WO2025250945A1 - Pim inhibitors and method of their use - Google Patents

Abstract

Compounds having activity as inhibitors of PIM are provided. The compounds have Structure (I): or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R¹, R², R³, L¹ and n are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and methods to modulate the activity of PIM are also provided.

Description

PIM INHIBITORS AND METHOD OF THEIR USE Cross-Reference to Related Application This application claims the benefit of U.S. Provisional Patent Application Serial No. 63/654,637, filed May 31, 2024, entitled, “PIM INHIBITORS AND METHOD OF THEIR USE,” the entirety of which is hereby incorporated by reference. BACKGROUND Technical Field Embodiments of the present disclosure are generally directed to compounds and methods for their preparation and use as therapeutic or prophylactic agents, for example for treatment of autoimmune diseases (e.g., lupus, systemic lupus erythematosus), cardiovascular diseases (e.g., cardio protection after ischemic injury, cardiac regeneration and angiogenesis), cancer, solid tumors (e.g., prostate cancer, pancreatic cancer, colorectal cancer, gastric cancer), hematological malignancies (e.g., acute myeloid leukemia (AML), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), multiple myeloma (MM)) and myelofibrosis (MF).. Description of Related Art The proto-oncogenic Proviral Integration Moloney (PIM) virus family of nuclear and cytoplasmic Ser/Thr kinases (PIM1, PIM2, and PIM3) are constitutively active when expressed and play a vital role in Systemic Lupus Erythematosus (SLE), and certain hematological malignancies (e.g., multiple myeloma). Additionally, PIM1 plays a key role in myelofibrosis and any solid tumors and selective PIM1 agents can induce the progression of the cell cycle, inhibition of apoptosis, and modulation of other signal transduction, including its own family pathways. Accordingly, there is a need to develop inhibitors that will directly target PIM in several diseases, such as multiple myeloma, prostate cancer, Burkitt's Lymphoma, oral cancer, lung cancer, colon cancer, lupus, systemic lupus erythematosus (SLE), Alzheimer's disease, myelofibrosis, or pulmonary fibrosis. Embodiments of the present disclosure fulfill this need and provide further related advantages.

1 #11053313.1 BRIEF SUMMARY PIM1 and lupus pathophysiology includes T cell activation and survival where PIM1 is upregulated downstream of IL-2 and IL-6, cytokines that are dysregulated in lupus. It promotes T cell proliferation, effector function, and resistance to apoptosis, contributing to the persistence of autoreactive T cells. In B cell function, PIM1 supports B cell survival and class switching, which can exacerbate autoantibody production—a hallmark of lupus. In additions, PIM1 role in Th17 differentiation promotes Th17 differentiation (involved in inflammation and autoimmunity), which is elevated in lupus patients. Further in immune cell metabolism, PIM1 regulates metabolic pathways that influence T and B cell activation, particularly glycolysis and mitochondrial health which is important in lupus pathogenesis. In brief, embodiments of the present disclosure provide compounds, including pharmaceutically acceptable salts, stereoisomers, and tautomers thereof, which are capable of inhibiting PIM (e.g., PIM1, PIM2, and/or PIM3). In one aspect, the disclosure provides compounds of Structure (I): pharmaceutically acceptable salts, stereoisomers, and tautomers thereof, wherein each of R¹, R², R³, L¹ and n are as defined below. In another aspect, pharmaceutical compositions comprising the disclosed compounds, and methods of use of the same for treatment of diseases (e.g., cancer and/or autoimmune diseases) are also provided. BRIEF DESCRIPTION OF THE DRAWINGS In the figures, identical reference numbers identify similar elements. The sizes and relative positions of elements in the figures are not necessarily drawn to scale. For example, the shapes of various elements and angles are not drawn to scale and some of these elements are enlarged and positioned to improve figure legibility. Further, the shapes of the elements as drawn, are not intended to convey any information regarding the actual shape of the elements and have been solely selected for ease of recognition in the figures.

2 #11053313.1 FIG.1A-1G shows relative IL-1β expression in systemic lupus erythematosus (SLE) peripheral blood mononuclear cells (PBMCs) for 7 different samples. The results in each figure (from left to right) show treatment effects for a control sample, TP3654, compound I-10a, and compound I-8. SLE PBMC samples were pretreated with DMSO and the testing agent at a concentration of 15 µM 1 hour prior to INF treatment. After 16 hours of INF treatment, the cells were further stimulated with 100 ng/mL of LPS. The mRNA levels of inflammasome IL-1β were measured in real time qPCR and ΔCT was calculated vs. β-actin. FIGs.1A-1G represent ΔΔCT for each treatment groups compared with control groups for IL-1β gene. FIG.2A-2G depicts relative TNFα expression in SLE PBMCs for 7 different samples. The results in each figure (left to right) show treatment effects for a control sample, TP3654, compound I-10a, and compound I-8. SLE PBMC samples were pretreated with DMSO and the testing agent at a concentration of 15 µM 1 hour prior to INF treatment. After 16 hours of INF treatment, the cells were further stimulated with 100 ng/mL of LPS. The mRNA levels of inflammasome TNFα were measured by real time qPCR and ΔCT calculated vs. β-actin. FIGs. 2A-2G represent ΔΔCT for each treatment groups compared with control groups for TNFα gene. FIG.3A illustrates a comparison of cytotoxic activity for Ixazomib (IC50 = 7.7 µM), compound I-8 (IC₅₀ = 7.9 µM), compound I-10a (IC₅₀ = 18.3 µM), and TP3654 (IC₅₀ = 779 µM) against MM.1S cells. FIG.3B illustrates a comparison of cytotoxic activity for Ixazomib (IC₅₀ = 7.6 µM), compound I-8 (IC50 = 8.3 µM), compound I-10a (IC50 = 15 µM), and TP3654 (IC50 = 17 µM) against MM.1R cells. FIG.3C shows activity for compounds of Structure (I) used in combination with Ixazomib against MM.1S cells. Compound I-8 had an IC₅₀ = 4.3 nM and compound I-10a had an IC50 = 7.1 nM when used in combination with Ixazomib, respectively. FIG.3D shows activity for compounds of Structure (I) used in combination with Ixazomib against MM.1R cells. Compound I-8 had an IC50 = 5.6 nM and compound I-10a had an IC₅₀ = 9.5 nM when used in combination with Ixazomib, respectively. FIGs.4A-4C show detection of dead and dying cells using CyQuant cytotoxicity assay kit (G6PD assay) for human renal proximal tubular epithelial cells (RPTEC). Cells were treated with TP3654 (FIG.4A), compound I-10a (FIG.4B), and compound I-8 (FIG.4C). Cells were then left to incubate for 24 hours and assayed for glucose 6-phosphate dehydrogenase release. An untreated control sample and completely lysed cells are shown for comparison. Fluorescence was measured in a microplate reader (excitation / emission ~530 / 590 nm).

3 #11053313.1 FIG.5A and 5B show mean plasma concentration profiles for samples treated with compound I-10a following single dose intravenous and oral administration. FIG.5A shows a linear scale while FIG.5B shows a semi-log scale. For each graph, circles correspond to G1 and triangles correspond to G2. Additional discussion of results can be found in Biological Example 12. FIG.6 shows the effect of compound I-10a on histopathology. The total histopathology score is plotted against each treatment group. From left to right shows the results for G1, G2, G3, and G4. For additional details, see Biological Example 3. FIG.7A shows histopathology results for mononuclear cell infiltration. FIG.7B shows histopathology results for tubular degeneration. FIG.7C shows histopathology results for glomerular membrane thickening. FIG.7D shows histopathology results for protein casts. FIG.7E shows histopathology results for tubular dilation. FIG.7F shows histopathology results for histopathology score. In each of the FIGs.7A-7F, the bars from left to right are for G1, G2, G3, and G4. Details of these studies can be found in Biological Example 13. DETAILED DESCRIPTION In the following description, certain specific details are set forth to provide a thorough understanding of various embodiments of the disclosure. However, one skilled in the art will understand that the disclosure may be practiced without these details. Unless the context requires otherwise, throughout the present specification and claims, the word "comprise" and variations thereof, such as, "comprises" and "comprising" are to be construed in an open, inclusive sense, that is, as "including, but not limited to". In the present description, any concentration range, percentage range, ratio range, or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated. As used herein, the terms "about" and "approximately" mean ± 20%, ± 10%, ± 5% or ± 1% of the indicated range, value, or structure, unless otherwise indicated. The terms "a" and "an" as used herein refer to "one or more" of the enumerated components. The use of the alternative (e.g., "or") should be understood to mean either one, both, or any combination thereof of the alternatives.

4 #11053313.1 Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present disclosure. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs. As used in the specification and claims, the singular form "a", "an" and "the" include plural references unless the context clearly dictates otherwise. "Amino" refers to the ˗NH2 radical. "Cyano" refers to the ˗CN radical. "Hydroxy" or "hydroxyl" refers to the ˗OH radical. "Oxo" refers to the =O substituent. "Alkyl" refers to a saturated, straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, having from one to twelve carbon atoms (C₁-C₁₂ alkyl), one to eight carbon atoms (C1-C8 alkyl) or one to six carbon atoms (C1-C6 alkyl), or any value within these ranges, such as C₄-C₆ alkyl and the like, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl and the like. The number of carbons referred to relates to the carbon backbone and carbon branching but does not include carbon atoms belonging to any substituents. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted. The term "alkynyl" refers to unsaturated straight or branched hydrocarbon radical, having 2 to 12 carbon atoms (C2-C12 alkynyl), two to nine carbon atoms (C2-C9 alkynyl), or two to six carbon atoms (C₂-C₆ alkynyl), or any value within these ranges, and having at least one carbon- carbon triple bond. Examples of alkynyl groups may be selected from the group consisting of ethynyl, propargyl, but-1 -ynyl, but-2-ynyl and the like. The number of carbons referred to relates to the carbon backbone and carbon branching but does not include carbon atoms belonging to any substituents. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted.

5 #11053313.1 "Alkoxy" refers to a radical of the formula ˗OR_a where R_a is an alkyl radical as defined above containing one to twelve carbon atoms (C1-C12 alkoxy), one to eight carbon atoms (C1-C8 alkoxy) or one to six carbon atoms (C₁-C₆ alkoxy), or any value within these ranges. Unless stated otherwise specifically in the specification, an alkoxy group is optionally substituted. "Aromatic ring" refers to a cyclic planar molecule or portion of a molecule (i.e., a radical) with a ring of resonance bonds that exhibits increased stability relative to other connective arrangements with the same sets of atoms. Generally, aromatic rings contain a set of covalently bound co-planar atoms and comprises a number of π-electrons (for example, alternating double and single bonds) that is even but not a multiple of 4 (i.e., 4n + 2 π-electrons, where n = 0, 1, 2, 3, etc.). Aromatic rings include, but are not limited to, phenyl, naphthenyl, imidazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridonyl, pyridazinyl, pyrimidonyl. Unless stated otherwise specifically in the specification, an "aromatic ring" includes all radicals that are optionally substituted. "Aryl" refers to a carbocyclic ring system radical comprising 6 to 18 carbon atoms, for example 6 to 10 carbon atoms (C₆-C₁₀ aryl) and at least one carbocyclic aromatic ring. For purposes of embodiments of this disclosure, the aryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, an aryl group is optionally substituted. "Cycloalkyl" refers to a non-aromatic monocyclic or polycyclic carbocyclic radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from three to fifteen ring carbon atoms (C₃-C₁₅ cycloalkyl), from three to ten ring carbon atoms (C3-C10 cycloalkyl), or from three to eight ring carbon atoms (C3-C8 cycloalkyl), or any value within these ranges such as three to four carbon atoms (C₃-C₄ cycloalkyl), and which is saturated or partially unsaturated and attached to the rest of the molecule by a single bond. Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group is optionally substituted.

6 #11053313.1 "Fused" refers to any ring structure described herein which is fused to another ring structure. "Halo" refers to bromo, chloro, fluoro, or iodo. "Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group is optionally substituted. "Haloalkynyl" refers to an alkynyl radical, as defined above, that is substituted by one or more halo radicals, as defined above. Unless stated otherwise specifically in the specification, a haloalkynyl group is optionally substituted. "Haloalkoxy" refers to a radical of the formula ˗OR_a where R_a is an haloalkyl radical as defined above. Unless stated otherwise specifically in the specification, a haloalkoxy group is optionally substituted. "Hydroxyalkyl" refers to an alkyl radical, as defined above that is substituted by one or more hydroxyl radical. The hydroxyalkyl radical is joined to the remainder of the molecule through an alkyl carbon atom. Unless stated otherwise specifically in the specification, a hydroxyalkyl group is optionally substituted. "Aminoalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more –NH₂ groups. The aminoalkyl radical is joined to the remainder of the molecule though an alkyl carbon atom. Unless stated otherwise specifically in the specification, an aminoalkyl group is optionally substituted. "Heterocyclyl" refers to a 3- to 18-membered, for example 3- to 10-membered or 3- to 8- membered, non-aromatic ring radical having one to ten ring carbon atoms (e.g., two to ten) and from one to six ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is partially or fully saturated and is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused, spirocyclic and/or bridged ring systems. Nitrogen, carbon, and sulfur atoms in a heterocyclyl radical are optionally oxidized, and nitrogen atoms may be optionally quaternized. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, hexahydro- 1H-pyrrolizine, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, piperidinyl, piperazinyl, 4-piperidonyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,

7 #11053313.1 thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, a heterocyclyl group is optionally substituted. "Heteroaryl" refers to a 5- to 18-membered, for example 5- to 6-membered, ring system radical comprising one to thirteen ring carbon atoms, one to six ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring. Heteroaryl radicals may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1- oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl group is optionally substituted. The term "substituted" as used herein means any of the above groups (e.g., alkyl, haloalkynyl, alkoxy, aryl, aminoalkyl, hydroxyalkyl, etc.) wherein at least one hydrogen atom (e.g., 1, 2, 3 or all hydrogen atoms) is replaced by a bond to a non-hydrogen substituent. Examples of non-hydrogen substituents include, but are not limited to amino, carboxyl, cyano, hydroxyl, halo, nitro, oxo, thiol, thioxo, alkyl, alkenyl, alkylcarbonyl, alkoxy, aryl, cyanoalkyl, cycloalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl and/or hydroxyalkyl substituents, each of which may also be optionally substituted with one or more of the above substituents. The term "effective amount" or "therapeutically effective amount" refers to that amount of a compound described herein that is sufficient to affect the intended application including but not limited to disease treatment, as defined below. The therapeutically effective amount may vary

8 #11053313.1 depending upon the intended treatment application (in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells, e.g., reduction of platelet adhesion and/or cell migration. The specific dose will vary depending on the compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried. As used herein, "treatment" or "treating" refer to an approach for obtaining beneficial or desired results with respect to a disease, disorder or medical condition including but not limited to a therapeutic effect and/or a prophylactic effect. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying, or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. In certain embodiments, for prophylactic benefit, the compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. The term "co-administration," "administered in combination with," and their grammatical equivalents, as used herein, encompass administration of two or more agents to an animal, including humans, so that both agents and/or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present. "Pharmaceutically acceptable salt" includes both acid and base addition salts. "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness of the free bases, which are biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S.M. Berge, et al., "Pharmaceutical Salts", J. Pharm. Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002.

9 #11053313.1 Preferred pharmaceutically acceptable acid addition salts are those that are pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response. Pharmaceutically acceptable acid addition salts which are formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2- dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like. "Pharmaceutically acceptable base addition salt" refers to those salts which retain the biological effectiveness of the free acids, which are biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S.M. Berge, et al., "Pharmaceutical Salts", J. Pharm. Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Preferred pharmaceutically acceptable base addition salts are those that are pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response. Pharmaceutically acceptable base addition salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol,

10 #11053313.1 dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. In some embodiments, pharmaceutically acceptable salts include quaternary ammonium salts such as quaternary amine alkyl halide salts (e.g., methyl bromide). The term "inhibitor" refers to a compound having the ability to inhibit a biological function of a target protein, whether by inhibiting the activity or expression of the protein. Accordingly, the term "inhibitor" is defined in the context of the biological role of the target protein. In some embodiments, inhibitors specifically interact with (e.g., bind to) a target. In some embodiments, the biological activity inhibited is the development, growth, or spread of a tumor. "Subject" refers to an animal, such as a mammal, for example a human. The methods described herein can be useful in both human therapeutics and veterinary applications. In some embodiments, the subject is a mammal, and in some embodiments, the subject is human. "Mammal" includes humans and both domestic animals such as laboratory animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like. "Prodrug" is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound described herein (e.g., compounds of Structure (I)). Thus, the term "prodrug" refers to a precursor of a biologically active compound that is pharmaceutically acceptable. In some embodiments, a prodrug is inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol.14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein. The term "prodrug" is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of an active compound, as described herein, are typically prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine

11 #11053313.1 manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino or thiol group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of a hydroxy functional group, or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound and the like. The term "in vivo" refers to an event that takes place in a subject's body. Embodiments disclosed herein are also meant to encompass all pharmaceutically acceptable compounds of Structure (I). Certain embodiments are also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products may result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes. Accordingly, embodiments include compounds produced by a process comprising administering a compound of this disclosure to a mammal for a period sufficient to yield a metabolic product thereof. Such products are typically identified by administering a radiolabeled compound of the disclosure in a detectable dose to an animal, such as rat, mouse, guinea pig, monkey, or to human, allowing sufficient time for metabolism to occur, and isolating its conversion products from the urine, blood or other biological samples. "Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. Often crystallizations produce a solvate of the compounds disclosed herein. As used herein, the term "solvate" refers to an aggregate that comprises one or more compounds of the disclosure with one or more molecules of solvent. In some embodiments, the solvent is water, in which case the solvate is a hydrate. Alternatively, in other embodiments, the solvent is an organic solvent. Thus, the compounds of the present disclosure may exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms. In some embodiments, the compounds of the disclosure are a true solvate, while in other cases, the compounds of the disclosure merely retain adventitious water or is a mixture of water plus some adventitious solvent. "Optional" or "optionally" means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, "optionally substituted aryl" means that

12 #11053313.1 the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution. A "pharmaceutical composition" refers to formulations of compounds of the disclosure and a medium generally accepted in the art for the delivery of compounds of the disclosure to mammals, e.g., humans. Such a medium includes all pharmaceutically acceptable carriers, diluents, or excipients therefor. "Pharmaceutically acceptable carrier, diluent or excipient" includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier. A "stereoisomer" refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof and includes "enantiomers", which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another. The compounds of the disclosure (i.e., compounds of Structure (I)) or their pharmaceutically acceptable salts may contain one or more centers of geometric asymmetry and may thus give rise to stereoisomers such as enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. Embodiments thus include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. Embodiments of the present disclosure include all manner of rotamers and conformationally restricted states of a compound of the disclosure. Atropisomers, which are stereoisomers arising because of hindered rotation about a single bond, where energy differences due to steric strain or other contributors create a barrier to rotation that is high enough to allow for

13 #11053313.1 isolation of individual conformers, are also included. As an example, certain compounds of the disclosure may exist as mixtures of atropisomers or purified or enriched for the presence of one atropisomer. In some embodiments, the compounds of Structure (I) are a mixture of enantiomers or diastereomers. In other embodiments, the compounds of Structure (I) are substantially one enantiomer or diastereomer. A "tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. Embodiments thus include tautomers of the disclosed compounds. The chemical naming protocol and structure diagrams used herein are a modified form of the I.U.P.A.C. nomenclature system, using the ACD/Name Version 9.07 software program and/or ChemDraw Profesional Version 17.0.0.206 software naming program (CambridgeSoft). For complex chemical names employed herein, a substituent group is typically named before the group to which it attaches. For example, cyclopropylethyl comprises an ethyl backbone with a cyclopropyl substituent. Except as described below, all bonds are identified in the chemical structure diagrams herein, except for all bonds on some carbon atoms, which are assumed to be bonded to sufficient hydrogen atoms to complete the valency. Compounds The disclosure provides compounds including pharmaceutically acceptable salts, stereoisomers, and tautomers thereof, which are capable of inhibiting PIM (e.g., PIM1, PIM2, and/or PIM3). Accordingly, one embodiment provides a compound having the following Structure (I): or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: each occurrence of R¹ is independently C1-C6 haloalkyl, C1-C6 haloalkoxy, cyano, C2-C6 haloalkynyl, or optionally substituted C₃-C₈ cycloalkyl; R² has one of the following structures:

14 #11053313.1 each occurrence of R^2a is independently C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, halo, C₁-C₆ haloalkyl, -OH, C₁-C₆ alkoxy, or -NH₂; R^2b is hydrogen or C1-C6 alkyl; R^2c is C₁-C₆ alkyl; R³ is hydrogen or C1-C6 alkyl; L¹ is a direct bond n is 1, 2, 3, 4, or 5; and m is 1, 2, 3, 4, or 5. In some embodiments, n is 1. In certain embodiments, n is 2. In some embodiments, n is 3. In certain embodiments, n is 4. In some embodiments, n is 5. In certain embodiments, R¹ is trifluoromethyl, trifluoromethoxy, difluoromethoxy, cyano, trifluoropropynyl, or cyclopropyl substituted with trifluoromethyl. In some embodiments, L¹ is a direct bond. In certain embodiments, L¹ is . In certain embodiments, has one of the following structures:

15 #11053313.1 , In some embodiments, has the following structure: . In certain embodiments, m is 1, 2, or 3. In some embodiments, m is 4 or 5. In some embodiments, R^2a C₂-C₃ hydroxyalkyl, fluoro, methoxy, -OH, or -NH₂. In certain embodiments, R^2b is hydrogen or methyl. In some embodiments, R^2c is methyl. In some embodiments, R² has one of the following structures: In certain embodiments, R² has the following structure:

16 #11053313.1 In some embodiments, R² has one of the following structures: In certain embodiments, R² has the following structure: . In some embodiments, R² has one of the following structures: In certain embodiments, R² has one of the following structures: In some embodiments, R² has one of the following structures: In certain embodiments, R² has one of the following structures: In some embodiments, R² has one of the following structures: In some embodiments, R³ is hydrogen. In certain embodiments, R³ is methyl. In some embodiments, R³ is unsubstituted. In some embodiments, R³ is substituted with halo, cyano, - NH2, or -OH. In some embodiments, R³ is ethyl, n-propyl, iso-propyl, sec-butyl, or n-butyl.

17 #11053313.1 In certain embodiments, the compound of Structure (I) exists as a salt form. In some embodiments, the salt form is a formic acid salt, a hydrochloric acid salt, or a trifluoroacetic acid salt. One embodiment provides a pharmaceutical composition comprising the compound of Structure (I), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable excipient. In various embodiments, the compound has one of the structures set forth in Table 1 below, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, polymorph, isotopologue, hydrate, or prodrug thereof. Compounds in Table 1 were prepared as described in the Examples or methods known in the art and analyzed by mass spectrometry and/or ¹H NMR. Table 1. Representative compounds of Structure (I)

18 #11053313.1

19 #11053313.1

20 #11053313.1

21 #11053313.1

22 #11053313.1 ^† also obtained as a formic acid (HCOOH) salt also obtained as a hydrochloric acid (HCl) salt ^Δ also obtained as a trifluoroacetic acid (TFA) salt It is understood that in the present description, combinations of substituents and/or variables of the depicted formulae are permissible only if such contributions result in stable compounds. In an additional embodiment, various compounds of the disclosure which exist in free base or acid form can be converted to their pharmaceutically acceptable salts by treatment with the appropriate inorganic or organic base or acid by methods known to one skilled in the art. Salts of the compounds of the disclosure can be converted to their free base or acid form by standard techniques. Methods for producing the compounds described herein is provided below. In general, starting components may be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc. or synthesized according to sources known to those skilled in the art (see, for example, Advanced Organic Chemistry:

23 #11053313.1 Reactions, Mechanisms, and Structure, 5th edition (Wiley, December 2000)) or prepared as described herein. It will also be appreciated by those skilled in the art that in the processes for preparing the compounds described herein the functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include, but are not limited to, hydroxy, amino, mercapto and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl (for example, t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for mercapto include -C(O)-R" (where R" is alkyl, aryl or arylalkyl), p-methoxybenzyl, trityl and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl or arylalkyl esters. Protecting groups are optionally added or removed in accordance with standard techniques, which are known to one skilled in the art and as described herein. The use of protecting groups is described in detail in Green, T.W. and P.G.M. Wutz, Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley. As one of skill in the art would appreciate, the protecting group may also be a polymer resin such as a Wang resin, Rink resin or a 2-chlorotrityl-chloride resin. It will also be appreciated by those skilled in the art, although such protected derivatives of compounds of this disclosure may not possess pharmacological activity as such, they may be administered to a mammal and thereafter metabolized in the body to form compounds of the disclosure which are pharmacologically active. Such derivatives may therefore be described as "prodrugs." Prodrugs of compounds of this disclosure are included within the scope of embodiments of the disclosure. Pharmaceutical Compositions Other embodiments are directed to pharmaceutical compositions. The pharmaceutical composition comprises anyone (or more) of the foregoing compounds and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated for oral administration. In other embodiments, the pharmaceutical composition is formulated for injection. In still more embodiments, the pharmaceutical compositions comprise a compound as disclosed herein and an additional therapeutic agent (e.g., anticancer agent). Non-limiting examples of such therapeutic agents are described herein below.

24 #11053313.1 Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections. In certain embodiments, a compound as described herein is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation. In specific embodiments, long-acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the compound is delivered in a targeted drug delivery system, for example, in a liposome coated with and organ-specific antibody. In such embodiments, the liposomes are targeted to and taken up selectively by the organ. In yet other embodiments, the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended-release formulation, or in the form of an intermediate release formulation. In yet other embodiments, the compound described herein is administered topically. In treatment methods according to embodiments of the disclosure, an effective amount of at least one compound of Structure (I) is administered to a subject suffering from or diagnosed as having such a disease, disorder, or medical condition. Effective amounts or doses may be ascertained by methods such as modeling, dose escalation studies or clinical trials, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease, disorder, or condition, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the treating physician. The compounds according to the disclosure are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from 10 to 5000 mg, from 100 to 5000 mg, from 1000 mg to 4000 mg per day, and from 1000 to 3000 mg per day are examples of dosages that are used in some embodiments. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician. In some embodiments, compounds of the disclosure are administered in a single dose. Typically, such administration will be by injection, e.g., intravenous injection, to introduce the agent quickly. However, other routes are used as appropriate. A single dose of a compound of the disclosure may also be used for treatment of an acute condition.

25 #11053313.1 In some embodiments, compounds of the disclosure are administered in multiple doses. In some embodiments, dosing is about once, twice, three times, four times, five times, six times, or more than six times per day. In other embodiments, dosing is about once a month, once every two weeks, once a week, or once every other day. In another embodiment compounds of the disclosure and another agent (e.g., anti-cancer agent) are administered together about once per day to about 6 times per day. In another embodiment the administration of compounds of the disclosure and an agent continues for less than about 7 days. In yet another embodiment the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary. Administration of compounds of the disclosure may continue as long as necessary. In some embodiments, compounds of the disclosure are administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, compounds of the disclosure are administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, compounds of the disclosure are administered chronically on an ongoing basis, e.g., for the treatment of chronic effects. In some embodiments, the compounds of the disclosure are administered in individual dosage forms. It is known in the art that due to intersubject variability in compound pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. In specific embodiments, pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the disclosed compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients are used as suitable to formulate the pharmaceutical compositions described herein: Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999). Provided herein are pharmaceutical compositions comprising one or more compounds of Structure (I), and a pharmaceutically acceptable carrier. Provided herein are pharmaceutical compositions comprising one or more compounds selected from compounds of Structure (I) and pharmaceutically acceptable diluent(s), excipient(s),

26 #11053313.1 and carrier(s). In certain embodiments, the compounds described are administered as pharmaceutical compositions in which one or more compounds selected from compounds of Structure (I) are mixed with other active ingredients, as in combination therapy. Encompassed herein are all combinations of actives set forth in the combination therapies section below and throughout this disclosure. In specific embodiments, the pharmaceutical compositions include one or more compounds of Structure (I). In a certain embodiment, pharmaceutical compositions of the compounds of Structure (I) are inhibitors of PIM (e.g., PIM1, PIM2, and/or PIM3). A pharmaceutical composition, as used herein, refers to a mixture of one or more compounds selected from compounds of Structure (I) with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients. In certain embodiments, the pharmaceutical composition facilitates administration of the compound to an organism. In some embodiments, therapeutically effective amounts of one or more compounds selected from compounds of Structure (I) provided herein are administered in a pharmaceutical composition to a mammal having a disease, disorder, or medical condition to be treated. In specific embodiments, the mammal is a human. In certain embodiments, therapeutically effective amounts vary depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. The compounds described herein are used singly or in combination with one or more therapeutic agents as components of mixtures. In one embodiment, one or more compounds selected from compounds of Structure (I) are formulated in aqueous solutions. In specific embodiments, the aqueous solution is selected from, by way of example only, a physiologically compatible buffer, such as Hank's solution, Ringer's solution, or physiological saline buffer. In other embodiments, one or more compounds selected from compounds of Structure (I) are formulated for transmucosal administration. In specific embodiments, transmucosal formulations include penetrants that are appropriate to the barrier to be permeated. In still other embodiments wherein the compounds described herein are formulated for other parenteral injections, appropriate formulations include aqueous or non-aqueous solutions. In specific embodiments, such solutions include physiologically compatible buffers and/or excipients. In another embodiment, compounds described herein are formulated for oral administration. Compounds described herein are formulated by combining the active compounds with, e.g., pharmaceutically acceptable carriers or excipients. In various embodiments, the compounds described herein are formulated in oral dosage forms that include, by way of example

27 #11053313.1 only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions, and the like. In certain embodiments, pharmaceutical preparations for oral use are obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as: for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In specific embodiments, disintegrating agents are optionally added. Disintegrating agents include, by way of example only, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. In one embodiment, dosage forms, such as dragee cores and tablets, are provided with one or more suitable coating. In specific embodiments, concentrated sugar solutions are used for coating the dosage form. The sugar solutions, optionally contain additional components, such as by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs and/or pigments are also optionally added to the coatings for identification purposes. Additionally, the dyestuffs and/or pigments are optionally utilized to characterize different combinations of active compound doses. In certain embodiments, therapeutically effective amounts of at least one of the compounds described herein are formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In specific embodiments, push-fit capsules contain the active ingredients in admixture with one or more filler. Fillers include, by way of example only, lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In other embodiments, soft capsules, contain one or more active compound that is dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers are optionally added. In still other embodiments, the compounds described herein are formulated for parental injection, including formulations suitable for bolus injection or continuous infusion. In specific embodiments, formulations for injection are presented in unit dosage form (e.g., in ampoules) or

28 #11053313.1 in multi-dose containers. Preservatives are, optionally, added to the injection formulations. In still other embodiments, the pharmaceutical compositions are formulated in a form suitable for parenteral injection as sterile suspensions, solutions, or emulsions in oily or aqueous vehicles. Parenteral injection formulations optionally contain formulatory agents such as suspending, stabilizing and/or dispersing agents. In specific embodiments, pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. In additional embodiments, suspensions of one or more compounds selected from compounds of Structure (I) are prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. In certain specific embodiments, aqueous injection suspensions contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension contains suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, in other embodiments, the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. Pharmaceutical compositions include at least one pharmaceutically acceptable carrier, diluent, or excipient, and one or more compounds selected from compounds of Structure (I), described herein as an active ingredient. The active ingredient is in free-acid or free-base form, or in a pharmaceutically acceptable salt form. In addition, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), as well as active metabolites of these compounds having the same type of activity. All tautomers of the compounds described herein are included within the scope of the compounds presented herein. Additionally, the compounds described herein encompass unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein. In addition, the pharmaceutical compositions optionally include other medicinal or pharmaceutical agents, carriers, adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, buffers, and/or other therapeutically valuable substances. Methods for the preparation of compositions comprising the compounds described herein include formulating the compounds with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid or liquid. Solid compositions include, but are not limited to,

29 #11053313.1 powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions, and creams. The form of the pharmaceutical compositions described herein include liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions also optionally contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and so forth. In some embodiments, pharmaceutical compositions comprising one or more compounds selected from compounds of Structure (I) illustratively takes the form of a liquid where the agents are present in solution, in suspension or both. Typically, when the composition is administered as a suspension, a first portion of the agent is present in solution and a second portion of the agent is present in particulate form, in suspension in a liquid matrix. In some embodiments, a liquid composition includes a gel formulation. In other embodiments, the liquid composition is aqueous. In certain embodiments, aqueous suspensions contain one or more polymers as suspending agents. Polymers include water-soluble polymers such as cellulosic polymers, e.g., hydroxypropyl methylcellulose, and water-insoluble polymers such as cross-linked carboxyl-containing polymers. Certain pharmaceutical compositions described herein comprise a mucoadhesive polymer, selected for example from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran. Pharmaceutical compositions also, optionally, include solubilizing agents to aid in the solubility of one or more compounds selected from compounds of Structure (I). The term "solubilizing agent" generally includes agents that result in formation of a micellar solution or a true solution of the agent. Certain acceptable nonionic surfactants, for example polysorbate 80, are useful as solubilizing agents, as can ophthalmically acceptable glycols, polyglycols, e.g., polyethylene glycol 400, and glycol ethers. Furthermore, pharmaceutical compositions optionally include one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric, and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.

30 #11053313.1 Compositions also, optionally, include one or more salts in an amount required to bring osmolality of the composition into an acceptable range. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate. Other pharmaceutical compositions optionally include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride. Compositions may include one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40. Compositions may include one or more antioxidants to enhance chemical stability where required. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite. In certain embodiments, aqueous suspension compositions are packaged in single-dose non-reclosable containers. Alternatively, multiple-dose reclosable containers are used, in which case it is typical to include a preservative in the composition. In alternative embodiments, other delivery systems for hydrophobic pharmaceutical compounds are employed. Liposomes and emulsions are examples of delivery vehicles or carriers useful herein. In certain embodiments, organic solvents such as N-methylpyrrolidone are also employed. In additional embodiments, the compounds described herein are delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials are useful herein. In some embodiments, sustained-release capsules release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization are employed. In certain embodiments, the formulations described herein comprise one or more antioxidants, metal chelating agents, thiol containing compounds and/or other general stabilizing agents. Examples of such stabilizing agents, include, but are not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about 0.1% to about 1% w/v methionine, (c) about 0.1% to about 2% w/v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w/v

31 #11053313.1 ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate 80, (g) 0.001% to about 0.05% w/v. polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof. In some embodiments, the concentration of one or more compounds selected from compounds of Structure (I) provided in the pharmaceutical compositions of the present disclosure is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125% , 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w, w/v, or v/v. In some embodiments, the concentration of one or more compounds selected from compounds of Structure (I) provided in the pharmaceutical compositions of the present disclosure is in the range from approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40 %, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, approximately 1% to approximately 10% w/w, w/v or v/v. In some embodiments, the amount the one or more compounds selected from compounds of Structure (I) provided in the pharmaceutical compositions of the present disclosure is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5

32 #11053313.1 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g. In some embodiments, the amount of the one or more compounds selected from compounds of Structure (I) provided in the pharmaceutical compositions of the present disclosure is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g. Packaging materials for use in packaging pharmaceutical compositions described herein include those found in, e.g., U.S. Pat. Nos. 5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment. For example, the container(s) includes one or more compounds described herein, optionally in a composition or in combination with another agent as disclosed herein. The container(s) optionally have a sterile access port (for example the container is an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). Such kits optionally comprise a compound with an identifying description or label or instructions relating to its use in the methods described herein. For example, a kit typically includes one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and/or devices) desirable from a commercial and user standpoint for use of a compound described herein. Non- limiting examples of such materials include, but not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and/or tube labels listing contents and/or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included. A label is optionally on or associated with the container. For example, a label is on a container when letters, numbers or other characters forming the label are attached, molded, or etched into the container itself, a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. In addition, a label is used to indicate that the contents are to be used for a specific therapeutic application. In addition, the label indicates directions for use of the contents, such as in the methods described herein. In certain embodiments, the pharmaceutical compositions are presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein.

33 #11053313.1 For example, the pack may (1) contain metal or plastic foil (e.g., a blister pack), (2) be accompanied by instructions for administration, (3) be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, is the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. In some embodiments, compositions containing a compound of Structure (I) formulated in a compatible pharmaceutical carrier are prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. Methods Embodiments of the present disclosure provide compounds that are useful as PIM (e.g., PIM1, PIM2, and/or PIM3) inhibitors in a host species. Therefore, the compounds of Structure (I) are also useful in the treatment of conditions mediated by PIM (e.g., PIM1, PIM2, and/or PIM3). The host or patient can belong to any mammalian species, for example a primate species, particularly humans; rodents, including mice, rats, hamsters, rabbits, horses, cows, dogs, cats, etc. Animal models are of interest for experimental investigations, providing a model for treatment of human disease. In one embodiment, the present disclosure is useful as an inhibitor of PIM (e.g., PIM1, PIM2, and/or PIM3). Therefore, the compounds of Structure (I) are also useful in the treatment of conditions resulting from overexpression of PIM (e.g., PIM1, PIM2, and/or PIM3) or PIM activity. Embodiments also relate to the use of compounds according to Structure (I) and/or physiologically acceptable salts thereof for the prophylactic or therapeutic treatment and/or monitoring of diseases that are caused, mediated, and/or modulated by PIM (e.g., PIM1, PIM2, and/or PIM3). Furthermore, embodiments relate to the use of compounds according to Structure (I) and/or physiologically acceptable salts thereof to produce a medicament for the prophylactic or therapeutic treatment and/or monitoring of diseases that are caused, mediated, and/or modulated by PIM (e.g., PIM1, PIM2, and/or PIM3). In certain embodiments, the disclosure provides the use of a compound according to Structure (I) or physiologically acceptable salts thereof, to produce a medicament for the prophylactic or therapeutic treatment of a PIM-mediated disorder. In another embodiment, the present disclosure relates to a method of treating diseases or conditions mediated by PIM (e.g., PIM1, PIM2, and/or PIM3) by administering to a patient in need thereof a therapeutically effective amount of the compound of Structure (I).

34 #11053313.1 Accordingly, some embodiments provide a method of treating a PIM mediated disease, the method comprising administering the compound of Structure (I), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof or the pharmaceutical composition comprising a compound of Structure (I) to a subject in need thereof. One embodiment provides a use of a compound of Structure (I) in the manufacture of a medicament for treating a PIM mediated disease. Yet another embodiment provides a compound of Structure (I) that is used for treating PIM mediated disease. In some embodiments, the method or use comprises inhibiting PIM1, PIM2, PIM3, or combinations thereof. In some embodiments, the PIM mediated disease is an autoimmune disease. In certain embodiments, the PIM mediated disease is an autoimmune eye disease. In some embodiments, the PIM mediated disease is a hematological malignancy, a solid tumor, or a combination thereof. In certain embodiments, the PIM mediated disease is a hematopoietic lymphoma, a diffuse large cell lymphoma, or a combination thereof. In some embodiments, the PIM mediated disease is multiple myeloma, prostate cancer, Burkitt’s Lymphoma, oral cancer, lung cancer, colon cancer, breast cancer, endometrial cancer, gastric cancer, pancreatic cancer, or combinations thereof. In some embodiments, the PIM mediated disease is triple negative breast cancer, non-small cell lung cancer, or a combination thereof. In some embodiments, the PIM mediated disease is multiple myeloma. In certain embodiments, the PIM mediated disease is lupus, Alzheimer’s disease, myelofibrosis, pulmonary fibrosis, bone marrow fibrosis, skin fibrosis, heart fibrosis, or combinations thereof. In some embodiments, the PIM mediated disease is systemic lupus erythematosus, cutaneous lupus erythematosus, drug-induced lupus, neonatal lupus, or combinations thereof. Also included herein are methods of treatment in which at least one compound of Structure (I) is administered in combination with an anti-inflammatory or a therapeutic agent. Anti- inflammatory agents include but are not limited to NSAIDs, non-specific and COX-2 specific cyclooxygenase enzyme inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor (TNF) antagonists, immunosuppressants and methotrexate. Examples of NSAIDs include, but are not limited to, ibuprofen, flurbiprofen, naproxen and naproxen sodium, diclofenac, combinations of diclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal, piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen, sodium nabumetone, sulfasalazine, tolmetin sodium, and hydroxychloroquine.

35 #11053313.1 Still other embodiments of the disclosure pertain to combinations in which at least one active agent is an immunosuppressant compound such as an immunosuppressant compound chosen from methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, and mycophenolate mofetil. The disclosed compounds of Structure (I) can be administered in combination with other known therapeutic agents, including anticancer agents. As used here, the term "anticancer agent" relates to any agent which is administered to a patient with cancer for the purposes of treating the cancer. In some embodiments the anti-cancer agents belong to the following categories Alkylating agents: such as altretamine, bendamustine, busulfan, carmustine, chlorambucil, chlormethine, cyclophosphamide, dacarbazine, ifosfamide, improsulfan, tosilate, lomustine, melphalan, mitobronitol, mitolactol, nimustine, ranimustine, temozolomide, thiotepa, treosulfan, mechloretamine, carboquone; apaziquone, fotemustine, glufosfamide, palifosfamide, pipobroman, trofosfamide, uramustine, TH-3024, VAL-0834; Platinum Compounds: such as carboplatin, cisplatin, eptaplatin, miriplatine hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin, satraplatin; lobaplatin, nedaplatin, picoplatin, satraplatin; DNA altering agents: such as amrubicin, bisantrene, decitabine, mitoxantrone, procarbazine, trabectedin, clofarabine; amsacrine, brostallicin, pixantrone, or laromustine; Topoisomerase Inhibitors: such as etoposide, irinotecan, razoxane, sobuzoxane, teniposide, topotecan; amonafide, belotecan, elliptinium acetate, or voreloxin; Microtubule modifiers: such as cabazitaxel, docetaxel, eribulin, ixabepilone, paclitaxel, vinblastine, vincristine, vinorelbine, vindesine, vinflunine; fosbretabulin, or tesetaxel; Antimetabolites: such as asparaginase3, azacitidine, calcium levofolinate, capecitabine, cladribine, cytarabine, enocitabine, floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, nelarabine, pemetrexed, pralatrexate, azathioprine, thioguanine, carmofur; doxifluridine, elacytarabine, raltitrexed, sapacitabine, tegafur, or trimetrexate; Anticancer antibiotics: such as bleomycin, dactinomycin, doxorubicin, epirubicin, idarubicin, levamisole, miltefosine, mitomycin C, romidepsin, streptozocin, valrubicin, zinostatin, zorubicin, daunurobicin, plicamycin; aclarubicin, peplomycin, or pirarubicin; Hormones/Antagonists: such as abarelix, abiraterone, bicalutamide, buserelin, calusterone, chlorotrianisene, degarelix, dexamethasone, estradiol, fluocortolone fluoxymesterone, flutamide, fulvestrant, goserelin, histrelin, leuprorelin, megestrol, mitotane,

36 #11053313.1 nafarelin, nandrolone, nilutamide, octreotide, prednisolone, raloxifene, tamoxifen, thyrotropin alfa, toremifene, trilostane, triptorelin, diethylstilbestrol; acolbifene, danazol, deslorelin, epitiostanol, orteronel, or enzalutamide; Aromatase inhibitors: such as aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, testolactone, or formestane; Small molecule kinase inhibitors: such as crizotinib, dasatinib, erlotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib, gefitinib, axitinib; afatinib, alisertib, dabrafenib, dacomitinib, dinaciclib, dovitinib, enzastaurin, nintedanib, lenvatinib, linifanib, linsitinib, masitinib, midostaurin, motesanib, neratinib, orantinib, perifosine, ponatinib, radotinib, rigosertib, tipifamib, tivantinib, tivozanib, trametinib, pimasertib, brivanib alaninate, or cediranib. In some embodiments, medicaments which are administered in conjunction with the compounds described herein include any suitable drugs usefully delivered by inhalation for example, analgesics, e.g. codeine, dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations, e.g. diltiazem; antiallergics, e.g. cromoglycate, ketotifen or nedocromil; anti- infectives, e.g. cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines or pentamidine; antihistamines, e.g. methapyrilene; anti-inflammatories, e.g. beclomethasone, flunisolide, budesonide, tipredane, triamcinolone acetonide or fluticasone; antitussives, e.g. noscapine; bronchodilators, e.g. ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, salbutamol, salmeterol, terbutalin, isoetharine, tulobuterol, orciprenaline or (-)-4-amino-3,5- dichloro-α-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]-amino]methyl]benzenemethanol; diuretics, e.g., amiloride; anticholinergics, e.g., ipratropium, atropine or oxitropium; hormones, e.g., cortisone, hydrocortisone or prednisolone; xanthines, e.g., aminophylline, choline theophyllinate, lysine theophyllinate or theophylline; and therapeutic proteins and peptides, e.g., insulin or glucagon. It will be clear to a person skilled in the art that, where appropriate, the medicaments are used in the form of salts (e.g., as alkali metal or amine salts or as acid addition salts) or as esters (e.g., lower alkyl esters) or as solvates (e.g., hydrates) to optimize the activity and/or stability of the medicament. The agents disclosed herein, or other suitable agents are administered depending on the condition being treated. Hence, in some embodiments the one or more compounds of the disclosure will be co-administered with other agents as described above. When used in combination therapy, the compounds described herein are administered with the second agent simultaneously or

37 #11053313.1 separately. This administration in combination can include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, a compound described herein and any of the agents described above can be formulated together in the same dosage form and administered simultaneously. Alternatively, a compound of the disclosure and any of the agents described above can be simultaneously administered, wherein both the agents are present in separate formulations. In another alternative, a compound of the present disclosure can be administered just followed by and any of the agents described above, or vice versa. In some embodiments of the separate administration protocol, a compound of the disclosure and any of the agents described above are administered a few minutes apart, or a few hours apart, or a few days apart. In some embodiments, the compounds of Structure (I) are administered as a monotherapy. In some embodiments, the methods of the disclosure can be performed either in vitro, in vivo, or as a combination thereof. The susceptibility of a particular cell to treatment with the compounds of Structure (I) can be particularly determined by in vitro tests, whether during research or clinical application. Typically, a culture of the cell is combined with a compound at various concentrations for a period which is sufficient to allow the active agents to inhibit PIM (e.g., PIM1, PIM2, and/or PIM3) activity, usually between about one hour and one week. In vitro treatment can be carried out using cultivated cells from a biopsy sample or cell line. In some embodiments, the IC₅₀ of the compounds of Structure (I) to inhibit PIM (e.g., PIM1, PIM2, and/or PIM3) was determined by the concentration of the compound required to inhibit 50% of the activity of PIM (e.g., PIM1, PIM2, and/or PIM3). It is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make, in a similar manner as described below, other compounds of Structure (I) not specifically illustrated below by using the appropriate starting components and modifying the parameters of the synthesis as needed. In general, starting components may be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc. or synthesized according to sources known to those skilled in the art (see, for example, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley, December 2000)) or prepared as described in this disclosure. The following examples are provided for purpose of illustration and not limitation.

38 #11053313.1 Abbreviations: °C (degree Celsius); ¹H NMR (proton Nuclear Magnetic Resonance); DCM (dichloromethane); DMSO (dimethylsulfoxide); eq (equivalent); EtOAc (ethyl acetate); g (gram); h (hour); MeOH (methanol); mg (milligram); min (minute); mL (milliliter); mmol (millimole); TFA (trifluoroacetic acid); THF (tetrahydrofuran); TLC (Thin Layer Chromatography); LDA (lithium diisopropylamide); AcOH (acetic acid); mCPBA (3- chloroperbenzoic acid). SYNTHETIC EXAMPLE 1 SYNTHESIS OF N-(1-(3-FLUOROPYRROLIDIN-3-YL)ETHYL)-3-(3- (TRIFLUOROMETHYL)PHENYL)IMIDAZO[1,2-B]PYRIDAZIN-6-AMINE FORMATE SALT Step 1: Synthesis of benzyl (E)-3-ethylidenepyrrolidine-1-carboxylate To a stirred solution of ethyltriphenylphosphonium bromide (35.0 g, 95.9 mmol, 1 eq) in THF (250 mL) at -78 °C, added n-butyllithium (2.5 M in hexane, 38.3 mL, 95.9 mmol, 1 eq) and reaction mixture was allowed to stir at ambient temperature for 2 h. Later, the red solution was cooled to -78° C, added a solution of 1-N-Cbz-pyrrolidinone (19.97 g, 91.1 mmol, 0.95 eq) in THF (50 mL) and allowed to warm to ambient temperature, stirred for 16h. After completion of reaction by TLC, diluted with water (200 mL) and extracted with ethyl acetate (3 × 100 mL). Combined organic layers were dried over Na2SO4, evaporated, and purified by silica gel column chromatography [eluted in 10% EtOAc in hexane] to afford benzyl (E)-3-ethylidenepyrrolidine-1- carboxylate as pale-yellow liquid (13 g, yield: 62%). TLC system: EtOAc/Petroleum ether (20:80) Rf value: ~0.8 LCMS Retention time = 3.82 min, 232.1 [M+H]⁺

39 #11053313.1 ¹H NMR (400 MHz, CDCl₃) δ: 7.39–7.29 (m, 5H), 5.42–5.38 (m, 1H), 5.14 (s, 2H), 3.99– 3.97 (m, 2H), 3.59–3.52 (m, 2H), 2.51 (brs, 2H), 1.65–1.61 (m, 3H). Step 2: Synthesis of benzyl 2-methyl-1-oxa-5-azaspiro[2.4]heptane-5-carboxylate To a stirred solution of benzyl (E)-3-ethylidenepyrrolidine-1-carboxylate (11 g, 47.6 mmol, 1 eq) in DCM (100 mL) under nitrogen at 0°C, added 3-chloroperoxybenzoic acid (12.3 g, 71.4 mmol, 1.5 eq). The mixture was allowed to warm to ambient temperature and stirred for 16 h. After completion of reaction by TLC, reaction mixture was cooled in an ice bath and quenched with addition of 10 % sodium carbonate solution (200 mL). The organic phase was separated, dried over Na2SO4, evaporated and purified by chromatography on silica gel (60-120 mesh) [eluted in 30% EtOAc in hexane] to afford benzyl 2-methyl-1-oxa-5-azaspiro[2.4]heptane-5-carboxylate (8.5 g, ~97%) as a pale yellow liquid.. TLC system: EtOAc/Petroleum ether (20:80) Rf value: ~0.30 LCMS Retention time = 3.22 min, 248.1 [M+H]⁺. 1H NMR (400 MHz, CDCl3): δ 7.38–7.30 (m, 5H), 5.14 (d, J = 3.6 Hz, 2H), 3.76–3.62 (m, 3H), 3.32 (dd, J = 12.4, 4.4 Hz, 1H), 3.21–3.15 (m, 1H), 2.25–2.17 (m, 1H), 1.89–1.82 (m, 1H), 1.33 (d, J = 5.6 Hz, 3H). Step 3: Synthesis of benzyl 3-fluoro-3-(1-hydroxyethyl)pyrrolidine-1-carboxylate To a stirred solution of benzyl 2-methyl-1-oxa-5-azaspiro[2.4]heptane-5-carboxylate (8.2 g, 33.2 mmol, 1 eq) in DCM (82 mL) under nitrogen cooled to -40° C, added HF-pyridine (6 mL) and flask was transferred to an ice batch (0° C) and stirred for 2 h. Later, additional 3.2 mL of HF- pyridine was added and continued stirring for 1h. After completion of starting material, reaction was quenched with 10% aq. sodium carbonate solution (30 mL) at 10 °C and allowed to room temperature. Solution was diluted with water (100 mL) and extracted with DCM (2 × 100 mL).

40 #11053313.1 Organic layer was dried over Na₂SO₄, filtered, evaporated and purified by silica gel (100-200 mesh) chromatography [Eluent: 35% to 60% EtOAc in hexane) to afford benzyl 3-fluoro-3-(1- hydroxyethyl)pyrrolidine-1-carboxylate (5.8 g, 72%) as a gummy liquid. TLC system: EtOAc/Petroleum ether (30:70) R_f value: ~0.20 1H NMR (400 MHz, CDCl3): δ 7.37–7.30 (m, 5H), 5.15–5.11 (m, 2H), 3.92–3.86 (m, 1H), 3.77–3.54 (m, 4H), 2.26–2.22 (m, 1H), 2.10–1.91 (m, 2H), 1.30–1.24 (m, 3H). Step 4: Synthesis of tert-butyl 3-fluoro-3-(1-hydroxyethyl)pyrrolidine-1-carboxylate To a stirred solution of benzyl 3-fluoro-3-(1-hydroxyethyl)pyrrolidine-1-carboxylate (3 g, 11.2 mmol, 1 eq) in MeOH (30 mL) under nitrogen atmosphere, added (Boc)2O (3.8 mL, 16.8 mmol, 1.5 eq) and palladium on carbon (10%, 300 mg). The reaction vessel was flushed with hydrogen and the mixture stirred under hydrogen balloon atmosphere for 16 h. After completion of reaction by TLC, mixture was filtered through a pad of diatomaceous earth (e.g., Celite®), washed with MeOH and evaporated to provide 3.8 g crude which was purified by silica gel column (100-200 mesh) chromatography [eluted in 25% EtOAc in hexane] to afford tert-butyl 3-fluoro-3- (1-hydroxyethyl)pyrrolidine-1-carboxylate (2.2 g, 84%) as gummy yellow liquid.. TLC system: EtOAc/ Petroleum ether (30:70) Rf value: ~0.4 (Ninhydrin stain) 1H NMR (400 MHz, CDCl₃): δ 3.93–3.85 (m, 1H), 3.69–3.57 (m, 2H), 3.52–3.44 (m, 2H), 2.24–2.18 (m, 1H), 2.02–1.93 (m, 2H), 1.47 (s, 9H), 1.28 (d, J = 6.4 Hz, 3H). Step 5: Synthesis of tert-butyl 3-fluoro-3-(1-((methylsulfonyl)oxy)ethyl)pyrrolidine-1- carboxylate To a stirred solution of tert-butyl 3-fluoro-3-(1-hydroxyethyl)pyrrolidine-1-carboxylate (2 g, 8.58 mmol, 1 eq) in DCM (20 mL) under nitrogen at 0°C, added Et₃N (4.8 mL, 34.3 mmol, 4

41 #11053313.1 eq), Mesyl chloride (1.4 mL, 17.2 mmol, 2 eq) and allowed to warm to room temperature, stirred for 2 h. After completion of reaction by TLC, cold water was added and extracted with DCM (2 × 30 mL). Combined organic layer was dried over Na2SO4, filtered and evaporated to afford tert- butyl 3-fluoro-3-(1-((methylsulfonyl)oxy)ethyl)pyrrolidine-1-carboxylate (2.5 g; crude) as yellow liquid. TLC system: EtOAc/Petroleum ether (30:70) R_f value: ~0.3 (Ninhydrin stain) 1H NMR (400 MHz, CDCl3) δ 4.94–4.87 (m, 1H), 3.71–3.48 (m, 4H), 3.08 (s, 3H), 2.23– 1.99 (m, 2H), 1.51 (d, J = 6.4 Hz, 3H), 1.47 (s, 9H). Step 6: Synthesis of tert-butyl 3-(1-azidoethyl)-3-fluoropyrrolidine-1-carboxylate To a stirred solution of tert-butyl 3-fluoro-3-(1-((methylsulfonyl)oxy)ethyl)pyrrolidine-1- carboxylate (2.5 g, 8.02 mmol, 1 eq) in DMF (50 mL) under nitrogen was added NaN3 (1.3 g, 20.1 mmol, 2.5 eq), and heated to 100 °C, stirred for 16 h. After completion of reaction by TLC, diluted with cold water (30 mL), and extracted with diethyl ether (3 × 50 mL). Combined organic layer was dried over Na₂SO₄ and evaporated to give a colorless oil 2.2 g which was purified by silica gel column chromatography [eluted in 10% EtOAc in hexane] to afforded tert-butyl 3-(1- azidoethyl)-3-fluoropyrrolidine-1-carboxylate (1.51 g, 63%) as yellow liquid. TLC system: EtOAc/Petroleum ether (30:70) R_f value: ~0.8 (Ninhydrin stain) 1H NMR (400 MHz, DMSO-d6) δ 3.85–3.3.76 (m, 1H), 3.53–3.47 (m, 2H), 3.44–3.38 (m, 1H), 3.31–3.27 (m, 1H), 2.06–1.95 (m, 2H), 1.40 (s, 9H), 1.32 (d, J = 6.8 Hz, 3H). Step 7: Synthesis of tert-butyl 3-(1-aminoethyl)-3-fluoropyrrolidine-1-carboxylate To a stirred solution of tert-butyl 3-(1-azidoethyl)-3-fluoropyrrolidine-1-carboxylate (1.5 g, 4.82 mmol, 1 eq) in MeOH (16 mL) under nitrogen was added palladium on carbon (10%, 160

42 #11053313.1 mg). The reaction vessel was flushed with hydrogen and the mixture stirred under hydrogen balloon atmosphere for 16 hours. After completion of reaction by TLC, reaction mixture was filtered through a pad of diatomaceous earth (e.g., Celite®), washed with MeOH, and evaporated to afford tert-butyl 3-(1-aminoethyl)-3-fluoropyrrolidine-1-carboxylate (1.30 g, 96%) as gummy yellow liquid. TLC system: MeOH/DCM (05:95) R_f value: ~0.1 (Ninhydrin stain) 1H NMR (400 MHz, DMSO-d6): 3.52–-3.42 (m, 2H), 3.39–3.27 (m, 2H), 2.97–2.89 (m, 1H), 2.02–1.85 (m, 2H), 1.38 (s, 9H), 1.03 (d, J = 6.4 Hz, 3H). Step 8: Synthesis of 3-bromo-6-chloroimidazo[1,2-b]pyridazine To a stirred solution of 6-chloroimidazo[1,2-b]pyridazine (4 g, 26.0 mmol, 1 eq) in chloroform (80 mL) at 0 °C, added N-bromosuccinimide (5.6 g, 31.2 mmol, 1.5 eq) and stirred at room temperature for 16h. After completion of reaction by TLC, diluted with water and extracted with DCM (2 × 40 mL), Organic layer washed with hypo solution (2 × 30 mL), dried over Na₂SO₄ and concentrated under reduced pressure to afford 3-bromo-6-chloroimidazo[1,2-b]pyridazine (4.2 g, 68%) as Off-white solid. TLC system: EtOAc/Petroleum ether (40:60) R_f value: ~0.45 LCMS Retention time = 2.91 min, 233.9 [M+H]^{+ 1}H NMR (400 MHz, CDCl₃) δ 7.91 (d, J = 9.2 Hz, 1H), 7.79 (s, 1H), 7.12 (d, J = 9.6 Hz, 1H). Step 9: Synthesis of 6-chloro-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine

43 #11053313.1 To a stirred degassed solution of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (4 g, 17.3 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(3-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane (4.71 g, 17.3 mmol, 1 eq) and K₂CO₃ (7.18 g, 51.9 mmol, 3 eq) in 1,4-dioxane:water (4:1 ratio) (80 mL) at room temperature was added Pd(PPh3)4 (1 g, 0.86 mmol, 0.05 eq). The reaction mixture was degassed with nitrogen for 10 min heated to 100 °C, stirred for 16 h in a sealed tube. After completion of reaction by TLC, volatiles were removed and purified by silica-gel (100-200 mesh) column chromatography [eluted in 40% EtOAc/hexane] to afford 6-chloro-3-(3- (trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine (2.2 g, 53%) as Off-white solid. TLC system: EtOAc/Petroleum ether (50:50) Rf value: ~0.20 LCMS Retention time = 3.84 min, 298.0 [M+H]^{+ 1}H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 8.29–8.26 (m, 1H), 8.13 (s, 1H), 8.00 (d, J = 9.6 Hz, 1H), 7.67–7.64 (m, 2H), 7.15 (d, J = 9.2 Hz, 1H). Step 10: Synthesis of tert-butyl 3-fluoro-3-(1-((3-(3-(trifluoromethyl)phenyl)imidazo[1,2- b]pyridazin-6-yl)amino)ethyl)pyrrolidine-1-carboxylate To a stirred degassed solution of tert-butyl 3-(1-aminoethyl)-3-fluoropyrrolidine-1- carboxylate (300 mg, 1.29 mmol, 1 eq), 6-chloro-3-(3-(trifluoromethyl)phenyl)imidazo[1,2- b]pyridazine (385 mg, 1.29 mmol, 1 eq) and NaO^tBu (186 mg, 1.94 mmol, 1.5 eq) in toluene (6 mL) at room temperature was added Davephos (76 mg, 0.19 mmol, 0.15 eq), Pd₂dba₃ (59 mg, 0.065 mmol, 0.05 eq). The reaction mixture was degassed with nitrogen for 10 min heated to 100 °C, stirred for 16 hours in a sealed tube. After completion of reaction by TLC, volatiles were removed and purified by silica-gel (100-200 mesh) column chromatography [eluted in 40% EtOAc/hexane] to afford tert-butyl 3-fluoro-3-(1-((3-(3-(trifluoromethyl)phenyl)imidazo[1,2- b]pyridazin-6-yl)amino)ethyl)pyrrolidine-1-carboxylate (200 mg, 31%) as light yellow solid.

44 #11053313.1 TLC system: Neat EtOAc (100%) Rf value: ~0.40 LCMS Retention time = 3.83 min, 494.2 [M+H]^{+ 1}H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.29 (t, 1H), 8.09 (s, 1H), 7.85 (d, J = 9.6 Hz, 1H), 7.72–7.65 (m, 2H), 7.38–7.33 (m, 1H), 6.85 (d, J = 9.6 Hz, 1H), 4.34–4.26 (m, 1H), 3.62– 3.46 (m, 4H), 2.15–2.08 (m, 2H), 1.39–1.30 (m, 12H) Step 11: Synthesis of N-(1-(3-fluoropyrrolidin-3-yl)ethyl)-3-(3- (trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-amine formate salt A solution of tert-butyl 3-fluoro-3-(1-((3-(3-(trifluoromethyl)phenyl)imidazo[1,2- b]pyridazin-6-yl)amino)ethyl)pyrrolidine-1-carboxylate (195 mg, 0.39 mmol, 1 eq.) in 4M HCl in 1,4-dioxane (2 mL) was stirred for 1h from 0°C to room temperature. After completion of starting material, reaction mixture was evaporated and purified by reverse phase column (eluent in 15% ACN and 0.01% formic acid in water) to afford N-(1-(3-fluoropyrrolidin-3-yl)ethyl)-3-(3- (trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-amine formate salt (30 mg, 20%) as off-white solid. TLC system: MeOH/DCM (15:85) R_f value: ~0.15 LCMS Retention time = 2.90 min, 394.2 [M+H]^{+ 1}H NMR (400 MHz, DMSO-d₆) δ 8.85–8.83 (m, 1H), 8.29 (d, J = 7.2 Hz, 1H), 8.17 (s, 1H; HCOOH), 8.09 (s, 1H), 7.84 (d, J = 9.6 Hz, 1H), 7.72–7.65 (m, 2H), 7.32 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 9.6 Hz, 1H), 4.32–4.23 (m, 1H), 3.15–2.96 (m, 4H), 2.12–1.86 (m, 2H), 1.33 (d, J = 6.8 Hz, 3H).

45 #11053313.1 SYNTHETIC EXAMPLE 2 SYNTHESIS OF N-(1-(3-FLUOROPYRROLIDIN-3-YL)ETHYL)-3-(3- (TRIFLUOROMETHYL)PHENYL)IMIDAZO[1,2-B]PYRIDAZIN-6-AMINE FORMATE SALT Step 1: Synthesis of tert-butyl 4-((trimethylsilyl)oxy)-3,6-dihydropyridine-1(2H)- carboxylate To a stirred solution of tert-butyl 4-oxopiperidine-1-carboxylate (1) (10.0 g, 50.2 mmol, 1 eq.) in DCM (100 mL) at -10° C under nitrogen, was added triethylamine (21.1 mL, 150.6 mmol, 3 eq.) and TMSOTf (13.6 mL, 75.3 mmol, 1.5 eq) and continued stirring for 30 min. After observing conversion by TLC, volatiles were evaporated under vacuum to afford crude tert-butyl 4-((trimethylsilyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (13 g, Crude compound) as pale brown oil. TLC system: EtOAc/Petroleum ether (30:70) Rf value: ~0.6 (Ninhydrin stain) Crude material was used in next step without purification. Step 2: Synthesis of tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate To a stirred solution of tert-butyl 4-((trimethylsilyl)oxy)-3,6-dihydropyridine-1(2H)- carboxylate (13 g, 47.9 mmol, 1 eq.) in acetonitrile (130 mL) under nitrogen at 0° C was added Selectfluor (20.4 g, 57.6 mmol, 1.2 eq.) and the mixture was allowed to warm to room temperature, stirred for 2 h. After completion of reaction by TLC, reaction mixture was evaporated in vacuum and purified by silica gel (60-120 mesh) chromatography [eluted in 30% EtOAc in hexane] to afford tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (5.8 g, 53% for two steps) as pale-yellow solid. TLC system: EtOAC/Petroleum ether (30:70)

46 #11053313.1 R_f value: ~0.2 (Ninhydrin stain) 1H NMR (400 MHz, CDCl3) δ 4.90–4.76 (m, 1H), 4.52–4.41 (m, 1H), 4.21–4.17 (m, 1H), 3.28–3.22 (m, 2H), 2.63–2.49 (m, 2H), 1.50 (s, 9H). Step 3: Synthesis of tert-butyl 3-fluoro-4-methylenepiperidine-1-carboxylate To a stirred solution of methyltriphenylphosphonium bromide (32.9 g, 92.2 mmol, 2 eq.) in THF (150 mL) at 0° C under nitrogen, was added Potassium tert-Butoxide (10.3 g, 92.2 mmol, 2 eq) and allowed to warm to room temperature, stirred for 1 h. Resulting pale yellow solution was cooled to 0° C, added a solution of tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (10 g, 46.08 mmol) in THF (50 mL) and stirred at room temperature for 16h. After completion of reaction by TLC, diluted with water (200 mL) and extracted with Ethyl acetate (2 × 200 mL). Combined organic layers were dried over Na₂SO₄, evaporated, and purified by silica gel (100-200 mesh) column chromatography [eluted in 10% EtOAc in hexane] to afford tert-butyl 3-fluoro-4- methylenepiperidine-1-carboxylate (8 g, yield: 62%) as yellow liquid. TLC system: EtOAc/Petroleum ether (10:90) R_f value: ~0.80 (Ninhydrin stain) 1H NMR (400 MHz, CDCl3): δ 5.10 (s, 1H), 4.98 (s, 1H), 4.89–4.76 (m, 1H), 3.77–3.73 (m, 1H), 3.62–3.48 (m, 2H), 3.30–3.25 (m, 1H), 2.52–2.43 (m, 1H), 2.21–2.15 (m, 1H), 1.47 (s, 9H). Step 4: Synthesis of tert-butyl 3-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate To a stirred solution of tert-butyl 3-fluoro-4-methylenepiperidine-1-carboxylate (6 g, 27.9 mmol, 1 eq) in THF (60 mL) at 0°C, added 0.5 M 9-BBN in THF (84 mL, 41.8 mmol, 1.5 eq) and heated to 70° C, stirred for 16 h. Reaction mixture was cooled to 0°C, quenched with 50 mL of 3N NaOH, stirred for 15 min, followed by addition of 50 mL of 30% H2O2 and stirred for 30 min. Compound was extracted with DCM (2 × 100 mL), organic layer was dried over Na₂SO₄ and evaporated. Obtained crude was purified by silica gel column chromatography [eluted in 15%

47 #11053313.1 EtOAc in hexane] to afford tert-butyl 3-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (2.7 g non-polar spot and 2.4 g polar spot, 78%) as off white gummy mass. TLC system: EtOAc/Petroleum ether (30:70) Rf value: ~0.2 (non-polar), 0.1 (polar) (Ninhydrin stain) 1H NMR (400 MHz, CDCl₃): δ 4.41–4.30 (m, 2H), 4.11 (brs, 1H), 3.83–3.79 (m, 1H), 3.73–3.69 (m, 1H), 2.79–2.71 (m, 2H), 1.85–1.78 (m, 2H), 1.45 (s, 9H). Step 5: Synthesis of tert-butyl 3-fluoro-4-formylpiperidine-1-carboxylate To a stirred solution of tert-butyl 3-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (4.87 g, 20.2 mmol, 1 eq) in dichloromethane (50 mL) at 0°C was added DMP (12.8 g, 30.3 mmol, 1.5 eq) and stirred at room temperature for 1h. After completion of reaction by TLC, quenched with sat NaHCO3 solution (100 mL) and extracted with DCM (2 × 100 mL). Organic layer was dried over Na₂SO₄ and evaporated in vacuo to give crude compound (5 g) which was purified by silica gel (100-200 mesh) chromatography [eluted with 70% EtOAc in hexane] to afford tert-butyl 3-fluoro-4-formylpiperidine-1-carboxylate (4.5 g, semi-pure) as yellow liquid. TLC system: EtOAc/ Petroleum ether (30:70) R_f value: ~0.4 (Ninhydrin stain) 1H NMR (400 MHz, CDCl3): δ 9.80 (s, 1H), 4.86–4.69 (m, 1H), 4.15–4.10 (m, 1H), 3.81– 3.75 (m, 1H), 3.16–3.00 (m, 2H), 2.77–2.70 (m, 1H), 2.02–1.98 (m, 1H), 1.65–1.62 (m, 1H), 1.46 (s, 9H). Step 6: Synthesis of tert-butyl 3-fluoro-4-(1-hydroxyethyl)piperidine-1-carboxylate To a stirred solution of tert-butyl 3-fluoro-4-formylpiperidine-1-carboxylate (4.5 g, 19.5 mmol, 1 eq) in DCM (45 mL) under nitrogen at 0°C was added 1 M MeMgBr in THF (49 mL, 48.7 mmol, 2.5 eq) and continued reaction for 2 hours at same temperature. After completion of reaction by TLC, quenched with sat. aq. NH4Cl (100 mL) and extracted with EtOAc (2 × 100 mL). Combined organic layer was dried over Na₂SO₄, evaporated and purified by silica gel (100-200

48 #11053313.1 mesh) column chromatography [eluted in 10% EtOAc in hexane] to afford tert-butyl 3-fluoro-4- (1-hydroxyethyl)piperidine-1-carboxylate (48%, 1 g non-polar spot and 1.3 g polar spot) as yellow liquid. TLC system: EtOAc/Petroleum ether (30:70) R_f value: ~0.35 (non-polar spot), 0.3 (polar spot) (Ninhydrin stain) 1H NMR (400 MHz, CDCl3): δ 4.55–4.39 (m, 1H), 4.16–4.11 (m, 2H), 2.72–2.60 (m, 2H), 1.76–1.73 (m, 1H), 1.66–1.59 (m, 1H), 1.46 (s, 9H), 1.42–1.39 (m, 2H), 1.24 (d, J = 6.4 Hz, 3H). Step 7: Synthesis of tert-butyl 3-fluoro-4-(1-((methylsulfonyl)oxy)ethyl)piperidine-1- carboxylate To a stirred solution of tert-butyl 3-fluoro-4-(1-hydroxyethyl)piperidine-1-carboxylate (1.65 g, 6.7 mmol, 1 eq) in DCM (17 ml) under nitrogen at 0°C was added Et3N (3.8 mL, 26.7 mmol, 4 eq.) and Mesylchloride (1.0 mL, 13.4 mmol, 2 eq.). The reaction mixture was allowed to warm to room temperature and stirred for 1 h. After completion of reaction by TLC, diluted with water (50 mL) and extracted with DCM (2 × 50 mL). Combined organic layer was dried over Na2SO4 and evaporated to afford crude tert-butyl 3-fluoro-4-(1- ((methylsulfonyl)oxy)ethyl)piperidine-1-carboxylate (2.05 g, crude) as yellow liquid. TLC system: EtOAc/Petroleum ether (40:60) R_f value: ~0.6 (Ninhydrin stain) 1H NMR (400 MHz, CDCl3) δ.5.12–5.05 (m, 1H), 4.49–4.29 (m, 2H), 4.15–4.11 (m, 1H), 3.03 (s, 3H), 2.69–2.59 (m, 2H), 1.86–1.70 (m, 2H), 1.49–1.42 (m, 13H). Step 8: Synthesis of tert-butyl 4-(1-azidoethyl)-3-fluoropiperidine-1-carboxylate To a stirred solution of tert-butyl 3-fluoro-4-(1-((methylsulfonyl)oxy)ethyl)piperidine-1- carboxylate (2.0 g, 6.15 mmol, 1 eq) in DMF (40 ml) at room temperature was added NaN3 (0.99 g, 15.4 mmol, 2.5 eq), and heated to 100 ^oC, stirred for 16 h. After completion of reaction by TLC, diluted with water (50 mL) and extracted with EtOAc (2 × 50 mL). Combined organic layer was

49 #11053313.1 dried over Na₂SO₄, evaporated and by silica gel (100-200 mesh) column chromatography [eluted in 5% EtOAc in hexane] to afford tert-butyl 4-(1-azidoethyl)-3-fluoropiperidine-1-carboxylate (1.30 g, 78%) as light-yellow liquid. TLC system: EtOAc/Petroleum ether (20:80) R_f value: ~0.7 (Ninhydrin stain) 1H NMR (400 MHz, CDCl3) δ 4.41–4.39 (m, 1H), 4.33–4.26 (m, 1H), 4.07–4.01 (m, 1H), 3.88–3.85 (m, 1H), 2.73–2.66 (m, 2H), 1.88–1.83 (m, 1H), 1.75–1.71 (m, 1H), 1.46 (s, 9H), 1.38– 1.33 (m, 4H). Step 9: Synthesis of tert-butyl 4-(1-aminoethyl)-3-fluoropiperidine-1-carboxylate To a stirred solution of tert-butyl 4-(1-azidoethyl)-3-fluoropiperidine-1-carboxylate (1.3 g, 4.78 mmol, 1 eq) in MeOH (13 mL) at room temperature was added 10% palladium on carbon (390 mg) and stirred for 16h under hydrogen balloon atmosphere. The mixture was filtered through a pad of diatomaceous earth (e.g., Celite®), washed with methanol, and evaporated to afford tert- butyl 4-(1-aminoethyl)-3-fluoropiperidine-1-carboxylate (1.0 g, 85%) as gummy yellow liquid. TLC system: MeOH/DCM (30:70) R_f value: ~0.1 (Ninhydrin stain) 1H NMR (400 MHz, DMSO-d6): δ 4.54–4.40 (m, 1H), 3.98–3.82 (m, 1H), 3.73–3.71 (m, 1H), 3.06–3.00 (m, 1H), 2.95–2.89 (m, 1H), 2.85– 2.75 (m, 1H), 1.73–1.55 (m, 2H), 1.39 (s, 9H), 1.23–1.16 (m, 1H), 0.97 (d, J = 6.4 Hz, 3H). Step 10: Synthesis of tert-butyl 3-fluoro-4-(1-((3-(3-(trifluoromethyl)phenyl)imidazo[1,2- b]pyridazin-6-yl)amino)ethyl)piperidine-1-carboxylate

50 #11053313.1 To a degassed solution of tert-butyl 4-(1-aminoethyl)-3-fluoropiperidine-1-carboxylate (297 mg, 1.20 mmol, 1.2 eq), 6-chloro-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine (300 mg, 1.00 mmol, 1 eq.), NaO^tBu (145 mg, 1.51 mmol, 1.5 eq), in Toluene (6 mL) at room temperature was added Davephos (59 mg, 0.15 mmol, 0.15 eq), Pd2dba3 (46 mg, 0.05 mmol, 0.05 eq). The reaction mixture was degassed with nitrogen for 10 min and stirred for 16h at 100°C in a seal tube. After completion of reaction by TLC, reaction mixture was filtered through a pad of diatomaceous earth (e.g., Celite®), washed with dioxane and evaporated followed by reverse phase grace column (Eluent: 50% ACN in 0.01% formic acid in water) afforded tert-butyl 3-fluoro-4-(1- ((3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)piperidine-1- carboxylate (65 mg, 11%) as an off white solid. TLC system: EtOAc/Petroleum ether (70%) Rf value: ~0.20 LCMS Retention time = 3.77 min, 508.2 [M+H]^{+ 1}H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.52 (t, J = 3.6 Hz, 1H), 8.07 (s, 1H), 7.79 (d, J = 9.6 Hz, 1H), 7.64–7.62 (m, 2H), 7.11 (d, J = 8.0 Hz, 1H), 6.77 (d, J = 9.6 Hz, 1H), 4.56– 4.42 (m, 1H), 4.35–4.30 (m, 1H), 4.09–3.99 (m, 1H), 3.78–3.74 (m, 1H), 2.95–2.82 (br, 2H), 2.17– 2.12 (m, 1H), 1.81–1.75 (m, 1H), 1.39 (s, 9H), 1.28–1.22 (m, 4H) Step 11: Synthesis of N-(1-(3-fluoropyrrolidin-3-yl)ethyl)-3-(3- (trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-amine (formate salt) a stirred solution of tert-butyl-3-fluoro-4-(1-((3-(3- (trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino) ethyl)piperidine-1-carboxylate (65 mg, 0.13 mmol, 1 eq.) in 1,4-dioxane (0.65 mL) at 0°C was added 4M HCl in 1,4-dioxane (0.65 mL) and stirred at room temperature for 2 h. The reaction mixture was evaporated, and triturated with diethyl ether (2 × 2 mL) to afford N-(1-(3-fluoropiperidin-4-yl)ethyl)-3-(3- (trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-amine HCl salt (49 mg, 94%) as brown solid. TLC system: MeOH/DCM (20:80) Rf value: ~0.15 LCMS Retention time = 2.21 min, 408.2 [M+H]⁺

51 #11053313.1 ¹H NMR (400 MHz, DMSO-d₆) δ 9.52 (brs, 2H), 8.63 (s, 1H), 8.53–8.49 (m, 2H), 8.14– 8.09 (m, 2H), 7.82 (d, J = 8.0 Hz, 1H), 7.74 (t, J = 8.0 Hz, 1H), 7.34 (d, J = 9.6 Hz, 1H), 4.97– 4.83 (m, 1H), 4.36–4.31 (m, 1H), 3.52–3.48 (m, 1H), 3.25–3.22 (m, 1H), 2.93–2.85 (m, 2H), 2.33– 2.30 (m, 1H), 2.01–1.97 (m, 1H), 1.73–1.70 (m, 1H), 1.23–1.19 (m, 3H) SYNTHETIC EXAMPLE 3 SYNTHESIS OF N-(1-(3-FLUOROPYRROLIDIN-3-YL)ETHYL)-7-METHYL-3-(3- (TRIFLUOROMETHYL)PHENYL)IMIDAZO[1,2-B]PYRIDAZIN-6-AMINE HCL SALT Step 1 & 2: Synthesis of 6-chloro-7-methylimidazo[1,2-b]pyridazine A solution of 2-bromo-1,1-diethoxyethane (10 g, 50.7 mmol, 1 eq) in 1N aq. HCl (50 mL, 5 V) was stirred at room temperature for 12 h. TLC indicated new polar spot. Diluted with water and extracted with 5% MeOH in DCM (2 × 100 mL). Organic layer was dried over Na2SO4 and evaporated to afford 2-bromoacetaldehyde (6.59 g, crude). The crude was taken forward to next step without further purification. As solution of 2-bromoacetaldehyde (6.5 g, 53.8 mmol, 2.2 eq.) and 1-N-6-chloro-5- methylpyridazin-3-amine (3.5 g, 24.4 mmol, 1 eq) in EtOH (35 mL) was heated at 90 ^oC for 3 h. After completion of reaction by TLC, volatiles were removed under vacuum and purified by silica gel column [eluted from EtOAc to 5% MeOH in DCM] to afford 6-chloro-7-methylimidazo[1,2- b]pyridazine (3.8 g, yield: 95%) as off white solid. TLC system: EtOAc (100%) Rf value: ~0.50 LCMS Retention time = 2.05 min, 168.0 [M+H]^{+ 1}H NMR (400 MHz, CDCl3) δ: 8.71 (s, 1H), 8.01 (s, 2H), 2.64 (s, 3H) Step 3: Synthesis of 3-bromo-6-chloro-7-methylimidazo[1,2-b]pyridazine

52 #11053313.1 To a stirred solution of 6-chloro-7-methylimidazo[1,2-b]pyridazine (2.5 g, 14.0 mmol, 1 eq.) in chloroform (50 mL) at 0 ° C was added NBS (3.2 g, 17 mmol, 1.2 eq.) and stirred at room temperature for 16h. After completion of reaction by TLC, diluted with water and extracted with DCM (2 × 40 mL). Organic layer was washed with hypo solution (2 × 90 mL), dried over Na2SO4, and concentrated under reduced pressure to afforded crude compound (4 g). Purified by silica gel (100-200 mesh) column chromatography [eluted in 2% MeOH in DCM] to afford 3-bromo-6- chloro-7-methylimidazo[1,2-b]pyridazine (3.0 g, 84%) as off-white solid. TLC system: EtOAc (100%) R_f value: ~0.6 LCMS Retention time = 3.16 min, 245.9 [M+H]^{+ 1}H NMR (400 MHz, CDCl₃) δ 7.77 (q, J = 1.2 Hz, 1H), 7.70 (s, 1H), 2.48 (d, J = 1.2 Hz, 3H) Step 4: Synthesis of 6-chloro-7-methyl-3-(3-(trifluoromethyl)phenyl)imidazo[1,2- b]pyridazine To a stirred degassed solution of 3-bromo-6-chloro-7-methylimidazo[1,2-b]pyridazine (2 g, 8.0 mmol, 1 eq.), 4,4,5,5-tetramethyl-2-(3-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane (2.2 g, 8.0 mmol, 1 eq.), K2CO3 (3.38 g, 24.0 mmol, 3.0 eq.) in 1,4-dioxane:water (4:1 ratio) (40 mL) at room temperature was added Pd(PPh₃)₄ (460 mg, 0.4 mmol, 0.05 eq.). The reaction mixture was degassed with nitrogen for 10 min, and heated to 100 °C, stirred for 16 h in a sealed tube. After completion of reaction by TLC, diluted with water and extracted with EtOAc (2 × 100 mL). Organic layer was dried over Na2SO4 and concentrated under reduced pressure to afforded crude compound. The crude compound was purified by silica gel column (100-200 mesh) [eluted in 40% EtOAc in hexane] to afford 6-chloro-7-methyl-3-(3-(trifluoromethyl)phenyl)imidazo[1,2- b]pyridazine (2g, 80%) as yellow solid.

53 #11053313.1 TLC system: EtOAc/Petroleum ether (50:50) Rf value: ~0.2 LCMS Retention time = 3.92 min, 312.0 [M+H]^{+ 1}H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 8.27–8.25 (m, 1H), 8.06 (s, 1H), 7.85 (s, 1H), 7.63 (d, J = 5.2 Hz, 2H), 2.50 (s, 3H) Step 5: Synthesis of tert-butyl 3-fluoro-3-(1-((7-methyl-3-(3- (trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)pyrrolidine-1-carboxylate To a degassed solution of 6-chloro-7-methyl-3-(3-(trifluoromethyl)phenyl)imidazo[1,2- b]pyridazine (300 mg, 0.96 mmol, 1 eq.), tert-butyl 3-(1-aminoethyl)-3-fluoropyrrolidine-1- carboxylate (280 mg, 1.20 mmol, 1.25 eq.), NaO^tBu (278 mg, 2.89 mmol, 3 eq.) in 1,4-dioxane (6 mL) at room temperature was added rac-BINAP (150 mg, 0.24 mmol, 0.25 eq.), Pd2(dba)3 (88 mg, 0.096 mmol, 0.1 eq.). The reaction mixture was degassed with nitrogen for 10 min and heated to 100°C, stirred for 16 h in a sealed tube. After completion of reaction by TLC, solvent was removed under reduced pressure to afford 400 mg crude material. The crude compound was purified by silica gel column (100-200 mesh) [Eluted in 70% EtOAc/hexane to 2% MeOH and DCM] to afford tert-butyl 3-fluoro-3-(1-((7-methyl-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6- yl)amino)ethyl)pyrrolidine-1-carboxylate (148 mg, 33%) as light yellow gummy liquid. TLC system: MeOH/DCM (5%) Rf value: ~0.20 LCMS Retention time = 5.30 min, 508.3 [M+H]⁺ Step 6: Synthesis of N-(1-(3-fluoropyrrolidin-3-yl)ethyl)-7-methyl-3-(3- (trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-amine (HCl salt)

54 #11053313.1 To solution of tert-butyl 3-fluoro-3-(1-((7-methyl-3-(3- (trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl )pyrrolidine-1-carboxylate (145 mg, 0.28 mmol) in 1,4-dioxane (1.5 mL) at 0 °C was added 4M HCl in 1,4-dioxane (1.5 mL) and stirred at room temperature for 2 h. TLC showed polar spot and starting material was consumed. Reaction mixture was evaporated and purified by reverse phase column (eluent: 7% ACN in 0.01% FA in water) and fractions was treated with to aq. HCl, lyophilized to afford N-(1- (3-fluoropyrrolidin-3-yl)ethyl)-7-methyl-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin- 6-amine HCl salt (62 mg, 54%) as off-white solid. TLC system: MeOH/DCM (20:80) R_f value: ~0.15 LCMS Retention time = 2.45 min, 408.2 [M+H]^{+ 1}H NMR (400 MHz, DMSO-d6) δ 9.67 (brs, 1H), 9.48 (brs, 1H), 8.69 (s, 1H), 8.51 (s, 1H), 8.33–8.31 (m, 1H), 8.03 (s, 1H), 7.82–7.78 (m, 2H), 6.84–6.82 (m, 1H), 4.63–4.54 (m, 1H), 3.67– 3.61 (m, 4H), 2.43 (s, 3H) 2.21–2.06 (m, 2H), 1.40 (d, J = 6.8 Hz, 3H) SYNTHETIC EXAMPLE 4 SYNTHESIS OF N-(1-(3-FLUOROPIPERIDIN-4-YL)ETHYL)-7-METHYL-3-(3- (TRIFLUOROMETHYL)PHENYL)IMIDAZO[1,2-B]PYRIDAZIN-6-AMINE HCL SALT Step 1: Synthesis of tert-butyl 3-fluoro-4-(1-((7-methyl-3-(3- (trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)piperidine-1-carboxylate

55 #11053313.1

To a degassed solution of tert-butyl 4-(1-aminoethyl)-3-fluoropiperidine-1-carboxylate (261 mg, 1.06 mmol, 1.1 eq.), 6-chloro-7-methyl-3-(3-(trifluoromethyl)phenyl)imidazo[1,2- b]pyridazine (300 mg, 0.96 mmol, 1 eq.), NaO^tBu (278 mg, 2.89 mmol, 3 eq.), in 1,4-dioxane (6 mL) at room temperature was added rac-BINAP (150 mg, 0.24 mmol, 0.25 eq.), Pd₂dba₃ (88 mg, 0.096 mmol, 0.1 eq.). The reaction mixture was degassed with nitrogen for 10 min and heated to 100 °C, stirred for 16 h in a sealed tube. After completion of reaction by TLC, reaction mixture was filtered through a pad of diatomaceous earth (e.g., Celite®), washed with dioxane and evaporated followed by reverse phase grace column (Eluent: 27% ACN in 0.01% FA in water) afforded tert-butyl 3-fluoro-4-(1-((7-methyl-3-(3-(trifluoromethyl)phenyl)imidazo[1,2- b]pyridazin-6-yl)amino)ethyl)piperidine-1-carboxylate (230 mg, 15% purity) as a light yellow solid. TLC system: EtOAc/Petroleum ether (7:3) Rf value: ~0.20 LCMS Retention time = 3.63 min, 522.3 [M+H]⁺ Ligand impurity was highlighting at 210 nm. Material was taken forward to next step for further purification. Step 2: Synthesis of N-(1-(3-fluoropiperidin-4-yl)ethyl)-7-methyl-3-(3- (trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-amine (HCl salt)

56 #11053313.1

To a stirred solution of tert-butyl 3-fluoro-4-(1-((7-methyl-3-(3- (trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)piperidine-1-carboxylate (180 mg, crude) was dissolved in 1,4-dioxane (1.8 mL) cooled to 0 °C and added 4M HCl in 1,4-dioxane (1.8 mL), stirred at room temperature for 2 h. Reaction mixture was evaporated and purified by reverse phase column (Eluent: 20 % ACN and 0.01% FA in water) and lyophilized by addition of 0.2 mL of 4 M aq. HCl to afford N-(1-(3-fluoropiperidin-4-yl)ethyl)-3-(3- (trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-amine HCl salt (29 mg, 7% over two steps) as off white solid. TLC system: MeOH/DCM (20:80) R_f value: ~0.20 LCMS Retention time = 2.17 min, 422.2 [M+H]^{+ 1}H NMR (400 MHz, DMSO-d₆) δ 9.19 (brs, 2H), 8.53–8.47 (m, 3H), 7.95 (s, 1H), 7.79– 7.77 (m, 1H), 7.71 (t, J = 7.6 Hz, 1H), 6.73–6.71 (m, 1H), 4.93–4.80 (m, 1H), 4.48–4.42 (m, 1H), 3.46 (merged, 1H), 3.20–3.17 (m, 1H), 2.96–2.83 (m, 2H), 2.43–2.40 (m, 1H), 2.37 (s, 3H), 2.02– 1.98 (m, 1H), 1.71–1.62 (m, 1H), 1.30 (d, J = 6.8 Hz, 3H)

57 #11053313.1 SYNTHETIC EXAMPLE 5 SYNTHESIS OF 6-(1-(3-FLUOROPYRROLIDIN-3-YL)ETHOXY)-3-(3- (TRIFLUOROMETHYL)PHENYL)IMIDAZO[1,2-B]PYRIDAZINE Step 1: Synthesis of benzyl 3-fluoro-3-(1-((3-(3-(trifluoromethyl)phenyl)imidazo[1,2- b]pyridazin-6-yl)oxy)ethyl)pyrrolidine-1-carboxylate To a stirred solution of benzyl 3-fluoro-3-(1-hydroxyethyl)pyrrolidine-1-carboxylate (300 mg, 1.01 mmol, 1 eq) in THF (4 mL) under nitrogen at 0° C, added NaH (36.3 mg, 1.51 mmol, 1.5 eq) and stirred for 30 min. Later, added a solution of 6-chloro-3-(3- (trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine (233 mg, 1.51 mmol, 1.5 eq) in 2 mL of THF. The resulting solution was stirred at room temperature for 16 h. After completion of reaction by TLC, quenched with Sat aq. NH4Cl (5 mL), diluted with water and extracted with ethyl acetate (2 × 30 ml). Combined organic layer was dried over Na2SO4, evaporated and purified by silica gel column (Eluent: 40% of EtOAc/Petroleum ether) to afford benzyl 3-fluoro-3-(1-((3-(3- (trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)oxy)ethyl)pyrrolidine-1-carboxylate (260 mg, 49%) as yellow gummy liquid. TLC system: EtOAc/Petroleum ether (50:50) Rf value: ~0.10

58 #11053313.1 LCMS Retention time = 4.29 min, 529.2 [M+H]⁺ Step 2: Synthesis of 6-(1-(3-fluoropyrrolidin-3-yl)ethoxy)-3-(3- (trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine To a stirred solution of benzyl 3-fluoro-3-(1-((3-(3-(trifluoromethyl)phenyl)imidazo[1,2- b]pyridazin-6-yl)oxy)ethyl)pyrrolidine-1-carboxylate (250 mg, 0.47 mmol) in MeOH (5 mL) at room temperature was added 10% palladium on carbon (50 mg) and reaction mixture was stirred for 16h under hydrogen balloon atmosphere. After completion of reaction by TLC, reaction mixture was filtered through a pad of diatomaceous earth (e.g., Celite®), washed with 10% MeOH/DCM and evaporated. Obtained crude was purified by Prep HPLC (FA buffer) and lyophilization provide 85 mg of desired product with LCMS 92% and 7% of unknown mass m/z 423. Material was re-purified by reverse phase Grace column (16% to 18% ACN and 0.1% FA in water) and added 0.6 mL of 2M HCl to the fractions, kept for lyophilization to afford 6-(1-(3- fluoropyrrolidin-3-yl)ethoxy)-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine HCl salt (32 mg, 17%) as light yellow solid. TLC system: MeOH/DCM (20:80) R_f value: ~0.2 LCMS Retention time = 2.45 min, 395.1 [M+H]^{+ 1}H NMR (400 MHz, DMSO-d₆) δ 9.82 (brs, 1H), 9.69 (brs, 1H), 8.62 (s, 1H), 8.47 (s, 1H), 8.37–8.36 (m, 1H), 8.30 (d, J = 9.6 Hz, 1H), 7.83–7.80 (m, 2H), 7.21 (d, J = 9.6 Hz, 1H), 5.43– 5.35 (m, 1H), 3.55–3.33 (m, 4H), 2.40–2.35 (m, 1H), 2.33–2.26 (m, 1H), 1.54 (d, J = 6.4 Hz, 3H). SYNTHETIC EXAMPLE 6 SYNTHESIS OF N-(1-(3-FLUORO-1-METHYLPYRROLIDIN-3-YL)ETHYL)-3-(3- (TRIFLUOROMETHYL)PHENYL)IMIDAZO[1,2-B]PYRIDAZIN-6-AMINE

59 #11053313.1 Step 1: Synthesis of tert-butyl 3-fluoro-3-(1-((3-(3-(trifluoromethyl)phenyl)imidazo[1,2- b]pyridazin-6-yl)amino)ethyl)pyrrolidine-1-carboxylate To a stirred degassed solution of tert-butyl 3-(1-aminoethyl)-3-fluoropyrrolidine-1- carboxylate (244 mg, 1.05 mmol, 1.25 eq), 6-chloro-3-(3-(trifluoromethyl)phenyl)imidazo[1,2- b]pyridazine (250 mg, 0.84 mmol, 1 eq) and NaO^tBu (202 mg, 2.10 mmol, 2.5 eq) in toluene (5 mL, 20 vol) at room temperature was added rac-BINAP (49.6 mg, 0.13 mmol, 0.15 eq), Pd₂dba₃ (38.5 mg, 0.042 mmol, 0.05 eq). The reaction mixture was degassed with nitrogen for 10 min heated to 100 °C, stirred for 20 h in a sealed tube. After completion of reaction by TLC, volatiles were removed and purified by reverse phase column (12 g, C18 column) [eluted in 30% to 35% ACN and 0.01% FA in Water] to afford tert-butyl 3-fluoro-3-(1-((3-(3- (trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)pyrrolidine-1-carboxylate (210 mg, 51%) as yellow gummy solid. TLC system: Neat EtOAc (100%) R_f value: ~0.35 LCMS Retention time = 4.1 min, 494.3 [M+H]^{+ 1}H NMR (400 MHz, CDCl₃) δ 8.73 (s, 1H), 8.00 (brs, 1H), 7.87–7.86 (m, 1H), 7.79–7.73 (m, 1H), 7.59–7.57 (m, 2H), 6.55–6.47 (m, 1H), 4.68–4.65 (m, 1H), 4.45–4.29 (m, 1H), 3.82–3.42 (m, 4H), 2.10–1.85 (m, 2H), 1.48–1.34 (m, 12H).

60 #11053313.1 Step 2: Synthesis of N-(1-(3-fluoropyrrolidin-3-yl)ethyl)-3-(3- (trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-amine To a stirred solution of tert-butyl 3-fluoro-3-(1-((3-(3- (trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)ethyl)pyrrolidine-1-carboxylate (210 mg, 0.43 mmol, 1 eq.) in DCM (2 mL, 10 vol) at 0°C was added 2M HCl in diethyl ether (1 mL, 5 vol) and allowed to stir at room temperature for 1h. After completion of starting material, reaction mixture was evaporated, washed with n-pentane (3 ml) and Et2O (2 × 3 mL) afforded HCl salt. The salt dissolved in water basified with 20 mL of 2 M Na₂CO₃ and extracted with 10% MeOH and DCM (2 × 30 mL) to afford N-(1-(3-fluoropyrrolidin-3-yl)ethyl)-3-(3- (trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-amine (100 mg, crud)) as a white solid. TLC system: neat EtOAc (100%) R_f value: ~0.01 LCMS retention time = 2.61 min, 394.2 [M+H]⁺ Material used in next step without further purification or characterization. Step 3: Synthesis of N-(1-(3-fluoro-1-methylpyrrolidin-3-yl)ethyl)-3-(3- (trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-amine

61 #11053313.1

To a stirred solution of N-(1-(3-fluoropyrrolidin-3-yl)ethyl)-3-(3- (trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-amine (100 mg, 0.25 mmol, 1.0 eq) in MeOH (2 mL, 20 vol) at 0 °C, added 37% aqueous Formaldehyde (114 mg, 1.27 mmol, 5.0 eq) and acetic acid (3 mg, 0.051 mmol, 0.2 eq). The reaction mixture was stirred for 15 min at 0 °C followed by addition of sodium cyanoborohydride (24 mg, 0.38 mmol, 1.5 eq) and continued for additional 30 min at 0 °C. After completion of reaction by TLC, reaction mixture concentrated under reduced pressure to provide 135 mg crude product. The crude material was purified by reverse phase column (Method: Mobile Phase A : 100% Acetonitrile and Mobile Phase B : 0.01% FA in Water, eluent: 28% to 32% ) to afford N-(1-(3-fluoro-1-methylpyrrolidin-3-yl)ethyl)-3-(3- (trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-amine as Off white solid (60 mg, yield: 58%). TLC system: MeOH/CH₂Cl₂ (10:90) Rf value: ~0.4 LCMS Retention time = 2.65 min, 408.1 [M+H]^{+ 1}H NMR (400 MHz, DMSO-d6) δ 8.84–8.82 (s, 1H), 8.31 (d, J = 7.6 Hz, 1H), 8.09 (s, 1H), 7.84 (d, J = 9.6 Hz, 1H), 7.72–7.66 (m, 2H), 7.33 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 9.6 Hz, 1H), 4.28–4.20 (m, 1H), 3.18–3.04 (m, 3H), 2.76–2.74 (m, 1H), 2.43 (s, 3H), 2.16 (t, J = 7.2 Hz, 1H), 2.10 (t, J = 7.2 Hz, 1H), 1.30 (d, J = 6.4 Hz, 3H).

62 #11053313.1 SYNTHETIC EXAMPLE 7 SYNTHESIS OF N-(1-(3-FLUORO-1-METHYLPYRROLIDIN-3-YL)ETHYL)-7-METHYL-3-(3- (TRIFLUOROMETHYL)PHENYL)IMIDAZO[1,2-B]PYRIDAZIN-6-AMINE To a stirred solution of N-(1-(3-fluoropyrrolidin-3-yl)ethyl)-7-methyl-3-(3- (trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-amine (100 mg, 0.25 mmol, 1.0 eq) in MeOH (2 mL, 20 vol) at 0 °C, added 37% aqueous formaldehyde (0.04 mL, 1.25 mmol, 5.0 eq), acetic acid (3 mg, 0.05 mmol, 0.2 eq) and stirred for 15 min. At same temperature, Sodium cyanoborohydride (24 mg, 0.37 mmol, 1.5 eq) was added and continued stirring for 30 min. After completion of reaction by TLC, reaction mixture concentrated under reduced pressure to provide 150 mg crude product. The crude material was purified by reverse phase column (Method: Mobile Phase A : 100% Acetonitrile and Mobile Phase B : 0.01% FA in Water, eluent: 28% to 32%) to afford N-(1-(3-fluoro-1-methylpyrrolidin-3-yl)ethyl)-7-methyl-3-(3- (trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-amine as an off white gummy (50 mg, yield: 49%). TLC system: MeOH/CH₂Cl₂ (10:90) Rf value: ~0.4 LCMS Retention time = 2.50 min, 422.2 [M+H]^{+ 1}H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.29 (d, J = 7.2 Hz, 1H), 8.06 (s, 1H), 7.75 (s, 1H), 7.71–7.64 (m, 2H), 6.07 (d, J = 8.8 Hz, 1H), 4.47–4.37 (m, 1H), 2.90–2.80 (m, 3H), 2.68– 2.58 (m, 1H), 2.28 (s, 3H), 2.26 (s, 3H), 2.12–1.99 (m, 2H), 1.34 (d, J = 6.8 Hz, 3H) SYNTHETIC EXAMPLE 8 SYNTHESIS OF 1-(3-FLUORO-1-(3-(3-(TRIFLUOROMETHYL)PHENYL)IMIDAZO[1,2-B]PYRIDAZIN-6- YL)PYRROLIDIN-3-YL)ETHAN-1-OL

63 #11053313.1 Step 1: Synthesis of benzyl 3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidine- 1-carboxylate To a stirred solution of benzyl 3-fluoro-3-(1-hydroxyethyl)pyrrolidine-1-carboxylate (2.0 g, 7.49 mmol, 1 eq) in dichloromethane (20 mL) at 0 °C, added Imidazole (1.01 g, 14.9 mmol, 2.0 eq) and TBS-Cl (1.69 g, 11.2 mmol, 1.5 eq). The reaction mixture was allowed to stir at room temperature for 16 h. After completion of reaction by TLC, diluted with water (80 mL) and extracted with dichloromethane (2 × 50 mL). Combined organic layers were dried over Na2SO4, evaporated and purified by silica gel column chromatography [eluted in 5% to 8% EtOAc in hexane] to afford benzyl 3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidine-1- carboxylate as yellow gummy liquid (2.2 g, yield: 70%). TLC system: EtOAc/Petroleum ether (30:70) R_f value: ~0.80 LCMS Retention time = 4.99 min, 382.2 [M+H]^{+ 1}H NMR (400 MHz, CDCl₃) δ: 7.37–7.30 (m, 5H), 5.14 (s, 2H), 3.96–3.93 (m, 1H), 3.66– 3.51 (m, 4H), 2.09–2.03 (m, 2H), 1.20 (d, J = 6.0 Hz, 3H), 0.91 (s, 9H), 0.08 (s, 6H). TBS reagent impurities observed along with desired product. Step 2: Synthesis of 3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidine To a stirred solution of benzyl 3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3- fluoropyrrolidine-1-carboxylate (2.2 g, 5.75 mmol, 1 eq) in MeOH (22 mL, 10 vol) at room temperature was added 10% palladium on carbon (220 mg) and stirred for 16h under hydrogen balloon atmosphere. After completion of reaction by TLC, reaction mixture was filtered through a pad of diatomaceous earth (e.g., Celite®), washed with MeOH and evaporated to afford 3-(1-((tert- butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidine (1.40 g, 98%) as yellow liquid. TLC system: neat Ethyl acetate (100%) Rf value: ~0.05 (Ninhydrin stain)

64 #11053313.1 ¹H NMR (400 MHz, CDCl₃): 4.00–3.93 (m, 1H), 3.16–3.10 (m, 1H), 3.00–2.88 (m, 3H), 2.03–1.85 (m, 2H), 1.20 (d, J = 6.4 Hz, 3H), 0.88 (s, 9H), 0.08 (s, 6H). TBS reagent impurities observed along with product. Step 3: Synthesis of 6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1-yl)- 3-(3-(trifluoromethyl) phenyl)imidazo[1,2-b]pyridazine To a stirred degassed solution of 3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3- fluoropyrrolidine (1.12 g, 4.54 mmol, 1.5 eq), 6-chloro-3-(3-(trifluoromethyl)phenyl)imidazo[1,2- b]pyridazine (900 mg, 3.03 mmol, 1 eq) and NaO^tBu (720 mg, 7.56 mmol, 2.5 eq) in toluene (9 mL) at room temperature was added Davephos (238 mg, 0.60 mmol, 0.2 eq), Pd2dba3 (277 mg, 0.3 mmol, 0.1 eq). The reaction mixture was degassed with nitrogen for 10 min and heated to 100 °C, stirred for 16 h in a sealed tube. After completion of reaction by TLC, volatiles were removed under vacuum and purified by reverse phase column (Method: Mobile Phase A : 100% Acetonitrile and Mobile Phase B : 0.01% FA in Water, eluent: 70% to 85% ) to afford 6-(3-(1-((tert- butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1-yl)-3-(3- (trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine (280 mg, 19%) as yellow gummy. TLC system: Neat EtOAc (100%) Rf value: ~0.40 LCMS Retention time = 5.67 min, 509.2 [M+H]^{+ 1}H NMR (400 MHz,CDCl3) δ 8.76 (s, 1H), 8.17–8.15 (m, 1H), 7.93 (s, 1H), 7.83 (d, J = 10 Hz, 1H), 7.57–7.55 (m, 2H), 6.67 (d, J = 10 Hz, 1H), 4.11–4.07 (m, 1H), 3.84–3.67 (m, 4H), 2.33–2.26 (m, 2H), 1.30 (d, J = 5.6 Hz, 3H), 0.89 (s, 9H), 0.12 (s, 6H) Step 4: Synthesis of 1-(3-fluoro-1-(3-(3-(trifluoromethyl)phenyl)imidazo[1,2- b]pyridazin-6-yl)pyrrolidin-3-yl)ethan-1-ol

65 #11053313.1 A solution of 6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1-yl)-3-(3- (trifluoromethyl) phenyl)imidazo[1,2-b]pyridazine (280 mg, 0.55 mmol, 1.0 eq.) in THF (5.6 mL, 20 vol) at 0 °C was added TBAF (1M in THF, 0.83 mL, 0.83 mmol, 1.5 eq) and stirred to room temperature for 3 h. After completion of starting material (by TLC), reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (2 × 15 mL). Organic layer dried over anhydrous Na₂SO₄, evaporated and purified by reverse phase column (Method: Mobile Phase A : 100% Acetonitrile and Mobile Phase B : 0.01% FA in Water, eluent: 30%) to afforded 1-(3-fluoro- 1-(3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl)ethan-1-ol (130 mg, 58%) as an off-white solid. TLC system: MeOH/DCM (5:95) Rf value: ~0.10 LCMS Retention time = 3.27 min, 395.2 [M+H]^{+ 1}H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.38 (d, J = 7.6 Hz, 1H), 8.18 (s, 1H), 7.96 (dd, J = 2.4, 10 Hz, 1H), 7.73–7.65 (m, 2H), 6.98 (d, J = 10 Hz, 1H), 5.28–5.22 (m, 1H), 3.92– 3.76 (m, 3H), 3.72–3.58 (m, 2H), 2.33–2.22 (m, 2H), 1.21 (d, J = 6.0 Hz, 3H). SYNTHETIC EXAMPLE 9 SYNTHESIS OF 1-(3-FLUOROPYRROLIDIN-3-YL)ETHAN-1-OL To a stirred solution of benzyl 3-fluoro-3-(1-hydroxyethyl)pyrrolidine-1-carboxylate (500 mg, 1.49 mmol, 1.0 eq) in MeOH (5 mL) at room temperature, was added 10% Pd/C (100 mg, 20% w/w). The reaction mixture was stirred at room temperature for 5 h under H₂ atmosphere. After completion of reaction by TLC, the reaction mixture was filtered through a pad of diatomaceous earth (e.g., Celite®), washed with MeOH (10 mL) and collected filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase column

66 #11053313.1 chromatography [elution with 5% ACN in 0.1% FA in H₂O] to afford 1-(3-fluoropyrrolidin-3- yl)ethan-1-ol as a colorless liquid (170 mg, yield: 68%). TLC system: MeOH/DCM (20:80) Rf value: ~0.2 (ninhydrin stain) 1H NMR (400 MHz, DMSO-d₆) δ: 8.34 (s, 1H; HCOOH), 3.79–3.73 (m, 1H), 3.25–3.19 (m, 1H), 3.14–3.07 (m, 3H), 2.03–1.90 (m, 2H), 1.13–1.10 (m, 3H) SYNTHETIC EXAMPLE 10 SYNTHESIS OF 1-(3-FLUORO-1-(3-(3-(TRIFLUOROMETHYL)PHENYL)IMIDAZO[1,2-B]PYRIDAZIN-6- YL)PYRROLIDIN-3-YL)ETHAN-1-AMINE Step 1: Synthesis of 1-(3-fluoro-1-(3-(3-(trifluoromethyl)phenyl)imidazo[1,2- b]pyridazin-6-yl)pyrrolidin-3-yl)ethyl methanesulfonate To a stirred solution of 1-(3-fluoro-1-(3-(3-(trifluoromethyl)phenyl)imidazo[1,2- b]pyridazin-6-yl)pyrrolidin-3-yl)ethan-1-ol (300 mg, 0.76 mmol, 1.0 eq) in DCM (6 mL) at 0°C, was added Et3N (0.3 mL, 2.28 mmol, 3.0 eq) followed by MsCl (0.3 mL, 1.14 mmol, 1.5 eq) and allowed to stir at room temperature for 2 h. After completion of reaction by TLC, diluted with water (30 mL) and extracted with DCM (2 × 30 mL). Combined organic layer was dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford 1-(3-fluoro-1-(3-(3- (trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl)ethyl methane sulfonate as a yellow gummy mass (350 mg, Crude). TLC system: MeOH/DCM (5:95) R_f value: ~0.4 1HNMR (400 MHz, CDCl3) δ: 8.85 (s, 1H), 8.08–8.06 (m, 1H), 7.95–7.94 (m, 1H), 7.83 (d, J = 10.0 Hz, 1H), 7.58–7.56 (m, 2H), 6.68 (d, J = 10.0 Hz, 1H), 5.06–5.00 (m, 1H), 3.90–3.75

67 #11053313.1 (m, 4H), 3.10 (s, 3H), 2.53–2.50 (m, 1H), 2.39–2.35 (m, 1H), 1.47–1.43 (m, 3H). Impurities observed. Step 2: Synthesis of 6-(3-(1-azidoethyl)-3-fluoropyrrolidin-1-yl)-3-(3- (trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine To a stirred solution of 1-(3-fluoro-1-(3-(3-(trifluoromethyl)phenyl)imidazo[1,2- b]pyridazin-6-yl)pyrrolidin-3-yl)ethyl methanesulfonate (350 mg, 0.74 mmol, 1.0 eq) in DMF (7 mL) at room temperature, was added NaN3 (120 mg, 1.85 mmol, 2.5 eq) and heated at 100°C for 6 h. After completion of reaction by TLC, reaction mixture was quenched with water (15 mL) and extracted with EtOAc (2 × 15 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford 6-(3-(1-azidoethyl)-3-fluoropyrrolidin-1-yl)-3- (3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine as yellow gum (240mg, Yield: 57% over two steps). TLC system: MeOH/DCM (5:95) R_f value: ~0.3 LCMS (m/z): 420.1 (M+H)⁺. Step 3: Synthesis of 1-(3-fluoro-1-(3-(3-(trifluoromethyl)phenyl)imidazo[1,2- b]pyridazin-6-yl)pyrrolidin-3-yl)ethan-1-amine To a stirred solution of 6-(3-(1-azidoethyl)-3-fluoropyrrolidin-1-yl)-3-(3- (trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine (240 mg, 0.57 mmol, 1 eq) in MeOH (5 mL) at room temperature, was added 10% Pd/C (70 mg, 30% w/w) and stirred for 16 h under H2 balloon atmosphere. After completion of reaction by TLC, reaction mixture was filtered through a pad of diatomaceous earth (e.g., Celite®), washed with 10% MeOH in DCM (2 × 10 mL) and

68 #11053313.1 collected filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase column chromatography (Grace) [elution with 20% ACN in 0.1% FA in H2O] to afford desired product with required purity however NMR was not clean. So, purified by Prep- HPLC, collected fractions were frozen and lyophilized to afford 1-(3-fluoro-1-(3-(3- (trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl)ethan-1-amine as off white solid (45 mg, yield: 18%). TLC system: MeOH/DCM (10:90) Rf value: ~0.2 LCMS(m/z): 394.2 (M+H)^{+ 1}H NMR (400 MHz, DMSO-d6) δ: 8.85 (s, 1H), 8.43 (d, J = 7.6 Hz, 1H), 8.18 (s, 1H), 7.99 (d, J = 10 Hz, 1H), 7.74–7.66 (m, 2H), 6.93 (d, J = 9.6 Hz, 1H), 6.25 (br, 2H), 3.85–3.80 (m, 2H), 3.77 (s, 1H), 3.66–3.59 (m, 1H), 3.42–3.36 (m, 1H), 2.43–2.18 (m, 2H), 1.22 (d, J = 6.0 Hz, 3H) SYNTHETIC EXAMPLE 11 SYNTHESIS OF 2-(3-FLUORO-1-(3-(3-(TRIFLUOROMETHYL)PHENYL)IMIDAZO[1,2-B]PYRIDAZIN-6- YL)PYRROLIDIN-3-YL)PROPAN-2-OL TFA SALT Step 1: Synthesis of benzyl 3-acetyl-3-fluoropyrrolidine-1-carboxylate To a stirred solution of benzyl 3-fluoro-3-(1-hydroxyethyl)pyrrolidine-1-carboxylate (680 mg, 2.55 mmol, 1.0 eq) in DCM (14 mL) at 0 °C, was added PCC (1.1 g, 5.09 mmol, 2.0 eq). The reaction mixture was stirred at room temperature for 16 h. After completion of reaction by TLC, filtered through a pad of diatomaceous earth (e.g., Celite®), washed with EtOAc (20 mL) and collected filtrate was concentrated under reduced pressure. Obtained crude product was purified by silica gel (100 - 200 mesh) column chromatography [elution with 10% EtOAc in Hexane] to afford benzyl 3-acetyl-3-fluoropyrrolidine-1-carboxylate as yellow liquid (550 mg, yield: 81%). TLC system: EtOAc/Hexane (30:70)

69 #11053313.1 R_f value: ~0.8 1H NMR (400 MHz, CDCl3) δ: 7.36–7.31 (m, 5H), 5.15–5.13 (m, 2H), 3.84–3.68 (m, 3H), 3.65–3.59 (m, 1H), 2.38–2.35 (m, 4H), 2.26–2.20 (m, 1H) Step 2: Synthesis of benzyl 3-fluoro-3-(2-hydroxypropan-2-yl)pyrrolidine-1-carboxylate To a stirred solution of benzyl 3-acetyl-3-fluoropyrrolidine-1-carboxylate (550 mg, 2.07 mmol, 1 eq) in THF (6 mL) at 0 °C, was added MeMgBr (3.0 M in Et2O) (1.4 mL, 4.15 mmol, 2.0 eq) and stirred at room temperature for 1 h. After completion of reaction by TLC, quenched with NH4Cl solution (50 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layer was dried over anhydrous Na₂SO_4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel (100 - 200 mesh) column chromatography [elution with 30% EtOAc in Hexane] to afford benzyl 3-fluoro-3-(2-hydroxypropan-2-yl)pyrrolidine-1-carboxylate as yellow gum (450 mg, yield: 72%). TLC system: EtOAc/Hexane (30:70) Rf value: ~0.2 1H NMR (400 MHz, CDCl₃) δ:7.37–7.30 (m, 5H), 5.19–5.11 (m, 2H), 3.77–3.53 (m, 4H), 2.23–2.04 (m, 2H), 1.82 (d, J = 5.6 Hz, 1H), 1.32 & 1.31 (2 s, 6H) Step 3: Synthesis of 2-(3-fluoropyrrolidin-3-yl)propan-2-ol To a stirred solution of benzyl 3-fluoro-3-(2-hydroxypropan-2-yl)pyrrolidine-1- carboxylate (420 mg, 1.49 mmol, 1.0 eq) in MeOH (4 mL) at room temperature, was added 10% Pd/C (42 mg, 10% Wt/Wt). The reaction mixture was stirred at room temperature for 2 h under H2 balloon atmosphere. After completion of reaction by TLC, reaction mixture was filtered through a pad of diatomaceous earth (e.g., Celite®), washed with MeOH (10 mL) and collected filtrate was

70 #11053313.1 concentrated under reduced pressure to afford 2-(3-fluoropyrrolidin-3-yl)propan-2-ol as black gummy liquid (220 mg, yield: Crude). TLC system: EtOAc/Hexane (100:00) Rf value: ^~0.1 (ninhydrin stain) 1H NMR (400 MHz, CDCl₃) δ: 3.17–3.04 (m, 2H), 3.00–2.97 (m, 1H), 2.96–2.92 (m, 1H), 2.14–1.89 (m, 2H), 1.30 (s, 6H) Step 4: Synthesis of 2-(3-fluoro-1-(3-(3-(trifluoromethyl)phenyl)imidazo[1,2- b]pyridazin-6-yl)pyrrolidin-3-yl)propan-2-ol (TFA salt) In a sealed tube to a degassed solution of 2-(3-fluoropyrrolidin-3-yl)propan-2-ol (92 mg, 0.5 mmol, 1.0 eq) and 6-chloro-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine (150 mg, 0.5 mmol, 1.0 eq) in Toluene (3 mL) at room temperature, was added NaOtBu (72 mg, 0.75 mmol, 1.5 eq) followed by Davephos (20 mg, 0.05 mmol, 0.1 eq) and Pd₂(dba)₃ (23 mg, 0.02 mmol, 0.05 eq). The reaction mixture was stirred at 100 °C for 16 h. After completion of reaction by TLC, the reaction mixture was filtered through a pad of diatomaceous earth (e.g., Celite®), washed with 10% MeOH in DCM (10 mL) and collected filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase column chromatography [elution with 25% ACN in 0.1% FA in H2O] followed by Prep-HPLC and lyophilized to afford 2-(3-fluoro-1-(3-(3- (trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl)propan-2-ol TFA as off white gummy (29 mg, Yield: 14%).

71 #11053313.1 TLC system: EtOAc/Hexane (70:30) Rf value: ~0.2 LCMS(m/z): 409.2 (M+H)^{+ 1}H NMR (400 MHz, DMSO-d6) δ: 8.90 (s, 1H), 8.41 (s, 1H), 8.37–8.35 (m, 1H), 8.09 (d, J = 10 Hz, 1H), 7.76–7.74 (m, 2H), 7.23 (d, J = 10 Hz, 1H), 5.13 (brs, 1H), 3.99–3.85 (m, 2H), 3.72–3.59 (m, 2H), 2.43–2.38 (m, 1H), 2.22–2.13 (m, 1H), 1.27 & 1.26 (2 s, 6H) Note: While purifying the final material, the compound below was isolated and characterized as a reaction byproduct. TLC system: EtOAc/Hexane (70:30) R_f value: ^~0.2 LCMS(m/z): 389.2 (M+H)^{+ 1}H NMR (400 MHz, CDCl₃) δ: 8.86 (s, 1H), 8.09–8.07 (m, 1H), 7.94 (s, 1H), 7.81 (d, J = 9.6 Hz, 1H), 7.56–7.54 (m, 2H), 6.70 (d, J = 10 Hz, 1H), 3.92 (d, J = 12.8 Hz, 1H), 3.82–3.78 (m, 2H), 3.51 (d, J = 12.4 Hz, 1H), 2.52–2.44 (m, 1H), 2.11–2.03 (m, 1H), 1.43 & 1.42 (2 s, 6H) SYNTHETIC EXAMPLE 12 SYNTHESIS OF 2-(3-FLUOROPYRROLIDIN-3-YL)PROPAN-2-OL HCL SALT Step 1: Synthesis of tert-butyl 3-acetyl-3-fluoropyrrolidine-1-carboxylate To a stirred solution of tert-butyl 3-fluoro-3-(1-hydroxyethyl)pyrrolidine-1-carboxylate (500 mg, 2.14 mmol, 1.0 eq) in DCM (20 mL) at 0 °C, was added PCC (555 mg, 2.57 mmol, 1.2 eq) and stirred at room temperature for 16 h. After completion of reaction by TLC, the reaction

72 #11053313.1 mixture was filtered through a pad of diatomaceous earth (e.g., Celite®), washed with DCM (30 mL) and collected filtrate was concentrated under reduced pressure to afford crude product. The crude product was purified by silica gel column (100 - 200) chromatography [elution with 15% EtOAc in Hexane] to afford tert-butyl 3-acetyl-3-fluoropyrrolidine-1-carboxylate as colorless gummy mass (250 mg, yield: 51%). TLC system: EtOAc/Hexane (30:70; ninhydrin stain) R_f value: ~0.4 1HNMR (400 MHz, CDCl3) δ: 3.76–3.63 (m, 3H), 3.54–3.50 (m, 1H), 2.36 (d, J = 4.8 Hz, 3H), 2.26–2.13 (m, 2H), 1.46 (s, 9H). Step 2: Synthesis of tert-butyl 3-fluoro-3-(2-hydroxypropan-2-yl)pyrrolidine-1- carboxylate To a stirred solution of tert-butyl 3-acetyl-3-fluoropyrrolidine-1-carboxylate (250 mg, 1.08 mmol, 1.0 eq) in THF (2.5 mL) at 0 °C, was added MeMgBr (1.0 M in THF) (1.3 mL, 1.29 mmol, 1.2 eq) and allowed to stir at room temperature for 1 h. After completion of reaction by TLC, the reaction mixture was quenched with NH₄Cl solution (10 mL) and extracted with EtOAc (2 × 10 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column (60 - 120) chromatography [elution with 20% EtOAc in Hexane] to afford tert-butyl 3-fluoro-3-(2-hydroxypropan-2- yl)pyrrolidine-1-carboxylate as a yellow gum (170 mg, Yield: 63%). TLC system: EtOAc/Hexane (50:50) R_f value: ~0.5 1H NMR (400 MHz, CDCl3): 3.67–3.46 (m, 4H), 2.09–2.05 (m, 1H), 1.86–1.83 (m, 1H), 1.47 (s, 9H), 1.31 (s, 6H). Step 3: Synthesis of 2-(3-fluoropyrrolidin-3-yl)propan-2-ol (HCl salt)

73 #11053313.1 To a stirred solution of tert-butyl 3-fluoro-3-(2-hydroxypropan-2-yl)pyrrolidine-1- carboxylate (170 mg, 0.69 mmol, 1.0 eq) in 1,4-dioxane (1.7 mL) at 0°C, was added 4 M HCl in 1,4-dioxane (0.86 mL, 3.45 mmol, 5 eq) and stirred at room temperature for 3 h. After completion of reaction by TLC, volatiles removed under vacuum, triturated with diethyl ether (30 mL), decanted, dried and lyophilized to afford 2-(3-fluoropyrrolidin-3-yl)propan-2-ol HCl as brown solid (110 mg, Yield: 92%). TLC system: MeOH/DCM (10:90) Rf value: ~0.1 1H NMR (400 MHz, DMSO-d₆): 9.50 (s, 2H), 5.25 (s, 1H), 3.54–3.42 (m, 1H), 3.39–3.36 (m, 1H), 3.29–3.23 (m, 2H), 2.37–2.19 (m, 1H), 2.11–2.02 (m, 1H), 1.19 (d, J = 3.6 Hz, 6H). SYNTHETIC EXAMPLE 13 SYNTHESIS OF 3-(2-FLUOROPROPAN-2-YL)-1-(3-(3-(TRIFLUOROMETHYL)PHENYL)IMIDAZO[1,2- B]PYRIDAZIN-6-YL)PYRROLIDIN-3-OL To a stirred solution of 2,2-dimethyl-5-(3-(3-(trifluoromethyl)phenyl)imidazo[1,2- b]pyridazin-6-yl)-1-oxa-5-azaspiro[2.4]heptane (100 mg, 0.28 mmol, 1.0 eq) in DCM (1 mL) at - 40° C, was added HF-Pyridine (0.1 mL, 1.0 vol) and stirred for 30 min. After that reaction mixture was cooled to 0°C and stirred for 30 min. After completion of reaction by TLC quenched with NaHCO₃ solution (10 mL) and extracted with DCM (2 × 5 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was

74 #11053313.1 purified by reverse phase column chromatography [elution with 28 - 30% ACN in 0.1% FA in H2O] to afford desired product. Obtained material was triturated with n-Pentane (10 mL), decanted, dried and lyophilized to afford 3-(2-fluoropropan-2-yl)-1-(3-(3- (trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-ol as off white solid (50 mg, Yield: 40%). TLC system: MeOH/DCM (15:85) R_f value: ~0.20 LCMS (m/z): 409.2 [M+H]^{+ 1}H NMR (400 MHz, DMSO-d₆): 9.05 (s, 1H), 8.34 (d, J = 7.6 Hz, 1H), 8.17 (s, 1H), 7.94 (d, J = 10 Hz, 1H), 7.72–7.64 (m, 2H), 6.98 (d, J = 10 Hz, 1H), 5.33 (s, 1H), 3.78–3.73 (m, 1H), 3.68–3.61 (m, 2H), 3.53–3.50 (m, 1H), 2.24–2.16 (m, 1H), 1.97–1.92 (m, 1H), 1.45 (d, J = 8.8 Hz, 3H), 1.40 (d, J = 9.2 Hz, 3H). SYNTHETIC EXAMPLE 14 SYNTHESIS OF 2-(3-FLUORO-1-(7-METHYL-3-(3-(TRIFLUOROMETHYL)PHENYL)IMIDAZO[1,2- B]PYRIDAZIN-6-YL)PYRROLIDIN-3-YL)PROPAN-2-OL In a sealed tube to a degassed solution of 6-chloro-7-methyl-3-(3- (trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine (200 mg, 0.64 mmol, 1.0 eq) and 2-(3- fluoropyrrolidin-3-yl)propan-2-ol (180 mg, 0.80 mmol, 1.25 eq) in toluene (4 mL) at room

75 #11053313.1 temperature, was added NaOtBu (154 mg, 1.60 mmol, 2.5 eq) followed by rac-BINAP (60 mg, 0.096 mmol, 0.15 eq) and Pd2(dba)3 (29.4 mg, 0.032 mmol, 0.05 eq). The reaction mixture was stirred at 100 °C for 16 h. After completion of reaction by TLC, the reaction mixture was filtered through a pad of diatomaceous earth (e.g., Celite®), washed with 5% MeOH in DCM (10 mL) and collected filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC, collected fractions were frozen and lyophilized to afford 2-(3-fluoro-1-(7-methyl-3- (3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl)propan-2-ol as off white solid (60 mg, Yield: 22%). TLC system: EtOAc/Hexane (100:00) Rf value: ~0.2 LCMS (m/z): 423.3 [M+H]^{+ 1}H NMR (400 MHz, DMSO-d6): 8.83 (s, 1H), 8.34 (d, J = 7.6 Hz, 1H), 8.15 (s, 1H), 7.82 (s, 1H), 7.71–7.64 (m, 2H), 5.04 (s, 1H), 4.17–4.05 (m, 1H), 3.89–3.83 (m, 1H), 3.76–3.71 (m, 1H), 3.63–3.54 (m, 1H), 2.45 (s, 3H), 2.42–2.32 (m, 1H), 2.12–2.06 (m, 1H), 1.25 (s, 6H). SYNTHETIC EXAMPLE 15 SYNTHESIS OF 1-(3-FLUORO-1-(3-(3-(TRIFLUOROMETHOXY)PHENYL)IMIDAZO[1,2-B]PYRIDAZIN-6- YL)PYRROLIDIN-3-YL)ETHAN-1-OL In a sealed tube to a degassed solution of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (2.0 g, 8.62 mmol, 1.0 eq) and 4,4,5,5-tetramethyl-2-(3-(trifluoromethoxy)phenyl)-1,3,2- dioxaborolane (2.4 g, 12.9 mmol, 1.5 eq) in 1,4-dioxane:water (4:1, 40 mL) at room temperature, was added K₂CO₃ (2.9 g, 21.5 mmol, 2.5 eq) followed by Pd(dppf)Cl₂DCM (703 mg, 0.86 mmol,

76 #11053313.1 0.1 eq) and stirred at 100°C for 16 h. After completion of reaction by TLC, the reaction mixture was filtered through a pad of diatomaceous earth (e.g., Celite®), washed with EtOAc (50 mL) and collected filtrate was concentrated under reduced pressure to afford crude product. The Crude product was purified by silica gel (100 - 200) column chromatography [elution with 20% EtOAc in DCM] to afford 6-chloro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine as yellow solid (1.5 g, Yield: 56%). TLC system: EtOAc/DCM (50:50) Rf value: ~0.3 1H NMR (400 MHz, CDCl₃) δ: 8.10 (s, 1H), 8.00–7.97 (m, 3H), 7.54 (t, J = 8.0 Hz, 1H), 7.25 (brs, 1H), 7.14 (d, J = 9.6 Hz, 1H). Step 2: Synthesis of 6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1-yl)- 3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine (trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine (500 mg, 1.59 mmol, 1.0 eq) and 3-(1-((tert- butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidine (580 mg, 2.38 mmol, 1.5 eq) in Toluene (10 mL) at room temperature, was added NaOtBu (380 mg, 3.99 mmol, 2.5 eq) followed by rac-BINAP (198 mg, 0.32 mmol, 0.2 eq) and Pd2(dba)3 (146 mg, 0.16 mmol, 0.1 eq). The reaction mixture was stirred at 100°C for 16 h. After completion of reaction by TLC, the reaction mixture was filtered through a pad of diatomaceous earth (e.g., Celite®), washed with 10% MeOH in DCM (20 mL) and collected filtrate was concentrated under reduced pressure to afford crude product. The Crude product was purified by silica gel (100 - 200) column chromatography [elution with 30% EtOAc in DCM] to afford 6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1-yl)-3- (3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine as brown gummy liquid (250 mg, Yield: 27%). TLC system: EtOAc/DCM (70:30) R_f value: ~0.3

77 #11053313.1 LCMS(m/z): 525.3 (M+H)⁺ Step 3: Synthesis of 1-(3-fluoro-1-(3-(3-(trifluoromethoxy)phenyl)imidazo[1,2- b]pyridazin-6-yl)pyrrolidin-3-yl)ethan-1-ol To a stirred solution of 6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1- yl)-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine (270 mg, 0.51 mmol, 1.0 eq) in THF (5.4 mL, 20 Vol) at 0°C, was added TBAF (1.0 M in THF) (1.0 mL, 1.03 mmol, 2 eq) and reaction mixture was stirred at room temperature for 3 h. After completion of reaction by TLC, the reaction mixture was quenched with NH₄Cl solution (10 mL) and extracted with EtOAc (2 × 20 mL). The combined organic layer was concentrated under reduced pressure and purified by reverse phase column chromatography [elution with 30 - 40% ACN in 0.1% FA in H₂O] to afford 1-(3-fluoro- 1-(3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl)ethan-1-ol as off white solid (65 mg, Yield: 38%). TLC system: MeOH/DCM (10:90) R_f value: ~0.3 LCMS(m/z): 411.43 (M+H)^{+ 1}H NMR (400 MHz, DMSO-d₆) δ: 8.49 (s, 1H), 8.13–8.11 (m, 2H), 7.97–7.94 (m, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.31–7.28 (m, 1H), 6.96 (d, J = 9.6 Hz, 1H), 5.26–5.23 (m, 1H), 3.92– 3.76 (m, 3H), 3.70–3.67 (m, 1H), 3.61–3.57 (m, 1H), 2.33–2.22 (m, 2H), 1.22–1.20 (m, 3H). SYNTHETIC EXAMPLE 16 SYNTHESIS OF 3-(6-(3-FLUORO-3-(1-HYDROXYETHYL)PYRROLIDIN-1-YL)IMIDAZO[1,2- B]PYRIDAZIN-3-YL)BENZONITRILE Step 1: Synthesis of 3-bromo-6-chloroimidazo[1,2-b]pyridazine

78 #11053313.1 To a stirred solution of 6-chloroimidazo[1,2-b]pyridazine (10 g, 65.1 mmol, 1.0 eq) in DCM (200 mL) at 0°C, was added NBS (17.4 g, 97.7 mmol, 1.2 eq) and stirred at room temperature for 16 h. After completion of reaction by TLC, reaction mixture was diluted with cold water (100 mL) and extracted with DCM (2 × 100 mL). Organic layer was washed with hypo solution (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude product. The crude product was triturated with n-pentane (2 × 50 mL), decanted and dried under vacuum to afford 3-bromo-6-chloroimidazo[1,2-b]pyridazine as yellow solid (11.8 g, Yield: 79%). TLC system: EtOAc/Hexane (40:60) Rf value: ~0.4 LCMS(m/z): 231.9 (M+H)⁺. Step 2: Synthesis of 3-(6-chloroimidazo[1,2-b]pyridazin-3-yl)benzonitrile In a sealed tube to a degassed solution of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (2.5 g, 10.7 mmol, 1.0 eq) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (3.79 g, 16.2 mmol, 1.5 eq) in 1,4-dioxane:water (4:1, 20 mL) at room temperature, was added K₂CO₃ (3.79 g, 26.9 mmol, 2.5 eq), Pd(PPh3)4 (622 mg, 0.54 mmol, 0.05 eq) and stirred at 100°C for 16 h. After completion of reaction by TLC, reaction mixture was filtered through a pad of diatomaceous earth (e.g., Celite®), washed with 10% MeOH in DCM (30 mL) and collected filtrate was concentrated. Obtained residue was diluted with water and extracted with EtOAc.

79 #11053313.1 Organic layer was dried over Na2SO4 and evaporated. Crude product was purified by reverse phase column chromatography [elution with 30 - 40% ACN in 0.1% FA in H2O] to afford 3-(6- chloroimidazo[1,2-b]pyridazin-3-yl)benzonitrile as yellow solid (900 mg, Yield: 33%). TLC system: EtOAc/Petroleum ether (100:00) R_f value: ~0.3 LCMS(m/z): 255.18 (M+H)⁺ Step 3: Synthesis of 3-(6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1- yl)imidazo[1,2-b]pyridazin-3-yl)benzonitrile In a sealed tube to a degassed solution of 3-(6-chloroimidazo[1,2-b]pyridazin-3- yl)benzonitrile (350 mg, 1.37 mmol, 1.0 eq) and 3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3- fluoropyrrolidine (510 mg, 2.06 mmol, 1.5 eq) in toluene (7 mL) at room temperature, was added NaOtBu (264 mg, 2.75 mmol, 2.0 eq) followed by rac-BINAP (171 mg, 0.27 mmol, 0.2 eq) and Pd₂(dba)₃ (88 mg, 0.14 mmol, 0.07 eq). The reaction mixture was stirred at 100°C for 16 h. After completion of reaction by TLC, reaction mixture was filtered through a pad of diatomaceous earth (e.g., Celite®), washed with 10% MeOH in DCM (10 mL) and collected filtrate was concentrated under reduced pressure to afford crude product. The Crude product was purified by silica gel (100 - 200) column chromatography [elution with 30 - 40% EtOAc in DCM] to afford 3-(6-(3-(1-((tert- butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)benzonitrile as brown gummy liquid (260 mg, Yield: 40%). TLC system: EtOAc/DCM (70:30) R_f value: ~0.3 LCMS(m/z): 466.43 (M+H)⁺. Step 4: Synthesis of 3-(6-(3-fluoro-3-(1-hydroxyethyl)pyrrolidin-1-yl)imidazo[1,2- b]pyridazin-3-yl)benzonitrile

80 #11053313.1 To a stirred solution of 3-(6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin- 1-yl)imidazo[1,2-b]pyridazin-3-yl)benzonitrile (260 mg, 0.56 mmol, 1.0 eq) in THF (5.0 mL) at 0°C, was added TBAF (1.0 M in THF) (1.1 mL, 1.18 mmol, 2 eq) and stirred at room temperature for 3 h. After completion of reaction by TLC, reaction mixture was quenched with NH₄Cl solution (10 mL) and extracted with EtOAc (2 × 10 mL). The combined organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by reverse phase column chromatography [elution with 20 - 30% ACN in 0.1% FA in H2O] to afford 3-(6-(3-fluoro-3-(1-hydroxyethyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)benzonitrile as white solid (100 mg, Yield: 51%). TLC system: MeOH/DCM (10:90) Rf value: ~0.3 LCMS(m/z): 352.42 (M+H)^{+ 1}H NMR (400 MHz, DMSO-d6) δ: 8.75–8.73 (m, 1H), 8.56–8.54 (m, 1H), 8.16 (s, 1H), 7.97–7.94 (m, 1H), 7.77–7.75 (m, 1H), 7.68 (t, J = 8.0 Hz, 1H), 6.97 (d, J = 9.6 Hz, 1H), 5.28– 5.23 (m, 1H), 3.93–3.78 (m, 3H), 3.72–3.65 (m, 1H), 3.63–3.58 (m, 1H), 2.33–2.22 (m, 2H), 1.23 (d, J = 6.4 Hz, 3H).27 mg was submitted for shipment 60 mg of was separated by Chiral HPLC. The collected fractions were evaporated and lyophilized to afford 3-(6-(3-fluoro-3-(1-hydroxyethyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin- 3-yl)benzonitrile (peak 1)as an off white solid (25.7 mg) and (peak 2) as a light brown solid (25.0 mg). Peak 1: LCMS(m/z): 352.3 (M+H)^{+ 1}H NMR (400 MHz, DMSO-d6) δ: 8.70 (s, 1H), 8.54 (d, J = 8.0 Hz, 1H), 8.41 (s, 1H), 8.11 (d, J = 10 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.75 (t, J = 8.0 Hz, 1H), 7.23 (d, J = 10 Hz, 1H), 3.95– 3.84 (m, 2H), 3.75–3.60 (m, 3H), 2.33–2.22 (m, 2H), 1.21 (d, J = 6.4 Hz, 3H). Peak 2: LCMS(m/z): 352.1 (M+H)⁺

81 #11053313.1 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.71 (s, 1H), 8.55 (d, J = 8.0 Hz, 1H), 8.38 (bs, 1H), 8.09 (d, J = 9.6 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.74 (t, J = 8.0 Hz, 1H), 7.20 (d, J = 9.6 Hz, 1H), 3.93–3.56 (br m, 5H), 2.33–2.23 (m, 2H), 1.21 (d, J = 6.4 Hz, 3H). SYNTHETIC EXAMPLE 17 SYNTHESIS OF 1-(1-(3-(3-(DIFLUOROMETHOXY)PHENYL)IMIDAZO[1,2-B]PYRIDAZIN-6-YL)-3- FLUOROPYRROLIDIN-3-YL)ETHAN-1-OL Step 1: Synthesis of 2-(3-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane In a sealed tube to a degassed solution of 1-bromo-3-(difluoromethoxy)benzene (2 g, 8.97 mmol, 1.0 eq) and B2(Pin)2 (2.7 g, 10.7 mmol, 1.2 eq) in DMF (40 mL) at room temperature, was added KOAc (2.6 g, 26.9 mmol, 3.0 eq) followed by Pd(dppf)Cl₂DCM (365 mg, 0.45 mmol, 0.05 eq) and stirred at 90°C for 16 h. After completion of reaction by TLC, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford 2-(3- (difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as brown gummy liquid (2.2 g, Crude). TLC system: EtOAc/Hexane (20:80) Rf value: ~0.6 Crude was used in next step. Step 2: Synthesis of 6-chloro-3-(3-(difluoromethoxy)phenyl)imidazo[1,2-b]pyridazine

82 #11053313.1 In a sealed tube to a degassed solution of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (800 mg, 2.96 mmol, 1.0 eq) and 2-(3-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (618 mg, 2.66 mmol, 0.9 eq) in 1,4-dioxane:water (4:1, 16 mL) at room temperature, was added K₂CO₃ (817 mg, 5.92 mmol, 2.0 eq) followed by Pd(dppf)Cl₂DCM (120 mg, 0.15 mmol, 0.05 eq) and stirred at 100°C for 16 h. After completion of reaction by TLC, reaction mixture was filtered through a pad of diatomaceous earth (e.g., Celite®), washed with 10% MeOH in DCM (20 mL) and collected filtrate was concentrated. Obtained residue was diluted with water and extracted with EtOAc. Organic layer was dried over Na2SO4 and evaporated. Crude product was purified by silica gel (100 - 200) column chromatography [elution with 30 - 40% EtOAc in Hexane] to afford 6-chloro-3-(3-(difluoromethoxy)phenyl)imidazo[1,2- b]pyridazine as off white solid (450 mg, Yield: 52%). TLC system: EtOAc/Hexane (50:50) Rf value: ~0.4 LCMS (m/z): 296.1 [M+H]⁺. Step 3: Synthesis of 6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1-yl)- 3-(3-(difluoromethoxy)phenyl)imidazo[1,2-b]pyridazine In a sealed tube to a degassed solution of 6-chloro-3-(3- (difluoromethoxy)phenyl)imidazo[1,2-b]pyridazine (400 mg, 1.35 mmol, 1.0 eq) and 3-(1-((tert- butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidine (502 mg, 2.03 mmol, 1.5 eq) in Toluene (8 mL) at room temperature, was added NaOtBu (325 mg, 3.38 mmol, 2.5 eq) followed by rac-BINAP

83 #11053313.1 (168 mg, 0.27 mmol, 0.2 eq) and Pd₂(dba)₃ (124 mg, 0.13 mmol, 0.1 eq). The reaction mixture was stirred at 100°C for 16 h. After completion of reaction by TLC, the reaction mixture was filtered through a pad of diatomaceous earth (e.g., Celite®), washed with 10% MeOH in DCM (10 mL) and collected filtrate was concentrated under reduced pressure. The Crude product was purified by silica gel (100 - 200) column chromatography [elution with 60 - 70% EtOAc in Hexane] to afford 6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1-yl)-3-(3- (difluoromethoxy)phenyl)imidazo[1,2-b]pyridazine as yellow gummy liquid (230 mg, Yield: 33%). TLC system: EtOAc/Hexane (70:30) Rf value: ~0.3 LCMS(m/z): 507.3 (M+H)⁺. Step 4: Synthesis of 1-(1-(3-(3-(difluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-yl)- 3-fluoropyrrolidin-3-yl)ethan-1-ol To a stirred solution of 6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1- yl)-3-(3-(difluoromethoxy)phenyl)imidazo[1,2-b]pyridazine (230 mg, 0.45 mmol, 1.0 eq) in THF (4.6 mL) at 0°C, was added TBAF (1.0 M in THF) (0.9 mL, 0.90 mmol, 2.0 eq) and stirred at room temperature for 2 h. After completion of reaction by TLC, the reaction mixture was quenched with NH₄Cl solution (5 mL), diluted with water (5 mL) and extracted with EtOAc (2 × 10 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The Crude product was purified by reverse phase column chromatography [elution with 30 - 35%

84 #11053313.1 ACN in 0.1% FA in H₂O] to afford 1-(1-(3-(3-(difluoromethoxy)phenyl)imidazo[1,2-b]pyridazin- 6-yl)-3-fluoropyrrolidin-3-yl)ethan-1-ol as white solid (45 mg, Yield: 25%). TLC system: MeOH/DCM (10:90) Rf value: ~0.3 LCMS(m/z): 393.2 (M+H)^{+ 1}H NMR (400 MHz, DMSO-d6) δ: 8.28–8.25 (m, 1H), 8.08 (s, 1H), 8.02–7.98 (m, 1H), 7.95–7.92 (m, 1H), 7.54–7.10 (m, 3H), 6.95 (d, J = 10 Hz, 1H), 5.23 (brs, 1H), 3.91–3.58 (m, 5H), 2.35–2.19 (m, 2H), 1.21 (d, J = 6.4 Hz, 3H) SYNTHETIC EXAMPLE 18 SYNTHESIS OF 1-(3-FLUORO-1-(7-METHYL-3-(3-(TRIFLUOROMETHOXY)PHENYL)IMIDAZO[1,2- B]PYRIDAZIN-6-YL)PYRROLIDIN-3-YL)ETHAN-1-OL Step 1: Synthesis of 6-chloro-7-methyl-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2- b]pyridazine In a sealed tube to a degassed solution of 3-bromo-6-chloro-7-methylimidazo[1,2- b]pyridazine (900 mg, 3.67 mmol, 1.0 eq) and 4,4,5,5-tetramethyl-2-(3- (trifluoromethoxy)phenyl)-1,3,2-dioxaborolane (1 g, 3.67 mmol, 1.0 eq) in 1,4-dioxane:water (4:1, 20 mL) at room temperature, was added K2CO3 (1.2 g, 9.18 mmol, 2.5 eq) followed by Pd(dppf)Cl₂DCM (299 mg, 0.36 mmol, 0.1 eq) and stirred at 100°C for 16 h. After completion of reaction by TLC, reaction mixture was filtered through a pad of diatomaceous earth (e.g., Celite®), washed with 10% MeOH in DCM (30 mL) and collected filtrate was concentrated under reduced pressure to afford crude product. The Crude product was purified by silica gel (100 - 200) column

85 #11053313.1 chromatography [elution with 10 - 20% EtOAc in DCM] to afford 6-chloro-7-methyl-3-(3- (trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine as yellow solid (800 mg, Yield: 70%). TLC system: EtOAC/DCM (20:80) Rf value: ~0.4 1H NMR (400 MHz, CDCl₃) δ: 8.03 (s, 1H), 7.98–7.96 (m, 2H), 7.85 (brs, 1H), 7.56–7.52 (m,1H), 7.24–7.22 (m, 1H), 2.50 (s, 3H). Step 2: Synthesis of 6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1-yl)- 7-methyl-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine In a sealed tube to a degassed solution of 6-chloro-7-methyl-3-(3- (trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine (400 mg, 1.22 mmol, 1.0 eq) and 3-(1-((tert- butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidine (453 mg, 1.83 mmol, 1.5 eq) in Toluene (8 mL) at room temperature, was added NaOtBu (293 mg, 3.06 mmol, 2.5 eq) followed by rac-BINAP (152 mg, 0.24 mmol, 0.2 eq) and Pd2(dba)3 (112 mg, 0.12 mmol, 0.1 eq). The reaction mixture was stirred at 100°C for 16 h. After completion of reaction by TLC, the reaction mixture was filtered through a pad of diatomaceous earth (e.g., Celite®), washed with 10% MeOH in DCM (10 mL) and collected filtrate was concentrated under reduced pressure to afford crude product. The Crude product was purified by silica gel (100 - 200) column chromatography [elution with 0 - 20% EtOAc in DCM] to afford 6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1-yl)-7- methyl-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine as yellow gummy liquid (240 mg, Yield: 98%). TLC system: MeOH/DCM (10:90) R_f value: ~0.4 LCMS(m/z): 539.4 (M+H)⁺. Step 3: Synthesis of 1-(3-fluoro-1-(7-methyl-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2- b]pyridazin-6-yl)pyrrolidin-3-yl)ethan-1-ol

86 #11053313.1 To a stirred solution of 6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1- yl)-7-methyl-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine (240 mg, 0.45 mmol, 1.0 eq) in THF (4.8 mL) at 0°C, was added TBAF (1.0 M in THF) (0.9 mL, 0.89 mmol, 2.0 eq) and stirred at room temperature for 2 h. After completion of reaction by TLC, the reaction mixture was quenched with NH₄Cl solution (5 mL) and extracted with EtOAc (2 × 20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude product. The Crude product was purified by reverse phase column chromatography [elution with 30 - 40% ACN in 0.1% FA in H2O] to afford 1-(3-fluoro-1-(7-methyl-3-(3- (trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl)ethan-1-ol as off white solid (72 mg, Yield: 40%). TLC system: MeOH/DCM (10:90) Rf value: ~0.3 LCMS(m/z): 425.2 (M+H)^{+ 1}H NMR (400 MHz, DMSO-d6) δ: 8.40–8.38 (m, 1H), 8.13–8.09 (m, 2H), 7.82 (s, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 5.20 (brs, 1H), 3.99–3.81 (m, 3H), 3.73–3.69 (m, 1H), 3.62–3.53 (m, 1H), 2.46 (s, 3H), 2.25–2.14 (m, 2H), 1.20 (d, J = 6.4 Hz, 3H).

87 #11053313.1 SYNTHETIC EXAMPLE 19 SYNTHESIS OF 3-(6-(3-FLUORO-3-(1-HYDROXYETHYL)PYRROLIDIN-1-YL)IMIDAZO[1,2- B]PYRIDAZIN-3-YL)BENZONITRILE Step 1: Synthesis of 3-(6-chloro-7-methylimidazo[1,2-b]pyridazin-3-yl)benzonitrile In a sealed tube to a degassed solution of 3-bromo-6-chloro-7-methylimidazo[1,2- b]pyridazine (1.5 g, 6.12 mmol, 1.0 eq) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzonitrile (2.1 g, 9.18 mmol, 1.5 eq) in 1,4-dioxane:water (4:1, 30 mL) at room temperature, was added K2CO3 (2.1 g, 15.3 mmol, 2.5 eq) followed by Pd(PPh3)4 (353 mg, 0.31 mmol, 0.05 eq) and stirred at 100°C for 16 h. After completion of reaction by TLC, the reaction mixture was filtered through a pad of diatomaceous earth (e.g., Celite®), washed with 10% MeOH in DCM (20 mL) and collected filtrate was concentrated. Obtained residue was diluted with water and extracted with EtOAc. Organic layer was dried over Na2SO4 and evaporated. Crude product was purified by silica gel (100 - 200) column chromatography [elution with 40 - 50% EtOAc in DCM] to afford 3-(6-chloro-7-methylimidazo[1,2-b]pyridazin-3-yl)benzonitrile as yellow solid (1.2 g, Yield: 73%). TLC system: EtOAc/DCM (50:50) R_f value: ~0.4 1H NMR (400 MHz, CDCl3) δ: 8.44 (s, 1H), 8.31–8.28 (m, 1H), 8.09 (s, 1H), 7.90 (s, 1H), 7.73–7.59 (m, 2H), 2.55 (s, 3H). Step 2: Synthesis of 3-(6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1- yl)-7-methylimidazo[1,2-b]pyridazin-3-yl)benzonitrile

88 #11053313.1 In a sealed tube to a degassed solution of 3-(6-chloro-7-methylimidazo[1,2-b]pyridazin-3- yl)benzonitrile (400 mg, 1.49 mmol, 1.0 eq) and 3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3- fluoropyrrolidine (552 mg, 2.24 mmol, 1.5 eq) in Toluene (8 mL) at room temperature, was added NaOtBu (429 mg, 4.47 mmol, 3 eq) followed by rac-BINAP (232 mg, 0.37 mmol, 0.25 eq) and Pd2(dba)3 (137 mg, 0.15 mmol, 0.1 eq). The reaction mixture was stirred at 100°C for 16 h. After completion of reaction by TLC, reaction mixture was filtered through a pad of diatomaceous earth (e.g., Celite®), washed with 10% MeOH in DCM (20 mL) and collected filtrate was concentrated under reduced pressure to afford crude product. The Crude product was purified by silica gel (100 - 200) column chromatography [elution with 20 - 30% EtOAc in DCM] to afford 3-(6-(3-(1-((tert- butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1-yl)-7-methylimidazo[1,2-b]pyridazin-3- yl)benzonitrile as yellow gummy liquid (230 mg, Yield: 28.6%). TLC system: EtOAC/DCM (50:50) Rf value: ~0.3 LCMS(m/z): 480.3 (M+H)⁺. Step 3: Synthesis of 3-(6-(3-fluoro-3-(1-hydroxyethyl)pyrrolidin-1-yl)imidazo[1,2- b]pyridazin-3-yl)benzonitrile

89 #11053313.1

To a stirred solution of 3-(6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin- 1-yl)-7-methylimidazo[1,2-b]pyridazin-3-yl)benzonitrile (230 mg, 0.48 mmol, 1.0 eq) in THF (4.6 mL) at 0°C, was added TBAF (1.0 M in THF) (0.96 mL, 0.96 mmol, 2 eq) and stirred at room temperature for 2 h. After completion of reaction by TLC, reaction mixture was quenched with NH4Cl solution (30 mL) and extracted with EtOAc (2 × 20 mL). The combined organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Crude product was purified by reverse phase column chromatography (Biotage) [elution with 30 - 40% ACN in 0.1% FA in H₂O] to afford 3-(6-(3-fluoro-3-(1-hydroxyethyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3- yl)benzonitrile as off white solid (45 mg, Yield: 26%). TLC system: MeOH/DCM (10:90) Rf value: ~0.3 LCMS(m/z): 366.2 (M+H)^{+ 1}H NMR (400 MHz, DMSO-d6) δ: 8.71–8.68 (m, 1H), 8.53–8.49 (m, 1H), 8.14 (s, 1H), 7.82 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.67 (t, J = 8.0 Hz, 1H), 5.20 (d, J = 6.0 Hz, 1H), 4.03–3.82 (m, 3H), 3.76–3.71 (m, 1H), 3.66–3.55 (m, 1H), 2.47 (s, 3H), 2.25–2.21 (m, 1H), 2.17–2.13 (m, 1H), 1.21 (d, J = 6.0 Hz, 3H).

90 #11053313.1 SYNTHETIC EXAMPLE 20 SYNTHESIS OF 1-(1-(3-(3-(DIFLUOROMETHOXY)PHENYL)-7-METHYLIMIDAZO[1,2-B]PYRIDAZIN-6- YL)-3-FLUOROPYRROLIDIN-3-YL)ETHAN-1-OL TFA SALT Step 1: Synthesis of 6-chloro-3-(3-(difluoromethoxy)phenyl)-7-methylimidazo[1,2- b]pyridazine In a sealed tube to a degassed solution of 3-bromo-6-chloro-7-methylimidazo[1,2- b]pyridazine (571 mg, 2.33 mmol, 1 eq) and 2-(3-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (566 mg, 2.10 mmol, 0.9 eq) in 1,4-dioxane:water (4:1, 14 mL) at room temperature, was added K₂CO₃ (715 mg, 5.18 mmol, 2.0 eq) followed by Pd(dppf)Cl₂DCM (106 mg, 0.13 mmol, 0.05 eq) and stirred at 100°C for 16 h. After completion of reaction by TLC, reaction mixture was filtered through a pad of diatomaceous earth (e.g., Celite®), washed with EtOAc (30 mL). Organic layer was washed with water, dried over Na2SO4, and concentrated under reduced pressure to afford crude product. Crude product was purified by silica gel (100 – 200 mesh) column chromatography [elution with 40% EtOAc in Hexane] to afford 6-chloro-3-(3- (difluoromethoxy)phenyl)-7-methylimidazo[1,2-b]pyridazine as yellow gummy solid (450 mg, Yield: 62%). TLC system: EtOAc/Hexane (50:50) Rf value: ~0.4 LCMS(m/z): 310.32 (M+H)^{+ 1}H NMR (400 MHz, CDCl3) δ: 8.01 (s, 1H), 7.88–7.85 (m, 2H), 7.49 (t, J = 8.0 Hz, 1H), 7.14 (d, J = 7.6 Hz,1H), 6.61 (t, J = 74.0 Hz, 1H), 2.50 (s, 3H).

91 #11053313.1 Step 2: Synthesis of 6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1-yl)- 3-(3-(difluoromethoxy)phenyl)-7-methylimidazo[1,2-b]pyridazine In a sealed tube to a degassed solution of 6-chloro-3-(3-(difluoromethoxy)phenyl)-7- methylimidazo[1,2-b]pyridazine (300 mg, 0.97 mmol, 1.0 eq) and 3-(1-((tert- butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidine (359 mg, 1.45 mmol, 1.5 eq) in Toluene (6 mL) at room temperature, was added NaOtBu (233 mg, 2.43 mmol, 2.5 eq) followed by rac-BINAP (120 mg, 0.19 mmol, 0.2 eq) and Pd2(dba)3 (89 mg, 0.097 mmol, 0.1 eq). The reaction mixture was stirred at 90°C for 16 h. After completion of reaction by TLC, the reaction mixture was filtered through a pad of diatomaceous earth (e.g., Celite®), washed with 10% MeOH in DCM (30 mL) and collected filtrate was concentrated under reduced pressure to afford crude product. The Crude product was purified by silica gel (100 – 200 mesh) column chromatography [elution with 40% EtOAc in Hexane] to afford 6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1-yl)- 3-(3-(difluoromethoxy)phenyl)-7-methylimidazo[1,2-b]pyridazine as a yellow gummy liquid (300 mg, Yield: 59%). TLC system: EtOAc/Hexane (50:50) R_f value: ~0.3 LCMS(m/z): 521.3 (M+H)⁺. Step 3: Synthesis of 1-(1-(3-(3-(difluoromethoxy)phenyl)-7-methylimidazo[1,2- b]pyridazin-6-yl)-3-fluoropyrrolidin-3-yl)ethan-1-ol (TFA salt)

92 #11053313.1

To a stirred solution of 6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1- yl)-3-(3-(difluoromethoxy)phenyl)-7-methylimidazo[1,2-b]pyridazine (300 mg, 0.57 mmol, 1.0 eq) in THF (6.0 mL) at 0°C, was added TBAF (1.0 M in THF) (1.1 mL, 1.15 mmol, 2.0 eq) and stirred at room temperature for 2 h. After completion of reaction by TLC, reaction mixture was quenched with NH₄Cl solution (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic layer was washed with brine solution (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude product. The Crude product was purified by reverse phase column chromatography [elution with 30 - 40% ACN in 0.1% FA in H2O] followed by Prep-HPLC and collected fractions were lyophilized to afford 1-(1-(3-(3- (difluoromethoxy)phenyl)-7-methylimidazo[1,2-b]pyridazin-6-yl)-3-fluoropyrrolidin-3-yl)ethan- 1-ol TFA salt as off white solid (60 mg, Yield: 26%). TLC system: MeOH/DCM (10:90) R_f value: ~0.2 LCMS(m/z): 407.2 (M+H)^{+ 1}H NMR (400 MHz, DMSO-d₆) δ: 8.38 (s, 1H), 8.12 (s, 1H), 7.99–7.97 (m, 2H), 7.59 (t, J = 8.0 Hz, 1H), 7.31 (t, J = 74 Hz, 1H), 7.23 (dd, J = 8 & 3.2 Hz, 1H), 5.21 (br, 1H), 4.05–4.02 (m, 1H), 3.90–3.79 (m, 3H), 3.72–3.63 (m, 1H), 2.54 (s, 3H), 2.23–2.15 (m, 2H), 1.20 (d, J = 6.4 Hz, 3H).

93 #11053313.1 SYNTHETIC EXAMPLE 21 SYNTHESIS OF 2-(3-FLUORO-1-(3-(3-(TRIFLUOROMETHOXY)PHENYL)IMIDAZO[1,2-B]PYRIDAZIN-6- YL)PYRROLIDIN-3-YL)PROPAN-2-OL TFA SALT (trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine (300 mg, 0.96 mmol, 1.0 eq) and 2-(3- fluoropyrrolidin-3-yl)propan-2-ol (168 mg, 1.19 mmol, 1.25 eq) in Toluene (6 mL) at room temperature, was added NaOtBu (184 mg, 1.92 mmol, 2.0 eq) followed by rac-BINAP (89 mg, 0.14 mmol, 0.15 eq) and Pd2(dba)3 (44 mg, 0.048 mmol, 0.05 eq). The reaction mixture was stirred at 85°C for 16 h. After completion of reaction by TLC, the reaction mixture was filtered through a pad of diatomaceous earth (e.g., Celite®), washed with 10% MeOH in DCM (20 mL) and collected filtrate was concentrated under reduced pressure. The Crude product was purified by reverse phase column chromatography [elution with 35 – 38% ACN in 0.1% FA in H2O] to afford desired product which was re-purified by Prep-HPLC. The collected fractions were freezed and lyophilized to afford 2-(3-fluoro-1-(3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6- yl)pyrrolidin-3-yl)propan-2-ol TFA as yellow semi solid (85 mg, Yield: 21%). TLC system: EtOAC/Hexane (100:00) R_f value: ~0.3 LCMS(m/z): 425.2 (M+H)^{+ 1}H NMR (400 MHz, DMSO-d₆) δ: 8.46 (brs, 1H), 8.42 (s, 1H), 8.11 (d, J = 9.6 Hz, 2H), 7.66 (t, J = 8.0 Hz, 1H), 7.41 (dd, J = 8.4 & 0.58 Hz 1H), 7.27 (d, J = 9.6 Hz, 1H), 5.05 (bs, 1H), 4.00–3.84 (m, 2H), 3.72–3.59 (m, 2H), 2.46–2.40 (m, 1H), 2.22–2.16 (m, 1H), 1.27 & 1.26 (2 s, 6H).

94 #11053313.1 SYNTHETIC EXAMPLE 22 SYNTHESIS OF 3-(6-(3-FLUORO-3-(2-HYDROXYPROPAN-2-YL)PYRROLIDIN-1-YL)IMIDAZO[1,2- B]PYRIDAZIN-3-YL)BENZONITRILE In a sealed tube to a degassed solution of 3-(6-chloroimidazo[1,2-b]pyridazin-3- yl)benzonitrile (300 mg, 1.18 mmol, 1.0 eq) and 2-(3-fluoropyrrolidin-3-yl)propan-2-ol (208 mg, 1.47 mmol, 1.25 eq) in Toluene (6 mL) at room temperature, was added NaOtBu (226 mg, 2.36 mmol, 2.0 eq) followed by rac-BINAP (110 mg, 0.17 mmol, 0.15 eq) and Pd2(dba)3 (54 mg, 0.059 mmol, 0.05 eq). The reaction mixture was stirred at 90°C for 16 h. After completion of reaction by TLC, the reaction mixture was filtered through a pad of diatomaceous earth (e.g., Celite®), washed with 10% MeOH in DCM (20 mL) and collected filtrate was concentrated under reduced pressure. Crude product was purified by reverse phase column chromatography [elution with 30% ACN in 0.1% FA in H₂O] to afford desired product up to 90% purity. Material was re-purified by Prep-HPLC and fractions were frozen, lyophilized to afford 3-(6-(3-fluoro-3-(2-hydroxypropan- 2-yl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)benzonitrile as white solid (68 mg, Yield: 16%). TLC system: EtOAc/Hexane (70:30) Rf value: ~0.3 LCMS(m/z): 366.2 (M+H)⁺ (99.71% pure) 1H NMR (400 MHz, DMSO-d6) δ: 8.76 (brs, 1H), 8.51 (d, J = 8.0 Hz, 1H), 8.41 (s, 1H), 8.10 (d, J = 10.0 Hz, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.74 (t, J = 8.0 Hz, 1H), 7.25 (d, J = 10.0 Hz, 1H), 3.99–3.85 (m, 2H), 3.74–3.60 (m, 2H), 2.44–2.40 (m, 1H), 2.22–2.16 (m, 1H), 1.29 & 1.26 (2 s, 6H)

95 #11053313.1 SYNTHETIC EXAMPLE 23 SYNTHESIS OF 2-(1-(3-(3-(DIFLUOROMETHOXY)PHENYL)IMIDAZO[1,2-B]PYRIDAZIN-6-YL)-3- FLUOROPYRROLIDIN-3-YL)PROPAN-2-OL TFA SALT In a sealed tube to a degassed solution of 6-chloro-3-(3- (difluoromethoxy)phenyl)imidazo[1,2-b]pyridazine (300 mg, 1.02 mmol, 1.0 eq) and 2-(3- fluoropyrrolidin-3-yl)propan-2-ol (224 mg, 1.52 mmol, 1.5 eq) in Toluene (6 mL) at room temperature, was added NaOtBu (195 mg, 2.03 mmol, 2.0 eq) followed by rac-BINAP (126 mg, 0.20 mmol, 0.2 eq) and Pd2(dba)3 (93 mg, 0.10 mmol, 0.1 eq). The reaction mixture was stirred at 90°C for 16 h. After completion of reaction by TLC, the reaction mixture was filtered through a pad of diatomaceous earth (e.g., Celite®), washed with 10% MeOH in DCM (20 mL) and collected filtrate was concentrated under reduced pressure. The Crude product was purified by silica gel (100 – 200 mesh) column chromatography [elution with 10% MeOH in DCM] followed by Prep- HPLC, collected fractions were frozen and lyophilized to afford 2-(1-(3-(3- (difluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-yl)-3-fluoropyrrolidin-3-yl)propan-2-ol TFA salt as off white solid (104 mg, Yield: 25%). TLC system: EtOAc/Hexane (70:30) R_f value: ~0.2 LCMS(m/z): 407.2 (M+H)^{+ 1}H NMR (400 MHz, DMSO-d₆) δ: 8.39 (s, 1H), 8.23 (s, 1H), 8.11 (d, J = 10.0 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.32 (t, J = 74 Hz, 1H), 7.27 (d, J = 9.6 Hz, 1H), 7.23 (dd, J = 8 & 2 Hz, 1H), 5.05 (br, 1H), 4.00–3.85 (m, 2H), 3.75–3.59 (m, 2H), 2.43–2.32 (m, 1H), 2.21–2.12 (m, 1H), 1.27 & 1.26 (2 s, 6H).

96 #11053313.1 SYNTHETIC EXAMPLE 24 SYNTHESIS OF 2-(3-FLUORO-1-(7-METHYL-3-(3-(TRIFLUOROMETHOXY)PHENYL)IMIDAZO[1,2- B]PYRIDAZIN-6-YL)PYRROLIDIN-3-YL)PROPAN-2-OL In a sealed tube to a degassed solution of 6-chloro-7-methyl-3-(3- (trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine (190 mg, 0.58 mmol, 1.0 eq) and 2-(3- fluoropyrrolidin-3-yl)propan-2-ol (128 mg, 0.87 mmol, 1.5 eq) in Toluene (4 mL) at room temperature, was added NaOtBu (111 mg, 1.16 mmol, 2.0 eq) followed by rac-BINAP (72.4 mg, 0.12 mmol, 0.2 eq) and Pd2(dba)3 (53.2 mg, 0.058 mmol, 0.1 eq). The reaction mixture was stirred at 90°C for 16 h. After completion of reaction by TLC, the reaction mixture was filtered through a pad of diatomaceous earth (e.g., Celite®), washed with 10% MeOH in DCM (20 mL) and collected filtrate was concentrated under reduced pressure. Obtained crude product was purified by Prep-HPLC, collected fractions were frozen and lyophilized to afford 2-(3-fluoro-1-(7-methyl- 3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl)propan-2-ol as off white solid (43 mg, Yield: 17%). TLC system: EtOAc/Hexane (70:30) R_f value: ~0.2 LCMS(m/z): 439.3 (M+H)^{+ 1}H NMR (400 MHz, DMSO-d₆) δ: 8.42 (s, 1H), 8.12–8.10 (m, 2H), 7.81 (s, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 5.05 (s, 1H), 4.18–4.05 (m, 1H), 3.88–3.82 (m, 1H), 3.75– 3.71 (m, 1H), 3.63–3.54 (m, 1H), 2.47 (s, 3H), 2.42–2.38 (m, 1H), 2.11–2.02 (m, 1H), 1.25 (s, 6H).

97 #11053313.1 SYNTHETIC EXAMPLE 25 SYNTHESIS OF 2-(1-(3-(3-(DIFLUOROMETHOXY)PHENYL)-7-METHYLIMIDAZO[1,2-B]PYRIDAZIN-6- YL)-3-FLUOROPYRROLIDIN-3-YL)PROPAN-2-OL TFA SALT In a sealed tube to a degassed solution of 6-chloro-3-(3-(difluoromethoxy)phenyl)-7- methylimidazo[1,2-b]pyridazine (300 mg, 0.97 mmol, 1.0 eq) and 2-(3-fluoropyrrolidin-3- yl)propan-2-ol (214 mg, 1.45 mmol, 1.5 eq) in Toluene (6 mL) at room temperature, was added NaOtBu (186 mg, 1.94 mmol, 2.0 eq) followed by rac-BINAP (120 mg, 0.19 mmol, 0.2 eq) and Pd2(dba)3 (89 mg, 0.097 mmol, 0.1 eq). The reaction mixture was stirred at 90°C for 16 h. After completion of reaction by TLC, the reaction mixture was filtered through a pad of diatomaceous earth (e.g., Celite®), washed with 10% MeOH in DCM (20 mL) and collected filtrate was concentrated under reduced pressure. Obtained crude product was purified by silica gel (100 – 200 mesh) column chromatography [elution with 5 - 10% MeOH in DCM] and Prep-HPLC. The collected fractions were frozen and lyophilized to afford 2-(1-(3-(3-(difluoromethoxy)phenyl)-7- methylimidazo[1,2-b]pyridazin-6-yl)-3-fluoropyrrolidin-3-yl)propan-2-ol TFA salt as off white solid (109 mg, Yield: 27%). TLC system: EtOAc/Hexane (70:30) R_f value: ~0.2 LCMS(m/z): 421.3 (M+H)^{+ 1}H NMR (400 MHz, DMSO-d₆) δ: 8.41 (s, 1H), 8.13 (s, 1H), 8.00–7.98 (m, 2H), 7.59 (t, J = 8.0 Hz, 1H), 7.31 (t, J = 74.0 Hz, 1H), 7.24 (dd, J = 8.0 & 2.0 Hz, 1H), 5.04 (br, 1H), 4.22–4.10 (m, 1H), 3.92–3.82 (m, 2H), 3.74–3.65 (m, 1H), 2.59 (s, 3H), 2.45–2.31 (m, 1H), 2.14–2.06 (m, 1H), 1.25 (s, 6H).

98 #11053313.1 SYNTHETIC EXAMPLE 26 SYNTHESIS OF 1-(3-FLUORO-1-(3-((3-(TRIFLUOROMETHYL)PHENYL)ETHYNYL)IMIDAZO[1,2- B]PYRIDAZIN-6-YL)PYRROLIDIN-3-YL)ETHAN-1-OL Step 1: Synthesis of 6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1- yl)imidazo[1,2-b]pyridazine In a sealed tube to a degassed solution of 6-chloroimidazo[1,2-b]pyridazine (350 mg, 2.27 mmol, 1.0 eq) and 3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidine (675 mg, 2.73 mmol, 1.25 eq) in Toluene (7 mL) at room temperature, was added NaOtBu (545 mg, 5.68 mmol, 2.5 eq) followed by rac-BINAP (282 mg, 0.45 mmol, 0.2 eq) and Pd2(dba)3 (208 mg, 0.23 mmol, 0.1 eq). The reaction mixture was stirred at 100°C for 16 h. After completion of reaction by TLC, the reaction mixture was filtered through a pad of diatomaceous earth (e.g., Celite®), washed with EtOAc (2 × 10 mL) and collected filtrate was concentrated under reduced pressure. The crude product was purified by silica gel (60 - 120) column chromatography [elution with 20% EtOAc in DCM] to afford 6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1-yl)imidazo[1,2- b]pyridazine as yellow liquid (380 mg, Yield: 45%). TLC system: EtOAC/Hexane (50:50) Rf value: ~0.1 LCMS(m/z): 365.2 (M+H)⁺ Step 2: Synthesis of 6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1-yl)- 3-iodoimidazo[1,2-b]pyridazine

99 #11053313.1 To a stirred solution of 6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1- yl)imidazo[1,2-b]pyridazine (380 mg, 1.04 mmol, 1.0 eq) in DMF (8 mL) at RT, was added NIS (281 mg, 1.25 mmol, 1.2 eq) and stirred for 16 h. After completion of reaction by TLC, diluted with cold water (50 mL) and extracted with DCM (2 × 20 mL). The combined organic layer was washed with hypo, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Crude product was purified by silica gel (100 – 200 mesh) column chromatography [elution with 20% EtOAc in DCM] to afford 6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1-yl)-3- iodoimidazo[1,2-b]pyridazine as yellow solid (420 mg, Yield: 82%). TLC system: EtOAc/Hexane (80:20) Rf value: ~0.3 LCMS(m/z): 491.51 (M+H)⁺. Step 3: Synthesis of 6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1-yl)- 3-((3-(trifluoromethyl)phenyl)ethynyl)imidazo[1,2-b]pyridazine In a sealed tube, to a degassed solution of 6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3- fluoropyrrolidin-1-yl)-3-iodoimidazo[1,2-b]pyridazine (400 mg, 0.82 mmol, 1.0 eq) and 1- ethynyl-3-(trifluoromethyl) benzene (160 mg, 0.82 mmol, 1.0 eq) in THF (8 mL) at room temperature, was added Et₃N (0.4 mL, 2.45 mmol, 3.0 eq) followed by CuI (16 mg, 0.08 mmol, 0.1 eq) and PdCl2(PPh3)2 (35 mg, 0.04 mmol, 0.05 eq). The reaction mixture was stirred at 70°C for 16 h. After completion of reaction by TLC, volatiles were removed under vacuum and purified by silica gel (100 – 200 mesh) column chromatography [elution with 25% EtOAc in Hexane] to afford 6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1-yl)-3-((3- (trifluoromethyl)phenyl)ethynyl)imidazo[1,2-b]pyridazine as brown gummy liquid (350 mg, Yield: 65%). TLC system: EtOAc/Hexane (70:30) R_f value: ~0.5 LCMS(m/z): 533.3 (M+H)⁺.

100 #11053313.1 Step 4: Synthesis of 1-(3-fluoro-1-(3-((3-(trifluoromethyl)phenyl)ethynyl)imidazo[1,2- b]pyridazin-6-yl)pyrrolidin-3-yl)ethan-1-ol To a stirred solution of 6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1- yl)-3-((3-(trifluoromethyl)phenyl)ethynyl)imidazo[1,2-b]pyridazine (350 mg, 0.66 mmol, 1.0 eq) in THF (5.0 mL) at 0°C, was added TBAF (1.0 M in THF) (1.0 mL, 0.98 mmol, 1.5 eq) and stirred at room temperature for 4 h. After completion of reaction by TLC, quenched with NH4Cl solution (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic layer was dried over Na2SO4, filtered, concentrated under reduced pressure and purified by reverse phase column chromatography [elution with 28 - 32% ACN in 0.1% FA in H₂O] to afford 1-(3-fluoro-1-(3-((3- (trifluoromethyl)phenyl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl)ethan-1-ol as off white solid (160 mg, Yield: 58%). TLC system: EtOAc/Hexane (100:00) R_f value: ~0.1 LCMS(m/z): 419.2 (M+H)^{+ 1}H NMR (400 MHz, DMSO-d₆) δ: 8.51 (br, 2H), 7.90–7.87 (m, 2H), 7.82 (d, J = 7.6 Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.06 (bs, 1H), 5.27–5.24 (m, 1H), 3.95–3.61 (m, 5H), 2.36–2.21 (m, 2H), 1.23–1.20 (m, 3H). SYNTHETIC EXAMPLE 27 SYNTHESIS OF 1-(3-FLUORO-1-(7-METHYL-3-((3- (TRIFLUOROMETHYL)PHENYL)ETHYNYL)IMIDAZO[1,2-B]PYRIDAZIN-6-YL)PYRROLIDIN-3- YL)ETHAN-1-OL

101 #11053313.1 Step 1: Synthesis of 6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1-yl)- 7-methylimidazo[1,2-b]pyridazine In a sealed tube to a degassed solution of 6-chloro-7-methylimidazo[1,2-b]pyridazine (300 mg, 1.79 mmol, 1.0 eq) and 3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidine (552 mg, 2.23 mmol, 1.25 eq) in Toluene (6 mL) at room temperature, was added NaO^tBu (429 mg, 4.47 mmol, 2.5 eq) followed by rac-BINAP (268 mg, 0.27 mmol, 0.2 eq) and Pd₂(dba)₃ (89.5 mg, 0.089 mmol, 0.05 eq). The reaction mixture was stirred at 100 °C for 16 h. After completion of reaction by TLC, reaction mixture concentrated under reduced pressure to afford 600 mg black gummy crude product. The crude product was purified by silica gel (100 - 200) column chromatography [elution with 20% EtOAc in DCM] to afford 6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3- fluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazine as yellow liquid (450 mg, Semi-pure). TLC system: EtOAC/Hexane (80:20) Rf value: ~0.2 LCMS(m/z): 379.3 (M+H)⁺; 40% purity with BINAP impurity. Step 2: Synthesis of 6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1-yl)- 3-iodo-7-methylimidazo[1,2-b]pyridazine To a stirred solution of 6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1- yl)-7-methylimidazo[1,2-b]pyridazine (450 mg, 1.19 mmol, 1.0 eq) in DMF (9 mL) at room temperature, was added NIS (335 mg, 1.48 mmol, 1.25 eq) and stirred for 16 h. After completion of reaction by TLC, reaction mixture was diluted with cold water (30 mL) and extracted with DCM (2 × 30 mL). The combined organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to afford crude product. The Crude product was purified by silica gel (100 - 200) column chromatography [elution with 20% EtOAc in petroleum ether] to afford 6-(3-(1-((tert- butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1-yl)-3-iodo-7-methylimidazo[1,2-b]pyridazine as yellow liquid (350 mg, Semi-pure).

102 #11053313.1 TLC system: EtOAc/Hexane (50:50) Rf value: ~0.65 1H NMR (400 MHz, CDCl₃) δ: 7.60–7.52 (m, 2H), 4.08–4.05 (m, 1H), 4.01–3.94 (m, 2H), 3.67–3.48 (m, 2H), 2.28 (s, 3H), 2.17–2.13 (m, 2H), 1.27 (d, 3H), 0.87 (s, 9H), 0.09 (s, 6H), impurities observed along with product and the material was taken forward to next step. Step 3: Synthesis of 6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1-yl)- 7-methyl-3-((3-(trifluoromethyl)phenyl)ethynyl)imidazo[1,2-b]pyridazine In a sealed tube to a degassed solution of 6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3- fluoropyrrolidin-1-yl)-3-iodo-7-methylimidazo[1,2-b]pyridazine (350 mg, 0.69 mmol, 1.0 eq) and 1-ethynyl-3-(trifluoromethyl)benzene (118 mg, 0.69 mmol, 1.0 eq) in THF (7 mL) at room temperature, was added Et3N (0.3 mL, 2.08 mmol, 3.0 eq) followed by CuI (13.2 mg, 0.069 mmol, 0.1 eq) and PdCl₂(PPh₃)₂ (20.8 mg, 0.029 mmol, 0.05 eq). The reaction mixture was stirred at 70 °C for 16 h. After completion of reaction by TLC, reaction mixture was concentrated under reduced pressure ad purified by silica gel (100 - 200) column chromatography [elution with 40% to 45% EtOAc in Hexane] to afford 6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3- fluoropyrrolidin-1-yl)-7-methyl-3-((3-(trifluoromethyl)phenyl)ethynyl) imidazo[1,2-b]pyridazine as yellow liquid (215 mg, 65% purity). TLC system: EtOAc/Hexane (70:30) Rf value: ~0.55 LCMS(m/z): 547.4 (M+H)⁺ Step 4: Synthesis of 1-(3-fluoro-1-(7-methyl-3-((3- (trifluoromethyl)phenyl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl)ethan-1-ol

103 #11053313.1 To a stirred solution of 6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1- yl)-7-methyl-3-((3-(trifluoromethyl)phenyl)ethynyl)imidazo[1,2-b]pyridazine (210 mg, 0.38 mmol, 1.0 eq) in THF (4.0 mL) at 0 °C, was added TBAF (1.0 M in THF) (0.6 mL, 0.57 mmol, 1.5 eq) and stirred at room temperature for 4 h. After completion of reaction by TLC, reaction mixture was quenched with NH4Cl solution (10 mL) and extracted with EtOAc (2 × 10 mL). The combined organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to afford crude product. The crude product was purified by reverse phase column chromatography [elution with 52 - 55% ACN in 0.1% FA in H₂O] to afford 1-(3-fluoro-1-(7-methyl-3-((3- (trifluoromethyl)phenyl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl)ethan-1-ol as off white solid (80 mg, Yield: 10% in 4 steps). TLC system: EtOAc/Hexane (100:00) R_f value: ~0.25 LCMS(m/z): 433.2 (M+H)^{+ 1}H NMR (400 MHz, DMSO-d₆) δ: 7.86–7.84 (m, 2H), 7.81–7.78 (m, 3H), 7.70 (t, J = 8.0 Hz, 1H), 5.19 (d, J = 6.0 Hz, 1H, D2O exchangeable proton), 4.03–3.83 (m, 3H), 3.74–3.69 (m, 1H), 3.63–3.54 (m, 1H), 2.46 (s, 3H), 2.32–2.10 (m, 2H), 1.20 (d, J = 3.6 Hz, 3H). SYNTHETIC EXAMPLE 28 SYNTHESIS OF 2-(3-FLUORO-1-(3-((3-(TRIFLUOROMETHYL)PHENYL)ETHYNYL)IMIDAZO[1,2- B]PYRIDAZIN-6-YL)PYRROLIDIN-3-YL)PROPAN-2-OL Step 1: Synthesis of 6-chloro-3-iodoimidazo[1,2-b]pyridazine

104 #11053313.1 To a stirred solution of 6-chloroimidazo[1,2-b]pyridazine (1 g, 6.54 mmol, 1.0 eq) in CHCl₃ (20 mL) at room temperature, was added NIS (1.75 g, 7.81 mmol, 1.2 eq) and stirred for 24 h. After completion of reaction by TLC, reaction mixture was diluted with cold water (80 mL) and extracted with DCM (3 × 70 mL). The combined organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Crude product was washed with n-pentane to afford 6- chloro-3-iodoimidazo[1,2-b]pyridazine as yellow solid (1.5 g, yield:83%). TLC system: EtOAc/Hexane (40:60) R_f value: ~0.35 1H NMR (400 MHz, CDCl3) δ: 7.92 (d, J = 9.2 Hz, 1H), 7.89 (s, 1H), 7.14 (d, J = 9.2 Hz, 1H). Step 2: Synthesis of 6-chloro-3-((3-(trifluoromethyl)phenyl)ethynyl)imidazo[1,2- b]pyridazine In a sealed tube to a degassed solution of 6-chloro-3-iodoimidazo[1,2-b]pyridazine (1 g, 3.58 mmol, 1.0 eq) and 1-ethynyl-3-(trifluoromethyl)benzene (0.5 mL, 3.58 mmol, 1.0 eq) in THF (20 mL) at room temperature, was added Et₃N (1.5 mL, 10.7 mmol, 3.0 eq) followed by CuI (68.4 mg, 0.36 mmol, 0.1 eq) and PdCl2(PPh3)2 (125 mg, 0.18 mmol, 0.05 eq). Again, degassed for 5 min and stirred at 80 °C for 16 h. After completion of reaction by TLC, reaction mixture was concentrated under reduced pressure and purified by silica gel (100 - 200) column chromatography [elution with 30% to 35% EtOAc in Hexane] to afford 6-chloro-3-((3- (trifluoromethyl)phenyl)ethynyl)imidazo[1,2-b]pyridazine as yellow liquid (650 mg, 56.5% yield). TLC system: EtOAc/Hexane (40:60) R_f value: ~0.20 1H NMR (400 MHz, CDCl3) δ: 8.05 (s, 1H), 7.96 (d, J = 9.2 Hz, 1H), 7.89 (s, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.16 (d, J = 9.2 Hz, 1H).

105 #11053313.1 Step 3: Synthesis of 2-(3-fluoro-1-(3-((3-(trifluoromethyl)phenyl)ethynyl)imidazo[1,2- b]pyridazin-6-yl)pyrrolidin-3-yl)propan-2-ol To a stirred solution of 6-chloro-3-((3-(trifluoromethyl)phenyl)ethynyl)imidazo[1,2- b]pyridazine (300 mg, 0.93 mmol, 1.0 eq) in NMP (3 mL) was added 2-(3-fluoropyrrolidin-3- yl)propan-2-ol (206 mg, 1.40 mmol, 1.50 eq) at room temperature. The reaction mixture was stirred at 100 °C for 16 h. After completion of reaction by TLC, the reaction mixture diluted with cold water (20 mL) and extracted with 10% MeOH/DCM to afford black gummy crude product. The crude product was purified by reverse phase column chromatography [elution with 50 - 55% ACN in 0.1% FA in H₂O] to afford 2-(3-fluoro-1-(3-((3- (trifluoromethyl)phenyl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl)propan-2-ol as brown solid (55 mg, Yield: 13.6%). TLC system: EtOAc/Hexane (80:20) R_f value: ~0.15 LCMS(m/z): 433.2 (M+H)^{+ 1}H NMR (400 MHz, DMSO-d₆) δ: 7.94 (d, J = 9.6 Hz, 1H), 7.87–7.85 (m, 3H), 7.80 (d, J = 8.0 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.02 (d, J = 9.6 Hz, 1H), 5.09 (bs, 1H), 3.98–3.73 (m, 2H), 3.67–3.56 (m, 2H), 2.47–2.33 (m, 1H), 2.18–2.08 (m, 1H), 1.26 & 1.24 (2 s, 6H). SYNTHETIC EXAMPLE 29 SYNTHESIS OF 2-(3-FLUORO-1-(7-METHYL-3-((3- (TRIFLUOROMETHYL)PHENYL)ETHYNYL)IMIDAZO[1,2-B]PYRIDAZIN-6-YL)PYRROLIDIN-3- YL)PROPAN-2-OL

106 #11053313.1 Step 1: Synthesis of 6-chloro-7-methylimidazo[1,2-b]pyridazine Step 2: Synthesis of 6-chloro-3-iodo-7-methylimidazo[1,2-b]pyridazine To a stirred solution of 6-chloro-7-methylimidazo[1,2-b]pyridazine (500 mg, 2.99 mmol, 1.0 eq) in CHCl₃ (10 mL) at 0 °C, was added NIS (808 g, 3.59 mmol, 1.2 eq) and stirred at room temperature for 16 h. After completion of reaction by TLC, the reaction mixture was diluted with cold water (10 mL) and extracted with DCM (2 × 20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel (100 – 200 mesh) column chromatography [elution with 25% to 28% EtOAc in Hexane] to afford 6-chloro-3-iodo-7-methylimidazo[1,2-b]pyridazine as light yellow solid (480 mg, 55%). TLC system: EtOAc/Hexane (40:60) R_f value: ~0.35 1H NMR (400 MHz, CDCl3) δ: 7.81–7.79 (m, 1H), 7.74 (s, 1H), 2.51 (s→m, 3H). Step 3: Synthesis of 6-chloro-7-methyl-3-((3- (trifluoromethyl)phenyl)ethynyl)imidazo[1,2-b]pyridazine In a sealed tube to a degassed solution of 6-chloro-3-iodo-7-methylimidazo[1,2- b]pyridazine (470 mg, 1.60 mmol, 1.0 eq) and 1-ethynyl-3-(trifluoromethyl)benzene (0.3 mL, 1.92 mmol, 1.2 eq) in THF (4.7 mL) at room temperature, was added Et3N (0.67 mL, 4.81 mmol, 3.0

107 #11053313.1 eq) followed by CuI (30.4 mg, 0.16 mmol, 0.1 eq) and PdCl₂(PPh₃)₂ (112 mg, 0.16 mmol, 0.1 eq). The reaction mixture was stirred at 90 °C for 16 h. After completion of reaction by TLC, the reaction mixture was filtered through a pad of diatomaceous earth (e.g., Celite®), washed with 10% MeOH in DCM. Filtrate was washed with cold water (2 × 20 ml), dried over anhydrous Na₂SO₄, evaporated and purified by silica gel (100 - 200) column chromatography [elution with 5% to 10% EtOAc in DCM] to afford 6-chloro-7-methyl-3-((3- (trifluoromethyl)phenyl)ethynyl)imidazo[1,2-b]pyridazine as a yellow solid (450 mg, yield: 83%). TLC system: EtOAc/Hexane (50:50) R_f value: ~0.40 LCMS Retention time = 2.68 min, 336.29 [M+H]⁺. Step 4: Synthesis of 2-(3-fluoro-1-(7-methyl-3-((3- (trifluoromethyl)phenyl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl)propan-2-ol (trifluoromethyl)phenyl)ethynyl)imidazo[1,2-b]pyridazine (300 mg, 0.896 mmol, 1.0 eq) in NMP (3 mL) was added 2-(3-fluoropyrrolidin-3-yl)propan-2-ol (263 mg, 1.79 mmol, 2.0 eq) at room temperature. The reaction mixture was stirred at 100 °C for 16 h. After completion of reaction by TLC, reaction mixture diluted with cold water (20 mL) and extracted with 10% MeOH/DCM, evaporated to afford black gummy crude product. The crude product was purified by reverse phase column chromatography [elution with 50 - 60% ACN in 0.1% FA in H₂O] to afford 2-(3-fluoro- 1-(7-methyl-3-((3-(trifluoromethyl)phenyl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3- yl)propan-2-ol as light Brown solid (68 mg, Yield: 17%). TLC system: EtOAc/Hexane (100:0) R_f value: ~0.22 LCMS(m/z): 447.3 (M+H)^{+ 1}H NMR (400 MHz, DMSO-d₆) δ: 7.86–7.78 (m, 5H), 7.70 (t, J = 8.0 Hz, 1H), 5.06 (s, 1H), 4.21–4.09 (m, 1H), 3.89–3.84 (m, 1H), 3.76–3.72 (m, 1H), 3.64–3.55 (m, 1H), 2.47 (s, 3H), 2.43–2.39 (m, 1H), 2.11–2.03 (m, 1H), 1.24 (s, 6H).

108 #11053313.1 SYNTHETIC EXAMPLE 30 SYNTHESIS OF 1-(3-FLUORO-1-(3-(3-(3,3,3-TRIFLUOROPROP-1-YN-1-YL)PHENYL)IMIDAZO[1,2- B]PYRIDAZIN-6-YL)PYRROLIDIN-3-YL)ETHAN-1-OL TFA SALT Step 1: Synthesis of 6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1- yl)imidazo[1,2-b]pyridazine Step 2: Synthesis of 6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1-yl)- 3-iodoimidazo[1,2-b]pyridazine Step 3: Synthesis of 3-(6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1- yl)imidazo[1,2-b]pyridazin-3-yl)benzaldehyde In a sealed tube to a degassed solution of 6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3- fluoropyrrolidin-1-yl)-3-iodoimidazo[1,2-b]pyridazine (1.1 g, 2.24 mmol, 1.0 eq ) and (3- formylphenyl)boronic acid (505 mg, 3.36 mmol, 1.5 eq) in 1,4-dioxane:water (4:1, 22 mL) at room temperature, was added K₂CO₃ (774 mg, 5.61 mmol, 2.5 eq) followed by Pd(dppf)Cl₂DCM (91.6 mg, 0.11 mmol, 0.05 eq) and stirred at 100°C for 16 h. After completion of reaction by TLC, the

109 #11053313.1 reaction mixture was quenched with water (30 mL) and extracted with EtOAc (2 × 30 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel (100 - 200) column chromatography [elution with 70 - 80% EtOAc in Hexane] to afford 3-(6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3- fluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)benzaldehyde as brown gummy solid (720 mg, Yield: 65%). TLC system: EtOAc/Hexane (50:50) Rf value: ~0.3 LCMS (m/z): 469.6 (M+H)^{+ 1}H NMR (400 MHz, CDCl3) δ: 10.09 (s, 1H), 8.84 (s, 1H), 8.38–8.36 (m, 1H), 7.96 (s, 1H), 7.85–7.82 (m, 2H), 7.64–7.60 (m, 1H), 6.67 (d, J = 9.6 Hz, 1H), 4.13–4.09 (m, 1H), 3.87– 3.68 (m, 4H), 2.33–2.20 (m, 2H), 1.34–1.31 (m, 3H), 0.90 (s, 9H), 0.13 and 0.12 (2 s, 6H). Step 4: Synthesis of 6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1-yl)- 3-(3-(2,2-dibromovinyl)phenyl)imidazo[1,2-b]pyridazine To a stirred solution of 3-(6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin- 1-yl)imidazo[1,2-b]pyridazin-3-yl)benzaldehyde (720 mg, 1.56 mmol, 1.0 eq) in DCM (11 mL) was added CBr₄ (1.2 g, 3.91 mmol, 2.5 eq) and the reaction mixture was cooled to 0°C, added PPh₃ (1.6 g, 6.26 mmol, 4.0 eq) portion wise. The reaction mixture was stirred at room temperature for 2 h. After completion of reaction by TLC, the reaction mixture was quenched with water (30 mL) and extracted with DCM (2 × 30 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude product. The crude product was purified by reverse phase column chromatography [elution with 40 - 50% ACN in 0.1% FA in H2O] to afford 6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1-yl)-3-(3-(2,2- dibromovinyl)phenyl)imidazo[1,2-b]pyridazine as brown gummy solid (390 mg, Yield: 40%). TLC system: EtOAc/Hexane (50:50) Rf value: ~0.4 LCMS (m/z): 625.3 (M+H+2)⁺

110 #11053313.1 ¹H NMR (400 MHz, CDCl₃) δ: 8.27 (s, 1H), 8.17–8.15 (m, 1H), 7.86 (s, 1H), 7.78 (d, J = 9.6 Hz, 1H), 7.55 (s, 1H), 7.51–7.43 (m, 2H), 6.63 (d, J = 10 Hz, 1H), 4.12–4.07 (m, 1H), 3.84– 3.66 (m, 4H), 2.29–2.23 (m, 2H), 1.31–1.29 (m, 3H), 10.90 (s, 9H), 0.13 (s, 6H). Step 5: Synthesis of 6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1-yl)- 3-(3-ethynylphenyl)imidazo[1,2-b]pyridazine To a stirred solution of 6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1- yl)-3-(3-(2,2-dibromovinyl)phenyl)imidazo[1,2-b]pyridazine (200 mg, 0.32 mmol, 1.0 eq) in ACN (2 mL) at room temperature was added DBU (0.2 mL, 1.28 mmol, 4.0 eq) and stirred at room temperature for 48 h. After completion of reaction by TLC, the reaction mixture was quenched with water (30 mL) and extracted with DCM (2 × 30 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford 6-(3-(1-((tert- butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1-yl)-3-(3-ethynylphenyl)imidazo[1,2- b]pyridazine as brown gummy solid (150 mg, Crude). TLC system: EtOAc/Hexane (50:50) Rf value: ~0.3 LCMS (m/z): 464.81 (M)⁺. Step 6: Synthesis of 6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1-yl)- 3-(3-(3,3,3-trifluoroprop-1-yn-1-yl)phenyl)imidazo[1,2-b]pyridazine To a stirred solution of K₂CO₃ (134 mg, 0.97 mmol, 3.0 eq) in DMF (6 mL, 40 Vol) at 0°C, was added TMEDA (0.07 mL, 0.48 mmol, 1.5 eq) followed by CuI (92 mg, 0.48 mmol, 1.5 eq) and stirred for 15 min. Later added CF₃TMS (0.2 mL, 1.29 mmol, 4 eq), stirred for 10 min followed by addition of a solution of 6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1-yl)- 3-(3-ethynylphenyl)imidazo[1,2-b]pyridazine (150 mg, 0.32 mmol, 1.0 eq) in DMF (1 mL). The

111 #11053313.1 resulting reaction mixture was stirred at room temperature for 16 h. After completion of reaction by TLC, reaction mixture was quenched with water (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic layer was washed with brine solution (20 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford 6-(3-(1-((tert- butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1-yl)-3-(3-(3,3,3-trifluoroprop-1-yn-1- yl)phenyl)imidazo[1,2-b]pyridazine as yellow gummy solid (160 mg, Crude). TLC system: EtOAc/Hexane (50:50) Rf value: ~0.5 LCMS (m/z): 533.45 (M+H)⁺; 62% purity. Step 7: Synthesis of 1-(3-fluoro-1-(3-(3-(3,3,3-trifluoroprop-1-yn-1- yl)phenyl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl)ethan-1-ol.TFA salt To a stirred solution of 6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyrrolidin-1- yl)-3-(3-(3,3,3-trifluoroprop-1-yn-1-yl)phenyl)imidazo[1,2-b]pyridazine (150 mg, 0.28 mmol, 1.0 eq) in ACN (1.5 mL) at 0°C, was added 2 N aq. HCl (0.8 mL, 5.0 Vol) and stirred at room temperature for 4 h. After completion of reaction by TLC, volatiles removed and purified by Prep- HPLC (TFA buffer). Collected fractions were freezed and lyophilized to afford 1-(3-fluoro-1-(3- (3-(3,3,3-trifluoroprop-1-yn-1-yl)phenyl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl)ethan-1- ol.TFA salt as off white solid (29 mg, Yield: 21% in 3 steps). TLC system: EtOAc/Hexane (50:50) R_f value: ~0.1 LCMS (m/z): 419.36 (M+H)^{+ 1}H NMR (400 MHz, DMSO-d₆) δ: 8.64 (s, 1H), 8.42 (d, J = 8.0 Hz, 1H), 8.38 (s, 1H), 8.08 (d, J = 9.6 Hz, 1H),7.74 (d, J = 7.6 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.20 (d, J = 9.6 Hz, 1H), 5.27 (br, 1H), 3.92–3.81 (m, 3H), 3.72–3.62 (m, 2H), 2.33–2.22 (m, 2H), 1.20 (d, J = 6.0 Hz, 3H).

112 #11053313.1 SYNTHETIC EXAMPLE 31 SYNTHESIS OF 2-(3-FLUORO-1-(3-(3-(3,3,3-TRIFLUOROPROP-1-YN-1-YL)PHENYL)IMIDAZO[1,2- B]PYRIDAZIN-6-YL)PYRROLIDIN-3-YL)PROPAN-2-OL TFA SALT Step 1: Synthesis of 3-(6-chloroimidazo[1,2-b]pyridazin-3-yl)benzaldehyde In a sealed tube to a degassed solution of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (4 g, 17.2 mmol, 1.0 eq) and (3-formylphenyl)boronic acid (3.8 g, 25.8 mmol, 1.5 eq) in 1,4- dioxane:water (4:1, 64 mL) at room temperature, was added K₂CO₃ (5.9 g, 43.1 mmol, 2.5 eq) followed by Pd(dppf)Cl2DCM (703 mg, 0.86 mmol, 0.05 eq) and stirred at 100°C for 16 h. After completion of reaction by TLC, reaction mixture was filtered through a pad of diatomaceous earth (e.g., Celite®), washed with EtOAc (50 mL), diluted with water (80 mL) and extracted with EtOAc (2 × 80 mL). The combined organic layer was dried over Na₂SO_4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel (100 – 200 mesh) column chromatography [elution with 55-70 % EtOAc in Hexane] to afford 3-(6-chloroimidazo[1,2- b]pyridazin-3-yl)benzaldehyde as yellow solid (2 g, yield: 55%). TLC system: EtOAc/Hexane (50:50) Rf value: ~0.2 LCMS (m/z): 258.38 (M+H)⁺. Step 2: Synthesis of 6-chloro-3-(3-(2,2-dibromovinyl)phenyl)imidazo[1,2-b]pyridazine

113 #11053313.1 To a stirred solution of 3-(6-chloroimidazo[1,2-b]pyridazin-3-yl)benzaldehyde (2 g, 7.78 mmol, 1.0 eq) in DCM (30 mL) at 0°C, was added CBr4 (6.4 g, 19.45 mmol, 2.5 eq) followed by TPP (8.1 g, 31.12 mmol, 4.0 eq) portion wise and stirred at room temperature for 5 h. After completion of reaction by TLC, the reaction mixture was diluted with water (40 mL) and extracted with DCM (2 × 40 mL). The combined organic layer was dried over Na₂SO_4, filtered, and concentrated under reduced pressure. The crude product was purified by reverse phase column chromatography [elution with 80-85 % ACN in 0.1% FA in H₂O] to afford 6-chloro-3-(3-(2,2- dibromovinyl)phenyl)imidazo[1,2-b]pyridazine as a yellow solid (2.5 g, yield: 78%). TLC system: EtOAc/Hexane (50:50) Rf value: ~0.7 LCMS (m/z): 412.34 (M+H)⁺. Step 3: Synthesis of 6-chloro-3-(3-ethynylphenyl)imidazo[1,2-b]pyridazine To a stirred solution of 6-chloro-3-(3-(2,2-dibromovinyl)phenyl)imidazo[1,2-b]pyridazine (2.5 g, 6.05 mmol, 1.0 eq) in ACN (25 mL) at room temperature, was added DBU (3.7 mL, 24.2 mmol, 4.0 eq) and stirred at room temperature for 16 h. After completion of reaction by TLC, the reaction mixture was diluted with water (45 mL) and extracted with EtOAc (2 × 45 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford 6-chloro-3-(3-ethynylphenyl)imidazo[1,2-b]pyridazine as a brown gummy solid (500 mg, Crude). TLC system: EtOAc/Hexane (50:50) Rf value: ~0.3 LCMS (m/z): 254.1 (M+H)⁺; 30% purity. Step 4: Synthesis of 2-(1-(3-(3-ethynylphenyl)imidazo[1,2-b]pyridazin-6-yl)-3- fluoropyrrolidin-3-yl)propan-2-ol

114 #11053313.1

To a stirred solution of 6-chloro-3-(3-ethynylphenyl)imidazo[1,2-b]pyridazine (200 mg, 0.79 mmol, 1.0 eq) in NMP (2 mL) at room temperature, was added 2-(3-fluoropyrrolidin-3- yl)propan-2-ol (232 mg, 1.58 mmol, 2.0 eq) and stirred at 100°C for 16 h. After completion of reaction by TLC, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic layer was dried over Na₂SO_4, filtered, and concentrated under reduced pressure. The crude product was purified by reverse phase column chromatography [elution with 40-45% ACN in 0.1% formic acid in H₂O] to afford 2-(1-(3-(3- ethynylphenyl)imidazo[1,2-b]pyridazin-6-yl)-3-fluoropyrrolidin-3-yl)propan-2-olas brown solid (90 mg, yield: 4% in 2 steps). TLC system: EtOAc/Hexane (100:00) R_f value: ~0.2 LCMS (m/z): 365.04 (M+H)⁺. Step 5: Synthesis of 2-(3-fluoro-1-(3-(3-(3,3,3-trifluoroprop-1-yn-1- yl)phenyl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl)propan-2-ol (TFA Salt) To a stirred solution of K2CO3 (97 mg, 0.70 mmol, 3.0 eq) in DMF (3.4 mL, 40 Vol) at 0°C, was added TMEDA (0.05 mL, 0.35 mmol, 1.5 eq) followed by CuI (67 mg, 0.35 mmol, 1.5 eq) and stirred for 15 min. Later, pre-cooled solution of CF3TMS (0.13 mL, 0.93 mmol, 4 eq) was added and stirred for 10 min followed by addition of a solution of 2-(1-(3-(3- ethynylphenyl)imidazo[1,2-b]pyridazin-6-yl)-3-fluoropyrrolidin-3-yl)propan-2-ol (85 mg, 0.23 mmol, 1.0 eq) in DMF (1 mL) and stirred at room temperature for 4 h. After completion of reaction by TLC, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 × 20

115 #11053313.1 mL). The combined organic layer was dried over Na₂SO_4, filtered, and concentrated under reduced pressure. The crude product was purified by Prep-HPLC (TFA buffer). Collected fractions were frozen and lyophilized to afford 2-(3-fluoro-1-(3-(3-(3,3,3-trifluoroprop-1-yn-1- yl)phenyl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl)propan-2-ol (TFA Salt) as an off white solid (45 mg, yield: 45%). TLC system: EtOAc/Hexane (50:50) R_f value: ~0.2 LCMS (m/z): 433.2 (M+H)^{+ 1}H NMR (400 MHz, DMSO-d₆) δ: 8.69 (s, 1H), 8.40–8.38 (m, 2H), 8.09 (d, J = 10 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.69–7.65 (m, 1H), 7.23 (d, J = 10 Hz, 1H), 5.14 (brs, 1H), 4.15– 3.85 (m, 2H), 3.73–3.60 (m, 2H), 2.44–2.38 (m, 1H), 2.21–2.11 (m, 1H), 1.26 (d, J = 6.8 Hz, 6H). SYNTHETIC EXAMPLE 32 SYNTHESIS OF 2-(3-FLUORO-1-(3-(3-((1-TRIFLUOROMETHYL)CYCLOPROPYL)PHENYL)IMIDAZO[1,2- B]PYRIDAZIN-6-YL)PYRROLIDIN-3-YL)PROPAN-2-OL Step 1: Synthesis of 6-chloro-3-(2-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine In a sealed tube to a degassed solution of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (116 mg, 0.5 mmol, 1.0 eq) and 3-(3-((1-trifluoromethyl)cyclopropyl)phenyl)boronic acid (115 mg, 0.5 mmol, 1.0 eq) in 1,4-dioxane:water (4:1, 10 mL) at room temperature, was added K₂CO₃ (346 mg, 2.5 mmol, 2.5 eq) followed by Pd(dppf)Cl2DCM (41 mg, 0.05 mmol, 0.1 eq) and stirred at 100°C for 16 h. After completion of reaction by TLC, the reaction mixture was filtered through a pad of diatomaceous earth (e.g., Celite®), washed with EtOAc (20 mL) and collected filtrate was concentrated under reduced pressure to afford crude product. The Crude product was purified by

116 #11053313.1 silica gel column chromatography to afford 6-chloro-3-(3-((1- trifluoromethy)cyclopropyl)phenyl)imidazo[1,2-b]pyridazine as yellow solid (84 mg, Yield: 50%). TLC system: EtOAc/Hexane (1:2) R_f value: ~0.3. Step 2: Synthesis of 2-(3-fluoro-1-(3-(3-((1- trifluoromethyl)cyclopropyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl)propan-2-ol to a degassed solution of 6-chloro-3-(3-((1- trifluoromethy)cyclopropyl)phenyl)imidazo[1,2-b]pyridazine (21 mg, 0.062 mmol, 1.0 eq) and 2- (3-fluoropyrrolidin-3-yl)propan-2-ol HCl (15 mg, 0.078 mmol, 1.25 eq) in Toluene (6 mL) at room temperature, was added NaOtBu (15 mg, 0.155 mmol, 2.5 eq) followed by rac-BINAP (8 mg, 0.012 mmol, 0.2 eq) and Pd2(dba)3 (6 mg, 0.006 mmol, 0.1 eq). The reaction mixture was stirred at 100°C for 16 h. After completion of reaction by TLC, the reaction mixture was diluted with ethyl estate, filtered through a pad of diatomaceous earth (e.g., Celite®), washed with brine, dried over Na₂SO_4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford 2-(3-fluoro-1-(3-(3-((1- trifluoromethyl)cyclopropyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl)propan-2-ol as yellow semi solid (5 mg, Yield: 17%). TLC system: EtOAC/Hexane (100:00) Rf value: ~0.1 LCMS(m/z): 448.2 (M+H)⁺.

117 #11053313.1 SYNTHETIC EXAMPLE 33 SYNTHESIS OF 2-(3-FLUORO-1-(3-(2-(TRIFLUOROMETHOXY)PHENYL)IMIDAZO[1,2-B]PYRIDAZIN-6- YL)PYRROLIDIN-3-YL)PROPAN-2-OL Step 1: Synthesis of 6-chloro-3-(2-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine In a sealed tube to a degassed solution of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (232 mg, 1.0 mmol, 1.0 eq) and 2-trifluoromethoxyphenylboronic acid (309 mg, 1.5 mmol, 1.5 eq) in 1,4-dioxane:water (4:1, 10 mL) at room temperature, was added K2CO3 (346 mg, 2.5 mmol, 2.5 eq) followed by Pd(dppf)Cl₂DCM (82 mg, 0.1 mmol, 0.1 eq) and stirred at 100°C for 16 h. After completion of reaction by TLC, the reaction mixture was filtered through a pad of diatomaceous earth (e.g., Celite®), washed with EtOAc (20 mL) and collected filtrate was concentrated under reduced pressure to afford crude product. The Crude product was purified by silica gel column chromatography to afford 6-chloro-3-(2-(trifluoromethoxy) phenyl) imidazo[1,2-b]pyridazine as yellow solid (195 mg, Yield: 31%). TLC system: EtOAc/Hexane (50:50) Rf value: ~0.3 Step 2: Synthesis of 2-(3-fluoro-1-(3-(2-(trifluoromethoxy) phenyl) imidazo[1,2- b]pyridazin-6-yl)pyrrolidin-3-yl)propan-2-ol

118 #11053313.1 In a sealed tube to a degassed solution of 6-chloro-3-(2- (trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine (19 mg, 0.062 mmol, 1.0 eq) and 2-(3- fluoropyrrolidin-3-yl)propan-2-ol HCl (15 mg, 0.078 mmol, 1.25 eq) in Toluene (6 mL) at room temperature, was added NaOtBu (15 mg, 0.155 mmol, 2.5 eq) followed by rac-BINAP (8 mg, 0.012 mmol, 0.2 eq) and Pd2(dba)3 (6 mg, 0.006 mmol, 0.1 eq). The reaction mixture was stirred at 100°C for 16 h. After completion of reaction by TLC, the reaction mixture was diluted with ethyl estate, filtered through a pad of diatomaceous earth (e.g., Celite®), washed with brine, dried over Na₂SO_4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford 2-(3-fluoro-1-(3-(2-(trifluoromethoxy)phenyl)imidazo[1,2- b]pyridazin-6-yl)pyrrolidin-3-yl)propan-2-ol as yellow semi solid (4 mg, Yield: 15%). TLC system: EtOAc/Hexane (100:00) R_f value: ~0.2 LCMS(m/z): 425.2 (M+H)⁺ BIOLOGICAL EXAMPLE 1 SYSTEMIC LUPUS ERYTHEMATOSUS – IN VITRO The present experiment was designed to explore the effect of a PIM inhibitor on systemic lupus erythematosus (SLE) progression. The inflammasome complex is a driver of organ damage in SLE. PIM is a critical regulator of lupus nephritis (LN) pathogenesis in patients with SLE. This study was to test our PIM inhibitors affect SLE inflammasome activation. hPBMC samples from seven SLE patients were bought from Precision for Medicine. These PBMCs were pretreated with/without PIM inhibitors and then stimulated by IFNα/LPS. The IL- 1β and TNFα were detected by real-time PCR assay. The hPBMCs from seven SLE patients were plated into 24-well tissue culture plates at a density 1 × 10⁶ cells/well in 0.5 mL IMDM, GlutaMAX™ Supplement (ThermoFisher, cat number: 31980030) plus 10% FBS plus eBioscience™ Phytohemagglutinin-L (PHA-L) solution (ThermoFisher, cat number: 00-4977-

119 #11053313.1 03). PBMCs were pretreated with the presence or absence of 15 µM compound I-10a, compound I-8, and TP3654 for 1 hour, 1000 unit/mL human IFNα for 16 hours. The next day, the cells were further stimulated with 100 ng/mL LPS (Millipore, cat number: L3012-5MG) for 5 hours. Structure of TP3654: Table A. Patient details for PBMC cell samples RNA isolation and real-time quantitative PCR Total RNA was isolated from human PBMCs using RNeasy plus universal mini kit (QIAGEN, cat number: 73404) following the manufacturer’s instruction.1 μg of total RNA was transcribed into cDNA using High-Capacity cDNA Reverse Transcription Kit with RNase Inhibitor (Thermofisher, cat number: 4374966). Real time PCR was performed in triplicate using FastStart Universal SYBR Green Master (Rox) (Millipore, cat number: 4913850001). Gene expression was normalized to β-actin and relative gene expression in treatment groups to control group without treatments was calculated by the comparative threshold cycle method and fold- change (FC) was expressed as 2−ΔΔCT. Statistical analysis

120 #11053313.1 Data are presented as the mean + SEM. The two-tailed unpaired Student's t-test was used for analysis of differences between simultaneously cultured control and SLE groups. For studies examining effects on samples with multiple treatment conditions, paired two-tailed student's t- test between untreated and treated groups was used. It was discovered that treatment with PIM inhibitors of Structure (I) reduces inflammasome activation in PBMCs from SLE patients compared to vehicle-treated controls. Inflammasome genes (i.e., IL-1β and TNFα) have been reported to have increased in human SLE monocytes compared with control monocytes. As shown in FIGs. 1A-1G, representative compounds of Structure (I) (i.e., compound I-8 and I-10a) induced a decrease of IL-1β gene expression significantly compared with vehicle group. Additionally, FIGs. 2A-2G show that representative compounds of Structure (I) significantly decrease TNFα expression in PBMCs after inflammasome stimulation. In sum, it was discovered that PIM inhibitors of the present disclosure reduce IL-1β/TNFα expression in PBMCs from lupus patients after stimulated with IFNα/LPS. PIM1 was shown to be a treatment target for SLE-associated inflammation, and PIM1 inhibitors of Structure (I) have therapeutic effect in human SLE inflammasome activation. BIOLOGICAL EXAMPLE 2 SYSTEMIC LUPUS ERYTHEMATOSUS – IN VIVO NZBWF1/J is a classic animal model of SLE which exhibits phenotypes like humans such as autoantibody formation, impairment in renal function and histological changes. As such, these characteristics make this assay a suitable model to test the efficacy of new chemical entities. At the age of 23 weeks, animal exhibits well established autoimmunity evident by presence of anti- dsDNA antibodies. NZBWF1/J (36) and normal control (12) female mice procured from Jackson laboratories are used. All animals are quarantined for 3-7 days and acclimatize for at least 2 days prior to experiment initiation. During this period, the animals are observed daily for clinical signs. Animals are be sacrificed at 36^th week of age. However, in case of any morbidity, animals are euthanized, and blood, urine, and kidneys are collected. BIOLOGICAL EXAMPLE 3 PROPHYLACTIC LUPUS MOUSE MODEL: EFFECT OF TEST COMPOUND I-10A IN SLE MODEL Experimental Protocol and Dose Administration

121 #11053313.1 NZBWF1/J (36) and normal control C57BL/6 (12) female mice were procured (Jackson Laboratories). All animals were quarantine for 2 weeks and acclimatize for at least 5 days prior to experiment initiation. During this period, the animals were observed daily for clinical signs. Prior to initiating the treatment at 20^th week, urine and blood were collected for basal proteinuria and plasma BUN & creatinine estimation respectively. Then NZBWF1/J mice were randomized based on urinary proteinuria and animal body weight into 3 different groups (G2, G3, & G4) and age matched (C57BL/6) were kept as such in the control group. Compound I-10a was freshly formulated and administered to the respective animals of each group as per the body weight. Animals in G1 and G2, vehicle and disease control group, were administered with vehicle. G3 and G4 group animals were administered with a single oral dose of Compound I-10a at 10 mg/kg and 30 mg/kg, respectively. Animals were treated either with vehicle or test compound from week 20 (prophylactic mode) up to week 35. Animal body weights were recorded at the time of randomization and twice a week thereafter. To evaluate the disease progression and effect of the test compound, urine was collected once in 2 weeks (from week 20 till week 34) and utilized for proteinuria estimation. Blood was collected under mild isoflurane anesthesia retro-orbitally, separated plasma was utilized for the estimation of creatinine and blood urea nitrogen (BUN). Plasma creatinine and BUN estimation were done once in 4 weeks. At the end of experiment CSF and blood were collected under mild isoflurane anesthesia and animals were euthanized using CO₂ asphyxiation method and kidneys were isolated, fixed in 10% NBF and processed tissue were used for histopathological evaluation. Effect of Compound I-10a evaluated in prophylactic SLE model using female NZBWF1/J mice in two doses of 10 and 30 mg/kg orally. Female NZBWF1/J mice prior to the treatment are at the age 20 week was treated with Compound I-10a orally. Throughout the treatment period both lower and higher dose groups show body weight changes when compared with vehicle treated mice indicating the Compound I-10a effect noted and mice were all well tolerated, and the body weights are within the safety limits. Group 2 mice at the week of 28 showed disease induction was observed with the increase of proteinuria and was signification at week 30 with 1.0 g/dL of proteinuria. Interestingly, stable disease with 10 mg/kg dose groups even though 30 mg/kg dose mice showed efficacy where proteinuria levels were at 0.5 g/dL. Such variability was not noticed at the age 32 week to the rest of the study period where 30 mg/kg groups mice had significantly improved efficacy in maintain proteinuria levels to below 0.5 g/dL. Whereas 10 mg/kg group mice at the 34^th week did not show efficacious. This effect at the 34^th week further confirms that Compound I-10a at higher dose is efficacious and tolerable.

122 #11053313.1 Similarly, the 30 mg/kg group showed dose dependent efficacy on holding of plasma blood urea nitrogen (BUN) levels until at the terminal 34^th week. Further in histopathology evaluation of Compound I-10a demonstrated high efficacy with the scores below 2 when compared with disease and 10 mg/kg groups. In summary, Compound I-10a is efficacious in prophylactic model of SLE. BIOLOGICAL EXAMPLE 4 THERAPEUTIC LUPUS MOUSE MODEL: EFFECT OF TEST COMPOUND I-10A IN SLE MODEL USING FEMALE, NZBWF1/J The effect of Compound I-10a on body weight is shown no significant change in body weight observed across the treatment group (G3 & G4) compared to disease control group (G2). The effect of Compound I-10a on proteinuria where the G2, disease control + vehicle (10 mg/kg, p.o. QD) showed a significant increase in BUN (gm/dL) compared to G1, Normal Control (WT) + Vehicle at weeks 32 & 34. G4 (Compound I-10a, 50 mg/kg) showed a significant decrease in BUN (gm/dL) compared to G2, disease control + vehicle at week 32. The effect of Compound I- 10a on plasma creatinine where the G2, disease control + vehicle (10 mg/kg, p.o. QD) showed significant increase in creatinine (mg/dL) compared to G1, Normal Control (WT) + Vehicle on week 32 & 34. G4 (Compound I-10a, 50 mg/kg) showed a significant decrease in creatinine (mg/dL) compared to G2, disease control + vehicle on week 32. Effect of Compound I-10a on Serum Anti dsDNA IgG Antibody G2, disease control + vehicle (10 mg/kg, p.o. QD) showed a significant increase in Serum Anti dsDNA IgG (ng/ml) Vs. G1, normal control (WT) + vehicle in week 34. G3 (compound I- 10a, 30mg/kg, p.o., QD) showed a significant decrease in Serum Anti dsDNA IgG (ng/mL) Vs G2, disease control + vehicle in week 34. G4 (compound I-10a, 50mg/kg), p.o. QD) showed a decrease in Serum Anti dsDNA IgG (ng/ml) Vs G2, disease control + vehicle in week 34. Histopathology Images (H & E Staining) Histopathology (Kidney) Observation (H & E Staining) Infiltration, mononuclear cells, pelvis, dilated tubules, degeneration tubules, and protein casts were assessed in both prophylactic and therapeutics model studies.

123 #11053313.1 BIOLOGICAL EXAMPLE 5 PK ORAL BIOAVAILABILITY EXPERIMENT Evaluate bioavailability, pharmacokinetics, and brain to plasma distribution in mouse plasma following oral and intravenous administration of Compound I-10a in male Swiss Albino Mouse. A total of 24 male Swiss albino mouse were allotted for the study. Animals were allotted to 2 groups containing 12 mice/group, on day of dosing all the animals were fasted 3 hours before dosing. The test formulation was administered as a single dose by intravenous and oral route via tail vein and oral gavage needle at a dose of 1 and 5 mg/kg with a dose volume of 5 and 10 mL/kg, respectively. Approximately 0.1 mL of blood sample from each animal was collected via retro orbital at predetermined time points (3 animals/timepoint) in pre-labeled Eppendorf tubes containing anticoagulant. After blood collection at 0.5 hours and 1 hour, after collection of CSF, whole blood was withdrawn and brain tissue was collected as a terminal sampling. Blood samples were centrifuged at 10000 rpm for 5 min under refrigeration (2-4°C) within 0.5 hours to obtain plasma. The separated plasma samples were collected in pre labeled tubes within 60 min of separation and stored at -20°C up to 24 hours. Post 24-hour sample collection, all plasma samples were transferred to deep freezer custodian to store below or at -70°C till shipment. Similarly, CSF and Brain were collected at 0.5 hours and 1hour time point by scarification. Tissues were blotted and dried and then transferred to 15 mL falcon tubes. Initially all tissue samples were stored at -20 ± 3°C. Later all brain tissue samples were homogenized with PBS at 1:4 ratio and the Brain homogenate was transferred to deep freezer (-70 ± 10°C) and stored until analysis. Mouse plasma, CSF and Brain homogenate concentrations were analyzed to quantify Compound I-10a (Peak 1) using a fit-for purpose LC-MS/MS method with LLOQ of 0.977 ng/mL. The PK parameters were evaluated using Phoenix WinNonlin^® Ent-Version 8.3 by non- compartmental analysis.

124 #11053313.1 A second study was also conducted and resulted in the following data: Intravenous administration of Compound I-10a at dose of 1 mg/kg to male Swiss Albino mice, revealed moderate clearances of 47.53 mL/min/kg and 69.91 mL/min/kg compared with normal hepatic blood flow (i.e., 90 mL/min/kg). Steady state and central compartment volume of distribution was found to be normal. Intravenous plasma half-life was 0.80 hours and rate of elimination (Kel) was found to be 0.86 per hour. Oral administration of Compound I-10a at dose of 5 mg/kg to male Swiss Albino mice, demonstrated no lag phase in absorption and time to reach peak concentration was 1 hour. Compound I-10a exhibited good systemic availability. Oral bioavailability was found to be 52% and 75%. Compound I-10a attained high systemic exposure with moderate clearance. Compound I- 10a demonstrated monophasic elimination. Oral bioavailability was to be found 52% and 75%. BIOLOGICAL EXAMPLE 6 INVITRO PIM KINASE INHIBITION EXPERIMENTS ADP-Glo™ is a novel bioluminescent, homogeneous assay for monitoring ADP producing biochemical reactions and thus it is an ideal assay for detecting enzyme activity using a wide variety of substrates. ADP-Glo is performed in 2 steps upon completion of kinase reaction: a

125 #11053313.1 combined termination of kinase reaction and depletion of remaining ATP in the first step, and conversion of generated ADP to ATP and the newly produced ATP to light output using luciferase/luciferin reaction in the second step. The luminescent signal generated is proportional to the ADP concentration produced and is correlated with the kinase activity. PIM1 inhibitors were screened using this ADP-Glo kit as a cell-free assay. Reagents PIM1 kinase enzyme system (Promega, cat: V4032), PIM1 10 µg (0.1 µg/µL), S6K Substrate, 1 mL (1 mg/mL) Reaction buffer A (5×): 200 mM Tris-HCl (pH 7.5), 100 mM MgCl₂ and 0.5 mg/mL BSA, DTT (0.1 M), ADP-Glo Kinase assay kit (Promega, cat: V9101), Ultra-Pure ATP solution, 10 mM ADP solution, 10 mM ADP-Glo reagent Kinase Detection buffer, Kinase Detection substrate Assay Protocol Step 1: Kinase Detection Reagent Preparation a. Equilibrate the Kinase Detection Buffer and Kinase Detection Substrate to room temperature before use. b. Transfer the entire volume of Kinase Detection Buffer into the amber bottle containing Kinase Detection Substrate to reconstitute the lyophilized substrate. This forms the Kinase Detection Reagent. c. Mix by gently vortexing, swirling, or inverting the contents to obtain a homogeneous solution. The Kinase Detection Substrate should go into solution in less than one minute. d. The Kinase Detection Reagent should be used immediately or dispensed into aliquots and stored at –20°C. Step 2: Thaw all components of PIM1 enzyme system and ATP, ADP on ice. Step 3: In a white 384 well plate, add the following reaction components bring the reaction volume up to 6 µL. Component 1.1 µL of 2× buffer A Component 2.1 µL of diluted S6K (final amount 7.6 µg, concentration 20 µM) Component 3.1 µL of diluted PIM1 (final amount 0.1425 ng, concentration 0.7 nM) Component 4.1 µL of chemical component (initial concentration 100 µM, 3-fold serial, 10 concentrations, and DMSO)

126 #11053313.1 Step 4: Step up the blank control as outlined in step 3, excluding the addition of the substrate, replace the substrate with an equal volume of distill H2O. Step 5. At the same time as the PIM1 kinase reaction, set up a Standard Curve for Conversion of ATP to ADP. Prepare 1 mL of 1 mM ATP and 500 µL of 1 mM ADP by diluting the supplied Ultra-Pure ATP and ADP in preferred 1× kinase reaction buffer. Add 90 µL of 1× kinase reaction buffer to wells B1–B12, C1–C12 and D1–D12 of a 96-well plate. Combine the 1 mM ATP and 1 mM ADP solutions prepared in Step 1 in wells A1–A12 as indicated to simulate the ATP and ADP concentrations at each percent conversion. Dilute the samples in wells A1–A12 by transferring 10 µL of the sample in well A1 to well B1, 10 µL from well A2 to well B2, etc. Mix well. This is the 100 µM series. Dilute the samples in wells B1–B12 by transferring 10 µL of the sample in well B1 to well C1, 10 µL from well B2 to well C2, etc. Mix well. This is the 10 µM series. Dilute the samples in wells C1–C12 by transferring 10 µL of the sample in well C1 to well D1, 10 µL from well C2 to well D2, I. Mix well. This is the 1 µM series. Step 6: After compounds were delivered into the reaction, followed 20 min later by addition of 1 µL diluted ATP (final concentration is 10 µM). Reaction was carried out at room temperature for 120 minutes. Step 7: Terminate the reaction and deplete the remaining ATP by adding 5 µL ADP-Glo reagent, shake the plate and incubate the reaction mixture for another 40 minutes at room temperature. Step 8: Add 10 µL of kinase detection reagent, shake the plate and then incubate the reaction mixture for another 30 minutes at room temperature. Step 9: Read the plate and using the conversion curve, determine the amount of ADP produced (nmol) in the presence and absence of substrate and calculate the kinase activity. Results Linearity of the ADP-Glo™ kinase assay. ATP to ADP conversion curves were prepared at the indicated ATP + ADP concentration ranges in 5 µL of 1× Reaction Buffer A in a solid white 384-well plate. The ADP-Glo kinase assay was performed using 5 µL of ADP-Glo reagent and 10 µL of kinase detection reagent at room temperature. Luminescence values represent the meaning of 2 replicates.

127 #11053313.1 Determination of PIM1 inhibitors selectivity was performed using ADP-Glo™ assay. PIM1 kinase assays were performed in 25 µL in the presence of serial dilution of PIM1 inhibitors – compound I-8 (IC₅₀ = 17µM) and TP3654 (356 nM). BIOLOGICAL EXAMPLE 7 EFFECT OF PIM INHIBITION OF MULTIPLE MYELOMA CELL VIABILITY Cellular Proliferation Assay To determine the cytotoxicity of PIM inhibitors and their impact on cells proliferation the CellTiter-Glo 2.0 assay (Promega, WI, USA) was performed according to the manufacturer’s protocol. MM.1S and MM.1R cells were seeded at density of 2 × 104 cells per well on 96-well microplate (Falcon white/clear bottom plate, Corning, NY, USA), 8 wells per group. After 72 h of culture the PIM inhibitors were applied to cells in growth medium in different concentration. Potential cytotoxicity of PIM inhibitors was tested after 72 hours of incubation. CellTiter-Glo Reagent was added in an equal volume (100 µL) to each well. The luminescence was recorded using Biotek H1. The untreated cells were indicated as a control. Furthermore, the background luminescence was determined in wells containing medium without cells. BIOLOGICAL EXAMPLE 8 MULTIPLE MYELOMA – IN VITRO TEST RESULTS Multiple Myeloma (MM) cell lines (EJM, IM-9, L-363, LP-1, MM-1R, MM.1S, MOLP-2, NCI-H929, OPM-2, RPMI8226 and U-266) and primary MM patient samples by CellTiter-Glo^® Cell Viability Assays (CTG) are tested. The in vitro efficacy of our PIM inhibitors was comparable to that of single pan-PIM inhibitor TP3654 used as a positive control. Cellular apoptosis experiments with Annexin V staining, cell cycle analysis with Edu/DAPI staining, flow cytometry, and bone marrow microenvironmental conditions on the most sensitive cells cultured under hypoxic conditions are being investigated and will be presented. Additionally, PIM kinase and downstream targets of PIM examined by western blot, trans well cell migration, invasion assay data. BIOLOGICAL EXAMPLE 9 MULTIPLE MYELOMA – IN VIVO TESTING Anti-tumor dose response efficacy of PIM inhibitors was evaluated against MM1.S (human MM) Xenograft in Female NOD.SCID Mice. All female NOD.SCID mice are injected

128 #11053313.1 subcutaneously (SC) in the right flank region with 0.2 mL of 5 × 10⁶ cell suspension (1× PBS: Matrigel; 1:1 ratio). After tumor development, tumor growth is measured by digital Vernier caliper. Further, tumor volume is calculated by the formula: Tumor volume (mm³) = (Length × Width²) / 2. Animals whose tumor volume reaches ~100-200 mm³ are selected for the experiment and randomized based on tumor volume (TV) into four groups G1-G4. Group G1 is treated with vehicle control (10 mL/kg, p.o., QD) for 21-36 days. Group G2 is treated with compound I-10a (15 mg/kg, dose, p.o., QD) for 21-36 days. Group G3 is treated with compound I-10a (30 mg/kg, dose, p.o., QD) for 21-36 days. Group G4 is treated with compound I-10a (45 mg/kg, dose, p.o., QD) for 36 days (survival group). BIOLOGICAL EXAMPLE 10 BIOCHEMICAL ASSAY RESULTS Representative compounds were tested for inhibitory activity against PIM according to the following procedures. Table 2. Activity of Representative Compounds

129 #11053313.1 For PIM1, PIM2, and PIM3 IC50 activity in Table 2: + IC50 concentration greater than 1000 nM ++ IC50 concentration ranging from greater than 350 to 1000 nM +++ IC₅₀ concentration ranging from greater than 100 to 350 nM ++++ IC₅₀ concentration ranging from greater than 10 to 100 nM +++++ IC50 concentration of 10 nM or less BIOLOGICAL EXAMPLE 11 IN VITRO SAFETY SECONDARY PHARMACOLOGY SelectScreen™ P450 profiling for the assessment of P450 isozyme inhibition by Compound I-10a The Predictor™ hERG Fluorescence Polarization Assay Kit was used to perform hERG channel biochemical binding studies in the absence of radioligand. Compound I-10a hERG activity and the measured low IC₅₀ of 26 mM (Life Technologies). Safety78Panel Assay on representative compounds of Structure (I) Safety 78 panel assays in the SafetyScan E/IC50 utilizing the Path Hunter enzyme fragment complementation (EFC), FLIPR based cellular screening, and KINOMEscan kinase binding assays were performed on Compound I-10a. BIOLOGICAL EXAMPLE 12 BIOAVAILABILITY AND CSF/BRAIN UPTAKE PHARMACOKINETIC STUDY OF COMPOUND I-10A IN MALE RATS The objective of this study was to evaluate bioavailability, pharmacokinetics and CSF and Brain uptake ratio of compound I-10a following intravenous bolus and oral administration in male rat at a dose of 1 mg/kg and 5 mg/kg, respectively.

130 #11053313.1 A total of 18 male rats were allotted for the study. Animals were allotted into 2 groups of 9 rat per group. In each group, the first three animals were used for PK study, next three and followed by three animals were used for 0.5 h and 1 h brain, CSF and blood collection purpose for intravenous and oral groups, respectively. On the day of the dosing all the animals were fasted overnight. Compound I-10a formulation was administered to G1 and G2 as a single dose by intravenous dose of 1 mg/kg and oral route at a dose of 5 mg/kg. Compound I-10a was administered with a dose volume of 2 & 10 mL/kg for intravenous and oral routes, respectively. Approximately 0.3 mL of blood sample from each animal was collected via retro jugular vein at predetermined time points at 0.083 (only IV), 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h intervals in pre-labeled tubes containing anticoagulant K2EDTA (20 µL per ml of blood). Blood sample was centrifuged at 5000 rpm for 10 min under refrigeration (2-4°C) to obtain plasma. For brain and CSF uptake study, after 0.5 h and 1 h CSF and the whole brain was withdrawn, and brain tissue was homogenized as a terminal sampling. Blood samples were centrifuged under refrigeration (2-4°C) within 0.5 h to obtain plasma. The separated plasma samples were collected in pre- labelled tubes within 60 min of separation and stored at -20°C up to 24 h. Post 24 h sample collection, all plasma samples were transferred to deep freezer custodian and stored below or at - 70°C until shipment to Bioanalysis. Brain tissues were blotted and dried and then transferred to 15 mL falcon tubes. Initially all tissue samples were stored at -20 ± 3°C. Later all brain tissue samples were homogenized with PBS at 1:4 ratio and the Brain homogenate was transferred to Deep freezer (-70 ± 10°C) and stored until bioanalysis. Plasma, CSF and Brain homogenate concentrations were analyzed to quantify compound I-10a using a fit-for purpose LC-MS/MS method with LLOQ of 0.977 ng/mL. The PK parameters were evaluated using Phoenix WinNonlin^® Ent-Version 8.3 by non-compartmental analysis. Mean Pharmacokinetic parameters of compound I-10a following intravenous and oral administration in rats:

131 #11053313.1 Intravenous administration of compound I-10a at dose of 1 mg/kg to male rats, revealed moderate clearance and it was 2.2-fold lower to normal hepatic blood flow (i.e.55 mL/min/kg). Steady state and central compartment volume of distribution was found to be normal compared to the normal whole-body distribution (2 L/kg). Oral administration of compound I-10a at dose of 5 mg/kg to male rats, demonstrated no lag phase in absorption and time to reach median peak concentration was 1 h. Compound I-10a exhibited low availability. Oral bioavailability was found to be 15% compared with intravenous dose. Brain to Plasma ratio and CSF to Plasma ratio at 0.5 h: Brain to Plasma ratio and CSF to Plasma ratio at 1 h: Compound I-10a attained systemic exposure with moderate clearance. Oral bioavailability was found to be 15%. Compound I-10a penetrates the Blood Brain Barrier and revealed higher exposure than plasma at 1 h. In Group 1 and Group 2 animals were cannulated during the acclimatization period. Jugular veins were used for catheterization for sampling.

132 #11053313.1 Note: Compound I-10a is a clear solution using the above vehicle and it is stable for 24 h post preparation. The study was conducted as serial sampling design in parallel phases. A total of 18 male rat were compound I-10a and design is summarized below: Formulations were administered as a single dose by oral and iv route via oral tube tail vein respectively. Post preparation, an aliquot of respective strengths was be quenched/directly submitted for assessment using LC-MS/MS or HPLC. Approximately 0.3 mL of blood sample from each animal were collected via jugular vein at predetermined time points at 0.083 (only IV), 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h intervals in pre- labeled tubes containing anticoagulant K2EDTA (20 µL per ml of blood). Group-1: Some animals were sacrificed at 0.5 h and some animals were sacrificed at 1 h post dose. Before sacrifice, blood was collected (to harvest plasma) then brain and CSF were collected. Group-2: Some animals were sacrificed at 0.5 h and some animals were sacrificed at 1 h post dose. Before sacrifice, blood was collected (to harvest plasma) then brain and CSF were collected. Blood samples were centrifuged at 5000 rpm for 10 min under refrigeration (2-4°C) within 0.5 h to obtain plasma. The separated plasma, Brain and CSF samples were collected in pre-labeled tubes and stored at -20°C up to 24 h. Post 24 h sample collection, all plasma and homogenized brain samples were transferred to deep freezer custodian to store below or at -70°C until analysis. Individual animal body weights for all animals recorded prior to dose administration. All plasma samples of the study were stored at -70 ± 10°C until analysis. The concentrations of compound I-10a in rat plasma samples were determined using a fit-for-purpose research LC-MS/MS method.

133 #11053313.1 Based on the individual plasma concentration time profiles, pharmacokinetic (PK) parameters were calculated by non-compartmental analysis by using Phoenix™ WinNonlin^® Version 8.3. All concentration values appearing below the lower limit of quantification was presented as “BLQs” and treated as zero concentration for PK calculation. PK parameters including (but not limited to) peak plasma concentration (C_max), time to reach the peak plasma concentration (Tmax), AUC0-t, AUC0-inf, T1/2, Kel, CL, Vd, Vss and MRTlast were evaluated and reported. Compound I-10a formulations were administered through IV and oral route via tail vein and oral gavage needle. A time gap of approximately 1-2 minutes was provided between the animals to facilitate easy dosing. Dose formulations were assessed for accuracy and found 115 % compared to the nominal concentration (0.5 mg/mL). All rats showed normal appearance and behavior during the study. There was no morbidity and mortality during the entire study period. Selected rat body weights are within ±20% of mean body weights. Individual concentrations of compound I-10a in rat plasma were quantified with the linearity range of 0.977 ng/mL to 1000 ng/mL with LLQC of 0.977 ng/mL. Intravenous administration of compound I-10a at dose of 1 mg/kg to male rats, revealed moderate clearance and it was 2.2-fold lower to normal hepatic blood flow (i.e., 55 mL/min/kg). Steady state and central compartment volume of distribution was found to be normal compared to the normal whole-body distribution (2 L/kg). Oral administration of compound I-10a at dose of 5 mg/kg to male rats, demonstrated no lag phase in absorption and time to reach median peak concentration was 1 h. Oral bioavailability was found to be 15% compared with intravenous dose. Compound I-10a attained systemic exposure with moderate clearance. Oral bioavailability was found to be 15%. Compound I-10a penetrated the Blood Brain Barrier and revealed higher exposure than plasma at 1 h. The following table shows mean toxicokinetic parameters of compound I-10a following single intravenous and oral administration.

134 #11053313.1 The following table shows mean plasma concentration of compound I-10a following single intravenous and oral administration. The following table shows brain to plasma ratio and CSF to plasma ratios at a 30-minute time point. The following table shows brain to plasma ratio and CSF to plasma ratios at a 60-minute time point.

135 #11053313.1 The following table shows a summary of clinical signs for groups of animals (9 males / group) that were treated with compound I-10a. BIOLOGICAL EXAMPLE 13 STUDY OF COMPOUND I-10A IN SLE MODEL Female (Nulliparous & Non-Pregnant) NZBWF1/J & C57BL/6 were selected as the test animals as it is commonly reported in literature to evaluate the effect of various test compounds in systemic lupus erythematous. The vehicle was 1% DMSO + 5% Tween 20 + 94% Milli Q Water. Unless otherwise indicated, data is shown as Mean ± S.E.M; * indicates a significant difference as compared to G2 # indicates a significant difference as compared to G1 Two-way ANOVA followed by Dunnett's Multiple Comparison Test #/* P < 0.05 #^#/**P < 0.01 #^###/****P < 0.0001 Unpaired T-Test $ P < 0.05

136 #11053313.1 NZBWF1/J (45) and normal control C57BL/6 (15) female mice were procured. All animals were allowed to quarantine for a week and acclimatize for 1 day prior to experiment initiation. During this period, the animals were observed daily for clinical signs. Prior to initiating the treatment at the 28^th week, urine and blood were collected for basal proteinuria and plasma BUN & creatinine estimation respectively. Then NZBWF1/J mice were randomized based on urinary proteinuria and animal body weight into 3 different groups (G2, G3 & G4) and Age matched (C57BL/6) were kept as such in the control group. Test compound I-10a was formulated and administered to the respective animals of each group as per the body weight. Animals in G1 and G2, vehicle and disease control group, were administered with vehicle. G3 and G4 group animals were administered with a single dose of compound I-10a at 30 mg/kg and 50 mg/kg, per orally respectively. Animals were treated either with vehicle or test compound from week 28 (Therapeutic mode) up to week 34. Animal body weights were recorded at the time of randomization and twice a week thereafter. To evaluate the disease progression and effect of the test compound, urine was collected once in 2 weeks (from week 28 till week 34) and utilized for proteinuria estimation. Blood was collected under mild isoflurane anesthesia retro- orbitally, separated plasma was utilized for the estimation of creatinine and blood urea nitrogen (BUN). Plasma creatinine and BUN estimation were done once in 4 weeks. At the end of the experiment CSF and blood were collected under mild isoflurane anesthesia and animals were euthanized using CO₂ asphyxiation method and kidney, Brain, Spleen were isolated and used for bioanalysis, other kidney fixed in 10% NBF and processed for histopathological evaluation. Animals were observed for any clinical signs to treatment throughout the study. Cage- side observations were made to detect any changes and general activity of the animals. After dose administration, all the animals were observed carefully for treatment related clinical signs, including morbidity and mortality. Prior to dosing initiation and once in two weeks thereafter (till week 34), animals were placed in metabolic cages, urine was collected and utilized to estimate proteinuria using instrument Selectra PRO S. Prior to dosing initiation and once in four weeks thereafter (till week 34), animals were anaesthetized under mild isoflurane anesthesia and blood was collected retro-orbitally. Collected blood was centrifuged at 3500 g for 15 minutes at 4℃, plasma was separated and utilized for the estimation of creatinine and BUN using instrument Selectra PRO S. At the time of termination, animals were euthanized humanely using CO2 asphyxiation method and kidneys were collected, fixed in the 10% NBF. Processed tissue sections were

137 #11053313.1 stained with H&E and PAS staining and scored for glomerular deposits, cellular proliferation and infiltration, tubular atrophy and cast formation. After completion of week 34, animals were dosed either with the vehicle or test compound I-10a.1 hour post dosing blood was collected for Plasma and Submitted for bioanalysis.2 hours post dosing, CSF, was collected under mild isoflurane anesthesia. Then animals were euthanized, and brain, Kidney and Spleen tissue samples were submitted for bio analysis. In bio analysis samples were prepared and compounds were extracted, and the supernatant was injected for LC-MS/MS bio analysis. Drug concentration of compound I-10a was calculated from respective calibration curve. The effect of compound I-10a on body weight is shown in the table below. No significant change in body weight observed across the treatment group (G3 & G4) compared to disease control group (G2). Data is shown as Mean ± SEM (n= 6-15) G2 showed a significant increase in BUN (mg/dL) compared to G1 at week 32 & 34. G4 showed a significant decrease in BUN (mg/dL) compared to G2 at week 32. The effect of compound I-10a on Proteinuria is shown in the table below. The effect of compound I-10a on Plasma Creatinine is shown in in the table below. G2 showed significant increase in creatinine (mg/dL) compared to G1 on week 32 & 34. G4 showed significant decrease in creatinine (mg/dL) compared to G2 on week 32.

138 #11053313.1 G2 group showed significant increase in plasma BUN (mg/dL) compared to G1, Vehicle control at week 32. G2 showed significant increase in Serum Anti dsDNA IgG (ng/mL) Vs. G1 on week 34. G3 showed significant decrease in Serum Anti dsDNA IgG (ng/mL) Vs. G2 on week 34. G4 showed decrease in Serum Anti dsDNA IgG (ng/mL) Vs. G2 on week 34. However statically not significant The impact of compound I-10a was assessed in a therapeutic model for systemic lupus erythematosus (SLE) using female NZBWF1/J mice. The treatment involved administering two oral doses of 30 and 50 mg/kg, starting at 28 weeks of age. During the treatment period, neither the lower nor higher dose groups exhibited significant changes in body weight compared to the vehicle-treated mice, suggesting that compound I-10a was well tolerated and that body weights remained within safe limits. In G2, disease onset was observed at week 28, characterized by an increase in proteinuria, which became significant by week 30, reaching approximately 2 g/dL.

139 #11053313.1 We observed a significant reduction in proteinuria in both the 30 mg/kg and 50 mg/kg dose groups by week 32. This effect was further observed until week 34, indicating that compound I- 10a is effective in a dose-dependent manner, while also maintaining plasma blood urea nitrogen (BUN) levels stable until the terminal week 34. The analysis of serum anti-dsDNA IgG antibodies revealed a decrease in anti-dsDNA antibody production at both doses. Additionally, histopathological evaluation of compound I-10a indicated a reduction in the total histopathology score in a dose-dependent manner. In summary, compound I-10a shows efficacy in the therapeutic model of systemic lupus erythematosus (SLE). The various embodiments described above can be combined to provide further embodiments. All the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the Application Data Sheet are incorporated herein by reference, in their entirety. Aspects of the embodiments can be modified, if necessary to employ concepts of the various patents, applications, and publications to provide yet further embodiments. These and other changes can be made to the embodiments considering the above-detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.

140 #11053313.1

Claims

CLAIMS 1. A compound having the following Structure (I): or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: each occurrence of R¹ is independently C1-C6 haloalkyl, C1-C6 haloalkoxy, cyano, C2-C6 haloalkynyl, or optionally substituted C₃-C₈ cycloalkyl; R² has one of the following structures: each occurrence of R^2a is independently C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ aminoalkyl, halo, C1-C6 haloalkyl, -OH, C1-C6 alkoxy, or -NH2; R^2b is hydrogen or C₁-C₆ alkyl; R^2c is C1-C6 alkyl; R³ is hydrogen or C₁-C₆ alkyl; L¹ is a direct bond n is 1, 2, 3, 4, or 5; and m is 1, 2, 3, 4, or 5. 2. The compound of claim 1, wherein n is 1. 3. The compound of any one of claims 1-2, wherein R¹ is trifluoromethyl, trifluoromethoxy, difluoromethoxy, cyano, trifluoropropynyl, or cyclopropyl substituted with trifluoromethyl.

141 #11053313.1

4. The compound of any one of claims 1-3, wherein L¹ is a direct bond. 5. The compound of any one of claims 1-3, wherein L¹ is . 6. The compound of any one of claims 1-5, wherein has one of the following structures: The compound of any one of claims 1-4, wherein has one of the following structures: The compound of any one of claims 1-6, wherein has one of the following structures:

142 #11053313.1 9. The compound of any one of claims 1-4, wherein has the following structure: . 10. The compound of any one of claims 1-9, wherein m is 1, 2, or 3. 11. The compound of any one of claims 1-10, wherein R^2a C₂-C₃ hydroxyalkyl, fluoro, methoxy, -OH, or -NH2. 12. The compound of any one of claims 1-11, wherein R^2b is hydrogen or methyl. 13. The compound of any one of claims 1-12, wherein R^2c is methyl. 14. The compound of any one of claims 1-13, wherein R² has one of the following structures:

143 #11053313.1 15. The compound of any one of claims 1-14, wherein R² has the following structure: . The compound of any one of claims 1-14, wherein R² has one of the following structures: 17. The compound of any one of claims 1-14, wherein R² has the following structure: . The compound of any one of claims 1-14, wherein R² has one of the following structures:

144 #11053313.1

19. The compound of any one of claims 1-14, wherein R² has one of the following structures: 20. The compound of claim 18, wherein R² has one of the following structures: 21. The compound of claim 20, wherein R² has one of the following structures: The compound of claim 19, wherein R² has one of the following structures: The compound of any one of claims 1-22, wherein R³ is methyl. 24. The compound of any one of claims 1-22, wherein R³ is hydrogen. 25. The compound of any one of claims 1-24, wherein the compound is selected from Table 1. 26. A salt form of the compound of any one of claims 1-25, wherein the salt form is a formic acid salt, a hydrochloric acid salt, or a trifluoroacetic acid salt.

145 #11053313.1

27. A pharmaceutical composition comprising the compound of any one of claims 1-25, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable excipient. 28. A method of treating a PIM mediated disease, the method comprising administering the compound of any one of claims 1-25, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof or the pharmaceutical composition of claim 27 to a subject in need thereof. 29. The method of claim 28, wherein the method comprises inhibiting PIM1, PIM2, PIM3, or combinations thereof. 30. The method of any one of claims 28-29, wherein the PIM mediated disease is an autoimmune disease. 31. The method of any one of claims 28-30, wherein the PIM mediated disease is an autoimmune eye disease. 32. The method of any one of claims 28-29, wherein the PIM mediated disease is a hematological malignancy, a solid tumor, or a combination thereof. 33. The method of any one of claims 28-29, wherein the PIM mediated disease is a hematopoietic lymphoma, a diffuse large cell lymphoma, or a combination thereof. 34. The method of any one of claims 28-29, wherein the PIM mediated disease is multiple myeloma, prostate cancer, Burkitt’s Lymphoma, oral cancer, lung cancer, colon cancer, breast cancer, endometrial cancer, gastric cancer, pancreatic cancer, or combinations thereof. 35. The method of claim 30, wherein the PIM mediated disease is triple negative breast cancer, non-small cell lung cancer, or a combination thereof.

146 #11053313.1

36. The method of any one of claims 28-30, wherein the PIM mediated disease is lupus, Alzheimer’s disease, myelofibrosis, pulmonary fibrosis, bone marrow fibrosis, skin fibrosis, heart fibrosis, or combinations thereof. 37. The method of claim 36, wherein the PIM mediated disease is systemic lupus erythematosus, cutaneous lupus erythematosus, drug-induced lupus, neonatal lupus, or combinations thereof. 38. The method of claim 34, wherein the PIM mediated disease is multiple myeloma.

147 #11053313.1