator, inosine monophosphate dehydrogenase inhibitor, insulin resistance improving agent, integrin α-4 / β-1 antagonist, integrin α-4 / β-7 antagonist, integrin α-E antagonist, integrin antagonist, integrin β-7 antagonist, interferon β ligand, interleukin 17E ligand inhibitor, interleukin ligand inhibitor, interleukin receptor 17A antagonist, interleukin receptor 17B antagonist, interleukin-1β ligand, interleukin-1β ligand modulator, interleukin-6 ligand inhibitor, JAK tyrosine kinase inhibitor, Jak1 tyrosine kinase inhibitor, JAK2 gene inhibitor, Jak3 tyrosine kinase inhibitor, Jun N-terminal kinase inhibitors, LanC-like protein 2 modulators, leukotriene BLT receptor antagonists, lipoxygenase modulators, L-selectin antagonists, MAdCAM inhibitors, matrix metalloproteinase inhibitors, matrix metalloproteinase modulators, melanocortin agonists,Membrane copper amine oxidase inhibitors, metalloproteinase-2 inhibitors, metalloproteinase-9 inhibitors, MIP3α ligand inhibitors, mitochondrial 10kDa heat shock protein stimulants, monocyte differentiation antigen CD14 inhibitors, mTOR inhibitors, mucin stimulants, NAD-dependent deacetylase sirtuin-1 stimulants, natriuretic peptide receptor C agonists, neureglin-4 ligands, nicotinic acetylcholine receptor agonists, nicotinic Ach receptor α4 subunit modulators, nicotinic Ach receptor α7 subunit stimulants, nicotinic Ach receptor β2 subunit modulators, NK1 receptor antagonists, NKG2D-activated NK receptor antagonists, nuclear factor κB inhibitors, opioid growth factor receptor agonists, opioid receptor antagonists, opioid receptor δ antagonists, oxidoreductase inhibitors, P2X7 purine receptor agonists, p38 MAP kinase inhibitors, PARP inhibitors, PDE4 inhibitors, PDGF receptor agonists, phagocytosis-stimulating peptide modulators, phosphorylated MurNAc pentapeptide transferase inhibitors, phospholipase A2 inhibitors, platelet-activating factor receptor antagonists, potassium channel inhibitors, PPARα agonists, PPARδ agonists, PPARγ agonists, protein CYR61 stimulants, protein fimH inhibitors, protein kinase Cα inhibitors, protein kinase Cβ inhibitors, protein kinase Cδ inhibitors, protein kinase Cε inhibitors, protein kinase Cη inhibitors, protein kinase Cθ inhibitors, protein kinase G inhibitors, pro Thein kinase inhibitors, P-selectin glycoprotein ligand-1 inhibitors, purine biosynthesis protein PurH inhibitors, retinoic acid receptor α-agonists, retinoic acid receptor β-agonists, retinoid receptor agonists, RNA polymerase inhibitors, SMAD-7 inhibitors, sodium channel inhibitors, somatostatin receptor agonists, sphingosine-1-phosphate phosphatase-1 stimulants, sphingosine-1-phosphate phosphatase modulators, sphingosine kinase 1 inhibitors, sphingosine kinase 2 inhibitors, sphingosine-1-phosphate receptor 1 agonists, sphingosine-1-phosphate receptor 1 antagonists, sphingosine-1-phosphate receptor 1 modulators,Sphingosine-1 phosphate receptor 5 modulator, STAT3 gene inhibitor, STAT-3 inhibitor, STAT4 inhibitor, stem cell antigen 1 inhibitor, superoxide dismutase modulator, superoxide dismutase stimulant, SYK kinase inhibitor, T cell surface glycoprotein CD28 inhibitor, TGFβ1 ligand inhibitor, thymrine agonist, THRβ agonist, TLR2 antagonist, TLR4 antagonist, TLR-9 agonist, TNFα ligand inhibitor, TNFα ligand modulator, TNF antagonist, TPL2 kinase inhibitor, trefoil factor modulator, tryptase inhibitor, tryptophan 5- Hydroxylase inhibitors, tumor necrosis factor 14 ligand modulators, TYK2 kinase inhibitors, type I TNF receptor antagonists, type II TNF receptor modulators, unspecified growth factor receptor modulators, vanilloid VR1 agonists, vitamin D3 receptor agonists, zonulin inhibitors, abatacept; acemannan; adalimumab; DCCT-10; apremilast; AST-120; valsalazid; valsalazid sodium; basiliximab; beclomethasone propionate; budesonide, D-9421; budesonide MMX; catridecacog; certolizumab pegol; Clostridium butyricum Butyricum), etanercept; fingolimod; glatiramer acetate; golimumab; infliximab; infliximab biosimilar; infliximab biosimilar; interferon β-1a; lenalidomide mesalazine; GED-0001; AJG-501; methenekephalin acetate and tridecacephamoltide acetate, mycophenolate mofetil; naltrexone; natalizumab, nitazoxanide; olsalazine n; Oprelbequin; Propionyl-L-carnitine; Recombinant interferon β-1a; Remestemcel-L, Rifaximin, Rituxima bropivacaine; Rosiglitazone; Salglamostim; Secukinumab; SPD-480; Tacrolimus, Tamibarotene; Teduglutide, Thalidomide; Tocilizumab RO-4877533; Tofacitinib, CP-690550; Swine whipworm eggs (Trichuris suis ova) ASP-1002; Ustekinumab,Valganciclovir; Vedolizumab, Zileuton; Anti-CD3 imaging agent (antibody fragment, cancer / autoimmune disease), ImaginAb; AVX-470; Cyclosporine CXCR1 / 2 ligand mAb (immunology), Eli Lilly; FFP-102; GSK-3050002; INN-108; IR-777; SGM-1019; Pegylodecakine; PF-06480605; PF-06651600; SER-287; Syn-1002; Thetanix, Tolerogenic dendritic cell therapy TOP-1288; VBY-036; VBY-129; 946414-98-8; BMS-936557; 99mTc-Annexin V-128, ABC-294640; Abrillumab; Aleque l, AMG-139; Amicelimod; APD-334; ASP-3291; Beclomethasone propionate; Vertilimumab, Cyclosporin crazakizumab; DLX-105; Dolucanatide, E-6011; ETX-201; FFP-104; Filgotinib, Foralumab, GED-0507-34-Levo, Gibinostat, GLPG-0974; GLPG-1205; Iberogast N (ulcerative colitis), Bayer; BAY98-7410; INV-103; JNJ-40346527; K(D)PT, KAG-308; KHK-4083; KRP-203; Larazotide acetate, CB-01-05-MMX; LY-3074828; Mesalamine and N-acetylcysteine; Midismase; Morglamostim follow-on biological agents, fosfomycin and carbapenem, Reponex; Pluripotent adult progenitor cell therapy (ischemia / cerebral palsy), Athersys / Healio s;NN-8828;Orokizumab, OvaSave, P-28-GST;PDA-002;PF-4236921;PF-547659;Prednisolone, PUR-0110;QBECO, RBX-2660;Naltrexone (converted);JKB-122;SB-012;Sotrastaurin;STNM-01;TAK-114;Tetomilast;Debio-0512, TRK-170;TRX-318;Vatelizumab;VB-201;ZP-1848;Zukapsaicin,ABT-494; alicaforsen; Ampion; BI-655066; briakinumab; cannabidiol; carotegastmethyl, covitrimod, dexamethasone sodium phosphate; elafibranol, etrolizumab, GS-5745; HMPL-004; LP-02; mesalazine; metronidazole mongersen; ocrelizumab; ozanimod; peficitinib, RHB-104; rifaximin, tildrakizumab, tralokinumab, brodalumab, lacini, It can be combined with nimod, precanatide, telotristat etiprate; infliximab biosimilar, Samsung Bioepis; AZD-058; and rifabutin and clarithromycin, as well as clofazimine.

[0386] Furthermore, a non-exclusive list of compounds that can be combined with the chemicals of this disclosure includes: 5-lipoxygenase inhibitors, e.g., dileuton, etalocibm, FPL-64170, E-3040, and BU-4601A; acetylcholinesterase inhibitors, e.g., BL-7040; ACTH receptor agonists, e.g., methenekephalin acetate and tridecactide acetate, and FAR-404; activin receptor antagonists, e.g., follistatin; acyltransferase inhibitors, e.g., AZD-0585; adrenocorticotropic hormone ligands, e.g., me Tenkephalin acetate and tridecactide acetate, and FAR-404; AKT1 gene inhibitor, e.g., vidofludimus; alkaline phosphatase modulator, e.g., recombinant human alkaline phosphatase (oral, ulcerative colitis), AM-Pharma; alkaline phosphatase stimulant, e.g., bovine alkaline phosphatase; androgen receptor agonist, e.g., PB-005; apolipoprotein C3 antagonist, e.g., AZD-0585; bactericidal permeable protein Stimulants, e.g., OPEVACAN; β-adrenergic receptor antagonists, e.g., NM-001; β-glucuronidase inhibitors, e.g., KD-018; B lymphocyte antigen CD20 inhibitors, e.g., ocrelizumab, rituximab; bradykinin receptor modulators, e.g., gibinostat; calcineurin inhibitors, e.g., tacrolimus, cyclosporine; calcium channel inhibitors, e.g., clotrimazole; cannabinoid CB1 receptor modulators, e.g., GWP42003-P, cannabidio Cannabinoid CB2 receptor modulators, e.g., GWP42003-P, cannabidiol; cannabinoid receptor antagonists, e.g., fingolimod; cannabinoid receptor modulators, e.g., GWP42003-P, cannabidiol; cathepsin S inhibitors, e.g., VBY-129, VBY-036; CCN protein stimulants, e.g., CSA-13; CCR3 chemokine antagonists, e.g., vertilimumab; CCR5 chemokine antagonists, e.g., HGS-1025;CCR9 chemokine antagonists, e.g., MLN-3126, bersilnon, CCX-025; CD3 modulators, e.g., visilizumab; CD40 ligand inhibitors, e.g., FFP-104; CD40 ligand receptor antagonists, e.g., FFP-104, FFP-102, tralizumab; CD49b antagonists, e.g., baterizumab; CD49d antagonists, e.g., ELND-004; CD89 agonists, e.g., HF-1020; cell adhesion molecule inhibitors, e.g., natalizumab, aricaforsen (intravenous), ASP-2002, ISIS-2302; chemokine CXC ligand inhibitors, e.g., CXCR1 / 2 ligand mAbs (immunology), Eli Lilly; CHST15 gene inhibitor, e.g., STNM-01; collagen modulator, e.g., adipose-derived stem cell therapy (Celution) System), Cytori, DCCT-10; CSF-1 agonists, e.g., Salglamostim, Morglamostim biosimilars and fosfomycin and carbapenems (intestinal, Crohn's disease), Reponex; CSF-1 antagonists, e.g., JNJ-40346527; CXC10 chemokine ligand inhibitors, e.g., 946414-98-8, BMS-936557; CXCR2 chemokine antagonists, e.g., Elbrixine; cyclic GMP phosphodiesterase inhibitors, e.g., CEL-031; cyclooxygenase 2 inhibitors, e.g., P-54; cyclooxygenase inhibitors, e.g., mesalazine, sodium 4-aminosalicylate, AJG-501, AGI-022; cyclooxygenase stimulants, e.g., Nicotinpolacrilex; cytochrome P450 3A4 inhibitors, e.g., KD-018; cytotoxic T lymphocyte protein 4 stimulants, e.g., abatacept; dihydroceramide Δ4 desaturates inhibitors, e.g., ABC-294640; dihydroorotate dehydrogenase inhibitors, e.g., vidofludimus; DNA polymerase inhibitors, e.g., valganciclovir; EGFR family tyrosine kinase receptor modulators, e.g., Neuregrin 4 (Crohn's disease / ulcerative colitis / necrotizing enterocolitis), Avexegen Therapeutics / Children's Hospital of Los Angeles;Eosinophil peroxidase inhibitors, e.g., AWEPOPD-01, AWEPO-003; eotaxin ligand inhibitors, e.g., vertilimumab; EP4 prostanoid receptor agonists, e.g., KAG-308; epidermal growth factor agonists, e.g., heparin-EGF-like factor, Scios Nova; epidermal growth factor ligand, e.g., Hebervis; estrogen receptor β agonist, e.g., prinavelel; factor XIII agonist, e.g., catridecacog; FGF-10 ligand, e.g., repifermin; FGF2 receptor agonist, e.g., F2A; fractalkine ligand inhibitor, e.g., E-6011; free fatty acid receptor 2 antagonist, e.g., GLPG-0974; GATA3 transcription factor inhibitor, e.g., SB-012; glucagon-like peptide 2 agonist, e.g., teduglutide, ZP-1848, NB-1002. Glucocorticoid agonists, e.g., budesonide, beclomethasone propionate, dexamethasone sodium phosphate, AJG-511, DOR-201, D-9421-C; GM-CSF receptor agonists, e.g., salglamostim, morglamostim biosimilars and fosfomycin and carbapenems (intestinal, Crohn's disease), Reponex; G protein-coupled receptor 84 antagonists, e.g., GLPG-1205; guanylate cyclase receptor agonists, e.g., dolucanatide, SP-333; histamine H2 receptor antagonists, e.g., bismuth, Medeva; histone acetyltransferase inhibitors, e.g., TIP60 inhibitors (ulcerative colitis / inflammatory bowel disease / autoimmune diseases), University of Pennsylvania; Histone deacetylase inhibitors, e.g., gibinostat; HLA class II antigen modulators, e.g., HLA class II protein modulators (Crohn's disease), Nextera AS; Hydrolase inhibitors, e.g., SC-56938; ICAM1 gene inhibitors, e.g., Aricaforsene; ICAM-1 inhibitors, e.g., Aricaforsene (intravenous), ISIS-2302; IL1 gene inhibitors, e.g., PLR-14; IL-10 agonists, e.g., pegylodecaquin, AM-0010;IL-10 gene stimulants, e.g., gene therapy (IL-10), Imperial College; IL-11 agonists, e.g., oprelbequin, YM-294; IL-12 antagonists, e.g., ustekinumab, briakinumab, apirimod; IL-12 gene inhibitors, e.g., RDP-58; IL-13 antagonists, e.g., tralokinumab, anlukinumab; IL-17 antagonists, e.g., secukinumab, vidofludimus; IL-2 antagonists, e.g., daclizumab; IL-2 receptor α subunit inhibitors, e.g., basiliximab, daclizumab, BSX-00 3. Ro-34-7375; IL-21 antagonists, e.g., NN-8828, ATR-107; IL-23 antagonists, e.g., tildrakizumab, ustekinumab, BI-655066, AMG-139, briakinumab, LY-3074828, apilimodo; IL-6 antagonists, e.g., tocilizumab, crazakizumab, olokizumab, HMPL-004, AMG-220, FM-101; IL-6 gene inhibitors, e.g., YSIL6-T-PS; IL-6 receptor modulators, e.g., tocilizumab Rizumab; IL-7 antagonist, e.g., interleukin-7 receptor modulator (ulcerative colitis / T-cell acute lymphoblastic leukemia); Effimune; IL-8 antagonist, e.g., erbrixine, clotrimazole; immunoglobulin G1 agonist, e.g., HF-1020; immunoglobulin G2 modulator, e.g., PF-547659; inosine monophosphate dehydrogenase inhibitor, e.g., mycophenolate mofetil; insulin resistance improver, e.g., elafibrano, rosigly Tazone, HE-3286, EGS-21; Integrin α4 / β1 antagonists, e.g., natalizumab, TRK-170, filategrast; Integrin α-4 / β-7 antagonists, e.g., etrolizumab, vedolizumab, abrilumab, carotegast-methyl, TRK-170, filategrast; Integrin α-E antagonists, e.g., etrolizumab; Integrin antagonists, e.g., baterizumab, ASP-2002; Integrin β7 antagonists, e.g., etrolizumab;Interferon-β ligands, e.g., interferon-β-1a, recombinant interferon-β-1a, Serono; interleukin-17E ligand inhibitors, e.g., anti-IL-17BR humanized antibody (pulmonary fibrosis / asthma / ulcerative colitis), Medical Research Council Technology; interleukin ligand inhibitors, e.g., HE-3286; interleukin receptor 17A antagonists, e.g., brodalumab; interleukin receptor 17B antagonists, e.g., anti-IL-17BR humanized antibody (pulmonary fibrosis / asthma / ulcerative colitis), Medical Research Council Technology; Interleukin-1β ligands, e.g., K(D)PT, PUR-0110, HMPL-004; Interleukin-1β ligand modulators, e.g., PUR-0110, HMPL-004; Interleukin-6 ligand inhibitors, e.g., PF-4236921; JAK tyrosine kinase inhibitors, e.g., tofacitinib, peficitinib; Jak1 tyrosine kinase inhibitors, e.g., ABT-494, tofacitinib, filgotinib, peficitinib, GLPG-0555, sorcitinib; JAK2 gene inhibitors, e.g., vidfludimus; Jak3 tyrosine kinase inhibitors, e.g., tofacitinib, peficitinib; Jun N-terminal kinase inhibitors, e.g., semapimod; LanC-like protein 2 modulators, e.g., BT-11; leukotriene BLT receptor antagonists, e.g., ONO-4057, etalosib, SC-53228, SC-52798; lipoxygenase modulators, e.g., mesalazine; L-selectin antagonists, e.g., BNP-001; MAdCAM inhibitors, e.g., vedolizumab, PF-547659; matrix me Taloproteinase inhibitors, e.g., D-5410; matrix metalloproteinase modulators, e.g., D-5410; melanocortin agonists, e.g., ASP-3291; membrane copper amine oxidase inhibitors, e.g., bepalimomab; metalloproteinase-2 inhibitors, e.g., KD-018, RWJ-68354; metalloproteinase-9 inhibitors, e.g., GS-5745; MIP3α ligand inhibitors, e.g., GSK-3050002;Mitochondrial 10kDa heat shock protein stimulants, e.g., INV-103; monocyte differentiation antigen CD14 inhibitors, e.g., CD14 anti-inflammatory agent, Cornell; mTOR inhibitors, e.g., P-2281; mucin stimulants, e.g., rebamipide; NAD-dependent deacetylase sirtuin-1 stimulants, e.g., SRT-2104; natriuretic peptide receptor C agonists, e.g., precanatide; neuregulin-4 ligands, e.g., neuregulin-4 (Crohn's disease / ulcerative colitis / necrotizing enterocolitis), Avexegen Therapeutics / C; Children's Hospital of Los Angeles; Nicotinic acetylcholine receptor agonists, e.g., TC-2403, nicotinic polarilex, nicotine; Nicotinic Ach receptor α4 subunit modulators, e.g., TC-2403; Nicotinic Ach receptor α7 subunit stimulants, e.g., GTS-21; Nicotinic Ach receptor β2 subunit modulators, e.g., TC-2403; NK1 receptor antagonists, e.g., KD-018, norpitantium besylate; NKG2D-activated NK receptor antagonists, e.g., NNC-0142-002; nucleus Factor κB inhibitors, e.g., KD-018, kovitrimod, CSA-13, HE-3286, HMPL-004, Avrina, mesalamine and N-acetylcysteine, P-54; opioid growth factor receptor agonists, e.g., methenkephalin acetate and tridecactide acetate, FAR-404; opioid receptor antagonists, e.g., naltrexone, IRT-103; opioid receptor δ antagonists, e.g., KD-018; oxidoreductase inhibitors, e.g., orsalazine; P2X7 purine receptor agonists, e.g., gibinostat; p38 MAP kinase inhibitors, e.g., RDP-58, Dramapimod, Semapimod, RWJ-68354; PARP inhibitors, e.g., EB-47, INO-1003; PDE4 inhibitors, e.g., Apremilast, Tetomirast, CC-1088; PDGF receptor agonists, e.g., Oprelbequin, YM-294; Phosphatosis-stimulating peptide modulators, e.g., 99mTc-RP-128; Phosphorylated MurNAc pentapeptide transferase inhibitors, e.g., SQ-641; Phospholipase A2 inhibitors, e.g., Vale Spradiv methyl; platelet-activating factor receptor antagonists, e.g., delsalazine sodium; potassium channel inhibitors, e.g., clotrimazole; PPARα agonists, e.g., ellafibranol (GFT-1007); PPARδ agonists, e.g., ellafibranol (GFT-1007); PPARγ agonists, e.g., rosiglitazone, GED-0507-34-Levo, etalosib; protein CYR61 stimulants, e.g., CSA-13; fimH protein inhibitors, e.g., EB-8018;Protein kinase Cα inhibitors, e.g., sotrastaurin (AEB-071); protein kinase Cβ inhibitors, e.g., sotrastaurin (AEB-071); protein kinase Cδ inhibitors, e.g., sotrastaurin (AEB-071); protein kinase Cε inhibitors, e.g., sotrastaurin (AEB-071); protein kinase Cη inhibitors, e.g., sotrastaurin (AEB-071); protein kinase Cθ inhibitors, e.g., sotrastaurin (AEB-071); protein kinase G inhibitors, e.g., CEL-031; protein kinase inhibitors, e.g., TOP-1288; P-selectin glycoprotein ligand-1 inhibitors, e.g., SEL-K2; purine biosynthesis proteins PurH inhibitors, e.g., mycophenolate mofetil; retinoic acid receptor α-agonists, e.g., tamibarotene; retinoic acid receptor β-agonists, e.g., tamibarotene; retinoid receptor agonists, e.g., tamibarotene; RNA polymerase inhibitors, e.g., rifaximin; SMAD-7 inhibitors, e.g., mongelsen (GED-0301); sodium channel inhibitors, e.g., ropivacaine; somatostatin receptor agonists, e.g., vapreotide; sphingosine 1-phosphate phosphatase 1 stimulants, e.g., APD-334; sphingosine 1-phosphate phosphatase modulators, e.g., SIP modulator (oral, multiple sclerosis / ulcerative colitis / rheumatoid arthritis), Akaal Pharma; Sphingosine kinase 1 inhibitors, e.g., ABC-294640; Sphingosine kinase 2 inhibitors, e.g., ABC-294640; Sphingosine 1-phosphate receptor 1 agonists, e.g., Ozanimod (RPC-1063), KRP-203; Sphingosine 1-phosphate receptor 1 antagonists, e.g., Amicelimod (MT-1303); Sphingosine 1-phosphate receptor 1 modulators, e.g., Fingolimod (FTY-720), Ozanimod (RPC-1063), Amicelimod (MT-1303); Sphingosine 1-phosphate receptor 5 modulators, e.g., Ozanimod; STAT3 gene inhibitors, e.g., Vidofludimus; STAT-3 inhibitors, e.g., TAK-114;STAT-4 inhibitors, e.g., STAT-4 antisense oligonucleotides (Crohn's disease / colitis), NIAIDs; stem cell antigen-1 inhibitors, e.g., Ampion, DMI-9523; superoxide dismutase modulators, e.g., Mydisumase, LT-0011; superoxide dismutase stimulants, e.g., superoxide dismutase; T cell surface glycoprotein CD28 inhibitors, e.g., abatacept; TGFβ1 ligand inhibitors, e.g., Mongelsen, GED-0301; thymrinago TLR-2 antagonists, e.g., Syn-1002; TLR-2 antagonists, e.g., VB-201; TLR-4 antagonists, e.g., JKB-122, VB-201; TLR-9 agonists, e.g., BL-7040, Covitrimod; TNFα ligand inhibitors, e.g., adalimumab, certolizumab pegol, infliximab biosimilar, infliximab, golimumab, ISIS-104838, CSA-13, DLX-105, adalimumab biosimilar, delsalazine sodium, Debio-0512 HMPL-004, DLX-105, infliximab biosimilars, AZD-9773, CYT-020-TNFQb, DOM-0200; TNFα ligand modulators, e.g., PUR-0110, CDP-571; TNF antagonists, e.g., etanercept, certolizumab pegol, AVX-470, onercept; trefoil factor modulators, e.g., AG-012; tryptase inhibitors, e.g., APC-2059; tryptophan 5-hydroxylase inhibitors Harmful agents, e.g., telotolithat etiprate; tumor necrosis factor 14 ligand modulators, e.g., SAR-252067; type I TNF receptor antagonists, e.g., DOM-0100; type II TNF receptor modulators, e.g., etanercept; unspecified growth factor receptor modulators, e.g., AP-005; vanilloid VR1 agonists, e.g., zucapsaicin; vitamin D3 receptor agonists, e.g., calcitriol; and zonulin inhibitors, e.g., larazotide acetate, AT-1001.

[0387] Furthermore, a non-exclusive list of compounds that can be combined with the chemicals of this disclosure includes: 14-3-3 protein η inhibitors, 5-lipoxygenase inhibitors, Abl tyrosine kinase inhibitors, ACTH receptor agonists, adenosine A3 receptor agonists, adenosine deaminase inhibitors, ADP-ribosylcyclase-1 modulators, ADP-ribosylation factor 6 inhibitors, adrenocorticotropic hormone ligands, aggrecanase-2 inhibitors, albumin modulators, AP1 transcription factor inhibitors, basidine inhibitors, Bcr protein inhibitors, B lymphocyte antigen CD19 inhibitors, and B lymphocyte antigen CD20 inhibitors. Harmful agents, B lymphocyte antigen CD20 modulators, B lymphocyte-stimulating factor ligand inhibitors, bradykinin receptor modulators, BRAF gene inhibitors, branched-chain amino acid aminotransferase 1 inhibitors, bromodomain-containing protein inhibitors, Btk tyrosine kinase inhibitors, cadherin-11 antagonists, calcineurin inhibitors, calcium channel inhibitors, carbonic anhydrase inhibitors, cathepsin K inhibitors, cathepsin S inhibitors, CCR1 chemokine antagonists, CCR2 chemokine antagonists, CCR 3 gene modulators, CCR5 chemokine antagonist, CD126 antagonist, CD29 modulator, CD3 modulator, CD39 agonist, CD4 agonist, CD4 antagonist, CD40 ligand inhibitor, CD40 ligand receptor antagonist, CD40 ligand receptor modulator, CD52 antagonist, CD73 agonist, CD79b modulator, CD80 antagonist, CD86 antagonist, CD95 antagonist, cell adhesion molecule inhibitor, cholinergic C-reactive protein inhibitors, clatherin stimulants, complement factor C5 inhibitors, complement factor stimulants, C-reactive protein inhibitors, CSF-1 antagonists, CXC10 chemokine ligand inhibitors, CXCR4 chemokine antagonists, cyclin-dependent kinase 1 inhibitors, cyclin-dependent kinase 2 inhibitors, cyclin-dependent kinase 4 inhibitors, cyclin-dependent kinase 5 inhibitors, cyclin-dependent kinase 6 inhibitors, cyclin-dependent kinase 7 inhibitors, cyclin-dependent kinase 9 inhibitors, cyclooxygenase 2 inhibitors,Cyclooxygenase 2 modulators, cyclooxygenase inhibitors, cytoplasmic phospholipase A2 inhibitors, cytotoxic T lymphocyte protein 4 modulators, cytotoxic T lymphocyte protein 4 stimulants, DHFR inhibitors, diamine acetyltransferase inhibitors, dihydroorotate dehydrogenase inhibitors, elongation factor 2 inhibitors, eotaxin 2 ligand inhibitors, EP4 prostanoid receptor antagonists, erythropoietin receptor agonists, Fas ligands, FGF-2 ligand inhibitors, FK506-binding protein-12 modulators, folate antagonists, folate receptor agonists, folate receptor β antagonists, folate receptor modulators, fractalkine ligand inhibitors, Fyn tyrosine kinase inhibitors, G protein-coupled receptor 15 antagonists, GABA A receptor modulators, glucocorticoid agonists, glucocorticoid antagonists, glucocorticoid-inducible leucine zipper stimulants, GM-CSF ligand inhibitors, GM-CSF receptor antagonists, GM-CSF receptor modulators, growth regulatory protein α ligand inhibitors, H with K with ATPase inhibitors, histamine H4 receptor antagonists, histone deacetylase inhibitors, histone deacetylase-6 inhibitors, HIV-1 gp120 protein inhibitors, HLA class II antigen DQ-2 α modulators, HLA class II antigen inhibitors, HLA class II antigen modulators, Hsp70 family inhibitors, hypoxia-inducible factor-1 inhibitors, IFNB gene stimulants, I-κB kinase β inhibitors, I-κB kinase inhibitors, IL-1 antagonists, IL-10 agonists, IL-11 agonists, IL-12 antagonists IL-15 antagonist, IL-17 antagonist, IL-17 receptor modulator, IL-2 agonist, IL-2 antagonist, IL-21 antagonist, IL-23 antagonist, IL-3 antagonist, IL-4 agonist, IL-6 antagonist, IL-6 receptor modulator, immunoglobulin antagonist, immunoglobulin G1 agonist, immunoglobulin G1 antagonist, immunoglobulin G1 modulator, immunoglobulin G2 antagonist, immunoglobulin G2 modulator,Immunoglobulin γFc receptor II modulators, immunoglobulin γFc receptor IIB antagonists, immunoglobulin κ modulators, immunoglobulin M antagonists, inducible nitric oxide synthase inhibitors, inosine monophosphate dehydrogenase inhibitors, insulin resistance improvers, integrin α1 / β1 antagonists, integrin α4 / β1 antagonists, integrin antagonists, interferon β ligands, interferon γ ligands, interleukin 17A ligand inhibitors, interleukin 17 F ligand inhibitors, interleukin-23A inhibitors, interleukin ligands, interleukin receptor 17A antagonists, interleukin-1β ligand inhibitors, interleukin-10 ligands, interleukin-2 ligands, interleukin-4 ligands, interleukin-6 ligand inhibitors, Itk tyrosine kinase inhibitors, JAK tyrosine kinase inhibitors, Jak1 tyrosine kinase inhibitors, Jak2 tyrosine kinase inhibitors, JAK3 gene inhibitors, Jak3 tyrosine kinase inhibitors, Jun N-terminal kinase inhibitors, KCNA voltage-gated potassium channel-3 modulators, Kelch-like ECH-related protein-1 modulators, Kit tyrosine kinase inhibitors, LanC-like protein-2 modulators, LITAF gene inhibitors, lymphocyte functional antigen-3 receptor antagonists, Lyn tyrosine kinase inhibitors, macrophage mannose receptor-1 modulators, MAdCAM inhibitors, MAP kinase modulators, MAP3K2 gene inhibitors, MAPKAPK5 inhibitors, matrix metalloproteinase inhibitors, MCL1 gene inhibitors, MEK protein kinase inhibitors, MEK-1 protein kinase inhibitors, MEK-2 protein kinase inhibitors, membrane copper amine oxidase inhibitors, metalloproteinase-2 inhibitors, metalloproteinase-9 inhibitors, midkine ligand inhibitors, mitochondrial 10kDa heat shock protein stimulants, mTOR complex 1 inhibitors, mTOR inhibitors, NAD ADP ribosyltransferase stimulants, NAMPT gene inhibitors, NFκB inhibitor stimulants, NFAT gene inhibitors, NFE2L2 gene stimulants, nicotinic acetylcholine receptor antagonists, NK cell receptor modulators,NKG2AB-activated NK receptor antagonists, NKG2D-activated NK receptor antagonists, nuclear factor E2-related factor 2 stimulants, nuclear factor κB inhibitors, nuclear factor κB modulators, nuclear factor κB p105 inhibitors, opioid growth factor receptor agonists, opioid receptor δ antagonists, osteoclast differentiation factor antagonists, osteoclast differentiation factor ligand inhibitors, oxidoreductase inhibitors, P2X7 purine receptor agonists, p38 MAP kinase α inhibitors, p38 MAP kinase inhibitors, PDE4 inhibitors, PDE5 inhibitors, PDGF receptor agonists, PDGF receptor antagonists, PDGF-B ligand inhibitors, PERK gene inhibitors, phosphoinositide 3 kinase δ inhibitors, phosphoinositide 3 kinase γ inhibitors, phospholipase A2 inhibitors, platelet activator receptor antagonists, PPARγ agonists, programmed cell death protein 1 modulators, prostaglandin D synthase stimulants, protein arginine deiminase inhibitors, protein tyrosine kinase inhibitors, purine biosynthesis protein PurH inhibitors, Rho-related protein kinase 2 inhibitors, seplase inhibitors, signaling molecule CD24 modulators, signaling inhibitors, sodium-glucose cotransporter 2 inhibitors, sphingosine 1-phosphate phosphatase modulators, STAT3 gene inhibitors, superoxide dismutase stimulants, SYK Amyly tyrosine kinase inhibitors, Syk tyrosine kinase inhibitors, syndecan 1 inhibitors, T cell receptor antagonists, T cell receptor modulators, T cell surface glycoprotein CD28 inhibitors, T cell surface glycoprotein CD28 stimulants, TAK1 binding protein modulators, talin modulators, T cell differentiation antigen CD6 inhibitors, T cell surface glycoprotein CD8 inhibitors, tenascin modulators, TGFβ agonists, thymrine agonists, TLR-2 antagonists, TLR-4 antagonists, TLR-9 antagonists, TNFα ligand inhibitors, TNFα ligand modulators, TNF antagonists, TNF gene inhibitors, TNF receptor modulators, TNFSF11 gene inhibitors, transcription factor p65 inhibitors, transcription factor RelB inhibitors, transferrin modulators, tumor necrosis factor 13C receptor antagonists, tumor necrosis factor 15 ligand inhibitors,Tumor necrosis factor ligand 13 inhibitors, tumor necrosis factor ligand inhibitors, type I IL-1 receptor antagonists, type I TNF receptor antagonists, type II TNF receptor modulators, unspecified GPCR agonists, VEGF receptor antagonists, VEGF-2 receptor antagonists, VEGF-2 receptor modulators, VEGF-B ligand inhibitors, X-linked apoptosis inhibitor protein inhibitors, Zap70 tyrosine kinase inhibitors, 99mTc-labeled annexin V-128, abatacept, abatacept biosimilar, ABBV-257 ABT-122, ABT-494, acalabrutinib, aceclofenac, actarit, MS-392, adalimumab, adalimumab biosimilar, adalimumab biosimilar, AK-106, ALX-0061, aminopterin, anakinra, anakinra biosimilar, anakinra biosimilar, ARG-301, ASLAN-003, ASP-5094, AT-132, AZD-9567, baricitinib, BI-655064, bimekizumab, BiP (rheumatoid arthritis), King's College London, BLHP-006, Bricibimod, BMS-986104, BMS-986142, ABBV-105, BTT-1023, Canakinumab, Cartistem, CCX-354, CD24-IgFc, Celecoxib, Celduratinib, Certolizumab Pegol, CF-101, CFZ-533, CHR-5154, Cibinetide, Cyclosporine, Clazakizumab, CNTO-6785, Corticotropin (Adrenocorticotropic Hormone), Mallinckrodt, CR-6086, CreaVax-RA, CWG-92, CWG -940, Cx-611, DE-098, Deflazacort, Rheumavax, Denosumab, Diaselein, Diclofenac, E-6011, Eicosapentaenoic acid monoglyceride, Etanercept, Etanercept biosimilar, Etanercept biosimilar, Etodolac, Etricoxib, Filgotinib, Fosdagrocolato, Gerilimunozumab, Ginsenoside CK, Gibinostat, Goat polyclonal antibody, Golimumab, GS-5745, GS-9876, GSK-3196165, HM-71224, HMPL-523,Sodium hyaluronate, IB-RA (for injection, rheumatoid arthritis), Innobioscience, IB-RA (oral, rheumatoid arthritis), Innobioscience, iguratimod, IMD-2560, imidazole salicylate, infliximab, infliximab biobetter, infliximab biosimilar, INSIX RA, interferon-γ biosimilar, interleukin-2 (for injection), interleukin-2 biosimilar, Biological agents, INV-103, IR-501, itorizumab, JNJ-40346527, Ka Shu Ning, KD-025, ketoprofen and omeprazole, leflunomide, rengilumab, LLDT-8, lumiracoxib, LY-3090106, masitinib, maprilumab, MBS-2320, MEDI-5117, meloxicam, methotrexate, MGD-010, misoprostol and diclofenac, MM-A01-01, monalizumab, MORAb-022, MPC-300-IV, MRC-375, nabumeton, namilumab, naproxen and esomeprazole, naproxen and esomeprazole strontium, Oka Latuzumab, Ofatumumab, OHR-118, Orokizumab, OM-89, Naproxen (oral sustained-release, analgesic) administered once daily, Alvogen, ONO-4059, Oralgam, Ozoralizumab, Peficitinib, Perbiprofen, PF-06687234, Piperidone hydrochloride, Piroxicam, Prednisolone, Prednisone, Prosorba, PRT-2607, PRTX-100, PRX-167700, QBSAU, Rabeximod, RCT-18, Recombinant human CD22 monoclonal antibody (intravenous injection), Lonn Ryonn Pharma / SinoMab Bioscience (Shenzhen), Recombinant human interleukin-1 receptor antagonist (rheumatoid arthritis), Shanghai Fudan-Zhangjiang Bio-Pharmaceutical, Recombinant Human Interleukin-2, Recombinant TNF Receptor 2-Fc Fusion Protein Variant, RG-6125, RhuDex, Rifabutin and Clarithromycin and Clofazimine, Rituximab, Rituximab Biosimilar, Rituximab Biosimilar, RPI-78, SAN-300, Sarilumab, SBI-087, Cericiclib, SHR-0302, Silkumab, Spabletinib, SSS-07, KDDF-201110-06, Syn-1002, T-5224, TAB-08, Tacrolimus, TAK-020, TAK-079, Tarenfluvir (Transdermal Spray Gel, Skin Diseases / Rheumatoid Arthritis), MIKA Pharma / GALENpharma, Technetium[99mTc] Chilmanocept, Technetium[99Tc] Methylenediphosphonate, Tenoxicam,Debio-0512, tocilizumab, tofacitinib, porcine whipworm eggs, umbilical cord-derived mesenchymal stem cells (intravenous administration, rheumatoid arthritis / liver disease), Alliancells / Zhongyuan Union, ustekinumab, VAY-736, VB-201, WF-10, XmAb-5871, YHB-1411-2;14-3-3 protein η inhibitors, e.g., anti-AGX-020mAbs (rheumatoid arthritis), Augurex;5-lipoxygenase inhibitors, e.g., tenoxicam, darbuferon, tebuferon, lycoferon, ZD-2138, etalosib, tenidap, tepoxaline, flobufen, SKF-86002, PGV-20229, L-708780, WY-28342, T-0757, T-0799, ZM -216800, L-699333, BU-4601A, SKF-104351, CI-986; Abl tyrosine kinase inhibitors, e.g., imatinib; ACTH receptor agonists, e.g., FAR-404, methenkephalin acetate and tridecactide acetate; adenosine A3 receptor agonists, e.g., CF-101; adenosine deaminase inhibitors, e.g., cladribine, pentostatin, FR-221647; ADP ribosylcyclase-1 modulators, e.g., indatuximab ravtansine; ADP-ribosylation factor 6 inhibitors, e.g., NAV-2729; adrenocorticotropic hormone ligands, e.g., corticotropin, Mallinckrodt, FAR-404, methenkephalin acetate and tridecactide acetate; aggrecanase-2 inhibitors, e.g., GIBH-R-001-2; albumin modulators, e.g., ALX-0061, ONS-1210; AP1 transcription factor inhibitors, e.g., T-5224, tarenfluvir, SP-10030; basi Din inhibitors, e.g., ERG-240; Bcr protein inhibitors, e.g., imatinib; B lymphocyte antigen CD19 inhibitors, e.g., XmAb-5871, MDX-1342; B lymphocyte antigen CD20 inhibitors, e.g., ocrelizumab, ofatumumab, rituximab, rituximab biosimilars, bertuzumab, rituximab biosimilars, okalatuzumab, BLX-301, IDEC-102, ABP-798, GP-2013, MK-8808, HLX-01, CT-P10,TL-011, PF-05280586, IBPM-001RX, IBI-301, AME-133v, BCD-020, BT-D004, SAIT-101; B lymphocyte antigen CD20 modulators, e.g., rituximab biosimilars, SBI-087, TRU-015, DXL-625; B lymphocyte stimulating ligand inhibitors, e.g., belimumab, RCT-18, bricibimod, tavarumab, atacicept, briovacept; Dikinin receptor modulators, e.g., gibinostat; BRAF gene inhibitors, e.g., binimetinib; branched-chain amino acid aminotransferase 1 inhibitors, e.g., ERG-240; bromodomain-containing protein inhibitors, e.g., RVX-297, ZEN-003694; Btk tyrosine kinase inhibitors, e.g., acalabrutinib, HM-71224, spelutinib, BTK inhibitors (rheumatoid arthritis), Humanwell Healthcare / Wuxi AppTech, BMS-986142, TAK-020, ONO-4059, TAS-5315, ABBV-105, AC-0025, RN-486, CG-026806, GDC-0834; Cadherin-11 antagonists, e.g., RG-6125; Calcineurin inhibitors, e.g., HS-378, Cyclosporine; Calcium channel inhibitors, e.g., RP-3128; Carbonic anhydrase inhibitors, e.g., Polmacoxib; Cathepsin K inhibitors, e.g., CRA-013783, T-5224, AM-3876, VEL-0230, NPI-2019; Cathepsin S inhibitors, e.g., MIV-247, AM-3876, RWJ-445380, NP I-2019; CCR1 chemokine antagonists, e.g., BX-471, BMS-817399, BI-638683, CCX-354, MLN-3701, MLN-3897, CP-481715, PS-375179; CCR2 chemokine antagonists, e.g., MK-0812, AZD-6942; CCR3 gene modulators, e.g., CM-102; CCR5 chemokine antagonists, e.g., Maraviroc, OHR-118, NIBR-6465, AZD-5672, AZD-8566; CD126 antagonists, e.g., Sarilumab; CD29 modulators, e.g., PF-06687234; CD3 modulators, e.g.,Oterixizumab; CD39 agonist, e.g., AAVS-CD39 / CD73 (rheumatoid arthritis), Arthrogen; CD4 agonist, e.g., Maraviroc; CD4 antagonist, e.g., Tregalizumab, Zanolimumab, MTRX-1011A, BW-4162W94, EP-1645, Clenoliximab; CD40 ligand inhibitor, e.g., Dapyrolizumab pegol; CD40 ligand receptor antagonist, e.g., BI-655064, Anti-CD40-XTEN, Teneriximab; CD40 ligand receptor modulator, e.g., CFZ-533; CD52 antagonist, e.g., Alemtuzumab; CD73 agonist, e.g., AAVS-CD39 / CD73 (rheumatoid arthritis), Arthrogen; CD79b modulator, e.g., MGD-010; CD80 antagonist, e.g., RhuDex, XENP-9523, ASP-2408, Abatacept Biobetter; CD86 antagonist, e.g., ES-210, Abatacept Biosuperior, ASP-2408, XENP-9523; CD95 antagonist, e.g., DE-098, CS-9507; Cell adhesion molecule inhibitor, e.g., Natalizumab, Aricaforsen, NPC-17923, TK-280, PD-144795; Choline kinase inhibitor, e.g., Choline kinase inhibitor (rheumatoid arthritis), UC San Diego; clatherin stimulants, e.g., alemtuzumab; complement C5 factor inhibitors, e.g., eculizumab; antisense oligonucleotides (rheumatoid arthritis), Leiden University Medical Center Center; complement factor stimulants, e.g., CM-101; C-reactive protein inhibitors, e.g., IB-RA (oral, rheumatoid arthritis), Innobioscience, ISIS-353512; CSF-1 antagonists, e.g., masitinib, FPA-008, JNJ-27301937, JNJ-40346527, PLX-5622, CT-1578, PD-360324, JNJ-28312141; CXC10 chemokine ligand inhibitors, e.g., 946414-98-8, BMS-936557; CXCR4 chemokine antagonists, e.g., plerixafor; cyclin-dependent kinase inhibitors, e.g.,CDK-1 / 2 / 5 / 7 / 9 inhibitors (cancer / tumor formation / rheumatoid arthritis), BioPatterns; cyclin-dependent kinase-2 inhibitors, e.g., sericiclib, BP-14; cyclin-dependent kinase-4 inhibitors, e.g., CDK-4 / 6 inhibitors (rheumatoid arthritis), Teijin; cyclin-dependent kinase-5 inhibitors, e.g., BP-14; cyclin-dependent kinase-6 inhibitors, e.g., CDK-4 / 6 inhibitors (rheumatoid arthritis), Teijin; cyclin-dependent kinase-7 inhibitors, e.g., BP-14, sericiclib; cyclin-dependent kinase 9 inhibitors, e.g., BP-14, celicyclib; cyclooxygenase 2 inhibitors, e.g., celecoxib, etoricoxib, polmacoxib, raflunimus, etodolac, meloxicam, IB-RA (for injection, rheumatoid arthritis), Innobioscience, IB-RA (for oral use, rheumatoid arthritis), Innobioscience, SKLB-023, meloxicam, lumiracoxib; cyclooxygenase 2 modulators, e.g., DRGT-46; cyclooxygenase inhibitors, e.g., aceclofenac, diclofenac, imida salicylate Zol, Naproxinod, Naproxen etemesyl, Misoprostol and Diclofenac, Nabumeton, Naproxen and Esomeprazole, Naproxen and Esomeprazole Strontium, Once-daily Naproxen (oral sustained-release, analgesic), Alvogen, Perbiprofen, LY-210073, Tenoxicam, Lycopheron, NS-398, Bromfenac, L-746483, LY-255283, Tenidap, Tepoxarin, Flobufen, Ibuprofen, Flurbiprofen, SKF-86002, SC-57666, WY-2 8342, CI-986, belmoprofen; cytoplasmic phospholipase A2 inhibitors, e.g., AVX-002; cytotoxic T lymphocyte protein-4 modulators, e.g., beratacept, ES-210; cytotoxic T lymphocyte protein-4 stimulants, e.g., abatacept, abatacept biosimilar, BMS-188667; DHFR inhibitors, e.g., methotrexate, MPI-2505, MBP-Y003; diamine acetyltransferase inhibitors, e.g., diminazene acetylate; dihydroorotate dehydrogenase inhibitors, e.g.,DHODH inhibitors (rheumatoid arthritis / autoimmune diseases), East China University of Science and Technology, ASLAN-003, laflunimus, leflunomide, HWA-486, ABR-224050; elongation factor 2 inhibitors, e.g., denileukin difutitox; eotaxin 2 ligand inhibitors, e.g., C, M-102; EP4 prostanoid receptor antagonist, e.g., CR-6086; erythropoietin receptor agonist, e.g., civinetide; Fas ligand, e.g., AP-300; FGF-2 ligand inhibitor, e.g., RBM-007; FK506 binding protein-12 modulator, e.g., temsirolimus; folate antagonist, e.g., methotrexate, MBP-Y003; folate receptor agonist, e.g., folate receptor modulator (chimeric protein, cancer / rheumatoid arthritis), Proda Biotech; Folate receptor modulators, e.g., technetium (99mTc) ethalphoratide; Fractalkine ligand inhibitors, e.g., E-6011; Fyn tyrosine kinase inhibitors, e.g., masitinib, raflunimus; G protein-coupled receptor 15 antagonists, e.g., GPR15 antagonist (rheumatoid arthritis / HIV-mediated enteropathy), Omeros; GABA A receptor modulators, e.g., raflunimus; glucocorticoid agonists, e.g., prednisolone, fosdaglucolato; glucocorticoid antagonists, e.g., REC-200; glucocorticoid-inducible leucine zipper stimulants, e.g., ART-G01; GM-CSF ligand inhibitors, e.g., namilumab, MORAb-022, renzilumab; GM-CSF receptor antagonists, e.g., mabrilimumab; GM-CSF receptor modulators, e.g., GSK-3196165; growth regulatory protein α-ligand inhibitors, e.g., T-5224; Hwith Kwith ATPase inhibitors, e.g., naproxen and esomeprazole, naproxen and esomeprazole strontium, ketoprofen and omeprazole, KEO-25001, HC-1004, PN-40020; histamine H4 receptor antagonists, e.g., treforant, GD-48; histone deacetylase inhibitors, e.g., gibinostat, CHR-5154; histone deacetylase 6 inhibitors, e.g., CKD-506; HIV-1 gp120 protein inhibitors, e.g., maraviloc; HLA class II antigen DQ-2α modulators, e.g., NexVax2; HLA class II antigen inhibitors, e.g., HLA-DR1 / DR4 inhibitors (rheumatoid arthritis), Provid;HLA class II antigen modulators, e.g., ARG-301; recombinant T cell receptor ligand (rheumatoid arthritis), Artielle; Hsp70 family inhibitors, e.g., gusperimus trihydrochloride; hypoxia-inducible factor-1 inhibitors, e.g., 2-methoxyestradiol; IFNB gene stimulants, e.g., ART-102; I-κB kinase β inhibitors, e.g., IMD-2560, IMD-0560; I-κB kinase inhibitors, e.g., bardoxolone methyl; IL-1 antagonists, e.g., lilonacept, IBBB-007-IL; antisense oligonucleotide (rheumatoid arthritis), Leiden University Medical Center; recombinant human interleukin-1 receptor antagonist (rheumatoid arthritis), Shanghai Fudan-Zhangjiang Bio-Pharmaceuticals; IL-10 agonists, e.g., pegilodecaquin; IL-11 agonists, e.g., oprelbequin; IL-12 antagonists, e.g., ustekinumab, briakinumab, ddRNAi therapy (rheumatoid arthritis), Medistheme / Benitec; IL-15 antagonists, e.g., AMG-714, BNZ-132-2; IL-17 antagonists, e.g., ixekizumab, secukinumab, KD-025; IL-17 receptor modulators, e.g., CNTO-6785 IL-2 agonists, e.g., interleukin-2 biosimilars; IL-2 antagonists, e.g., IB-RA (for injection, rheumatoid arthritis), Innobioscience; IB-RA (oral, rheumatoid arthritis), Innobioscience; BNZ-132-2; IL-21 antagonists, e.g., NN-8828; BNZ-132-2; IL-23 antagonists, e.g., ustekinumab; briakinumab; IL-3 antagonists, e.g., anti-IL-3mAbs (rheumatoid arthritis), University of Regensburg; IL-4 agonists, e.g., SER-130-AMI;IL-6 antagonists, e.g., olokizumab, crazakizumab, sirukmab, SA-237, tocilizumab, ALX-0061, FB-704A, OP-R003; peptide IL-6 antagonists, MEDI-5117, T-5224; humanized anti-IL-6 mAbs, tocilizumab biosimilars, IL-6 neutralizing human antibodies, anti-IL-6 antibodies, RN-486, BLX-1002, AMG-220, FM-101, K-832, BLX-1025, esonalimod, TA-383; IL-6 receptor modulators, e.g., tocilizumab, tocilizumab Rizumab biosimilar, RO-4877533; immunoglobulin antagonist, e.g., iguratimod; immunoglobulin G1 agonist, e.g., canakinumab, infliximab biobetter, infliximab biosimilar, BX-2922, STI-002, HF-1020; immunoglobulin G1 antagonist, e.g., YHB-1411-2; immunoglobulin G1 modulator, e.g., CFZ-533, renzilumab; immunoglobulin G2 antagonist, e.g., denosumab; immunoglobulin G2 modulator, e.g. For example, PF-547659; immunoglobulin γFc receptor II modulator, e.g., MGD-010; immunoglobulin γFc receptor IIB antagonist, e.g., XmAb-5871; immunoglobulin κ modulator, e.g., rengirumab; immunoglobulin M antagonist, e.g., IB-RA (for injection, rheumatoid arthritis), Innobioscience; IB-RA (for oral use, rheumatoid arthritis), Innobioscience; inducible nitric oxide synthase inhibitor, e.g., SKLB-023; inosine monophosphate dehydrogenase inhibitor. Drugs, e.g., mycophenolate mofetil; insulin resistance improving agents, e.g., rosiglitazone, THR-0921, HE-3286, BLX-1002; integrin α1 / β1 antagonists, e.g., SAN-300; integrin α4 / β1 antagonists, e.g., natalizumab; integrin antagonists, e.g., PEG-HM-3, CY-9652; interferon β ligands, e.g., recombinant interferon β-la, TA-383; interferon γ ligands, e.g., interferon γ biosimilars;Interleukin-17A ligand inhibitors, e.g., ABT-122, bimekizumab, ABBV-257; interleukin-17F ligand inhibitors, e.g., bimekizumab; interleukin-23A inhibitors, e.g., guselkumab; interleukin ligands, e.g., IBBB-007-IL; interleukin receptor 17A antagonists, e.g., brodalumab; interleukin-1β ligand inhibitors, e.g., canakinumab, lilonacept, T-5224, gevokizumab Mab, BLX-1002, LY-2189102, PMI-001, K-832, CDP-484; Interleukin-10 ligand, e.g., PF-06687234; Interleukin-2 ligand, e.g., Denileukin Difutitox, Recombinant Interleukin-2, Interleukin-2 Biologics, Recombinant Human Interleukin-2, Interleukin-2 (for injection); Interleukin-4 ligand, e.g., Tetravil; Interleukin-6 Ligand inhibitors, e.g., gerimumuzumab, PF-4236921; Itk tyrosine kinase inhibitors, e.g., ARN-4079; JAK tyrosine kinase inhibitors, e.g., tofacitinib, SHR-0302, celduratinib, peficitinib, deuterated tofacitinib analog, SD-900, CVXL-0074; Jak1 tyrosine kinase inhibitors, e.g., ABT-494, baricitinib, ruxolitinib, filgotinib, tofacitinib, itacitinib, peficitinib Citinib, NIP-585, CS-944X, YJC-50018, GLPG-0555, MRK-12; Jak2 tyrosine kinase inhibitors, e.g., baricitinib, ruxolitinib, CT-1578; JAK3 gene inhibitors, e.g., GBL-5b; Jak3 tyrosine kinase inhibitors, e.g., desernotinib, tofacitinib, peficitinib, AC-0025, CS-944X, DNX-04042, MTF-003, ARN-4079, PS-020613; Jun N-terminal kinase inhibitors, e.g., IQ-1S; KCNA voltage-gated potassium channel-3 modulators, e.g., MRAD-P1; Kelch-like ECH-related protein-1 modulators, e.g., dimethyl fumarate; Kit tyrosine kinase inhibitors, e.g., imatinib, masitinib;LanC-like protein 2 modulator, e.g., BT-11; LITAF gene inhibitor, e.g., GBL-5b; Lymphocyte functional antigen-3 receptor antagonist, e.g., alefacept; Lymph tyrosine kinase inhibitor, e.g., macitinib; Macrophage mannose receptor 1 modulator, e.g., technetium[99mTc]chilmanocept; MAdCAM inhibitor, e.g., PF-547659; MAP kinase modulator, e.g., SKLB-023; MAP3K2 gene inhibitor, e.g., GBL-5b; MAPKAPK5 inhibitor, e.g., GLPG-0259; Matrix metalloproteinase inhibitor, e.g., GLPG-0259; MCL1 gene inhibitor, e.g., celicinib Crib; MEK protein kinase inhibitors, e.g., binimetinib, AD-GL0001; MEK-1 protein kinase inhibitors, e.g., binimetinib; MEK-2 protein kinase inhibitors, e.g., binimetinib; Membrane copper amine oxidase inhibitors, e.g., BTT-1023, PRX-167700, bepalimomab; Metalloproteinase-2 inhibitors, e.g., ERG-240; Metalloproteinase-9 inhibitors, e.g., GS-5745, ERG-240; Midkine ligand inhibitors, e.g., CAB-102; Mitochondrial 10kDa heat shock protein stimulants, e.g., INV-103; mTOR complex 1 inhibitors, e.g., everolimus; mTOR inhibitors, e.g., everolimus, temsirolimus; NAD ADP-ribosyltransferase stimulants, e.g., denileukin difutitox; NAMPT gene inhibitors, e.g., ART-D01; NFκB inhibitor stimulants, e.g., denosumab; NFAT gene inhibitors, e.g., T-5224; NFE2L2 gene stimulants, e.g., bardoxolone methyl; nicotinic acetylcholine receptor antagonists, e.g., RPI-78, RPI-MN; NK cell receptor modulators, e.g., masitinib; NKG2AB-activated NK receptor antagonists, e.g., monalizumab; NKG2D-activated NK receptor antagonists, e.g., NNC-0142-002; nuclear factor E2-related factor 2 stimulants, e.g., dimethyl fumarate;Nuclear factor κB inhibitors, e.g., bardoxolone methyl, IB-RA (for injection, rheumatoid arthritis), Innobioscience, dehydroxymethyl epoxyquinomycin, HE-3286, IMD-0560, MP-42, tarenfluvir, VGX-1027, SKLB-023, SP-650003, MG-132, SIM-916, VGX-350, VGX-300, GIT-027, SP-100030, MLN-1145, NVP-IKK-005; nuclear factor κB modulators, e.g., REM-1086; nuclear factor κB p105 inhibitors, e.g., REM-1086; opioid growth factor receptor agonists, e.g., methenkephalin acetate and tridecactide acetate, FAR-404; opioid receptor δ antagonists, e.g., HS-378; osteoclast differentiation factor antagonists, denosumab, cyclic peptide mimetic (arthritis); Rheumatism / Osteoporosis), University of Michigan; Osteoclast differentiation factor ligand inhibitors, e.g., denosumab; Oxidoreductase inhibitors, e.g., etodolac, imidazole salicylate; P2X7 purine receptor agonists, e.g., gibinostat; p38 MAP kinase α inhibitors, e.g., VX-745, BMS-582949 prodrug, BMS-751324; p38 MAP kinase inhibitors, e.g., BCT-197, rosmapimod, ARRY-797; PDE4 inhibitors, e.g., apremilast; PDE5 inhibitors, e.g., PDE5 inhibitors (rheumatoid arthritis), University of Rochester; PDGF receptor agonists, e.g., oprelbequin; PDGF receptor antagonists, e.g., imatinib, masitinib; PDGF-B ligand inhibitors, e.g., SL-1026; PERK gene inhibitors, e.g., binimetinib; phosphoinositide-3-kinase δ inhibitors, duvelisib, RP-6503, CT-732, INK-007, GNE-293; phosphoinositide-3-kinase γ inhibitors, e.g., duvelisib, RP-6503; phospholipase A2 inhibitors, e.g., AVX-002, human secreted phospholipase A2 [IIA type] integrin binding inhibitor peptide (rheumatoid arthritis / asthma / Alzheimer's disease / cancer), University of California, Davis, AK-106, Valesprazib Methyl, Ro-31-4493, BM-162353, Ro-23-9358, YM-26734; Platelet-activating factor receptor antagonists, e.g., piperidone hydrochloride; PPARγ agonists, e.g., rosiglitazone, THR-0921, rosiglitazone XR, etalosib; Programmed cell death protein 1 modulators, e.g., INSIX RA; ​​Prostaglandin D synthase stimulants, e.g., HF-0220; Protein arginine deiminase inhibitors, e.g., PAD inhibitors (rheumatoid arthritis), Leiden University Medical Center / LURIS; Protein tyrosine kinase inhibitors, e.g., leflunomide; Purine biosynthesis protein PurH inhibitors, e.g., mycophenolate mofetil; Rho-related protein kinase 2 inhibitors, e.g., KD-025;Seplase inhibitors, e.g., anti-fibroblast-activating protein (FAP) antibody radiotracer (rheumatoid arthritis), Hoffmann-La Roche / Radboud University; signaling molecule CD24 modulators, e.g., CD24-IgFc; signaling inhibitors, e.g., imatinib; sodium-glucose cotransporter 2 inhibitors, e.g., THR-0921; sphingosine-1-phosphate phosphatase modulators, e.g., S1p modulator (oral, multiple sclerosis / ulcerative colitis / rheumatoid arthritis), Akaal Pharma; STAT3 gene inhibitors, e.g., bardoxolone methyl, vidofludimus; superoxide dismutase stimulants, e.g., imisopasem manganese; SYK family tyrosine kinase inhibitors, e.g., MK-8457; Syk tyrosine kinase inhibitors, e.g., fostamatinib, entospretinib, KDDF-201110-06, HMPL-523, celduratinib, AB-8779, GS-9876, PRT-2607, CVXL-0074, CG-103065, CG-026806; syndecan-1 inhibitors, e.g., indatuximab, ravtansine; T cell receptor antagonists, e.g., TCR inhibitor SCHOOL peptide (systemic / topical, rheumatoid arthritis / dermatitis / scleroderma), SignaBlok, CII modified peptide (rheumatoid arthritis), Peking University; T cell receptor modulator, e.g., ARG-301; T cell surface glycoprotein CD28 inhibitor, e.g., abatacept, beratacept, abatacept biosimilar, RhuDex, BMS-188667; T cell surface glycoprotein CD28 stimulant, e.g., TAB-08; TAK1 binding protein modulator, e.g., epigallocatechin 3-gallate; Talin modulator, e.g., truncated Talin regulator (rheumatoid arthritis), KayteeBio; T cell differentiation antigen CD6 inhibitor, e.g., itorizumab; T cell surface glycoprotein CD8 inhibitor, e.g., tregalizumab; tenascin modulator, e.g., Tetravil; TGFβ agonist, e.g., tregalizumab; thymrine agonist, e.g., Syn-1002; TLR-2 antagonist, e.g., VB-201, P-13;TLR-4 antagonists, e.g., VB-201, P-13; TLR-9 antagonists, e.g., P-13; TNFα ligand inhibitors, e.g., adalimumab biosimilar YHB-1411-2, adalimumab, infliximab, infliximab biosimilar, recombinant humanized anti-TNFα monoclonal antibody, certolizumab pegol, golimumab, ozoralizumab, AT-132, etanercept biosimilar, ISIS-104838 ISU-202, CT-P17, MB-612, Debio-0512, Anti-TNFα Human Monoclonal Antibody, Infliximab Biobetter, UB-721, KN-002, DA-3113, BX-2922, R-TPR-015, BOW-050, PF-06410293, CKD-760, CHS-1420, GS-071, ABP-710, STI-002, BOW-015, FKB-327, BAX-2200, HLX-03, BI-6 95501, CNTO-148, MYL-1401AABP-501, HOT-3010, BAX-2923, SCH-215596, ABT-D2E7, BAT-1406, Xpro-1595, Atsttrin, SSS-07, Golimumab Biosimilar, TA-101, Adalimumab Biosimilar, BLX-1002, ABX-0401, TAQ-588, Golimumab Biosimilar, TeHL-1, Preculumab b), PMI-001, tgAAV-TNFR:Fc, K-832, CYT-007-TNFQb, SSR-150106, PassTNF, Verigen, DOM-0200, DOM-0215, AME-527, Anti-TN F-αmAb, GENZ-38167, BLX-1028, CYT-020-TNFQb, CC-1080, CC-1069; TNFα ligand modulators, such as MM-A01-01, CDP-571, Camobucol;TNF antagonists, e.g., etanercept, certolizumab pegol, etanercept biosimilars, etanercept biosimilars, DNX-114, TNF antagonist and IL-12 antagonist (rheumatoid arthritis), University of Oxford, BN-006, SCB-131, pegsnercept, GBL-5b, ACE-772, onercept, DE-096, PN-0615, renercept, ITF-1779, MDL-201112, BAX-2200, SCB-808, DA-3853, HD-203; TNF gene inhibitors, e.g., GIBH-R-001-2; TNF receptor modulators, e.g., recombinant TNF receptor 2-Fc fusion protein variants, T-0001, tgAAV-TNFR:F c; TNFSF11 gene inhibitors, e.g., denosumab; transcription factor p65 inhibitors, e.g., REM-1086; transcription factor RelB inhibitors, e.g., REM-1086; transferrin modulators, e.g., methotrexate, MBP-Y003; tumor necrosis factor 13C receptor antagonists, e.g., VAY-736; tumor necrosis factor 15 ligand inhibitors, e.g., anti-TL1A antibody (rheumatoid arthritis / inflammatory bowel disease), NIAMS; tumor necrosis factor ligand 13 inhibitors, e.g., A Tacicept; Tumor necrosis factor ligand inhibitors, e.g., ABBV-257, etanercept biosimilar, ABT-122; Type I IL-1 receptor antagonists, e.g., Anakinra, Anakinra biosimilar, Anakinra biosimilar, AXXO; Type I TNF receptor antagonists, e.g., NM-9405; Type II TNF receptor modulators, etanercept, SCB-131, etanercept biosimilar, etanercept biosimilar, e.g., BAX- 2200, SCB-808, LBEC-0101, DMB-3853, DWP-422, BT-D001, DA-3853; non-specific GPCR agonists, e.g., NCP-70X; VEGF receptor antagonists, e.g., 2-methoxyestradiol, NSC-650853, SL-1026; VEGF-2 receptor antagonists, e.g., CG-026806; VEGF-2 receptor modulators, e.g., VEGFR2 neutralizing antibody (rheumatoid arthritis), University of Rochester;VEGF-B ligand inhibitors, e.g., CSL-346; X-linked apoptosis inhibitor protein inhibitors, e.g., IAP inhibitors (oral), Pharmascience; and Zap70 tyrosine kinase inhibitors, e.g., MK-8457, CT-5332. Combinations for metabolic diseases or conditions

[0388] Examples of metabolic disorders include, but are not limited to, diabetes mellitus, including type 1 and type 2 diabetes mellitus, metabolic syndrome, dyslipidemia, obesity, impaired glucose tolerance, hypertension, elevated serum cholesterol, and elevated triglycerides. Examples of therapeutic agents used to treat metabolic disorders include antihypertensive agents and lipid-lowering agents. Further therapeutic agents used to treat metabolic disorders include insulin, sulfonylurea drugs, peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists (such as thiazolidinediones like pioglitazone), biguanides, α-glucosidase inhibitors, vitamin E, and incretin mimetic agents. Accordingly, one aspect of the present disclosure is a method for treating a metabolic disorder, comprising administering the chemicals of the present disclosure in combination with one or more compounds useful for treating the metabolic disorder to a subject in need, particularly a human subject. [Examples]

[0389] The following embodiments are included to demonstrate specific embodiments of the Disclosure. Those skilled in the art will understand that the techniques disclosed in the following embodiments represent techniques that function well in the implementation of the Disclosure and can therefore be considered to constitute a particular form for such implementation. However, those skilled in the art will understand that many modifications can be made in the specific embodiments disclosed, without departing from the spirit and scope of the Disclosure, and still achieving similar or comparable results. Equipment and methods X-ray powder diffraction (XRPD)

[0390] X-ray powder diffraction (XRPD) analysis was performed using a copper wire (Cu Kα, λ=1.541874) with a diffractometer (PANalytical XPERT-PRO, PANalytical BV, Almelo, Netherlands). The sample was spread uniformly on a zero-background sample plate. The generator was operated at a voltage of 45kV and an amperage of 40mA. The slits were a solar slit of 0.02rad, a scattering prevention slit of 1.0°, and a divergent slit. Scanning was performed from 2 to 40°2θ with a step size of 0.0167. Data analysis was performed using X'Pert Viewer V1.2d (PANalytical BV, Almelo, Netherlands). X-ray powder diffraction analysis was also performed using a copper wire (Cu Kα, λ=1.541874) with a diffractometer (Rigaku MiniFlex, Rigaku, Tokyo). The sample was spread uniformly on a zero-background sample plate. The generator was operated at a voltage of 40kV and an amperage of 15mA. Scanning was performed from 2° to 40°2°θ with a step size of 0.050° and a speed of 2–8° / min. Data analysis was also performed using X'Pert Data Viewer V1.2d (PANalytical BV, Almelo, Netherlands). Differential Scanning Calorimetry (DSC)

[0391] Differential scanning calorimetry (DSC) was performed using a Q2000 (TA Instruments, New Castle, DE). Samples were placed in crimped or open Tzero standard aluminum pans containing 1–5 mg of material, and heated to 20–300°C or higher at a rate of 10°C / min. The sample pan and reference pan were purged with nitrogen at a rate of 50 mL / min. Data analysis was completed using Universal Analysis 2000 Version 4.5A (TA Instruments, New Castle, DE). Thermogravimetric analysis (TGA)

[0392] Using thermogravimetric analysis (TGA), 1–10 mg of material was placed in a weigh pan using either a Q5000 or Q500 (TA Instruments, New Castle, DE), and the sample weight loss was evaluated as a function of temperature by heating the sample to over 350°C at a rate of 10°C / min. The sample pan and reference pan were purged with nitrogen at 60 mL / min and 40 mL / min, respectively. Data analysis was completed using Universal Analysis 2000 Version 4.5A (TA Instruments, New Castle, DE).

[0393] Thermogravimetric-mass spectrometry (TG-MS) was used to identify volatile gas emissions. Sample weight loss as a function of temperature was evaluated by placing 1–10 mg of material in a weighing pan and heating the sample to completely desolvate the material at a rate of 20°C / min using a Discovery TGA (TA Instruments, New Castle, DE). The sample pan and reference pan were under nitrogen purging at 60 mL / min and 40 mL / min, respectively. Data analysis was completed using TRIOS (TA Instruments, New Castle, DE). The mass spectrometer was a Discovery MS (TA Instruments, New Castle, DE) benchtop quadrupole system. Dynamic water vapor adsorption (DVS)

[0394] Hygroscopicity was tested using dynamic water vapor adsorption (DVS, TA Q5000 SA, TA Instruments, New Castle, DE or DVS, DVS Intrinsic, Surface Measurement Systems, London, UK). Samples (2-20 mg) were placed in aluminum DVS pans and mounted on the sample side of a twin-pan balance. Water adsorption and desorption were tested as a function of relative humidity (RH) at 25°C. Relative humidity was increased from 5%RH to 95%RH in 10% RH increments, and then decreased to 5%. Each relative humidity increment was given an equilibrium time of 180 minutes unless the weight change % was less than 0.002% in 30 minutes. Data analysis was performed using Universal Analysis 2000 version 4.7A (TA Instruments, New Castle, DE) for TA DVS execution and Microsoft Excel for SMS DVS execution. Proton nuclear magnetic resonance ( 1 (H NMR)

[0395] Proton nuclear magnetic resonance ( 1 ¹H NMR spectra were acquired using a Varian 400-MR 400MHz instrument equipped with a 7620AS sample changer. Default proton parameters were as follows: spectral width: 14 to -2 ppm (6397.4 Hz), relaxation delay: 1 second, pulse: 45°C, acquisition time: 2.049 seconds, number of scans or repetitions: 8, temperature: 25°C. Samples were prepared in dimethyl sulfoxide-d6 unless otherwise specified. Offline analysis was performed using Mnova software.

[0396] List of abbreviations and acronyms [Table 1] Example 1. Compound I, Form I Formation of 4-(((R)-1-amino-1-oxopropan-2-yl)amino)-6-chloro-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide by coupling reaction of 4-(((R)-1-amino-1-oxopropan-2-yl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)chloro-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide by 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazin-3-carbonitri [ka]

[0397] 4-(((R)-1-amino-1-oxopropan-2-yl)amino)-6-chloro-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (1.0 equivalent, coefficient of determination), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (1.6 equivalents), XPhos (0.05 equivalents), palladium acetate (0.025 equivalents), and 2-methyltetrahydrofuran (17.0 vols) were added to the reactor. The resulting mixture was stirred, and a solution of tribasic potassium phosphate (2.0 equivalents) in water (2.5 vols) was added to the mixture. The reaction mixture was stirred and heated at approximately 75°C for approximately 4 hours, then cooled to approximately 40°C. The resulting slurry was filtered. The cake was washed with toluene (9.0 vol), acetonitrile (5.0 vol), and citric acid aqueous solution (10% w / w), and dried at approximately 40°C. The solid was placed in a reactor and slurried in N-methyl-2-pyrrolidinone (5.0 vol) at approximately 40°C. The slurry was filtered and washed with N-methyl-2-pyrrolidinone (2.0 vol), and the resulting organic saturation was concentrated to approximately 5 vol. The mixture was placed in a reactor, followed by diatomaceous earth (200% w / w), trisodium trithiocyanurate hydrate (0.3 equivalents), and Darco G-60 (50% w / w), and mixed at approximately 40°C for approximately 2 hours. The mixture was filtered, and the filtrate was concentrated to approximately 1 vol. Ethanol (18.0 vol) was added at approximately 40°C, and the mixture was aged at approximately 50°C for approximately 2 hours. Water (18.0 vol) was added at approximately 35°C, the mixture was allowed to mature for approximately 2 hours, and then cooled to approximately 20°C over approximately 3 hours. The slurry was filtered and washed with water (5.0 vol). The contents of the reactor were filtered, and the cake was dried at approximately 40°C for approximately 21 hours to obtain 4-(((R)-1-amino-1-oxopropan-2-yl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide.

[0398] 1H NMR (400MHz, methanol-d4)δ 8.76(d,J=2.2Hz,1H),8.69-8.63(m,2H),8.05(d,J=4.8Hz,1H),7.88(s,1H),7.22(d,J=5.1Hz,1H),4.91(t,J=7.6Hz,2H),4.73 (dd,J=8.2,4.4Hz,2H),4.52-4.28(m,3H),3.80-3.40(m,5H),2.76(dd,J=13.9,7.0Hz,2H),2.24(s,2H),1.29(d,J=1.7Hz,6H). Amide dehydration reaction of 4-(((R)-1-amino-1-oxopropan-2-yl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide to 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (compound I) [ka]

[0399] 4-(((R)-1-amino-1-oxopropan-2-yl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide and THF (17.0 vol) were added to the reactor. Pyridine (5.0 equivalents) was added and the mixture was cooled to approximately 0°C. Trifluoroacetic anhydride (2.9 equivalents) was added and the resulting mixture was stirred at approximately 0°C for approximately 1 hour. Sodium carbonate solution (1 M, 15 vol) was added over approximately 1 hour and the mixture was heated to approximately 20°C over approximately 1 hour. Water (20.0 vol) and ethyl acetate (20.0 vol) were added, the mixture was filtered through Celite, and rinsed with ethyl acetate (20.0 vol). The layers were separated and the aqueous stream was extracted with 2-methyltetrahydrofuran (20.0 vol). The organic slurry was combined and washed with saturated ammonium chloride aqueous solution (20.0 vol). The resulting organic slurry was solvent-exchanged to ethanol (15.0 vol), and n-heptane (50.0 vol) was added over approximately 1 hour at approximately 20°C. After aging the slurry for approximately 3 hours, the slurry was filtered, and the cake was washed with n-heptane (2.0 vol). The resulting cake was dried at approximately 50°C to obtain 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (compound I).

[0400] 1 1H NMR (400MHz, DMSO-d6):δ 8.89(t,J=5.8Hz,1H),8.81(s,1H),8.78(d,J=7.2Hz,1H),8.61(d,J=2.4Hz,1H), 8.22(s,1H),7.85(d,J=4.4Hz,1H),7.10(d,J=4.8Hz,1H),4.86(p,J=6.9Hz,1H), 4.40(ddd,J=49.2,9.2,2.0Hz,1H),3.75(dddd,J=37.2,14.4,5.2,2.0Hz,1H),3. 43(m,1H),1.72(d,J=7.2Hz,3H),1.19(d,J=1.6Hz,3H),1.18(d,J=1.2Hz,3H)ppm.

[0401] 13 C NMR(100MHz,DMSO-d6):δ 167.5,152.0,149.7,149.2,141.7,133.8,130.6,127.3,119.7,118.5,117.2,110.1,106.9,104.0,96 .9(d,J=177.8Hz),93.5,69.5(d,J=19.9Hz),39.4,(m),26.1(d,J=3.8Hz),24.7(d,J=3.8Hz),18.5ppm.

[0402] Compound I, form I, is the crystalline, non-solvated form of Compound I free base. Form I was prepared by concentrating the Compound I free base prepared above from pure ethyl acetate to dryness and then crystallizing it.

[0403] The XRPD pattern of morphology I is shown in Figure 1. The DSC curve of morphology I is shown in Figure 2. The DSC data shows an endothermic event with an initiation temperature of approximately 155°C, followed by another endothermic event with an initiation temperature of approximately 175°C. The TGA of morphology I is shown in Figure 3. The smallest weight loss (approximately 1% by weight) observed in the TGA data from room temperature to approximately 155°C indicates that morphology I is non-solvated. Example 2. Compound I Form II

[0404] Compound I form II is the crystalline, non-solvated form of Compound I free base. Form II was prepared by adding Compound I form I to approximately 1 mL of pure ethyl acetate, forming a slurry, and stirring at room temperature for approximately 7 days. The solid was isolated using a NANOSEP centrifuge filter.

[0405] The XRPD pattern of morphology II is shown in Figure 4. The DSC curve of morphology II is shown in Figure 5. The DSC data shows an endothermic event with an onset temperature of approximately 191°C due to melting of morphology II. The TGA of morphology II is shown in Figure 6. The smallest weight loss (approximately 1 wt%) observed in the TGA data from room temperature to approximately 200°C indicates that morphology II is non-solvated. Example 3. Compound I Form III

[0406] Compound I form III is the crystalline, non-solvated form of the free base of Compound I. Form III was prepared by heating Compound I form V to approximately 110°C in a variable-temperature XRPD.

[0407] The XRPD pattern for morphology III is shown in Figure 7. Example 4. Compound I Form IV

[0408] Compound I form IV is the crystalline non-solvated form of the free base of Compound I. Form IV was prepared by adding 6.69 g of Compound I to approximately 75 mL of pure ethanol at approximately 40°C to 50°C, and then adding a crystal species using Compound I form II. The slurry was held overnight, then cooled to approximately 10°C, and the solid was isolated using a disposable frit-equipped funnel.

[0409] The XRPD pattern of morphology IV is shown in Figure 8. The DSC curve of morphology IV is shown in Figure 9. The DSC data shows an endothermic event with an onset temperature of approximately 192°C, resulting from the melting of morphology IV. The TGA of morphology IV is shown in Figure 10. The smallest weight loss (less than 1% by weight) observed in the TGA data indicates that the sample is non-solvable. The DVS of morphology IV is shown in Figure 11. DVS analysis showed that morphology IV is non-hygroscopic, absorbing less than 1% by weight of water at 25°C and 95% RH. No morphological changes were observed in the XRPD analysis of the sample after DVS analysis. Example 5. Compound I Form V

[0410] Compound I form V is the crystalline monohydrate form of the free base of Compound I. Form V was prepared by adding approximately 2 g of Compound I form VI to approximately 10 mL of pure ethyl acetate and stirring overnight at room temperature. The solid was isolated using a Buchner funnel and filter paper.

[0411] The XRPD pattern of morphology V is shown in Figure 12. The DSC curve of morphology V is shown in Figure 13. The endothermic event at an initiation temperature of approximately 71°C is due to dehydration of morphology V and conversion to morphology III. The endothermic event at an initiation temperature of approximately 152°C is due to melting of morphology III. The exothermic event at an initiation temperature of approximately 171°C and the endothermic event at an initiation temperature of approximately 189°C are due to crystallization and melting of morphology II or IV, respectively. The TGA of morphology V is shown in Figure 14. Based on the TGA weight loss up to approximately 100°C, the amount of water corresponds to approximately 1 molar equivalent (theoretically 4 wt%) of water. The DVS of morphology V is shown in Figure 15. Example 6. Compound I Form VI

[0412] Compound I, form VI, is the semi-crystalline hydrated form of Compound I free base. Form VI was prepared by adding 0.3 g of Compound I free base to 45 mL of water and stirring at room temperature for approximately 6 days. The solid was isolated using a Buchner funnel and filter paper.

[0413] The XRPD pattern of morphology VI is shown in Figure 16. The DSC curve of morphology VI is shown in Figure 17. The endothermic event at an initiation temperature of approximately 47°C is due to dehydration of morphology VI. Endothermic events at initiation temperatures of approximately 111°C and approximately 123°C were not investigated. The TGA of morphology VI is shown in Figure 18. Based on the TGA weight loss from room temperature to approximately 140°C, the amount of water corresponds to approximately 1.25 molar equivalents (theoretically approximately 5.2 wt%) of water. The DVS of morphology VI is shown in Figure 19. Example 7. Compound I Form VII

[0414] Compound I form VII is the crystalline water:THF solvated form of Compound I free base. Form VII was prepared by dissolving approximately 2 g of Compound I free base in approximately 40 mL of THF at room temperature, and then drying by rotary evaporation.

[0415] The XRPD pattern of morphology VII is shown in Figure 20. The DSC curve of morphology VII is shown in Figure 21. The endothermic events at starting temperatures of approximately 17°C and 54°C are due to the desolvation of morphology VII. The endothermic events at starting temperatures of approximately 138°C and 187°C were not investigated. The TGA of morphology VII is shown in Figure 22. The TGA data shows a weight loss of approximately 7.9 wt% from room temperature to approximately 160°C, indicating that morphology VII is solvated. This was later confirmed by TGA-MS analysis, which showed decreases in water and THF, respectively. The DVS of morphology VII is shown in Figure 23. Example 8. Compound I Form VIII

[0416] Compound I form VIII is the crystalline water:ACN solvated form of Compound I free base. Form VIII was prepared by slurring Compound I form VII in ACN at room temperature. The solid was isolated using a Buchner funnel and filter paper.

[0417] The XRPD pattern of morphology VIII is shown in Figure 24. The DSC curve of morphology VIII is shown in Figure 25. The endothermic events at starting temperatures of approximately 17°C and 99°C are due to the desolvation of morphology VIII. The TGA of morphology VIII is shown in Figure 26. The TGA data shows a weight loss of approximately 1.4 wt% from room temperature to approximately 52°C, and another weight loss of approximately 6.6 wt% from approximately 52°C to approximately 160°C, indicating that morphology VIII is being solvated. This was later confirmed by TGA-MS analysis, which showed decreases in water and THF, respectively. The DVS of morphology VIII is shown in Figure 27. Example 9. Compound Form I IX

[0418] Compound I form IX is the crystalline water:2-MeTHF solvated form of the free base of Compound I. Form IX was prepared by slurring Compound I form VII in 2-MeTHF at room temperature. The solid was isolated using a Buchner funnel and filter paper.

[0419] The XRPD pattern of morphology IX is shown in Figure 28. The DSC curve of morphology IX is shown in Figure 29. The endothermic events at starting temperatures of approximately 20°C and 79°C are due to the desolvation of morphology IX. The TGA of morphology IX is shown in Figure 30. The TGA data shows a weight loss of approximately 2.7 wt% from room temperature to approximately 50°C, and another weight loss of approximately 15.5 wt% from approximately 50°C to approximately 114°C, indicating that morphology IX is being solvated. This was later confirmed by TGA-MS analysis, which showed decreases in water and 2-MeTHF, respectively. The DVS of morphology IX is shown in Figure 31. Example 10. Compound I Form X

[0420] Compound I form X is highly likely to be the crystalline, structurally identical solvated form of compound I free base. Form X was prepared by adding compound I free base to approximately 1 mL of IPA, forming a slurry, and stirring at room temperature for approximately 7 days. Form X was also prepared in a similar manner using acetone or MTBE. The solid was isolated using a NANOSEP centrifugation filter.

[0421] The XRPD pattern of morphology X is shown in Figure 32. The DSC curve of morphology X is shown in Figure 33. The endothermic event with an initial temperature of approximately 43°C is due to the desolvation of morphology X. The TGA of morphology X is shown in Figure 34. The TGA data shows a weight loss of approximately 5.1% by weight from room temperature to approximately 150°C, indicating that morphology X is solvated. A sample of morphology X was heated to approximately 150°C using TGA and then analyzed by XRPD. The results showed that upon desolvation, morphology X is converted to morphology XIII. Example 11. Compound I Form XI

[0422] Compound I form XI is highly likely to be the crystalline, structurally identical solvated form of Compound I free base. Form XI was prepared by adding approximately 1 mL of Compound I free base to MIBK, forming a slurry, and stirring at room temperature for approximately 7 days. Form XI was also prepared in the same manner using THF. The solid was isolated using a NANOSEP centrifugation filter.

[0423] The XRPD pattern of morphology XI is shown in Figure 35. Example 12. Compound I, Form XII

[0424] Compound I form XII is the crystalline form of compound I free base. Form XII was prepared as a mixture with compound I form V by adding compound I free base to approximately 1 mL of toluene to form a slurry and stirring at room temperature for approximately 7 days. Form XII was prepared in the same manner using heptane. The solid was isolated using a NANOSEP centrifugation filter.

[0425] The XRPD pattern of compound form I-XII is shown in Figure 36. Example 13. Compound I, Form XIII

[0426] Compound I form XIII is the crystalline non-solvated form of the free base of Compound I. Form I was prepared by desolvating Compound I form X in a TGA at 150°C.

[0427] The XRPD pattern of compound form I-XIII is shown in Figure 37. Example 14. Compound I, amorphous form

[0428] The amorphous form of compound I is the non-crystalline, non-solvated form of compound I free base. The amorphous form was prepared by slurring approximately 0.3 g of semicrystalline compound I free base in 10 mL of 2-MeTHF overnight at room temperature. After the solid was converted to compound I form IX, the solid was filtered and dried overnight in a vacuum oven at 100°C.

[0429] The amorphous XRPD pattern is shown in Figure 38. Example 15. Compound I monocitrate form I

[0430] Compound I monocitrate form I is the crystalline non-solvated monocitrate of Compound I. Monocitrate form I was prepared by adding 1 mL of EtOH containing 1.5 molar equivalents of citric acid to a slurry of approximately 0.2 g of free base Compound I in 3 mL of EtOH at room temperature and stirring overnight.

[0431] The XRPD pattern of monocitrate form I is shown in Figure 39. The DSC curve of monocitrate form I is shown in Figure 40. The DSC data shows two endothermic events with starting temperatures of approximately 145°C and 187°C, respectively, due to the conversion to compound I monocitrate form II and the decrease in citrate. The TGA of monocitrate form I is shown in Figure 41. The smallest weight loss (approximately 0.6% by weight) observed in the TGA data from room temperature to approximately 150°C indicates that monocitrate form I is non-solvable. The DVS of monocitrate form I is shown in Figure 42. 1 The 1H NMR spectrum is shown in Figure 43. NMR analysis indicates that compound I monocitrate form I contains approximately 1 molar equivalent of citrate. Example 16. Compound I monocitrate form II

[0432] Compound I monocitrate form II is the crystalline non-solvated monocitrate of Compound I. Monocitrate form II was prepared by heating Compound I monocitrate form I in a variable temperature XRPD at 170°C.

[0433] The XRPD pattern of monocitrate form II is shown in Figure 44. Example 17. Compound I monocitrate form III

[0434] Compound I monocitrate form III is the crystalline monohydrate form of compound I monocitrate. Monocitrate form III was prepared by slurring approximately 1 g of compound I form II with 1.5 molar equivalents of citric acid in 20 mL of EtOH overnight at 20°C.

[0435] The XRPD pattern of monocitrate form III is shown in Figure 45. The DSC curve of monocitrate form III is shown in Figure 46. The endothermic events at starting temperatures of approximately 25°C and 159°C are due to the decrease in water and the decomposition of citrate, respectively. The TGA of monocitrate form III is shown in Figure 47. Based on the TGA weight loss, the amount of water corresponds to approximately 1.5 molar equivalents (theoretically 4.1 wt%) of water. The DVS of monocitrate form III is shown in Figure 48. Example 18. Compound I monocitrate form IV

[0436] Compound I monocitrate form IV is likely the crystalline monohexafluoro-2-propanol solvated form of compound I monocitrate. Monocitrate form VI was prepared by dissolving compound I monocitrate in 20 mL of hexafluoro-2-propanol at room temperature, and then removing the hexafluoro-2-propanol using a rotary evaporator. The resulting solid was then isolated and analyzed by XRPD.

[0437] The XRPD pattern of monocitrate form IV is shown in Figure 49. The DSC curve of monocitrate form IV is shown in Figure 50. The endothermic events at starting temperatures of approximately 75°C and 183°C are attributed to the decrease of hexafluoro-2-propanol and the decomposition of citrate, respectively. The endothermic event at a starting temperature of approximately 139°C was not investigated. The TGA of monocitrate form IV is shown in Figure 51. The weight loss (approximately 22.5% by weight) observed in the TGA data from room temperature to approximately 140°C indicates that form monocitrate form IV is solvated. This was later confirmed to be hexafluoro-2-propanol by TGA-MS analysis. The DVS of monocitrate form IV is shown in Figure 52. Example 19. Compound I Hemicitrate Form I

[0438] Compound I hemicitrate form I is the crystalline monohydrate hemicitrate of Compound I. Hemicitrate form I was prepared by adding Compound I monocitrate form I to approximately 1 mL of EtOH / water (73.7:26.3 v / v), forming a slurry, and stirring at room temperature for approximately 6 days. The solid was isolated using a NANOSEP centrifugation filter.

[0439] The XRPD pattern of hemicitrate form I is shown in Figure 53. The DSC curve of hemicitrate form I is shown in Figure 54. The endothermic events at starting temperatures of approximately 70°C and 153°C are attributed to the decrease in water and the decomposition of citrate, respectively. The endothermic event at a starting temperature of approximately 133°C was not investigated. The TGA of hemicitrate form I is shown in Figure 55. The weight loss (approximately 2.8 wt%) observed in the TGA data from room temperature to approximately 100°C indicates that hemicitrate form I is being solvated. This was later confirmed to be water by TGA-MS analysis. Based on the TGA weight loss, the amount of water corresponds to approximately 1 molar equivalent (theoretically 3.3 wt%) of water. The weight loss (approximately 15 wt%) observed in the TGA data from approximately 140°C to approximately 200°C was confirmed by TGA-MS analysis to be the decomposition of citrate, which produces water and carbon dioxide. The DVS of hemicitrate form I is shown in Figure 56. Hemicitrate form I 1 The 1H NMR spectrum is shown in Figure 57. Example 20. Compound I monoHCl form I

[0440] Compound I monoHCl form I is the crystalline non-solvated monohydrochloride salt of Compound I. MonoHCl form I was prepared by slurring approximately 0.2 g of free Compound I base in 3 mL of EtOH and adding 1 mL of EtOH containing approximately 1.5 molar equivalents of concentrated hydrochloric acid at room temperature. The solid was isolated using a NANOSEP centrifugation filter.

[0441] The XRPD pattern of monoHCl form I is shown in Figure 58. The DSC curve of monoHCl form I is shown in Figure 59. The TGA of monoHCl form I is shown in Figure 60. The smallest weight loss (approximately 0.2% by weight) observed in the TGA data from room temperature to approximately 100°C indicates that monoHCl form I is non-solvable. The DVS of monoHCl form I is shown in Figure 61. Example 21. Compound I monomaleate form I

[0442] Compound I monomaleate form I is the crystalline non-solvated monomaleate of Compound I. Monomaleate form I was prepared by slurring approximately 0.2 g of free Compound I base in 3 mL of EtOH and adding 1 mL of EtOH containing approximately 1.5 molar equivalents of maleic acid at room temperature. The solid was isolated using a NANOSEP centrifugation filter.

[0443] The XRPD pattern of monomaleate form I is shown in Figure 62. The DSC curve of monomaleate form I is shown in Figure 63. The DSC data shows an endothermic event with an onset temperature of approximately 188°C, resulting from the melting / decomposition of monomaleate form I. The TGA of monomaleate form I is shown in Figure 64. The smallest weight loss (less than 0.1% by weight) observed in the TGA data from room temperature to approximately 100°C indicates that monomaleate form I is non-solvable. The DVS of monomaleate form I is shown in Figure 65. 1 The 1H NMR spectrum is shown in Figure 66. NMR analysis indicates that monomaleate form I contains approximately 1 molar equivalent of maleic acid. Example 22. Compound I Hemifumarate Form I

[0444] Compound I hemi-fumarate form I is the crystalline, non-solvated hemi-fumarate of Compound I. Hemi-fumarate form I was prepared by slurring approximately 0.2 g of free Compound I base in 3 mL of EtOH and adding 1 mL of EtOH containing approximately 1.5 molar equivalents of fumaric acid at room temperature. The solid was isolated using a NANOSEP centrifugation filter.

[0445] The XRPD pattern of hemi-fumarate form I is shown in Figure 67. The DSC curve of hemi-fumarate form I is shown in Figure 68. The first thermal event is a baseline shift from approximately 83°C to approximately 91°C due to a glass transition. The second thermal event, with an onset temperature of approximately 151°C, was not investigated. The TGA of hemi-fumarate form I is shown in Figure 69. The smallest weight loss (approximately 0.8 wt%) observed in the TGA data from room temperature to approximately 50°C indicates that hemi-fumarate form I is non-solvable. The DVS of hemi-fumarate form I is shown in Figure 70. 1 The 1H NMR spectrum is shown in Figure 71. NMR analysis indicates that hemi-fumarate form I contains approximately 0.5 molar equivalents of fumarate. Example 23. Compound I monofumarate form I

[0446] Compound I monofumarate form I is the crystalline non-solvated monofumarate of Compound I. Monofumarate form I was prepared by storing Compound I hemifumarate form I, prepared as described above, in a sealed container at room temperature for 6 months. The solid was isolated using a NANOSEP centrifugation filter.

[0447] The XRPD pattern of monocitrate form I is shown in Figure 72. The DSC curve of monocitrate form I is shown in Figure 73. The TGA of monocitrate form I is shown in Figure 74. The smallest weight loss (approximately 0.4% by weight) observed in the TGA data from room temperature to approximately 100°C indicates that monofumarate form I is non-solvable. The DVS of monocitrate form I is shown in Figure 75. 1 The 1H NMR spectrum is shown in Figure 76. NMR analysis indicates that compound I monofumarate form I contains approximately 1 molar equivalent of fumaric acid. Example 24. Compound I hemi-L-tartrate form I

[0448] Compound I hemi-L-tartrate form I is the crystalline hydrated form of the hemi-L-tartrate of Compound I. Hemi-L-tartrate form I was prepared by adding 1 mL of EtOH containing 1.5 molar equivalents of L-tartaric acid to a slurry of approximately 0.1 g of free base of Compound I in approximately 3 mL of EtOH at room temperature and stirring overnight. The solid was isolated using a NANOSEP centrifugation filter.

[0449] The XRPD pattern of hemi-L-tartrate form I is shown in Figure 77. The DSC curve of hemi-L-tartrate form I is shown in Figure 78. The endothermic event at an onset temperature of approximately 65°C is due to the decrease in water. The endothermic event at an onset temperature of approximately 127°C was not investigated. The TGA of hemi-L-tartrate form I is shown in Figure 79. The TGA data shows a weight loss of approximately 4.8% by weight from room temperature to approximately 65°C, indicating that form I is solvated. This was later confirmed to be water by TGA-MS analysis. The DVS of hemi-L-tartrate form I is shown in Figure 80. 1 The 1H NMR spectrum is shown in Figure 81. NMR analysis indicates that compound I hemi-L-tartrate form I contains approximately 0.5 molar equivalents of L-tartaric acid. Example 25. Compound I Mono-ESA Form I

[0450] Compound I mono-ESA form I is the crystalline hydrated monoethanesulfonate of Compound I. Mono-ESA form I was prepared by adding 1 mL of EtOH containing 1.5 molar equivalents of ethylsulfonic acid to a slurry of approximately 0.1 g of free Compound I base in 3 mL of EtOH at room temperature and stirring overnight. The solid was isolated using a NANOSEP centrifugation filter.

[0451] The XRPD pattern of monoESA form I is shown in Figure 82. The DSC curve of monoESA form I is shown in Figure 83. The endothermic event at an onset temperature of approximately 86°C is due to the decrease in water. The endothermic event at an onset temperature of approximately 123°C was not investigated. The TGA of monoESA form I is shown in Figure 84. The TGA data shows a weight loss of approximately 3.5 wt% from room temperature to approximately 86°C, indicating that monoESA form I is solvated. This was later confirmed to be water by TGA-MS analysis. The DVS of monoESA form I is shown in Figure 85. 1 The 1H NMR spectrum is shown in Figure 86. NMR analysis indicates that mono-ESA form I contains approximately 1 molar equivalent of ESA. Example 26. Compound I hemiglycolate form I

[0452] Compound I hemiglycolate form I is the crystalline, non-solvated hemiglycolate of Compound I. Hemiglycolate form I was prepared by adding 1 mL of EtOH containing 1.5 molar equivalents of glycolic acid to a slurry of approximately 0.1 g of free Compound I base in 3 mL of EtOH at room temperature and stirring overnight. The solid was isolated using a NANOSEP centrifugation filter.

[0453] The XRPD pattern of hemiglycolate form I is shown in Figure 87. The DSC curve of hemiglycolate form I is shown in Figure 88. The DSC data shows one endothermic event with an onset temperature of approximately 107°C. This endothermic event is most likely melting of hemiglycolate form I. The TGA of hemiglycolate form I is shown in Figure 89. The smallest weight loss (approximately 0.4 wt%) observed in the TGA data from room temperature to approximately 100°C indicates that hemiglycolate form I is non-solvable. The DVS of hemiglycolate form I is shown in Figure 90. 1 The 1H NMR spectrum is shown in Figure 91. NMR analysis indicates that hemiglycolate form I contains approximately 0.5 molar equivalents of glycolic acid. Example 27. Compound I sulfate form I

[0454] Compound I sulfate form I is the crystalline non-solvated sulfate of Compound I. Sulfate form I was prepared by slurring approximately 0.2 g of free base Compound I in 3 mL of EtOH, adding 1 mL of EtOH containing 1.5 molar equivalents of sulfuric acid at room temperature, and stirring overnight. The solid was isolated using a NANOSEP centrifugation filter.

[0455] The XRPD pattern of sulfate form I is shown in Figure 92. The DSC curve of sulfate form I is shown in Figure 93. The endothermic event at an initiation temperature of approximately 44°C is due to the desolvation of sulfate form I. Endothermic events at initiation temperatures of approximately 126°C and 164°C were not investigated. The TGA of sulfate form I is shown in Figure 94. The weight loss (approximately 2.1% by weight) observed in the TGA data from room temperature to approximately 100°C suggests that sulfate form I may be solvated with water or ethanol. Example 28. Compound I Phosphate Form I

[0456] Compound I phosphate form I is the crystalline, non-solvated form of the phosphate of Compound I. Phosphate form I was prepared by slurring approximately 0.2 g of free Compound I base in 3 mL of EtOH, adding 1 mL of EtOH containing 1.5 molar equivalents of phosphoric acid at room temperature, and stirring overnight. The solid was isolated using a NANOSEP centrifugation filter.

[0457] The XRPD pattern of phosphate form I is shown in Figure 95. The DSC curve of phosphate form I is shown in Figure 96. The endothermic event at an initiation temperature of approximately 46°C is due to the desolvation of phosphate form I. Endothermic events at initiation temperatures of approximately 146°C and approximately 179°C were not investigated. The TGA of phosphate form I is shown in Figure 97. The weight loss (approximately 4.2% by weight) observed in the TGA data from room temperature to approximately 120°C indicates that phosphate form I is solvated with either water or ethanol. A sample of phosphate form I was heated to approximately 100°C in the TGA and then analyzed by XRPD. The results showed that phosphate form I loses its crystallinity upon desolvation. Example 29. Compound I hemi-HCl form I

[0458] Compound I hemiHCl form I is the crystalline hydrated hemi hydrochloride of Compound I. HemiHCl form I was prepared by adding 1 mL of EtOH and 0.5 molar equivalents of concentrated hydrochloric acid to approximately 0.1 g of free Compound I base at room temperature and stirring overnight. The solid was isolated using a NANOSEP centrifuge filter.

[0459] The XRPD pattern of hemiHCl form I is shown in Figure 98. The DSC curve of hemiHCl form I is shown in Figure 99. The endothermic event at an initiation temperature of approximately 80°C is due to desolvation. The TGA of hemiHCl form I is shown in Figure 100. The weight loss (approximately 5.5 wt%) observed in the TGA data from room temperature to approximately 130°C indicates that hemiHCl form I is being solvated. This was later confirmed to be water by TGA-MS analysis. The DVS of hemiHCl form I is shown in Figure 101. Example 30. Compound I Cocrystal Form I

[0460] Compound I cocrystal form I is the crystalline 2-MeTHF:water solvated form of the cocrystal of Compound I and 4-(((S)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide ("Compound A"). The alaninamide stereocenter in 6-chloro-4-(((R)-1-cyanoethyl)amino)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide was epimerized by heating in IPA at 70°C. The resulting mixture of 6-chloro-4-(((R)-1-cyanoethyl)amino)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide and its diastereomer, 6-chloro-4-(((R)-1-cyanoethyl)amino)-N-((S)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide, was isolated from IPA and heptane at 0°C. The mixture was treated at 80°C with 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitride, palladium acetate, X-Phos, and an aqueous solution of K3PO4 in 2-MeTHF to obtain a mixture of compound I and compound A. The final reaction mixture was treated at 40°C with trithiocyanurate trisodium hydrate, activated carbon, and diatomaceous earth, and then filtered through diatomaceous earth to obtain 2-MeTHF solutions of compound I and compound A. After washing the 2-MeTHF solutions of compound I / compound A with water, a 1:1 crystalline cocrystal of compound I and compound A was crystallized by concentration by distillation.

[0461] The XRPD pattern of compound I cocrystal form I is shown in Figure 102. The DSC curve of compound I cocrystal form I is shown in Figure 103. The DSC data shows two endothermic events at starting temperatures of approximately 43°C and 239°C, respectively, due to the desolvation of water and 2-MeTHF. The TGA of compound I cocrystal form I is shown in Figure 104. The weight loss observed in the TGA data from room temperature to approximately 65°C (approximately 1.6 wt%) and from approximately 65°C to approximately 200°C (approximately 6.6 wt%) indicates that compound I cocrystal form I is being solvated. This was later confirmed by TGA-MS analysis to be water and 2-MeTHF, respectively.

Claims

1. Crystal morphology of compound I: 【Transformation 5】 A crystalline form of compound I, characterized by an X-ray powder diffraction pattern measuring with a Cu-Kα diffractometer, which includes peaks (±0.2°) at 7.5, 12.3, and 7.2°²θ.

2. i) One or more peaks at 19.1°2θ±0.2°, 22.7±0.2°, or 15.1±0.2°; ii) Diffraction diagrams substantially as shown in Figure 1; iii) Differential scanning calorimetry (DSC) curves including endothermic heating at approximately 155.3°C (start temperature) and approximately 174.7°C (start temperature); iv) Differential scanning calorimetry (DSC) curves substantially as shown in Figure 2; v) Thermogravimetric analysis (TGA) showing a weight loss of approximately 1.0% by weight up to approximately 150°C; or vi) The crystal morphology according to claim 1, further characterized by thermogravimetric analysis (TGA) including a thermogram substantially as shown in Figure 3.

3. Crystal morphology of compound I: 【Transformation 6】 A crystalline form of compound I, form II, characterized by an X-ray powder diffraction pattern measuring with a Cu-Kα diffractometer, which includes peaks (±0.2°) at 7.5, 14.6, and 17.8°²θ.

4. i) One or more peaks at 22.8°2θ±0.2°, 26.7±0.2°, or 22.0±0.2°; ii) Diffraction diagrams substantially as shown in Figure 4; iii) Differential scanning calorimetry (DSC) curve including endothermic heating at approximately 190.7°C (start temperature); iv) Differential scanning calorimetry (DSC) curves substantially as shown in Figure 5; v) Thermogravimetric analysis (TGA) showing a weight loss of approximately 1.0% by weight up to approximately 200°C; or vi) The crystal morphology according to claim 3, further characterized by thermogravimetric analysis (TGA) including a thermogram substantially as shown in Figure 6.

5. Crystal morphology of compound I: 【Transformation 7】 A crystalline form of compound I form IV, characterized by an X-ray powder diffraction pattern measuring with a Cu-Kα diffractometer, which includes peaks (±0.2°) at 10.1, 10.7, and 17.9°²θ.

6. i) One or more peaks at 17.3°2θ±0.2°, 11.7±0.2°, or 21.7±0.2°; ii) Diffraction diagrams substantially as shown in Figure 8; iii) Differential scanning calorimetry (DSC) curve including endothermic heating at approximately 192.0°C (start temperature); iv) Differential scanning calorimetry (DSC) curves substantially as shown in Figure 9; v) Thermogravimetric analysis (TGA) showing a weight loss of approximately 0.8% by weight up to approximately 200°C; vi) Thermogravimetric analysis (TGA) including a thermogram substantially as shown in Figure 10; or vii) The crystal morphology according to claim 5, further characterized by a dynamic water vapor adsorption (DVS) curve substantially as shown in Figure 11.

7. Crystal morphology of compound I: 【Transformation 8】 A crystalline form of compound I form V, which is a monohydrate, characterized by an X-ray powder diffraction pattern measuring with a Cu-Kα diffractometer, which includes peaks (±0.2°) at 11.8, 25.9, and 20.7°²θ.

8. i) One or more peaks at 16.8°2θ±0.2°, 23.1±0.2°, or 18.5±0.2°; ii) Diffraction diagram substantially as shown in Figure 12; iii) Differential scanning calorimetry (DSC) curves including endothermic reactions at approximately 70.5°C (start temperature), approximately 151.6°C (start temperature), and approximately 189.1°C (start temperature); iv) Differential scanning calorimetry (DSC) curves substantially as shown in Figure 13; v) Thermogravimetric analysis (TGA) showing a weight loss of approximately 3.6% by weight up to approximately 100°C; vi) Thermogravimetric analysis (TGA) including a thermogram as substantially shown in Figure 14; or vii) The crystal morphology according to claim 7, further characterized by a dynamic water vapor adsorption (DVS) curve substantially as shown in Figure 15.

9. The crystalline form according to claim 7, containing approximately 1 molar equivalent of water.

10. Crystal morphology of compound I: 【Chemistry 9】 A crystalline form of compound I form VI, which is a monohydrate and is characterized by an X-ray powder diffraction pattern measuring with a Cu-Kα diffractometer, which includes peaks (±0.2°) at 4.9, 5.6, and 7.4°²θ.

11. i) One or more peaks at 8.4°2θ±0.2°, 12.3±0.2°, or 27.2±0.2°; ii) Diffraction diagrams substantially as shown in Figure 16; iii) Differential scanning calorimetry (DSC) curves including endothermic reactions at approximately 47.0°C (start temperature), approximately 111.1°C (start temperature), and approximately 122.9°C (start temperature); iii) Differential scanning calorimetry (DSC) curves, substantially as shown in Figure 17; v) Thermogravimetric analysis (TGA) showing a weight loss of approximately 5.2% by weight up to approximately 140°C; vi) Thermogravimetric analysis (TGA) including a thermogram as substantially shown in Figure 18; or vii) The crystal morphology according to claim 10, further characterized by a dynamic water vapor adsorption (DVS) curve substantially as shown in Figure 19.

12. The crystalline form according to claim 10, containing approximately 1.25 molar equivalents of water.

13. Crystalline form of monocitrate of compound I: 【Chemistry 10】 A crystalline form of compound I monocitrate, characterized by an X-ray powder diffraction pattern measuring with a Cu-Kα diffractometer, which includes peaks (±0.2°) at 5.7, 7.0, and 22.7°²θ.

14. i) One or more peaks at 19.6°2θ±0.2°, 15.6±0.2°, or 8.1±0.2°; ii) Diffraction diagrams substantially as shown in Figure 39; iii) Differential scanning calorimetry (DSC) curves including endothermic heating at approximately 145.2°C (start temperature) and approximately 186.6°C (start temperature); iv) Differential scanning calorimetry (DSC) curves substantially as shown in Figure 40; v) Thermogravimetric analysis (TGA) showing a weight loss of approximately 0.6% by weight up to approximately 150°C; vi) Thermogravimetric analysis (TGA) including a thermogram as substantially shown in Figure 41; vii) The crystal morphology according to claim 13, further characterized by a dynamic water vapor adsorption (DVS) curve substantially as shown in Figure 42.

15. The crystalline form according to claim 13, comprising approximately 1 molar equivalent of citric acid.

16. Crystal morphology of compound I: 【Chemistry 11】 (Compound I Form III), characterized by a crystalline form having an X-ray powder diffraction pattern measured with a Cu-Kα diffractometer, including peaks (±0.2°) at 21.2, 12.3, and 10.7°²θ; or A crystalline form of compound I (compound I form VII), which is a water:tetrahydrofuran (THF) solvate, characterized by an X-ray powder diffraction pattern measured with a Cu-Kα diffractometer, which includes peaks at 4.0, 25.8, and 6.9°²θ (±0.2°); or A crystalline form of compound I (compound I form VIII), which is a water:acetonitrile (ACN) solvate, characterized by an X-ray powder diffraction pattern measuring with a Cu-Kα diffractometer, including peaks at 8.0, 25.8, and 6.1°²θ (±0.2°); or A crystalline form of compound I (compound I form IX), which is water:2-methyltetrahydrofuran (Me-THF) solvate, characterized by an X-ray powder diffraction pattern measured with a Cu-Kα diffractometer, which includes peaks at 9.4, 4.5, and 18.3°2θ (±0.2°); or A crystalline form of compound I (compound I form X), which is an isopropyl alcohol (IPA) solvate, characterized by an X-ray powder diffraction pattern measured with a Cu-Kα diffractometer, which includes peaks (±0.2°) at 4.0, 7.0, and 8.2°²θ; or A crystalline form of compound I (compound I form XI), which is a methyl isobutyl ketone (MIBK) solvate, characterized by an X-ray powder diffraction pattern measured with a Cu-Kα diffractometer, which includes peaks at 4.0, 6.9, and 14.5°²θ (±0.2°); or A crystalline form of compound I (compound I form XII) characterized by an X-ray powder diffraction pattern measured with a Cu-Kα diffractometer, which includes peaks at 7.7, 11.7 and 26.1°²θ (±0.2°); or A crystalline form of compound I (compound I form XIII) characterized by an X-ray powder diffraction pattern measured with a Cu-Kα diffractometer, which includes peaks at 7.6, 14.6, and 17.9°²θ (±0.2°); or A crystalline form of compound I (compound I monocitrate form II), which is a monocitrate, characterized by an X-ray powder diffraction pattern measured with a Cu-Kα diffractometer, including peaks at 5.6, 7.0, and 24.2°²θ (±0.2°); or A crystalline form of compound I (compound I monocitrate form III), which is a monocitrate and is characterized by an X-ray powder diffraction pattern measured with a Cu-Kα diffractometer, which includes peaks at 6.3, 18.8, and 7.7°²θ (±0.2°); or A crystalline form of compound I (compound I monocitrate form IV), which is a monocitrate, characterized by an X-ray powder diffraction pattern measured with a Cu-Kα diffractometer, which includes peaks at 26.8, 25.7, and 25.1°²θ (±0.2°); or A crystalline form of compound I (compound I hemicitrate form I), which is a hemicitrate and is characterized by an X-ray powder diffraction pattern measured with a Cu-Kα diffractometer that includes peaks (±0.2°) at 6.1, 7.4, and 17.1°²θ; or A crystalline form of compound I (compound I monoHCl form I), which is a monohydrochloric acid (HCl) salt, characterized by an X-ray powder diffraction pattern measured with a Cu-Kα diffractometer, which includes peaks at 6.9, 20.7, and 16.9°²θ (±0.2°); or A crystalline form of compound I (compound I monomaleate form I), which is a monomaleate, and is characterized by an X-ray powder diffraction pattern measured with a Cu-Kα diffractometer, which includes peaks at 7.4, 6.1, and 23.2°²θ (±0.2°); or A crystalline form of compound I (compound I hemi-fumarate form I), which is a hemi-fumarate, and is characterized by an X-ray powder diffraction pattern measured with a Cu-Kα diffractometer, which includes peaks at 7.7, 6.8, and 13.0°²θ (±0.2°); or A crystalline form of compound I (compound I monofumarate form I), which is a monofumarate, and is characterized by an X-ray powder diffraction pattern measured with a Cu-Kα diffractometer, which includes peaks at 6.1, 7.8, and 18.7°²θ (±0.2°); or A crystalline form of compound I (compound I hemy-L-tartrate form I), which is a hemy-L-tartrate, characterized by an X-ray powder diffraction pattern measured with a Cu-Kα diffractometer, which includes peaks at 8.5, 5.2 and 18.6°²θ (±0.2°); or A crystalline form of compound I (compound I monoESA form I), which is a monoethanesulfonic acid (ESA) salt, characterized by an X-ray powder diffraction pattern measuring with a Cu-Kα diffractometer, including peaks at 6.4, 10.9, and 19.0°²θ (±0.2°); or A crystalline form of compound I (compound I hemiglycolate form I), which is a hemiglycolate, and is characterized by an X-ray powder diffraction pattern measured with a Cu-Kα diffractometer, which includes peaks at 6.2, 8.0, and 22.9°²θ (±0.2°); or A crystalline form of compound I (compound I sulfate form I), which is a sulfate, characterized by an X-ray powder diffraction pattern measured with a Cu-Kα diffractometer, which includes peaks at 5.5, 4.9, and 11.1°²θ (±0.2°); or A crystalline form of compound I (compound I phosphate form I), which is a phosphate, and is characterized by an X-ray powder diffraction pattern measured with a Cu-Kα diffractometer, which includes peaks at 4.8, 9.7, and 16.9°²θ (±0.2°); or A crystalline form of compound I (compound I hemiHCl form I), which is a hemihydrochloride (HCl) salt, characterized by an X-ray powder diffraction pattern measured with a Cu-Kα diffractometer, including peaks at 5.6, 9.2, and 11.2°²θ (±0.2°); or A crystalline form of compound I (compound I cocrystal form I), which is a cocrystal of compound I and 4-(((S)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide, characterized by an X-ray powder diffraction pattern measured with a Cu-Kα diffractometer, which includes peaks (±0.2°) at 19.1, 10.3, and 9.4°2θ.

17. A pharmaceutical composition comprising a crystalline form according to any one of claims 1 to 16 and a pharmaceutically acceptable carrier.

18. A method for treating an inflammatory condition in a patient who needs treatment for an inflammatory condition, comprising administering to the patient a therapeutically effective amount of the crystalline form described in any one of claims 1 to 16 or the pharmaceutical composition described in claim 17.

19. The method according to claim 18, wherein the inflammatory condition is selected from inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), psoriasis, and rheumatoid arthritis.

20. The method according to claim 19, wherein the inflammatory state is IBD.

21. The method according to claim 19, wherein the inflammatory state is rheumatoid arthritis.

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