5 / 5-5 / 6-bisaryl compounds as transforming growth factor-Β activated kinase inhibitors

Abstract

5 / 5-5 / 6 bisaryl compounds that inhibit transforming growth factor-β activated kinase (TAK1); compositions comprising the same; and their use for treating cancers and inflammatory diseases.

Description

5 / 5-5 / 6-BISARYL COMPOUNDS AS TRANSFORMING GROWTH FACTOR-β ACTIVATED KINASE INHIBITORS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. provisional patent application no. 63 / 697,731, which was filed September 23, 2024, and which is hereby incorporated by reference in its entirety. TECHNICAL FIELD

[0002] The present disclosure relates to 5 / 5-5 / 6-bisaryl compounds that are inhibitors of transforming growth factor-β activated kinase (TAK1), pharmaceutical compositions comprising the same, and their use in treating cancer and inflammatory diseases. BACKGROUND

[0003] This section introduces aspects that may help facilitate a better understanding of the disclosure. Accordingly, these statements are to be read in this light and are not to be construed as admissions about what is or is not prior art.

[0004] Protein kinases add the terminal γ-phosphate group of adenosine triphosphate (ATP) to other proteins' tyrosine, threonine, or serine residues to regulate the state or function of the client proteins. Protein phosphorylation plays a crucial role in cellular signaling pathways, regulating activities such as cell growth, proliferation, differentiation, and apoptosis. A disruption of tightly regulated phosphorylation can often result in numerous diseases, including inflammatory disorders, cancer, and autoimmune diseases. As a result, targeting disease-associated kinases with specific inhibitors has emerged as an appealing strategy for drug development.

[0005] While there are over 500 protein kinases in the cell, only a handful (less than 10%) have been successfully drugged in the clinic. Transforming growth factor-β-activated kinase 1 (TAK1), a serine / threonine kinase, plays pathological roles in cancer and inflammatory diseases, but a clinical candidate specifically developed against this kinase is lacking. TAK1 is activated by various proinflammatory cytokines and ligands such as TNF, interleukin-1β (IL-1β), lipopolysaccharide (LPS), and transforming growth factor beta (TGFβ). Upon activation, it initiates downstream signaling cascades, leading to the activation of major inflammatory pathways such as c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and nuclear factor-κβ (NF-κβ) (Trends Pharmacol. Sci., 2012, 33, 522–530). These pathways play significant roles in developing inflammatory disorders such as rheumatoid arthritis (RA),  inflammatory bowel diseases (IBD), and pneumoconiosis. Various studies suggested that IL-1β, IL-6, and TNF are overexpressed in RA and IBP, which contribute to joint erosion and tissue destruction. Genome-wide association studies (GWAS) have identified several loci associated with TAK1-TNF signaling, highlighting TAK1 as a potential therapeutic target. For instance, a GWAS meta-analysis involving RA patients from Asia revealed significant enrichment of MAP3K7 (TAK1 inhibitor) and the TAK1 activator protein TAB1. The therapeutic potential of TAK1 inhibition has been demonstrated in preclinical models of various inflammatory diseases. TAK1 is also implicated in various cancers.

[0006] Small molecule inhibitors of TAK1, such as 5Z-7-oxozeaenol and takinib, have shown efficacy in reducing inflammation and tissue damage in experimental models (Open Biol., 2020, 10, 9, 200099; J. of Pain Res., 2024, 17, 2287-2298). Morpholino-imidazo[1,2-b]pyridazine compounds as Tak1 inhibitors are reported in RSC Med. Chem., 2024, 15, 178-192. Pharmacokinetic studies revealed that some of the imidazo[1,2-b]pyridazine compounds had poor oral bioavailability.

[0007] Therefore, it is an object of the present disclosure to provide a compound that potently inhibits TAK1 inhibitors and has good oral bioavailability. This and other objects and advantages, as well as inventive features, will be apparent from the detailed description. SUMMARY

[0008] Provided is a compound of formula (I):wherein: each X is independently N, NRa, or CRb, wherein Rais selected from H, C1-C6alkyl, C3-C8cycloalkyl, hetero C1-C6 alkyl, C1-C6 alkylcarbonyl, arylcarbonyl, hetero C1-C6 alkylcarbonyl, amide, and sulfonamide; and Rbis selected from H, cyano, halo, alkoxy, C1-C6alkyl, trifluoro C1- C6 alkyl, halo C1-C6 alkyl, dihalo C1-C6 alkyl, hydroxy C1-C6 alkyl, alkoxy C1-C6 alkyl, C3-C8 cycloalkyl, hetero C1-C6 alkyl, amino C1-C6 alkyl, cyano C1-C6 alkyl, C1-C6 dialkylaminoalkyl, morpholinyl C1-C6alkyl, piperazinyl C1-C6alkyl, C1-C6dialkylaminocarbonyl, C1-C6  dialkylaminosulfonyl, hydroxyaryl, alkoxyaryl, carboxylic acid, ester, ORd, and NRdRd, wherein each Rdis independently selected from hydrogen, C1-C6alkyl, hetero C1-C6alkyl and heteroaryl; wherein alkyl is optionally substituted with C1-C6 alkyl or hetero C1-C6 alkyl; The bond between X-X or X-C in a 5-membered ring can be a single bond or a double bond; each E is independently N or CRc, wherein Rc is H or halogen; W is H, aryl, heteroaryl, ORd, NRdRd, CRdRdRd, wherein each Rd is independently selected from hydrogen, C1-C6alkyl, hetero C1-C6alkyl, and heteroaryl; and Y is a 4- to 12-membered mono or bi-cyclic ring, wherein the bi-cyclic ring is a fused bi- cyclic ring, a bridged bi-cyclic ring, or a spiro bi-cyclic ring, substituted with one or more groups selected from R1-R8 based on the ring size and represented by a structure:wherein, T is sp3-carbon, sp2-carbon or N; each R1, R2, R3, R4, R5, R6, R7, and R8 is independently selected from H, halo, nitro, CN, C1-C6 alkyl, amino C1-C6 alkyl, hydroxy C1-C6 alkyl, alkoxy C1-C6 alkyl, C3-C8 cycloalkyl, aryl, heteroaryl, and hetero C1-C6 alkyl; or any two R groups from R1-R8, together with the carbon atom to which they are attached, form a 3- to 8-membered cyclic ring; and Q is O, S, S=O, SO2, NRaor CRbRb, wherein Raand each Rbis independently as defined above or the two Rb together with the carbon atom to which they are attached, form a 3- to 6- membered cyclic ring, which optionally contains one or more heteroatoms, wherein each heteroatom is independently N, S or O, or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof.

[0009] In some embodiments, each X is independently N, NRa or CRb, wherein Ra is H or C1-C6 alkyl; and Rbis a group selected from H, cyano, halo, alkoxy, C1-C6alkyl, trifluoro C1-C6alkyl and C3-C8 cycloalkyl; wherein alkyl is optionally substituted with C1-C6 alkyl or hetero C1-C6 alkyl.

[0010] In some embodiments, the Y is: .

[0011] In some embodiments, the Y is:.

[0012] In some embodiments, the Y is: wherein X is as defined above.

[0013] In some embodiments of Y, each X is independently selected from CH2, O, S, S=O, SO2, NH, N-alkyl, N-heteroalkyl, amide, sulfonamide, urea and carbamate.

[0014] In some embodiments, the Y is:   .

[0015] In some embodiments, the Y is: .

[0016] In some embodiments, the Y is: .

[0017] In some embodiments of the compound of formula (I), the W is H.

[0018] In some embodiments of the compound of formula (I), each E is independently CH or C- halogen.

[0019] In some embodiments of the compound of formula (I), each E is independently CH or C- halogen; each X is independently N, NH, C-C1-C4 alkyl, C-C3-C8 cycloalkyl, or C-ORd, wherein Rdis C1-C4alkyl; W is H; and

[0020] In some embodiments of the compound of formula (I), each X is independently N, NH, or C- C1-C4 alkyl. In some embodiments of the compound of formula (I), each X is independently N, NH, or C- C3-C8cycloalkyl. In some embodiments of the compound of formula (I), each X is independently N, NH, or C-ORd, wherein Rd is C1-C4 alkyl.

[0021] In some embodiments the compound of formula (I) is:                     or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof.

[0022] Provided is a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof, and a pharmaceutically acceptable excipient.

[0023] Further provided is a method of inhibiting transforming growth factor-β activated kinase (TAK1) in a patient in need thereof, which the method comprises administering to the patient an inhibitory effective amount of the compound of formula (I), a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof, or a pharmaceutical composition comprising the compound and a pharmaceutically acceptable excipient.

[0024] In some embodiments, the patient has cancer. In some embodiments, the patient has an inflammatory disease. In some embodiments, the inflammatory disease is arthritis. The compound can be administered orally, intravenously, intramuscularly, dermally, rectally, nasally, otically, or ocularly.

[0025] Further provided is a method of treating cancer in a patient in whom the transforming growth factor-β activated kinase (TAK1) is overexpressed, wherein the method comprises administering to the patient a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof, or a pharmaceutical composition comprising the compound and a pharmaceutically acceptable excipient.

[0026] In some embodiments, the cancer is selected from the group consisting of multiple myeloma, lung cancer, liver cancer, thyroid cancer, colon cancer, pancreatic cancer, leukemia, lymphoma, ovarian cancer, breast cancer, throat cancer, head and neck cancer, prostate cancer, brain cancer, stomach cancer, anal cancer, and melanoma. In some embodiments, the cancer is multiple myeloma.

[0027] The compound can be administered orally, intravenously, intramuscularly, dermally, rectally, nasally, otically, or ocularly. 1  BRIEF DESCRIPTION OF THE DRAWINGS

[0028] The above and other objects, features, and advantages of the present disclosure will be apparent when the description is read in conjunction with the drawings.

[0029] FIG. 1 shows the in-house kinase screening of compounds 1-51 using the ADP-GLO kinase assay. The compounds inhibited TAK1 at a 200 nM concentration.

[0030] FIG. 2 shows the in-house kinase screening compounds 52-104 using the ADP-GLO kinase assay. The compounds inhibited TAK1 at a 200 nM concentration.

[0031] FIG. 3 shows the screening of compounds 1-51 for cell growth inhibition against the MPC-11 cell line at a 200 nM concentration.

[0032] FIG. 4 shows the screening of compounds 52-104 for cell growth inhibition against the MPC-11 cell line at a 200 nM concentration.

[0033] FIG. 5 shows the in vivo efficacy of compounds 19 and 76 against multiple myeloma cancer. The compounds were able to inhibit the proliferation of RPMI8226, a multiple myeloma cell line, in a mouse model.

[0034] FIG. 6A shows the TNF-α expression levels of compound 76 in macrophages against TAK1 inhibitors. The compound inhibited lipopolysaccharides (LPS)-induced TNF-α production.

[0035] FIG.6B shows the IL-6 expression levels of compound 76 in macrophages against TAK1 inhibitors. The compound inhibited LPS-induced IL-6 in macrophages.

[0036] FIG. 7 shows the in-house kinase screening compounds 105-158 using the ADP-GLO kinase assay. The compounds inhibited TAK1 at a 200 nM concentration.

[0037] FIG. 8 shows the screening of compounds 117-158 for cell growth inhibition against multiple myeloma cancer. The compounds were able to inhibit the proliferation of the NCI-H929 cell line at a 200 nM concentration. DETAILED DESCRIPTION

[0038] For the purposes of promoting an understanding of the principles of the present disclosure, reference will now be made to the embodiments illustrated in the drawings, and specific language will be used to describe the same. It will nevertheless be understood that no limitation of the scope of the claimed invention is thereby intended.

[0039] The present disclosure is predicated, at least in part, on the discovery that the imidazo[1,2- b] pyridazine moiety, which is found in many approved and experimental drugs, binds to the  hinge region of kinases; substitutions at positions 2, 3, 6, 7, and 8 dictate kinase selectivity and potency. The imidazo[1,2-b]pyridazine scaffold has been explored to inhibit various kinases. For example,5 / 6-5 / 6-bisaryl compounds  comprising imidazo[1,2-b] pyridazine core can be transforminggrowth factor-β activated kinase (TAK1) inhibitors. The compounds can be substituted at the C6 position with a moiety such as a morpholine or a piperidine to obtain TAK 1 inhibition (RSC Med. Chem., 2024, 15, 178-192). However, the compounds have poor oral bioavailability.

[0040] In view of the above, the present disclosure provides 5 / 5-5 / 6-bisaryl compounds comprising imidazo[2,1-b][1,3,4]thiadiazol-2-yl  core that are transforming growth factor-βactivated kinase (TAK1) inhibitors.

[0041] Imidazothiadiazole hinge-binding to the region of kinases can have superior PK properties compared to imidazo[1,2-b]pyridazine, which features a six-five fused nitrogen-containing heterocyclic system, Imidazo[2,1-b][1,3,4]thiadiazole is a five-five fused heterocyclic system incorporating sulfur and nitrogen atoms. It is well known in art that reducing ring size not only enhances drug-like properties such as bioavailability and selectivity but also opens new avenues for developing innovative therapeutic agents (ACS Med. Chem. Lett., 2021, 12, 12, 1942–1947;  J. Med. Chem., 2022, 65, 13, 8699–8712). Additionally, the presence of a sulfur atom can enhance bioactivity, structural diversity, binding affinity, metabolic stability, and compatibility with various functional groups in drug design.

[0042] Provided is a compound of formula (I):wherein, each X is independently N, NRa, or CRb, wherein Ra is selected from H, C1-C6 alkyl, C3-C8cycloalkyl, hetero C1-C6alkyl, C1-C6alkylcarbonyl, arylcarbonyl, hetero C1-C6alkylcarbonyl, amide, and sulfonamide; and Rb is selected from H, cyano, halo, alkoxy, C1-C6 alkyl, trifluoro C1-C6alkyl, halo C1-C6alkyl, dihalo C1-C6alkyl, hydroxy C1-C6alkyl, alkoxy C1- C6 alkyl, C3-C8 cycloalkyl, hetero C1-C6 alkyl, amino C1-C6 alkyl, cyano C1-C6 alkyl, C1-C6 dialkylaminoalkyl, morpholinyl C1-C6alkyl, piperazinyl C1-C6alkyl, C1-C6  dialkylaminocarbonyl, C1-C6 dialkylaminosulfonyl, hydroxyaryl, alkoxyaryl, carboxylic acid, ester, ORd, and NRdRd, wherein each Rdis independently selected from hydrogen, C1-C6alkyl, hetero C1-C6 alkyl and heteroaryl; wherein alkyl is optionally substituted with C1-C6 alkyl or hetero C1-C6alkyl; The bond between X-X or X-C in a 5-membered ring can be a single bond or a double bond; each E is independently N or CRc, wherein Rcis H or halogen; W is H, aryl, heteroaryl, ORd, NRdRd, CRdRdRd, wherein each Rdis independently selected from hydrogen, C1-C6 alkyl, hetero C1-C6 alkyl, and heteroaryl; and Y is a 4- to 12-membered mono or bi-cyclic ring, wherein the bi-cyclic ring is a fused bi- cyclic ring, a bridged bi-cyclic ring, or a spiro bi-cyclic ring, substituted with one or more groups selected from R1-R8 based on the ring size and represented by a structure:wherein, T is sp3-carbon, sp2-carbon or N; each R1, R2, R3, R4, R5, R6, R7, and R8 is independently selected from H, halo, nitro, CN, C1-C6 alkyl, amino C1-C6 alkyl, hydroxy C1-C6 alkyl, alkoxy C1-C6 alkyl, C3-C8 cycloalkyl, aryl, heteroaryl, and hetero C1-C6 alkyl; or any two R groups from R1-R8, together with the carbon atom to which they are attached, form a 3- to 8-membered cyclic ring; and Q is O, S, S=O, SO2, NRaor CRbRb, wherein Raand each Rbis independently as defined above or the two Rb together with the carbon atom to which they are attached, form a 3- to 6- membered cyclic ring, which optionally contains one or more heteroatoms, wherein each heteroatom is independently N, S or O, or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof.

[0043] In some embodiments of the compound of formula (I), each X is independently N, NRa or CRb, wherein Rais H or C1-C6alkyl and Rbis selected from H, cyano, halo, alkoxy, C1-C6alkyl, trifluoro C1-C6 alkyl, and C3-C8 cycloalkyl; wherein alkyl is optionally substituted with C1-C6  alkyl or hetero C1-C6 alkyl; and wherein the bond between X-X or X-C in a 5-membered ring can be a single bond or a double bond.

[0044] In some embodiments, the Y is:.

[0045] In some embodiments, the Y is:.

[0046] In some embodiments, the Y is:  wherein X is as defined above.

[0047] In some embodiments of Y, each X is independently selected from CH2, O, S, S=O, SO2, NH, N-alkyl, N-heteroalkyl, amide, sulfonamide, urea and carbamate.

[0048] In some embodiments, the Y is:   .

[0049] In some embodiments, the Y is: .

[0050] In some embodiments, the Q is selected from O, S, S=O, SO2, NH, N-alkyl, N-heteroalkyl, N-amide, N-sulfonamide, CH2, CHF, CF2, C-hydroxyalkyl, C-alkoxyalkyl, C-aminoalkyl, C- hydroxyheteroaryl, C-alkoxy heteroaryl, C-amino heteroaryl, CHOH, CHNH2, C(alkyl)2, C(heteroalkyl)2, and a spiro ring such as C(cyclic alkyl)2or C(cyclic heteroalkyl)2;

[0051] In some embodiments of the compound of formula (I), the Y is: .

[0052] In some embodiments of the compound of formula (I), the W is H.

[0053] In some embodiments of the compound of formula (I), each E is independently CH or C- halogen; each X is independently N, NH, C- C1-C4alkyl, C- C3-C8cycloalkyl, or C-ORd, wherein Rd is C1- C4alkyl; W is H; and   .

[0054] In some embodiments of the compound of formula (I), each X is independently N, NH, or C-C1-C4alkyl. In some embodiments of the compound of formula (I), each X is independently N, NH, or C- C3-C8 cycloalkyl. In some embodiments of the compound of formula (I), each X is independently N, NH, or C-ORd, wherein Rdis C1-C4alkyl.

[0055] In some embodiments, each E is independently CH; each X is independently N, NH, C- C2H5or C-OCH3; W is H; and Y is:

[0056] In some embodiments, the compound of formula (I) is:                  oor a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof.

[0057] In some embodiments, the compound of formula (I) is a TAK1 inhibitor. The compounds can inhibit the proliferation of several cancers and can treat inflammatory diseases such as arthritis. In some embodiments, the prodrugs, bifunctional analogs, such as Protac or molecular degraders, cell-specific conjugates, such as antibody conjugates, and various formulations of the compounds of formula (I) to improve biological activity are provided.

[0058] The term "substituted" refers to a functional group in which one or more hydrogen atoms contained therein are replaced by one or more non-hydrogen atoms. The term "functional group" or "substituent" refers to a group that can be, or is, substituted onto a molecule. Examples of substituents or functional groups include, but are not limited to, a halo (e.g., F, Cl, Br, and I); an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups including carboxylic acids, carboxylates, and  carboxylate esters; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, azides, hydroxylamines, cyano, nitro groups, N-oxides, hydrazides, and enamines; and other heteroatoms in various other groups. Non-limiting examples of substituents, which can be bonded to a substituted carbon atom (or other atom, such as nitrogen) include F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO, NO2, ONO2, azido, CF3, OCF3, R, O (oxo), S (thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, (CH2)0-2P(O)OR2, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2)0-2N(R)C(O)R, (CH2)0-2N(R)C(O)OR, (CH2)0-2N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, and C(=NOR)R wherein R can be hydrogen or a carbon-based moiety, and wherein the carbon-based moiety can itself be further substituted; for example, where R can be hydrogen, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl, any alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl or R can be independently mono- or multi-substituted; or when two R groups bonded to a nitrogen atom or to adjacent nitrogen atoms can, together with the nitrogen atom or atoms to which they are bonded, form a heterocyclyl, the heterocycle can be mono- or independently multi-substituted.

[0059] The terms "optionally substituted" and "optional substituents" indicate that the groups in question are either unsubstituted or substituted with one or more of the substituents specified. When the groups in question are substituted with more than one substituent, the substituents may be the same or different. When used with the terms "independently," "independently are," and "independently selected from," the groups in question may be the same or different. Certain of the herein defined terms may occur more than once in the structure and, upon such occurrence, each term shall be defined independently of the other.

[0060] The term " alkyl" refers to substituted or unsubstituted straight-chain and branched alkyl groups and cycloalkyl groups having from 1 to about 20 carbon atoms (e.g., C1-C20), 1 to 12 carbons (e.g., C1-C12), 1 to 8 carbon atoms (e.g., C1-C8), or, in some embodiments, from 1 to 6 carbon atoms (e.g., C1-C6). Examples of straight-chain alkyl groups include those with from 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. The term "alkyl" encompasses n-alkyl, isoalkyl, and anteisoalkyl groups, as well as other branched chain forms of  alkyl. Representative substituted alkyl groups can be substituted one or more times with any of the groups listed herein, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, carbonyl, and halogen groups.

[0061] The term "alkenyl" refers to substituted or unsubstituted straight-chain and branched divalent alkenyl and cycloalkenyl groups having from 2 to 20 carbon atoms (e.g., C2-C20), 2 to 12 carbons (e.g., C2-C12), 2 to 8 carbon atoms (e.g., C2-C8) or, in some embodiments, from 2 to 4 carbon atoms (e.g., C2-C4) and at least one carbon-carbon double bond. Examples of straight- chain alkenyl groups include those with from 2 to 8 carbon atoms, such as -CH=CH-, - CH=CHCH2-, and the like. Examples of branched alkenyl groups include, but are not limited to, -CH=C(CH3)- and the like.

[0062] The term "alkynyl" refers to an unsaturated monovalent chain of carbon atoms, including at least one triple bond, which may be optionally branched. In various embodiments that include alkynyl, illustrative examples include lower alkynyl, such as C2-C6, C2-C4 alkynyl, and the like.

[0063] The term "hydroxyalkyl" refers to alkyl groups substituted with at least one hydroxyl (- OH) group.

[0064] The term "cycloalkyl" refers to substituted or unsubstituted cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group can have 3 to about 8-12 ring members, whereas in other embodiments, the number of ring carbon atoms ranges from 3 to 4, 5, 6, or 7. In some embodiments, cycloalkyl groups can have 3 to 6 carbon atoms (e.g., C3-C6). Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like.

[0065] The term "acyl" refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom. The carbonyl carbon atom is also bonded to another carbon atom, which can be part of a substituted or unsubstituted alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl group or the like. In the special case wherein the carbonyl carbon atom is bonded to a hydrogen, the group is a "formyl" group, an acyl group as the term is defined herein. An acyl group can include 0 to about 12-40, 6-10, 1-5 or 2-5 additional carbon atoms bonded to the carbonyl group. An acryloyl group is an example of an acyl group. An acyl group can also include heteroatoms within the meaning herein. A nicotinoyl group (pyridyl-3-carbonyl) is an example of an acyl group within the meaning herein. Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and cryloyl groups and the like. When the group containing the carbon atom that is bonded to the  carbonyl carbon atom contains a halogen, the group is termed a "haloacyl" group. An example is a trifluoroacetyl group.

[0066] The term "carbonyl" refers to a —C(O)R group, wherein R is alkyl, aryl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heteroaryl, heterocyclyl, or amino. The term "C1-6carbonyl" refers to a group that may be preceded by an alkyl group of up to 5 carbon atoms. It may also be called an "alkylcarbonyl". Examples include —C(O)R, —CH2C(O)R, —CH2CH2C(O)R, and — CH2CH2CH2C(O)R.

[0067] The term "aryl" refers to substituted or unsubstituted cyclic aromatic hydrocarbons that do not contain heteroatoms in the ring. Thus aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, aryl groups contain about 6 to about 14 carbons (e.g., C6-C14) or from 6 to 10 carbon atoms (e.g., C6-C10) in the ring portions of the groups. Aryl groups can be unsubstituted or substituted, as defined herein. Representative substituted aryl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2- substituted phenyl, 3- substituted phenyl, 4- substituted phenyl, 5- substituted phenyl, or 6-substituted phenyl or 2-8 substituted naphthyl groups, which can be substituted with carbon or non-carbon groups such as those listed herein.

[0068] The term "heteroaryl" represents aromatic ring comprising at least one hetero atom such as N, S, O, or Se. Heteroaryl in the present disclosure may be any hetero aryl. Heteroaryl includes, but is not limited to, pyrrolidinyl, azetidinyl, piperidynyl, piperazinyl, morpholinyl, chromanyl, indolinonyl, isoindolinonyl, furanyl, pyrrolidinyl, pyridinyl, pyrazinyl, pyrimidinyl, triazinyl, thiophenyl, tetrahydrofuranyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, triazyolyl, tetrazolyl, benzoxazolinyl, benzthiazolinyl, benzimidazolinyl groups, or any combination thereof.

[0069] The term "halogen" refers to an atom selected from fluorine, chlorine, bromine, and iodine.

[0070] The term "heterocycloalkyl" refers to a non-aromatic heterocycle where one or more of the ring-forming atoms is / are a heteroatom, such as an O, N, or S atom. Heterocycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems as well as spirocycles. Example heterocycloalkyl groups include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4- dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, and the like. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the nonaromatic heterocyclic ring, for example phthalimidyl, naphthalimidyl, and benzo derivatives  of heterocycles. A heterocycloalkyl group having one or more fused aromatic rings can be attached though either the aromatic or non-aromatic portion. Also included in the definition of hetero-cycloalkyl are moieties where one or more ring-forming atoms are substituted by 1 or 2 oxo or sulfido groups. In some embodiments, the heterocycloalkyl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heterocycloalkyl group contains 3 to about 20, 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 triple bonds.

[0071] It is understood that each of alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkylene, and heterocycle may be optionally substituted with independently selected groups such as alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, carboxylic acid and derivatives thereof, including esters, amides, and nitrites, hydroxy, alkoxy, acyloxy, amino, alky and dialky-lamino, acylamino, thio, and the like, and combinations thereof.

[0072] The term "amine" refers to primary, secondary, and tertiary amines having, e.g., the formula N(group)3 wherein each group can independently be H or non-H, such as alkyl, aryl, and the like. Amines include, but are not limited to, R-NH2, for example, alkylamines, arylamines, alkylarylamines; R2NH, wherein each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines and the like; and R3N, wherein each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like. The term "amine" also includes ammonium ions.

[0073] The term "amino group" refers to a substituent of the form -NH2, -NHR, -NR2, -NR3+, wherein each R is independently selected, and protonated forms of each, except for -NR3+, which cannot be protonated. Accordingly, any compound substituted with an amino group can be viewed as an amine. An "amino group" can be a primary, secondary, tertiary, or quaternary amino group. An "alkylamino" group includes a monoalkylamino, a dialkylamino, and a trialkylamino group.

[0074] The term "compound" as used herein, is meant to include all stereoisomers, geometric isomers, and tautomers of the structures depicted.

[0075] The compounds desribed herein as "optical isomers" may contain one or more chiral centers, or may otherwise be capable of existing as multiple stereoisomers. In various embodiments, the compounds are not limited to any particular stereochemical requirement, and the compounds, and compositions, methods, uses, and medicaments that include them, may be optically pure or any of a variety of stereoisomeric mixtures, including racemic and other mixtures of enantiomers, other mixtures of diastereomers, and the like. Such mixtures of stereoisomers  may include a single stereochemical configuration at one or more chiral centers, while including mixtures of stereochemical configuration at one or more other chiral centers.

[0076] Similarly, the compounds described herein may include geometric centers, such as cis, trans, E, and Z double bonds. In various embodiments, the compounds are not limited to any particular geometric isomer requirement, and the compounds, and compositions, methods, uses, and medicaments that include them, may be pure or any of a variety of geometric isomer mixtures. Such mixtures of geometric isomers may include a single configuration at one or more double bonds, while including mixtures of geometry at one or more other double bonds.

[0077] The term "SP3carbon" refers to a tetravalent carbon that forms single covalent bonds (sigma bonds) with atoms. The bonds formed are of equal strength and at an angle of 109.5o, due to which the central carbon atom is tetrahedral in shape. The steric number of carbon is 4.

[0078] The term "SP2carbon" refers to a carbon that forms two single bonds and one double bond between three atoms and has trigonal planer geometry. The steric number of carbon is 3.

[0079] Provided are pharmaceutically acceptable salts of the above-described compounds and the preparation and use thereof. Salts can be prepared during the final isolation and purification of the compound or separately by reacting the compound with a suitable acid.

[0080] The term "pharmaceutically acceptable salt" refers to salts or zwitterionic forms of compounds described herein. Examples of the salts of the compounds described herein include, but are not limited to, hydrochloride salt, hydrobromide salt, hydroiodide salt, sulfate salt, bisulfate salt, 2-hydroxyethansulfonate salt, phosphate salt, hydrogen phosphate salt, acetate salt, adipate salt, alginate salt, aspartate salt, benzoate salt, bisulfate salt, butyrate salt, camphorate salt, camphorsulfonate salt, digluconate salt, glycerolphosphate salt, hemisulfate salt, heptanoate salt, hexanoate salt, formate salt, succinate salt, fumarate salt, maleate salt, ascorbate salt, isethionate salt, salicylate salt, methanesulfonate salt, mesitylenesulfonate salt, naphthylenesulfonate salt, nicotinate salt, 2-naphthalenesulfonate salt, oxalate salt, pamoate salt, pectinate salt, persulfate salt, 3-phenylproprionate salt, picrate salt, pivalate salt, propionate salt, trichloroacetate salt, trifluoroacetate salt, phosphate salt, glutamate salt, bicarbonate salt, paratoluenesulfonate salt, undecanoate salt, lactate salt, citrate salt, tartrate salt, gluconate salt, methanesulfonate salt, ethanedisulfonate salt, benzene sulfonate salt, and p-toluenesulfonate salt. Any reference compounds of the present disclosure appearing herein are intended to include compounds of the present disclosure as well as pharmaceutically acceptable salts or hydrates thereof.

[0081] In some embodiments, provided is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof,  and a pharmaceutically acceptable excipient. Any suitable excipient, as well- known in the art, can be used. The excipient can vary based on the particular route of administration (see, e.g., Remington’s The Science and Practice of Pharmacy, 23rded. (2020)). The term “excipient” is an umbrella term that refers to any inactive substance included in a pharmaceutical composition alongside the active pharmaceutical ingredient (API),e.g., diluents, carriers, binders, lubricants, disintegrants, stabilizers, preservatives, enhancers, and glidants.

[0082] TAK1 is a key signaling molecule whose inhibition can induce cancer cell death, suppress inflammation, reduce bone destruction, and protect against muscle fibrosis and neurodegeneration (Cell Chemical Biology, 2017, 24 (4), 1029-1039). TAK1 is a pivotal regulatory signaling node in the biochemical signaling pathways that mediate the production of proinflammatory cytokine responses in immune cells. The activation of TAK1 can lead to the expression of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) or interleukin-6 (IL-6), for example. Examples of conditions or diseases in which TAK1 can be expressed, such as overexpressed, include, but are not limited to, cancers, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, neuroinflammation, diabetes, inflammatory myopathies, cellular stress, neurological disorders, and vascular diseases.

[0083] In view of the above, provided is a method of inhibiting a transforming growth factor-β activated kinase (TAK1) in a patient in need thereof. The method comprises administering to the patient an inhibitory effective amount of compound of formula (I), a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof, or a pharmaceutical composition comprising the compound and a pharmaceutically acceptable excipient. In some embodiments, the patient has a cancer or an inflammatory disease. In some embodiments, the inflammatory disease is arthritis.

[0084] Further in view of the above, a method of treating cancer in a patient, in whom the TAK1 is overexpressed, is provided. The method comprises administering to the patient a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof, or a pharmaceutical composition comprising the compound and a pharmaceutically acceptable excipient.

[0085] Examples of cancers include, but are not limited to, multiple myeloma, lung cancer, liver cancer, thyroid cancer, colon cancer, pancreatic cancer, leukemia, lymphoma, ovarian cancer, breast cancer, throat cancer, head and neck cancer, prostate cancer, brain cancer, stomach cancer, anal cancer, and melanoma. In some embodiments, the cancer is multiple myeloma.

[0086] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof, can be administered orally, intravenously, intramuscularly, dermally, rectally, nasally, otically, or ocularly.

[0087] The terms “inhibit,” “inhibiting,” “inhibited,” and “inhibition” with regard to inhibiting TAK1 in a patient, such as a patient with cancer or an inflammatory disease, refer to any degree of inhibition of TAK1 in the patient, wherein any degree of inhibition is beneficial to the patient. Desirably, the inhibition of TAK1 inhibits the growth and / or metastasis of cancer in a patient with cancer or reduces inflammation in a patient with an inflammatory disease.

[0088] Inhibition as low as 10%, for example, can be beneficial, although desirably the inhibition is at least about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% and can approach 100%. Inhibition of cancer can be evidenced by the reduction in size of a tumor, a reduction in the number of tumors, the prevention of metastasis, and the elimination of one or more tumors. Reduction of inflammation can be evidenced by a reduction in the level of one or more pro-inflammatory cytokines and / or a reduction in the level of one or more blood cells involved in inflammation.

[0089] The terms “treat,” “treating,” “treated,” or “treatment” (with respect to a disease or condition) are used to describe an approach for obtaining beneficial or desired results, including and preferably clinical results and includes, but is not limited to, one or more of the following: improving a condition associated with a disease, curing a disease, lessening the severity of a disease, delaying progression of a disease, alleviating one or more symptoms associated with a disease, increasing the quality of life of one suffering from a disease, prolonging survival and / or prophylactic or preventative treatment.

[0090] The term " inhibitory effect" refers to the ability of a compound to reduce or block a specific biological or chemical activity, enzyme, or receptor, thereby preventing, suppressing, or altering its normal function. The term “inhibitory effective amount” means any amount of a compound or a pharmaceutical composition comprising the compound that is sufficient to achieve an “inhibitory effect”.

[0091] The term "pharmaceutical composition" includes a therapeutically effective amount or an inhibitory effective amount of one or more compounds for treating a patient with a disease or condition such as cancer or inflammatory diseases. The composition may include other components and / or ingredients, including, but not limited to, other therapeutically active compounds and / or one or more pharmaceutically acceptable excipients and the like.

[0092] The term "therapeutic effect" refers to a beneficial local or systemic effect in animals, particularly mammals and, more particularly, humans, caused by the administration of a compound. The term "therapeutically effective amount" means the amount of a compound that is effective to treat a disease or a disorder, such as cancer or inflammatory disease, at a reasonable benefit / risk ratio. The therapeutically effective amount of such compound will vary depending  upon the patient and the disease or disorder being treated, the weight and age of the patient, the severity of the disease or disorder, the manner of administration, and the like, which can readily be determined by one of skill in the art.

[0093] The compounds can be administered in unit dosage forms and / or compositions containing one or more pharmaceutically acceptable carriers, adjuvants, diluents, excipients, and / or vehicles, and combinations thereof. As used herein, the term "administering" and its formatives generally refer to any and all means of introducing compounds to the patient including, but not limited to, by oral, intravenous, intratumoral, intramuscular, subcutaneous, transdermal, topically, and like routes of administration.

[0094] For oral administration, the compounds can be formulated readily by combining the active compound(s) with pharmaceutically acceptable carriers, excipients, or diluents well-known in the art. Such carriers, excipients, or diluents enable the compounds to be formulated as tablets, pills, powders, dragees, capsules, liquids, gels, syrups, slurries, suspensions, solutions, and the like for oral ingestion by a subject to be treated. Useful dosages of the compounds can be determined by comparing their in vitro activity with their in vivo activity in animal models.

[0095] Methods of the extrapolation of effective dosages in mice and other animals to human subjects are known in the art. Indeed, the dosage of the compounds can vary significantly depending on the condition of the subject, the age of the subject, the type of disease the subject is experiencing or at risk of experiencing, the particular compounds used, how advanced the pathology is, the route of administration of the compounds and the possibility of co-usage of other therapeutic treatments or additional drugs in combination therapies. The amount of the composition required for use in treatment (e.g., the therapeutically effective amount or dose) will vary not only with the particular application, but also with the salt selected (if applicable) and the characteristics of the subject (such as, for example, age, condition, sex, the subject’s body surface area and / or mass, tolerance to drugs) and will ultimately be at the discretion of the attendant physician, clinician, or otherwise.

[0096] The compositions comprising the compound (s) can be formulated in a unit dosage form, each dosage containing from about 5 to about 1,000 mg (1 g), more usually about 100 mg to about 500 mg, of the active ingredient. In some embodiments, the compositions provided herein contain from about 5 mg to about 50 mg of the active ingredient. One having ordinary skill in the art will appreciate that this embodies compounds or compositions containing about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, or about 45 mg to about 50 mg of the active ingredient.

[0097] In some embodiments, the compositions provided herein contain from about 50 mg to about 500 mg of the active ingredient. One having ordinary skill in the art will appreciate that this embodies compounds or compositions containing about 50 mg to about 100 mg, about 100 mg to about 150 mg, about 150 mg to about 200 mg, about 200 mg to about 250 mg, about 250 mg to about 300 mg, about 350 mg to about 400 mg, or about 450 mg to about 500 mg of the active ingredient.

[0098] In some embodiments, the compositions provided herein contain from about 500 mg to about 1,000 mg of the active ingredient. One having ordinary skill in the art will appreciate that this embodies compounds or compositions containing about 500 mg to about 550 mg, about 550 mg to about 600 mg, about 600 mg to about 650 mg, about 650 mg to about 700 mg, about 700 mg to about 750 mg, about 750 mg to about 800 mg, about 800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg to about 950 mg, or about 950 mg to about 1,000 mg of the active ingredient.

[0099] The active compound may be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0100] The term "patient" includes human and non-human animals, such as companion animals (dogs and cats and the like) and livestock animals. Livestock animals are animals raised for food production. The patient to be treated is preferably a mammal, in particular a human being.

[0101] The compounds of the present disclosure can also be used in combination with other compounds or known drugs that are used to treat cancer. In view of the above, also provided is a pharmaceutical combination. The pharmaceutical combination comprises (i) a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof, and (ii) a therapeutically effective amount of another therapeutic agent.

[0102] The combination can be in a single pharmaceutical composition, which comprises at least one pharmaceutically acceptable excipient, or separate pharmaceutical compositions, each of which comprises at least one pharmaceutically acceptable excipient, and wherein the separate pharmaceutical compositions can be formulated to be administered by the same or different routes. When formulated as separate compositions, the compositions can be administered simultaneously or sequentially in either order. The pharmaceutical combination can be used to  treat a patient in need of TAK1 inhibition, such as a patient with cancer or an inflammatory disease.

[0103] The other therapeutic agent can be an anti-cancer drug, as well-known in the art. Examples of the known anti-cancer drugs that can be used to treat lung cancer, thyroid cancer, pancreatic cancer, and breast cancer include, but are not limited to carboplatin, cisplatin, paclitaxel, capecitabine, gemcitabine, fluorouracil, everlolimus, doxorubicin, alectinib, afatinib, brigatinib, gefitinib, ceritinib, crizotinib, entrectinib, imatinib, lorlatinib, osimertinib, sorafenib, vandetanib, cabozantinib, erlotinib, sunitinib, alectinib, lenvatinib, trametinib, selpercatinib, and pralsetinib. In some embodiments, the anti-cancer drug can be TAK 1 inhibitor, as well-known in the art.

[0104] The other therapeutic agent can be an anti-TNF or anti-IL-6 drug, as well-known in the art. Examples of the known anti-TNF or anti-IL-6 drugs that can be used include, but are not limited to, infliximab, adalimumab, etanercept, certolizumab pegol, golimumab, pralsetinib, tocilizumab, sarilumab, siltuximab,olokizumab, sirukumab, and ziltivekimab.

[0105] The therapeutic agents can be administered in amounts to provide the desired therapeutic effects. The effective dosage range for each therapeutic agent can be determined in accordance with dosage range-finding techniques, which are well-known in the art. Effective dosage ranges for known therapeutic agents have already been established.

[0106] It will be appreciated by persons skilled in the art that the present disclosure is not limited by what has been particularly shown and described herein above. Rather the scope of the present disclosure includes both combinations and sub-combinations of the various features described hereinabove as well as variations and modifications which would occur to persons skilled in the art upon reading the specification and which are not in the prior art. EXAMPLES

[0107] The following examples serve to illustrate the present disclosure. The examples are not intended to limit the scope of the claimed invention in any way.

[0108] Compounds of type I, such as 1-104, inhibited Tak1 at 20 nM (FIGs.1-2). The degree of Tak1 inhibition depended on the substitution pattern of the compounds, with ethyl, isopropyl, cyclopropyl, and methoxy-substituted indazoles displaying the highest Tak1 inhibition (Table 1). At sub-micromolar concentrations, such as 200 nM, the compounds were able to inhibit the proliferation of MPC-11, a multiple myeloma-type cell line, which can be sensitive to TAK1  inhibitors (FIGs. 3-4) (RSC Med. Chem., 2024, 15, 178-192). Compounds were able to inhibit the proliferation of another MM line, RPMI8226, in a mouse model (FIG. 5). The compounds inhibited LPS-induced TNF-α production and IL-6 in macrophages (FIG.6).

[0109] Table 1 shows the IC50 values of compounds against TAK1. Table 1

[0110] Cell culture: MPC-11 cell lines were used. MPC-11 cells were maintained in DMEM with 10% FBS, and H292 cells were maintained in RPMI with 10% heat-inactivated FBS. All cells were cultured at 37 °C in a humidified atmosphere containing 5% CO2.4-5x103cells were seeded in 96-well plates and  incubated for 24 hours. Cells were then treated with various concentrations of indicated compounds for 72 hours. After the indicated period of treatment, CellTiter-Blue cell viability assay reagent (Promega®) was added, and the cells were incubated for 3 hours. Fluorescence (λex / em = 560 / 590 nm) of each well was quantified via Biotek Cytation 5 multi-mode reader. Experiments were performed in triplicates, with data reported as the mean and standard deviation of three data points. Readings from treated groups were normalized to cells treated with DMSO.

[0111] Animal Efficacy experiment: The RPMI-8226 tumor cells are cultured in RPMI1640 medium supplemented with 10% heat- inactivated fetal bovine serum, 100U / ml penicillin and 100 µg / ml streptomycin at 37 ℃ in an atmosphere of 5% CO2in air. The cells growing in an exponential growth phase were harvested and counted for tumor inoculation. Each mouse was inoculated subcutaneously at the right flank with the RPMI-8226 tumor cells (1e7per mouse) in 0.1 mL RPMI 1640 medium with 50% matrigel for tumor development. Eighteen animals were randomized using block randomization by Excel based upon their tumor volume (around 100 mm3). This ensured that all the groups were comparable at the baseline. Tumor volume was measured three times per week in two dimensions using a caliper, and the volume was expressed in mm3using the formula: V = 0.5 a x b2, where a and b are the long and short diameters of the tumor, respectively.

[0112] Cytokine Analysis Using ELISA: The levels of pro-inflammatory cytokines IL-6 and TNF-α are measured using ELISA kits. THP- 1 cells are seeded at a density of 1x105 / well and treated with 50 ng / mL phorbol 12-myristate 13- acetate (PMA) for 24 hours to differentiate them into macrophages. After 24 hours, the PMA- containing medium was replaced with PMA-free medium, and the cells were incubated for another 24 hours to allow them to stabilize. Differentiated THP-1 macrophages were treated with TAK1 inhibitors following the stimulation with 100 nM LPS to induce cytokine production. After 24 hours of LPS stimulation and treatment, the supernatants were collected. ELISA plates were coated with specific antibodies for TNF-α and IL-6. Supernatants were added to the wells, and protocol was performed. The intensity of the color was measured at 450 nm using a plate reader. As illustrated in Fig.6A and Fig.6B, the TAK 1 inhibitor, e.g., compound 76, reduces the levels of TNF-α and IL-6, respectively. Experimental

[0113] General methods for synthesis and characterization of compounds All reactions utilizing air-sensitive or moisture-sensitive reagents were performed in dried glassware under an atmosphere of argon (Ar), using commercially purchased solvents and  reagents without further purification unless otherwise noted.1H NMR(500 MHz) and13C NMR(126 MHz) spectra were recorded using a Bruker AV-III-500-HD NMR (Bruker, USA), Coupling constants were reported in Hertz, and peak shifts are reported in δ (ppm) relative to CDCl3(1H 7.26 ppm,13C 77.16 ppm), CD3OD (1H 3.31 ppm,13C 49.00 ppm), dimethyl sulfoxide (DMSO)-d6 (1H 2.50 ppm,13C 39.52 ppm) using Me4Si as an internal standard.1H NMR data were reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), and integration). Multiplicities are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, or combinations thereof. High-resolution mass spectroscopy (HRMS) spectra were recorded using the electron spray ionization (ESI) technique and TOF mass analysis on LTQ Orbitrap (Research Instrumentation Center in the Department of Chemistry at Purdue University). All the synthesized compounds were characterized using1H and13C NMR and HRMS data.

[0114] General procedure for amination:In a 20 mL microwave vial 2-bromo-5-iodoimidazo[2,1-b][1,3,4]thiadiazole (1 mmol) was dissolved in MeCN (2 mL) followed by the addition of 1.2 equiv. of amine and 3 equiv of DIPEA. Reaction was stirred at 100 °C for two hours. After completion, the reaction was concentrated and purified via flash column chromatography using ethyl acetate:hexanes (80:20) to yield the desired product.

[0115] (2S,6R)-4-(5-iodoimidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2,6-dimethylmorpholineOff-white solid (96%).1H NMR (500 MHz, DMSO-d6) δ 7.09 (s, 1H), 3.74 – 3.66 (m, 2H), 3.65 – 3.55 (m, 2H), 2.88 – 2.67 (m, 2H), 1.14 (d, J = 6.2 Hz, 6H);13C NMR (126 MHz, DMSO-d6) δ 164.76, 140.45, 136.62, 70.91, 62.98, 53.11, 18.83. HRMS (ESI) m / z calcd for C10H14IN4OS [M + H]+363.9854, found 363.9856.

[0116] 9-(5-iodoimidazo[2,1-b][1,3,4]thiadiazol-2-yl)-3-oxa-9-azaspiro[5.5]undecane White solid (95%).1H NMR (500 MHz, DMSO) δ 7.06 (s, 1H), 3.55 (t, J = 5.2 Hz, 4H), 3.41 (t, J = 5.8 Hz, 4H), 1.59 (t, J = 5.9 Hz, 4H), 1.46 (t, J = 5.2 Hz, 4H).13C NMR (126 MHz, DMSO) δ 164.55, 140.58, 136.42, 62.87, 62.84, 44.46, 35.72, 34.46, 29.62.

[0117] 9-(5-iodoimidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-oxa-9-azaspiro[5.5]undecanePale yellow solid (89%).1H NMR (500 MHz, DMSO) δ 7.06 (s, 1H), 3.55 – 3.49 (m, 2H), 3.43 – 3.38 (m, 4H), 3.37 (s, 2H), 1.54 – 1.49 (m, 8H);13C NMR (126 MHz, DMSO) δ 164.51, 140.57, 136.41, 75.07, 68.45, 62.80, 44.53, 32.46, 31.94, 31.54, 21.86.

[0118] 6-(5-iodoimidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-oxa-6-azaspiro[3.4]octaneWhite solid (81%).1H NMR (500 MHz, DMSO) δ 7.06 (s, 1H), 4.61 (d, J = 6.1 Hz, 2H), 4.49 (d, J = 6.1 Hz, 2H), 3.69 (s, 2H), 3.43 (t, J = 6.9 Hz, 2H), 2.30 (t, J = 7.0 Hz, 2H);13C NMR (126 MHz, DMSO) δ 160.90, 140.29, 136.36, 79.82, 62.64, 57.67, 48.64, 45.59, 35.04.

[0119] 5-iodo-2-(4-(methylsulfonyl)piperazin-1-yl)imidazo[2,1-b][1,3,4]thiadiazolePale yellow solid (86%).1H NMR (500 MHz, DMSO) δ 7.10 (s, 1H), 3.58 – 3.54 (m, 4H), 3.28 – 3.25 (m, 4H), 2.92 (s, 3H);13C NMR (126 MHz, DMSO) δ 164.59, 140.69, 136.69, 63.17, 48.03, 44.84, 34.95.

[0120] 1-(5-iodoimidazo[2,1-b][1,3,4]thiadiazol-2-yl)-4-methylpiperidin-4-ol  Off-white solid (92%).1H NMR (500 MHz, DMSO) δ 7.06 (s, 1H), 4.51 (s, 1H), 3.50 (dt, J = 12.9, 4.2 Hz, 2H), 3.40 (dt, J = 12.9, 7.6 Hz, 2H), 1.58 – 1.54 (m, 4H), 1.15 (s, 3H);13C NMR (126 MHz, DMSO) δ 164.28, 140.60, 136.38, 66.26, 62.81, 45.50, 37.39, 30.10.

[0121] (S)-4-(5-iodoimidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-methylmorpholineOff-white solid (84%).1H NMR (500 MHz, DMSO) δ 7.08 (s, 1H), 3.92 – 3.86 (m, 1H), 3.65 – 3.56 (m, 4H), 3.17 (td, J = 12.4, 3.7 Hz, 1H), 2.86 (dd, J = 12.8, 10.8 Hz, 1H), 1.14 (d, J = 6.1 Hz, 3H);13C NMR (126 MHz, DMSO) δ 164.95, 140.46, 136.62, 71.01, 65.34, 63.06, 53.79, 47.64, 18.80.

[0122] (R)-4-(5-iodoimidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-methylmorpholineOff-white solid (81%).1H NMR (500 MHz, DMSO) δ 7.09 (s, 1H), 3.94 – 3.83 (m, 1H), 3.65 – 3.55 (m, 4H), 3.17 (td, J = 12.4, 3.8 Hz, 1H), 2.86 (dd, J = 12.8, 10.8 Hz, 1H), 1.14 (d, J = 6.1 Hz, 3H);13C NMR (126 MHz, DMSO) δ 164.94, 140.46, 136.62, 71.01, 65.34, 62.98, 53.79, 47.64, 18.80.

[0123] 4-(5-iodoimidazo[2,1-b][1,3,4]thiadiazol-2-yl)morpholine1H NMR (400 MHz, DMSO) δ 7.11 (s, 1H), 3.73 (t, J = 4.8 Hz, 4H), 3.43 (t, J = 4.9 Hz, 4H).13C NMR (101 MHz, DMSO) δ 165.14, 140.48, 136.63, 65.61, 63.06, 48.35.

[0124] General procedure for the Suzuki Coupling: A solution of iodo substrate (1 equiv), boronic acid substrate (1.1 equiv), Pd(dppf)Cl2^DCM (10 mol%), Cs2CO3(1.5 equiv), K3PO4(1.5 equiv) and 0.5 mL water in degassed 1,4 dioxane (5 mL) was stirred at 130 ^C in a sealed microwave vial for 16 hours. After completion the reaction was extracted with ethyl acetate and water. The organic phase was concentrated and purified via flash silica gel column chromatography to yield the desired product.

[0125] Example 1: (2S,6R)-2,6-dimethyl-4-(5-(3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2- yl)morpholine (1) Off-white solid (59%).1H NMR (500 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.86 (dd, J = 8.7, 1.6 Hz, 1H), 7.53 – 7.48 (m, 2H), 3.79 – 3.69 (m, 4H), 2.89 – 2.80 (m, 2H), 2.52 – 2.46 (m, 5H), 1.16 (d, J = 6.1 Hz, 6H);13C NMR (126 MHz, DMSO-d6) δ 165.16, 141.96, 140.69, 140.23, 127.66, 127.58, 123.96, 122.79, 120.99, 115.83, 110.98, 70.94, 53.27, 18.87, 12.11. HRMS (ESI) m / z calcd for C18H22N6OS [M + H]+369.14976, found 369.15071.

[0126] Example 2: (2S,6R)-2,6-dimethyl-4-(5-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[2,1- b][1,3,4]thiadiazol-2-yl)morpholine (2)Off-white solid (43%)1H NMR (500 MHz, DMSO-d6) δ 9.02 (t, J = 1.5 Hz, 1H), 8.60 (d, J = 2.0 Hz, 1H), 7.60 (s, 1H), 3.76 – 3.67 (m, 4H), 2.85 – 2.77 (m, 2H), 2.51 (s, 3H), 1.15 (d, J = 6.0 Hz, 6H);13C NMR (126 MHz, DMSO-d6) δ 165.41, 151.71, 146.24, 141.78, 141.20, 128.14, 125.01, 124.68, 118.21, 114.13, 70.92, 53.18, 18.84, 12.63. HRMS (ESI) m / z calcd for C17H21N7OS [M + H]+370.14500, found 370.14478.

[0127] Example 3: 5-(2-((2S,6R)-2,6-dimethylmorpholino)imidazo[2,1-b][1,3,4]thiadiazol-5-yl)-1H-indazol-3- amine (3) Synthesized by using (3-cyano-4-fluorophenyl)boronic acid as boronic substrate. After the reaction, the reaction mixture was concentrated, and crude was refluxed with hydrazine monohydrate (5 equiv) in 3 mL ethanol without further purification. After completion, the product was purified by flash chromatography using dichloromethane:methanol(90:10). Off-white solid (84%)1H NMR (500 MHz, DMSO-d6) δ 8.25 (s, 1H), 7.75 (dd, J = 8.7, 1.6 Hz, 1H), 7.37 (s, 1H), 7.29 (d, J = 8.7 Hz, 1H), 3.80 (d, J = 2.5 Hz, 1H), 3.77 (d, J = 2.5 Hz, 2H), 3.76 – 3.68 (m, 3H), 2.85 – 2.77 (m, 2H), 1.16 (d, J = 6.1 Hz, 6H);13C NMR (126 MHz, DMSO-d6) δ 165.13, 149.89, 140.92, 140.31, 128.00, 126.77, 124.38, 119.00, 116.71, 114.51, 110.44, 71.03, 53.22, 18.86. HRMS (ESI) m / z calcd for C17H21N7OS [M + H]+370.14500, found 370.14449.

[0128] Example 4: (2S,6R)-4-(5-(6-fluoro-3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2,6- dimethylmorpholine (4)Off-white solid (64%)1H NMR (500 MHz, DMSO-d6) δ 8.41 (d, J = 6.9 Hz, 1H), 7.39 – 7.31 (m, 2H), 3.76 – 3.67 (m, 3H), 3.66 (d, J = 2.4 Hz, 1H), 3.31 (s, 3H), 2.85 – 2.74 (m, 2H), 1.14 (d, J = 6.1 Hz, 6H);13C NMR (126 MHz, DMSO-d6) δ 165.08, 159.47, 157.51, 142.42, 140.98, 140.05, 139.95, 130.21, 130.12, 121.99, 119.59, 119.17, 110.99, 110.85, 96.87, 96.65, 70.87, 53.22, 18.82, 11.91. HRMS (ESI) m / z calcd for C18H21FN6OS [M + H]+387.14033, found 387.13958.

[0129] Example 5: (2S,6R)-4-(5-(3-ethyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2,6- dimethylmorpholine (5) Off-white solid (55%).1H NMR (500 MHz, DMSO-d6) δ 8.39 (s, 1H), 7.81 (dd, J = 8.7, 1.6 Hz, 1H), 7.50 (d, J = 8.2 Hz, 2H), 3.75 – 3.66 (m, 4H), 2.95 (q, J = 7.6 Hz, 2H), 2.81 (dd, J = 12.5, 10.6 Hz, 2H), 2.51 – 2.46 (m, 1H), 1.34 (t, J = 7.6 Hz, 3H), 1.14 (d, J = 6.1 Hz, 6H);13C NMR (126 MHz, DMSO-d6) δ 165.07, 147.29, 140.72, 140.40, 127.57, 127.46, 123.88, 121.86, 120.87, 115.89, 111.07, 70.86, 53.22, 20.53, 18.82, 13.80. HRMS (ESI) m / z calcd for C19H24N6OS [M + H]+383.16541, found 383.16546.

[0130] Example 6: (2S,6R)-4-(5-(3-cyclopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2,6- dimethylmorpholine (6)Off-white solid (58%).1H NMR (500 MHz, CDCl3) δ 8.39 (d, J = 1.5 Hz, 1H), 7.79 (dd, J = 8.6, 1.6 Hz, 1H), 7.46 (d, J = 8.6 Hz, 1H), 7.42 (s, 1H), 3.81 (ddd, J = 10.7, 6.3, 2.6 Hz, 2H), 3.70 (dd, J = 12.7, 2.5 Hz, 2H), 2.90 (dd, J = 12.5, 10.7 Hz, 2H), 2.29 (tt, J = 8.4, 5.1 Hz, 1H), 1.29 (d, J = 6.2 Hz, 6H), 1.18 (dt, J = 6.1, 3.1 Hz, 2H), 1.10 – 1.04 (m, 2H).13C NMR (126 MHz, CDCl3) δ 164.73, 148.83, 140.51, 127.04, 124.70, 122.02, 121.53, 116.47, 110.25, 71.10, 53.45, 18.66, 8.87, 6.89. HRMS (ESI) m / z calcd for C20H22N6OS [M + H]+395.165405, found 395.16535.

[0131] Example 7: (2S,6R)-4-(5-(1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2,6- dimethylmorpholine (7) Off-white solid (42%).1H NMR (500 MHz, CDCl3) δ 8.68 (s, 1H), 8.36 (d, J = 8.7 Hz, 1H), 8.25 (s, 1H), 7.56 (d, J = 7.7 Hz, 2H), 7.07 (s, 1H), 3.81 (s, 3H), 3.75 – 3.66 (m, 3H), 2.98 – 2.88 (m, 2H), 1.37 – 1.30 (m, 6H). HRMS (ESI) m / z calcd for C17H18N6OS [M + H]+355.134106, found 355.13382.

[0132] Example 8: (2S,6R)-4-(5-(1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2,6- dimethylmorpholine (8)Off-white solid (55%).1H NMR (500 MHz, DMSO) δ 9.05 (d, J = 2.1 Hz, 1H), 8.73 (d, J = 2.1 Hz, 1H), 8.20 (d, J = 1.2 Hz, 1H), 7.64 (s, 1H), 3.74 (td, J = 10.6, 3.1 Hz, 4H), 2.92 – 2.79 (m, 2H), 1.17 (d, J = 6.0 Hz, 6H). 13C NMR (126 MHz, DMSO) δ 165.57, 151.03, 146.63, 141.39, 134.20, 128.31, 124.97, 124.88, 119.03, 114.63, 70.98, 53.19, 18.88. HRMS (ESI) m / z calcd for C16H17N7OS [M + H]+356.129355, found 356.12920.

[0133] Example 9: 2S,6R)-4-(5-(1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2,6- dimethylmorpholine (9)Off-white solid (50%).1H NMR (500 MHz, DMSO) δ 11.72 (s, 1H), 8.75 (d, J = 2.1 Hz, 1H), 8.44 (d, J = 2.1 Hz, 1H), 7.56 – 7.39 (m, 2H), 6.50 (dd, J = 3.4, 1.8 Hz, 1H), 3.72 (dq, J = 10.8,  2.9 Hz, 4H), 2.83 (dd, J = 12.8, 11.0 Hz, 2H), 1.16 (d, J = 6.2 Hz, 6H).13C NMR (126 MHz, DMSO) δ 165.33, 147.96, 140.79, 140.22, 127.52, 127.47, 125.96, 124.29, 119.80, 117.77, 100.73, 70.96, 53.20, 18.88. HRMS (ESI) m / z calcd for C17H18N6OS [M + H]+355.134106, found 355.13398.

[0134] Example 10: (2S,6R)-2,6-dimethyl-4-(5-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[2,1- b][1,3,4]thiadiazol-2-yl)morpholine (10)Off-white solid (64%).1H NMR (500 MHz, CDCl3) δ 9.19 – 9.01 (m, 1H), 8.86 (d, J = 1.9 Hz, 1H), 8.29 (d, J = 2.0 Hz, 1H), 7.43 (s, 1H), 7.15 – 7.02 (m, 1H), 3.80 (dqd, J = 12.5, 6.1, 2.5 Hz, 2H), 3.74 – 3.62 (m, 2H), 2.87 (dd, J = 12.6, 10.7 Hz, 2H), 2.44 – 2.29 (m, 3H), 1.28 (d, J = 6.2 Hz, 6H). HRMS (ESI) m / z calcd for C18H20N6OS [M + H]+369.149756, found 369.14959.

[0135] Example 11: 2-((3R,5S)-3,5-dimethylpiperidin-1-yl)-5-(3-methyl-1H-indazol-5-yl)imidazo[2,1- b][1,3,4]thiadiazole (11)Off-white solid (54%).1H NMR (500 MHz, DMSO) δ 8.33 (s, 1H), 7.82 (dd, J = 8.7, 1.6 Hz, 1H), 7.57 – 7.41 (m, 2H), 3.82 – 3.63 (m, 2H), 2.63 (t, J = 12.1 Hz, 2H), 1.72 (q, J = 7.9 Hz, 3H), 0.88 (d, J = 6.3 Hz, 6H), 0.78 (d, J = 11.8 Hz, 1H). HRMS (ESI) m / z calcd for C19H22N6S [M + H]+367.170490, found 367.17015.

[0136] Example 12: 1-(4-(5-(3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperazin-1- yl)ethan-1-one (12) Off-white solid (55%).1H NMR (500 MHz, DMSO) δ 8.33 – 8.23 (m, 1H), 7.85 (dd, J = 8.8, 1.6 Hz, 1H), 7.50 (d, J = 8.7 Hz, 2H), 3.63 (dd, J = 6.7, 3.9 Hz, 4H), 3.56 (dd, J = 6.6, 3.7 Hz, 2H), 3.47 (dd, J = 6.6, 4.1 Hz, 2H), 2.51 (s, 3H), 2.05 (s, 3H). HRMS (ESI) m / z calcd for C18H19N7OS [M + H]+382.145004, found 382.145004.

[0137] Example 13: 1-(4-(5-(6-fluoro-3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperazin- 1-yl)ethan-1-one (13)Off-white solid (45%).1H NMR (500 MHz, DMSO) δ 8.41 (d, J = 7.0 Hz, 1H), 7.43 – 7.27 (m, 2H), 3.62 (dd, J = 6.7, 4.0 Hz, 4H), 3.54 (dd, J = 6.7, 3.8 Hz, 2H), 3.45 (dd, J = 6.5, 4.1 Hz, 2H), 2.50 (s, 3H), 2.04 (s, 3H). HRMS (ESI) m / z calcd for C18H18FN7OS [M + H]+400.135583, found 400.13523.

[0138] Example 14: 2,2,6,6-tetramethyl-4-(5-(3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2- yl)morpholine (14)Off-white solid (50%).1H NMR (500 MHz, DMSO) δ 8.27 (s, 1H), 7.85 (d, J = 8.6 Hz, 1H), 7.62 – 7.43 (m, 2H), 3.41 (q, J = 4.1 Hz, 4H), 2.50 (d, J = 3.7 Hz, 3H), 1.23 (d, J = 4.4 Hz, 12H).13C  NMR (126 MHz, DMSO) δ 165.24, 141.93, 140.51, 140.22, 127.62, 127.47, 123.96, 122.79, 121.03, 115.84, 110.98, 71.57, 56.67, 28.53. HRMS (ESI) m / z calcd for C20H24N6OS [M + H]+397.181056, found 397.18067.

[0139] Example 15: 4-(5-(6-fluoro-3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2,2,6,6- tetramethylmorpholine (15)Off-white solid (45%).1H NMR (500 MHz, DMSO) δ 8.41 (d, J = 7.0 Hz, 1H), 7.37 (dt, J = 11.4, 1.5 Hz, 1H), 7.33 (d, J = 3.6 Hz, 1H), 3.39 (t, J = 2.5 Hz, 4H), 3.31 (d, J = 1.3 Hz, 3H), 1.26 – 1.20 (m, 12H). HRMS (ESI) m / z calcd for C20H23FN6OS [M + H]+415.171634, found 415.17113.

[0140] Example 16: (2S,6R)-4-(5-(1H-indazol-4-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2,6- dimethylmorpholine (16)White solid (38%).1H NMR (500 MHz, CDCl3) δ 8.34 (d, J = 4.5 Hz, 1H), 7.78 (dd, J = 5.4, 2.7 Hz, 1H), 7.69 – 7.55 (m, 1H), 7.48 (q, J = 3.3 Hz, 2H), 3.78 (ddt, J = 12.7, 6.4, 3.1 Hz, 2H), 3.75 – 3.57 (m, 2H), 2.86 (ddd, J = 14.8, 11.0, 4.2 Hz, 2H), 1.27 (d, J = 6.2 Hz, 6H). HRMS (ESI) m / z calcd for C17H18N6OS [M + H]+355.134106, found 355.13391.

[0141] Example 17: (2S,6R)-2,6-dimethyl-4-(5-(1-methyl-1H-indazol-6-yl)imidazo[2,1-b][1,3,4]thiadiazol-2- yl)morpholine (17) Off-white solid (55%).1H NMR (500 MHz, CDCl3) δ 8.07 – 7.96 (m, 2H), 7.76 (d, J = 8.3 Hz, 1H), 7.60 (d, J = 8.4 Hz, 2H), 4.11 (s, 3H), 3.80 (ddd, J = 10.5, 6.1, 2.5 Hz, 2H), 3.68 (dd, J = 12.7, 2.5 Hz, 2H), 2.90 (dd, J = 12.5, 10.6 Hz, 2H), 1.29 (d, J = 6.2 Hz, 6H).13C NMR (126 MHz, CDCl3) δ 165.21, 140.20, 132.78, 132.50, 125.62, 125.08, 122.98, 121.37, 119.86, 118.52, 114.40, 104.83, 71.09, 53.44, 35.48, 18.69. HRMS (ESI) m / z calcd for C18H20N6OS [M + H]+369.149756, found 369.14933.

[0142] Example 18: (2S,6R)-4-(5-(3-isopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2,6- dimethylmorpholine (18)Synthetic Procedure: 5-bromo-3-isopropyl-1H-indazole (1 equiv.), bis(pinacolato)diboron (1.05 equiv.), potassium acetate (3 equiv.) and anhydrous DMSO (0.26 M) were charged into a round bottom flask. After degassing the resulting reaction mixture with nitrogen for 15 minutes, 1,1- [Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (5 mol%) was added. The reaction was then heated to 90 °C under nitrogen. After stirring for 20 hours, the reaction mixture was cooled to room temperature and was extracted with diethyl ether. The resulting mixture was transferred to a separation funnel, and the lower layer was discarded. The upper layer was washed with 1.0 M magnesium sulfate twice and brine solution, dried over sodium sulfate, and concentrated to dryness. The residue is purified on a silica gel column chromatography eluting with hexane- EtOAc (4:1) to afford the desired compound. HRMS (ESI) m / z calcd for C16H23BN2O2 [M + H]+287.193083, found 287.19318. This substrate was then taken as boronic ester substrate for Suzuki reaction. Off-white solid (40%).1H NMR (500 MHz, CDCl3) δ 8.48 (s, 1H), 7.76 (ddd, J = 10.2, 3.5, 1.6 Hz, 1H), 7.47 (dd, J = 8.8, 3.0 Hz, 1H), 7.41 (s, 1H), 3.89 – 3.74 (m, 2H), 3.74 – 3.64 (m, 2H), 3.47 (dtd, J = 14.0, 7.0, 1.7 Hz, 1H), 2.89 (ddt, J = 12.5, 10.6, 2.2 Hz, 2H), 1.60 –  1.42 (m, 6H), 1.32 – 1.19 (m, 6H).13C NMR (126 MHz, CDCl3) δ 164.77, 152.82, 140.64, 127.03, 124.66, 121.37, 117.16, 110.25, 71.08, 53.47, 28.06, 22.05, 18.65. HRMS (ESI) m / z calcd for C20H24N6OS [M + H]+397.181056, found 397.18049.

[0143] Example 19: (2S,6R)-4-(5-(3-methoxy-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2,6- dimethylmorpholine (19)Synthetic Procedure: 5-bromo-3-methoxy-1H-indazole (1 equiv.), bis(pinacolato)diboron (1.05 equiv.), potassium acetate (3 equiv.) and anhydrous DMSO (0.26 M) were charged into a round bottom flask. After degassing the resulting reaction mixture with nitrogen for 15 minutes, 1,1- [Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (5 mol%) was added. The reaction was then heated to 90 °C under nitrogen. After stirring for 20 hours, the reaction mixture was cooled to room temperature and was extracted with diethyl ether. The resulting mixture was transferred to a separation funnel, and the lower layer was discarded. The upper layer was washed with 1.0 M magnesium sulfate twice and brine solution, dried over sodium sulfate, and concentrated to dryness. The residue is purified on a silica gel column chromatography eluting with hexane- EtOAc (4:1) to afford the desired compound. HRMS (ESI) m / z calcd for C14H19BN2O3 [M + H]+275.156698, found 275.15663. This substrate was then taken as boronic ester substrate for Suzuki reaction. Off-white solid (50%).1H NMR (500 MHz, CDCl3) δ 9.01 (s, 1H), 8.20 (dd, J = 1.6, 0.8 Hz, 1H), 7.85 (dd, J = 8.8, 1.6 Hz, 1H), 7.46 – 7.30 (m, 2H), 4.13 (s, 3H), 3.80 (ddd, J = 10.7, 6.3, 2.6 Hz, 2H), 3.75 – 3.62 (m, 2H), 2.88 (dd, J = 12.5, 10.6 Hz, 2H), 1.29 (d, J = 6.2 Hz, 6H).13C NMR (126 MHz, DMSO) δ 160.12, 153.66, 137.00, 122.36, 121.15, 111.47, 108.09, 105.33, 66.39, 51.46, 48.69, 13.97. HRMS (ESI) m / z calcd for C18H20N6O2S [M + H]+385.144671, found 385.14443.

[0144] Example 20: 9-(5-(3-isopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-3-oxa-9- azaspiro[5.5]undecane (20) Off-white solid (58%).1H NMR (500 MHz, CDCl3) δ 8.46 – 8.41 (m, 1H), 7.80 (dd, J = 8.7, 1.6 Hz, 1H), 7.47 (dd, J = 8.7, 0.8 Hz, 1H), 7.39 (s, 1H), 3.77 – 3.69 (m, 4H), 3.58 – 3.51 (m, 4H), 3.46 (p, J = 7.0 Hz, 1H), 1.77 – 1.71 (m, 4H), 1.59 (t, J = 5.4 Hz, 4H), 1.51 (d, J = 7.0 Hz, 6H).13C NMR (126 MHz, CDCl3) δ 164.87, 152.94, 140.56, 126.99, 124.71, 121.58, 121.44, 116.99, 110.13, 63.28, 44.31, 35.81, 34.67, 29.57, 27.91, 22.04. HRMS (ESI) m / z calcd for C23H28N6OS [M + H]+437.212356, found 437.21243.

[0145] Example 21: 9-(5-(3-isopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-oxa-9- azaspiro[5.5]undecane (21)White solid (45%).1H NMR (500 MHz, CDCl3) δ 8.46 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.50 – 7.44 (m, 1H), 7.39 (s, 1H), 3.78 – 3.61 (m, 2H), 3.58 – 3.41 (m, 7H), 1.74 – 1.58 (m, 8H), 1.56 – 1.45 (m, 6H). HRMS (ESI) m / z calcd for C23H28N6OS [M + H]+437.212356, found 437.21225.

[0146] Example 22: 1-(5-(3-isopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-4-methylpiperidin- 4-ol (22)White solid (51%).1H NMR (500 MHz, DMSO) δ 8.50 (s, 1H), 7.78 (dd, J = 8.7, 1.6 Hz, 1H), 7.52 – 7.46 (m, 2H), 4.54 (s, 1H), 3.65 – 3.55 (m, 2H), 3.55 – 3.46 (m, 3H), 1.68 – 1.56 (m, 4H),  1.40 (d, J = 6.9 Hz, 6H), 1.17 (s, 3H). HRMS (ESI) m / z calcd for C20H24N6OS [M + H]+397.181056, found 397.18079.

[0147] Example 23: 1-(5-(3-methoxy-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-4-methylpiperidin- 4-ol (23)Off-white solid (40%).1H NMR (500 MHz, MeOD) δ 8.24 (d, J = 1.3 Hz, 1H), 7.82 (dd, J = 8.8, 1.6 Hz, 1H), 7.36 (d, J = 9.6 Hz, 2H), 4.08 (s, 3H), 3.66 (dt, J = 13.1, 4.2 Hz, 2H), 3.53 (ddd, J = 13.3, 9.5, 5.0 Hz, 2H), 1.80 – 1.68 (m, 4H), 1.28 (s, 3H). HRMS (ESI) m / z calcd for C18H20N6O2S [M + H]+385.144671, found 385.14476.

[0148] Example 24: 4-(5-(3-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)- 2,2,6,6-tetramethylmorpholine (24)Light brown solid (45%).1H NMR (500 MHz, DMSO) δ 8.99 (d, J = 2.0 Hz, 1H), 8.70 (d, J = 2.1 Hz, 1H), 7.63 (s, 1H), 3.42 (s, 4H), 2.34 – 2.25 (m, 1H), 1.24 (s, 12H), 1.03 (d, J = 6.7 Hz, 4H). HRMS (ESI) m / z calcd for C21H25N7OS [M + H]+424.191955, found 424.19158.

[0149] Example 25: 4-(5-(3-ethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2,2,6,6- tetramethylmorpholine (25) Off-white solid (42%).1H NMR (500 MHz, CDCl3) δ 9.20 – 8.96 (m, 1H), 8.57 (q, J = 2.0 Hz, 1H), 7.46 (s, 1H), 3.38 (d, J = 3.0 Hz, 4H), 3.07 (qd, J = 7.6, 3.3 Hz, 2H), 1.51 – 1.44 (m, 3H), 1.34 (d, J = 3.0 Hz, 12H).13C NMR (126 MHz, CDCl3) δ 165.38, 162.8, 151.73, 148.30, 146.85, 127.50, 125.53, 118.9, 113.87, 71.49, 56.97, 28.44, 21.18, 13.07. HRMS (ESI) m / z calcd for C20H25N7OS [M + H]+412.191955, found 412.19193.

[0150] Example 26: (S)-4-(5-(3-isopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2- methylmorpholine (26)Off-white solid (34%).1H NMR (500 MHz, CDCl3) δ 8.43 (s, 1H), 7.78 (d, J = 8.6 Hz, 1H), 7.49 (d, J = 8.6 Hz, 2H), 4.04 (dd, J = 11.8, 3.6 Hz, 1H), 3.83 – 3.69 (m, 3H), 3.66 (d, J = 12.5 Hz, 1H), 3.46 (p, J = 7.0 Hz, 1H), 3.32 (td, J = 12.1, 3.7 Hz, 1H), 2.97 (dd, J = 12.3, 10.4 Hz, 1H), 1.51 (d, J = 6.9 Hz, 6H), 1.28 (d, J = 6.1 Hz, 3H). HRMS (ESI) m / z calcd for C19H22N6OS [M + H]+383.165405, found 383.16515.

[0151] Example 27: (R)-4-(5-(3-methoxy-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2- methylmorpholine (27)  Light brown solid (48%).1H NMR (500 MHz, CDCl3) δ 9.21 (d, J = 26.7 Hz, 1H), 8.32 – 8.13 (m, 1H), 7.90 – 7.75 (m, 1H), 7.43 – 7.23 (m, 2H), 4.27 – 3.92 (m, 4H), 3.72 (ddp, J = 35.9, 23.2, 11.8 Hz, 4H), 3.38 – 3.20 (m, 1H), 2.94 (dq, J = 22.8, 11.6 Hz, 1H), 1.29 (dd, J = 26.8, 10.7 Hz, 3H).13C NMR (126 MHz, CDCl3) δ 165.05, 158.41, 141.76, 140.98, 127.86, 126.89, 125.82, 121.20, 116.17, 112.81, 110.12, 71.26, 65.71, 56.22, 54.17, 47.62, 18.65. HRMS (ESI) m / z calcd for C17H18N6O2S [M + H]+371.129021, found 371.12917.

[0152] Example 28: (S)-4-(5-(3-methoxy-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2- methylmorpholine (28)Off-white solid (42%).1H NMR (500 MHz, CDCl3) δ 9.18 (s, 1H), 8.21 (d, J = 1.5 Hz, 1H), 7.84 (dd, J = 8.7, 1.6 Hz, 1H), 7.40 – 7.30 (m, 2H), 4.13 (d, J = 1.1 Hz, 3H), 4.03 (dd, J = 11.7, 3.6 Hz, 1H), 3.82 – 3.61 (m, 4H), 3.28 (td, J = 12.2, 3.7 Hz, 1H), 2.95 (dd, J = 12.4, 10.5 Hz, 1H), 1.28 (d, J = 6.2 Hz, 3H). HRMS (ESI) m / z calcd for C17H18N6O2S [M + H]+371.129021, found 371.12898.

[0153] Example 29: (R)-4-(5-(3-isopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2- methylmorpholine (29)Off-white solid (40%).1H NMR (500 MHz, CDCl3) δ 8.43 (s, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.51 – 7.36 (m, 2H), 4.03 (dd, J = 11.8, 3.5 Hz, 1H), 3.82 – 3.69 (m, 3H), 3.68 – 3.62 (m, 1H), 3.46 (p, J = 7.0 Hz, 1H), 3.31 (td, J = 12.2, 3.6 Hz, 1H), 2.96 (dd, J = 12.3, 10.4 Hz, 1H), 1.51 (d, J = 7.0 Hz, 6H), 1.28 (d, J = 6.2 Hz, 3H). HRMS (ESI) m / z calcd for C19H22N6OS [M + H]+383.165405, found 383.165405.

[0154] Example 30:  (1R,4R)-5-(5-(3-isopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-oxa-5- azabicyclo[2.2.1]heptane (30)Off-white solid (36%).1H NMR (500 MHz, CDCl3) δ 8.45 (s, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 7.40 (s, 1H), 4.77 (s, 1H), 4.56 (s, 1H), 4.10 (d, J = 8.0 Hz, 1H), 3.92 (d, J = 8.0 Hz, 1H), 3.62 (dd, J = 9.6, 1.8 Hz, 1H), 3.56 (d, J = 9.6 Hz, 1H), 3.50 – 3.39 (m, 1H), 2.08 (d, J = 3.4 Hz, 2H), 1.51 (d, J = 7.0 Hz, 6H). HRMS (ESI) m / z calcd for C19H20N6OS [M + H]+381.149756, found 381.14949.

[0155] Example 31: (1S,4S)-5-(5-(3-isopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-oxa-5- azabicyclo[2.2.1]heptane (31)Off-white solid (34%).1H NMR (500 MHz, CDCl3) δ 8.45 (d, J = 1.8 Hz, 1H), 7.79 (dt, J = 8.7, 1.7 Hz, 1H), 7.47 (dd, J = 8.7, 2.0 Hz, 1H), 7.41 (s, 1H), 4.77 (s, 1H), 4.56 (t, J = 1.9 Hz, 1H), 4.09 (dd, J = 8.0, 2.0 Hz, 1H), 3.92 (dt, J = 8.0, 1.7 Hz, 1H), 3.62 (dt, J = 9.5, 1.7 Hz, 1H), 3.56 (d, J = 9.7 Hz, 1H), 3.50 – 3.40 (m, 1H), 2.12 – 2.05 (m, 2H), 1.51 (dd, J = 7.0, 1.8 Hz, 6H). HRMS (ESI) m / z calcd for C19H20N6OS [M + H]+381.149756, found 381.14940.

[0156] Example 32: (1R,4R)-5-(5-(3-methoxy-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-oxa-5- azabicyclo[2.2.1]heptane (32)  Off-white solid (44%).1H NMR (500 MHz, CDCl3) δ 9.23 (s, 1H), 8.23 (d, J = 1.5 Hz, 1H), 7.84 (dd, J = 8.7, 1.5 Hz, 1H), 7.39 (s, 1H), 7.34 (d, J = 8.7 Hz, 1H), 4.79 – 4.74 (m, 1H), 4.60 (d, J = 1.8 Hz, 1H), 4.13 (s, 3H), 4.06 (d, J = 8.0 Hz, 1H), 3.93 (d, J = 1.4 Hz, 1H), 3.60 (d, J = 1.5 Hz, 1H), 3.56 (s, 1H), 2.06 (s, 2H). HRMS (ESI) m / z calcd for C17H16N6O2S [M + H]+369.113371, found 369.11312.

[0157] Example 33: (1S,4S)-5-(5-(3-methoxy-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-oxa-5- azabicyclo[2.2.1]heptane (33)Off-white solid (46%).1H NMR (500 MHz, CDCl3) δ 9.42 (s, 1H), 8.25 – 8.19 (m, 1H), 7.83 (dd, J = 8.7, 1.6 Hz, 1H), 7.39 (s, 1H), 7.35 – 7.30 (m, 1H), 4.75 (d, J = 1.9 Hz, 1H), 4.59 (d, J = 1.7 Hz, 1H), 4.12 (s, 3H), 4.05 (d, J = 8.0 Hz, 1H), 3.91 (dd, J = 8.0, 1.5 Hz, 1H), 3.60 (dd, J = 9.6, 1.5 Hz, 1H), 3.55 (d, J = 9.5 Hz, 1H), 2.07 – 2.04 (m, 2H). HRMS (ESI) m / z calcd for C17H16N6O2S [M + H]+369.113371, found 369.11335.

[0158] Example 34: 7-(5-(3-methoxy-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-4-oxa-7- azaspiro[2.5]octane (34)Off-white solid (41%).1H NMR (500 MHz, CDCl3) δ 9.07 (s, 1H), 8.19 (s, 1H), 7.83 (d, J = 8.6 Hz, 1H), 7.42 (s, 1H), 7.35 (d, J = 8.7 Hz, 1H), 4.13 (s, 3H), 3.92 (t, J = 4.9 Hz, 2H), 3.62 (t, J = 4.9 Hz, 2H), 3.48 (s, 2H), 0.98 – 0.89 (m, 2H), 0.76 – 0.69 (m, 2H). HRMS (ESI) m / z calcd for C18H18N6O2S [M + H]+383.129021, found 383.12895.

[0159] Example 35:  7-(5-(3-isopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-4-oxa-7- azaspiro[2.5]octane (35)Off-white solid (35%).1H NMR (500 MHz, CDCl3) δ 8.42 (d, J = 1.5 Hz, 1H), 7.77 (dd, J = 8.7, 1.6 Hz, 1H), 7.48 (d, J = 8.7 Hz, 1H), 7.41 (s, 1H), 3.98 – 3.89 (m, 2H), 3.65 – 3.57 (m, 2H), 3.53 (s, 2H), 3.44 (p, J = 7.1 Hz, 1H), 1.50 (d, J = 7.0 Hz, 6H), 0.97 – 0.90 (m, 2H), 0.74 – 0.66 (m, 2H). HRMS (ESI) m / z calcd for C20H22N6OS [M + H]+395.165405, found 395.16506.

[0160] Example 36: 5-(3-isopropyl-1H-indazol-5-yl)-2-(4-(methylsulfonyl)piperazin-1-yl)imidazo[2,1- b][1,3,4]thiadiazole (36)Off-white solid (39%).1H NMR (500 MHz, CDCl3) δ 8.38 (s, 1H), 7.78 (dd, J = 8.8, 1.6 Hz, 1H), 7.48 (d, J = 8.6 Hz, 1H), 7.42 (s, 1H), 3.69 (t, J = 5.1 Hz, 4H), 3.51 – 3.41 (m, 5H), 2.85 (s, 3H), 1.50 (d, J = 7.0 Hz, 6H). HRMS (ESI) m / z calcd for C19H23N7O2S2[M + H]+446.143292, found 446.14239.

[0161] Example 37: 5-(3-methoxy-1H-indazol-5-yl)-2-(4-(methylsulfonyl)piperazin-1-yl)imidazo[2,1- b][1,3,4]thiadiazole (37)  Off-white solid (44%).1H NMR (500 MHz, DMSO) δ 12.00 (s, 1H), 8.16 – 8.12 (m, 1H), 7.86 (dd, J = 8.8, 1.7 Hz, 1H), 7.50 (s, 1H), 7.42 (dd, J = 8.8, 0.8 Hz, 1H), 4.01 (s, 3H), 3.62 (t, J = 5.1 Hz, 4H), 3.32 (s, 4H), 2.93 (s, 3H).13C NMR (126 MHz, DMSO) δ 165.13, 157.13, 141.30, 140.94, 127.75, 127.57, 125.16, 120.55, 114.93, 111.56, 111.21, 56.33, 48.09, 44.85, 35.01. HRMS (ESI) m / z calcd for C17H19N7O3S2 [M + H]+434.106907, found 434.10631.

[0162] Example 38: 4-(5-(3-isopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2,2- dimethylmorpholine (38)Off-white solid (36%).1H NMR (500 MHz, CDCl3) δ 8.44 (s, 1H), 7.77 (dd, J = 8.7, 1.6 Hz, 1H), 7.47 (d, J = 8.7 Hz, 1H), 7.45 – 7.37 (m, 1H), 3.94 – 3.87 (m, 2H), 3.54 – 3.49 (m, 2H), 3.46 (p, J = 6.9 Hz, 1H), 3.33 (s, 2H), 1.52 (d, J = 6.9 Hz, 6H), 1.34 (s, 6H).13C NMR (126 MHz, CDCl3) δ 165.31, 152.87, 140.64, 126.92, 124.69, 121.40, 117.16, 110.22, 71.11, 59.75, 57.50, 47.90, 28.00, 24.39, 22.04. HRMS (ESI) m / z calcd for C20H24N6OS [M + H]+397.181056, found 397.18085.

[0163] Example 39: 4-(5-(3-methoxy-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2,2- dimethylmorpholine (39)Off-white solid (49%).1H NMR (500 MHz, CDCl3) δ 9.32 (s, 1H), 8.20 (d, J = 1.6 Hz, 1H), 7.84 (dd, J = 8.7, 1.6 Hz, 1H), 7.37 (s, 1H), 7.34 (d, J = 8.8 Hz, 1H), 4.13 (s, 3H), 3.89 (dd, J = 6.1, 4.1 Hz, 2H), 3.57 – 3.51 (m, 2H), 3.27 (s, 2H), 1.33 (s, 6H).13C NMR (126 MHz, CDCl3) δ 165.32, 158.39, 141.74, 127.05, 125.80, 121.30, 116.11, 112.79, 110.10, 71.11, 59.75, 57.68,  56.22, 47.76, 24.37. HRMS (ESI) m / z calcd for C18H20N6O2S [M + H]+385.144671, found 385.14480.

[0164] Example 40: 4-(5-(3-cyclopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)morpholine (40)White solid (52%).1H NMR (500 MHz, MeOD) δ 8.40 (d, J = 3.2 Hz, 1H), 7.77 (dd, J = 8.8, 3.1 Hz, 1H), 7.43 (d, J = 8.9 Hz, 1H), 7.39 (s, 1H), 3.91 – 3.72 (m, 4H), 3.55 – 3.46 (m, 4H), 2.31 – 2.21 (m, 1H), 1.06 (dt, J = 8.1, 4.0 Hz, 4H);13C NMR (126 MHz, MeOD) δ 208.66, 165.37, 148.02, 141.01, 140.43, 127.85, 125.93, 124.22, 121.37, 120.85, 115.72, 110.18, 65.50, 7.86, 6.20; HRMS (ESI) m / z calcd for C18H18N6OS [M+H]+367.134106, found 367.13341.

[0165] Example 41: 4-(5-(6-fluoro-3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2,2- dimethylmorpholine (41)Off-white solid (61%).1H NMR (500 MHz, MeOD) δ 8.49 (d, J = 7.0 Hz, 1H), 7.37 (d, J = 4.0 Hz, 1H), 7.22 (d, J = 11.5 Hz, 1H), 3.88 (t, J = 5.1 Hz, 2H), 3.52 (t, J = 4.0 Hz, 2H), 3.35 (s, 2H), 2.54 (s, 3H), 1.32 (s, 6H);13C NMR (126 MHz, MeOD) δ 165.39, 160.11, 158.14, 142.95, 141.08, 139.89, 129.15, 129.04, 122.17, 118.94, 118.70, 111.28, 111.14, 95.84, 95.62, 70.96, 59.30, 57.08, 23.15, 10.17; HRMS (ESI) m / z calcd for C18H19FN6OS [M+H]+387.140334, found 387.13967

[0166] Example 42: 9-(5-(3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-3-oxa-9- azaspiro[5.5]undecane (42) White solid (64%).1H NMR (500 MHz, DMSO) δ 8.28 (s, 1H), 7.86 (dd, J = 8.7, 1.6 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.48 (s, 1H), 3.56 (t, J = 5.3 Hz, 4H), 3.52 – 3.47 (m, 4H), 2.50 (s, 3H), 1.69 – 1.60 (m, 4H), 1.48 (t, J = 5.3 Hz, 4H).13C NMR (126 MHz, DMSO) δ 165.08, 141.91, 140.88, 140.19, 127.53, 127.45, 123.89, 122.79, 121.12, 115.63, 110.95, 62.89, 44.50, 35.75, 34.51, 29.68, 12.17; HRMS (ESI) m / z calcd for C21H24N6OS [M+H]+409.181056, found 409.18037

[0167] Example 43: 9-(5-(3-ethyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-3-oxa-9- azaspiro[5.5]undecane (43)Off-white solid (55%).1H NMR (500 MHz, DMSO) δ 8.36 (d, J = 1.5 Hz, 1H), 7.83 (dd, J = 8.7, 1.6 Hz, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.48 (s, 1H), 3.56 (t, J = 5.3 Hz, 4H), 3.54 – 3.45 (m, 4H), 2.94 (q, J = 7.6 Hz, 2H), 1.68 – 1.59 (m, 4H), 1.48 (t, J = 5.4 Hz, 4H), 1.34 (t, J = 7.6 Hz, 3H);13C NMR (126 MHz, DMSO) δ 165.05, 147.25, 140.90, 140.37, 127.52, 127.43, 123.87, 121.90, 121.03, 115.73, 111.05, 62.89, 44.51, 35.75, 34.49, 29.70, 20.43, 13.76; HRMS (ESI) m / z calcd for C22H26N6OS [M+H]+423.196706, found 423.19595

[0168] Example 44: 9-(5-(3-cyclopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-3-oxa-9- azaspiro[5.5]undecane (44) Off-white solid (58%).1H NMR (500 MHz, DMSO) δ 8.40 (d, J = 1.6 Hz, 1H), 7.81 (dd, J = 8.7, 1.6 Hz, 1H), 7.52 – 7.45 (m, 2H), 3.55 (t, J = 5.3 Hz, 4H), 3.52 – 3.46 (m, 4H), 2.26 (tt, J = 7.9, 5.4 Hz, 1H), 1.67 – 1.59 (m, 4H), 1.47 (t, J = 5.3 Hz, 4H), 1.03 – 0.96 (m, 4H);13C NMR (126 MHz, DMSO) δ 165.04, 147.15, 140.93, 140.42, 127.44, 123.90, 121.83, 121.07, 115.45, 111.15, 62.88, 44.52, 35.75, 34.49, 29.70, 8.74, 7.59; HRMS (ESI) m / z calcd for C23H26N6OS [M+H]+435.196706, found 435.19566

[0169] Example 45: 9-(5-(3-cyclopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-oxa-9- azaspiro[5.5]undecane (45)Off-white solid (56%).1H NMR (500 MHz, DMSO) δ 8.40 (d, J = 1.6 Hz, 1H), 7.81 (dd, J = 8.7, 1.6 Hz, 1H), 7.50 – 7.47 (m, 2H), 3.54 – 3.48 (m, 6H), 3.39 (s, 2H), 2.26 (tt, J = 7.9, 5.5 Hz, 1H), 1.60 – 1.51 (m, 8H), 1.00 (dt, J = 9.4, 2.5 Hz, 4H);13C NMR (126 MHz, DMSO) δ 165.00, 147.16, 140.92, 140.43, 127.44, 123.90, 121.78, 121.06, 115.46, 111.16, 75.03, 68.46, 44.62, 32.58, 31.96, 31.64, 21.87, 8.78, 7.55; HRMS (ESI) m / z calcd for C23H26N6OS [M+H]+435.196706, found 435.19584

[0170] Example 46: 9-(5-(3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-oxa-9- azaspiro[5.5]undecane (46) Off-white solid (60%).1H NMR (500 MHz, DMSO) δ 8.28 (s, 1H), 7.86 (dd, J = 8.7, 1.6 Hz, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.48 (s, 1H), 3.55 – 3.51 (m, 2H), 3.51 – 3.45 (m, 4H), 3.38 (s, 2H), 2.50 (s, 3H), 1.58 – 1.47 (m, 8H);13C NMR (126 MHz, DMSO) δ 165.03, 141.92, 140.87, 140.20, 127.54, 127.44, 123.90, 122.79, 121.11, 115.67, 110.95, 75.12, 68.46, 44.58, 32.46, 31.97, 31.60, 21.86, 12.15; HRMS (ESI) m / z calcd for C21H24N6OS [M+H]+409.181056, found 409.1803.

[0171] Example 47: 9-(5-(3-ethyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-oxa-9- azaspiro[5.5]undecane (47)Off-white solid (54%).1H NMR (500 MHz, DMSO) δ 8.36 (d, J = 1.5 Hz, 1H), 7.83 (dd, J = 8.7, 1.6 Hz, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.48 (s, 1H), 3.56 – 3.51 (m, 2H), 3.51 – 3.45 (m, 4H), 3.39 (s, 2H), 2.94 (q, J = 7.6 Hz, 2H), 1.60 – 1.50 (m, 8H), 1.34 (t, J = 7.6 Hz, 3H);13C NMR (126 MHz, DMSO) δ 164.99, 147.25, 140.89, 140.38, 127.52, 127.41, 123.87, 121.90, 121.02, 115.76, 111.05, 75.06, 68.46, 44.59, 32.53, 31.95, 31.62, 21.87, 20.44, 13.75; HRMS (ESI) m / z calcd for C22H26N6OS [M+H]+423.196706, found 423.1958.

[0172] Example 48: 6-(5-(3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-oxa-6- azaspiro[3.4]octane (48)  White solid (61%).1H NMR (500 MHz, DMSO) δ 8.31 (d, J = 1.7 Hz, 1H), 7.87 (dd, J = 8.7 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.47 (s, 1H), 4.62 (d, J = 6.2 Hz, 2H), 4.51 (d, J = 6.2 Hz, 2H), 3.74 (s, 2H), 3.50 (t, J = 6.9 Hz, 2H), 2.51 (s, 3H), 2.32 (t, J = 7.0 Hz, 2H);13C NMR (126 MHz, DMSO) δ 161.33, 141.91, 140.60, 140.18, 127.49, 127.35, 123.88, 122.80, 121.20, 115.64, 110.91, 79.89, 57.58, 48.53, 45.60, 35.02, 12.17; HRMS (ESI) m / z calcd for C18H18N6OS [M+H]+367.134106, found 367.13347.

[0173] Example 49: 6-(5-(3-cyclopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-oxa-6- azaspiro[3.4]octane (49)Off-white solid (56%).1H NMR (500 MHz, DMSO) δ 8.43 (s, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.51 – 7.44 (m, 2H), 4.62 (d, J = 6.2 Hz, 2H), 4.52 (d, J = 6.2 Hz, 2H), 3.75 (s, 2H), 3.52 (t, J = 6.9 Hz, 2H), 2.33 (t, J = 6.9 Hz, 2H), 2.27 (tt, J = 8.0, 5.2 Hz, 1H), 1.01 (dt, J = 9.4, 3.1 Hz, 4H);13C NMR (201 MHz, DMSO) δ 161.39, 147.17, 140.63, 127.32, 123.92, 121.87, 121.15, 115.49, 111.11, 79.89, 57.65, 48.52, 45.61, 35.04, 8.71, 7.68; HRMS (ESI) m / z calcd for C20H20N6OS [M+H]+393.149756, found 393.14903.

[0174] Example 50: 6-(5-(3-ethyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-oxa-6- azaspiro[3.4]octane (50)Off-white solid (48%).1H NMR (500 MHz, DMSO) δ 8.39 (d, J = 1.6 Hz, 1H), 7.84 (dd, J = 8.8, 1.6 Hz, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.48 (s, 1H), 4.62 (d, J = 6.2 Hz, 2H), 4.51 (d, J = 6.2 Hz, 2H), 3.73 (s, 2H), 3.50 (t, J = 6.9 Hz, 2H), 2.95 (q, J = 7.6 Hz, 2H), 2.32 (t, J = 6.9 Hz, 2H), 1.35 (t, J = 7.6 Hz, 3H);13C NMR (126 MHz, DMSO) δ 161.33, 147.25, 140.61, 140.35, 127.47,  127.32, 123.84, 121.92, 121.12, 115.73, 111.00, 79.89, 57.59, 48.48, 45.59, 35.00, 20.43, 13.77; HRMS (ESI) m / z calcd for C19H20N6OS [M+H]+381.149756, found 381.14908.

[0175] Example 51: 5-(3-methyl-1H-indazol-5-yl)-2-(4-(methylsulfonyl)piperazin-1-yl)imidazo[2,1- b][1,3,4]thiadiazole (54)Off-white solid (58%).1H NMR (500 MHz, DMSO) δ 8.26 (s, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.53 – 7.47 (m, 2H), 3.66 – 3.61 (m, 4H), 3.32 – 3.30 (m, 4H), 2.93 (s, 3H), 2.51 (s, 3H);13C NMR (126 MHz, DMSO) δ 165.01, 142.00, 140.25, 127.67, 123.96, 122.80, 120.93, 115.85, 110.98, 48.11, 44.87, 40.50, 40.33, 40.22, 40.17, 40.00, 39.83, 39.67, 39.50, 34.99, 12.18; ; HRMS (ESI) m / z calcd for C17H19N7O2S2 [M+H]+418.111992, found 418.11292.

[0176] Example 52: 4-methyl-1-(5-(3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4- ol (55)Off-white solid (60%).1H NMR (500 MHz, DMSO) δ 8.27 (s, 1H), 7.86 (dd, J = 8.7, 1.6 Hz, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.47 (s, 1H), 4.53 (s, 1H), 3.60 (dt, J = 13.0, 4.2 Hz, 2H), 3.47 (dt, J = 9.7, 4.5 Hz, 2H), 2.50 (s, 3H), 1.66 – 1.57 (m, 4H), 1.17 (s, 3H);13C NMR (126 MHz, DMSO) δ 164.86, 141.92, 140.93, 140.21, 127.56, 127.43, 123.93, 122.80, 121.12, 115.72, 110.95, 66.34, 45.60, 37.42, 30.09, 12.14; HRMS (ESI) m / z calcd for C18H20N6OS [M+H]+369.149756, found 369.15054.

[0177] Example 53: 5-(3-methyl-1H-indazol-5-yl)-2-(4-methylpiperazin-1-yl)imidazo[2,1-b][1,3,4]thiadiazole (56) Off-white solid (40%). HRMS (ESI) m / z calcd for C17H19N7S [M+H]+354.15009, found 354.15103.

[0178] Example 54: 5-(6-fluoro-3-methyl-1H-indazol-5-yl)-2-(4-methylpiperazin-1-yl)imidazo[2,1- b][1,3,4]thiadiazole (57)Off-white solid (35%). HRMS (ESI) m / z calcd for C17H18FN7S [M+H]+372.140668, found 372.1414.

[0179] Example 55: 9-(5-(6-fluoro-3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-3-oxa-9- azaspiro[5.5]undecane (58)White solid (62%).1H NMR (500 MHz, DMSO) δ 8.44 (d, J = 7.1 Hz, 1H), 7.36 (d, J = 11.5 Hz, 1H), 7.33 (d, J = 3.8 Hz, 1H), 3.54 (t, J = 1.4 Hz, 4H), 3.45 (t, J = 4.4 Hz, 4H), 2.48 (s, 3H), 1.60 (t, J = 4.6 Hz, 4H), 1.45 (t, J = 5.4 Hz, 4H);13C NMR (126 MHz, DMSO) δ 165.00, 159.44, 157.48, 142.37, 141.15, 139.97, 139.87, 130.13, 130.03, 121.88, 119.59, 118.87, 111.15, 111.01, 96.87, 96.66, 62.86, 44.45, 35.72, 34.47, 29.63, 12.01; HRMS (ESI) m / z calcd for C21H23FN6OS [M+H]+427.171634, found 427.17246.

[0180] Example 56:  (2R,6R)-2,6-dimethyl-4-(5-(3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2- yl)morpholine (59)White solid (55%).1H NMR (500 MHz, DMSO) δ 8.27 (s, 1H), 7.85 (dd, J = 8.7, 1.6 Hz, 1H), 7.50 (d, J = 9.4 Hz, 2H), 4.10 (td, J = 6.3, 3.5 Hz, 2H), 3.57 (dd, J = 12.6, 3.5 Hz, 2H), 3.23 (dd, J = 12.6, 6.1 Hz, 2H), 2.50 (s, 3H), 1.20 (d, J = 6.4 Hz, 6H);13C NMR (126 MHz, DMSO) δ 165.72, 141.95, 140.22, 127.54, 123.93, 122.78, 121.00, 115.77, 110.97, 65.26, 52.85, 17.86, 12.13; HRMS (ESI) m / z calcd for C18H20N6OS [M+H]+369.149756, found 369.14959.

[0181] Example 57: (2R,6R)-4-(5-(6-fluoro-3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2,6- dimethylmorpholine (60)Off-white solid (48%).1H NMR (500 MHz, DMSO) δ 8.40 (d, J = 7.1 Hz, 1H), 7.37 (d, J = 11.5 Hz, 1H), 7.34 (d, J = 3.7 Hz, 1H), 4.08 (td, J = 6.2, 3.3 Hz, 2H), 3.55 (dd, J = 12.6, 3.5 Hz, 2H), 3.20 (dd, J = 12.6, 6.1 Hz, 2H), 1.18 (d, J = 6.4 Hz, 6H);13C NMR (126 MHz, DMSO) δ 165.67, 159.46, 157.51, 142.43, 140.90, 140.06, 139.96, 130.19, 130.10, 121.97, 119.59, 119.19, 111.02, 110.88, 96.88, 96.67, 65.24, 52.83, 17.83, 11.96; HRMS (ESI) m / z calcd for C18H19FN6OS [M+H]+387.140334, found 387.13997.

[0182] Example 58: (S)-2-methyl-4-(5-(3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2- yl)morpholine (61) Off-white solid (58%).1H NMR (500 MHz, DMSO) δ 8.27 (d, J = 1.5 Hz, 1H), 7.85 (dd, J = 8.7, 1.6 Hz, 1H), 7.50 (t, J = 4.3 Hz, 2H), 3.97 – 3.86 (m, 1H), 3.70 – 3.61 (m, 4H), 3.21 (td, J = 11.9, 3.7 Hz, 1H), 2.90 (dd, J = 12.2, 11.0 Hz, 1H), 2.50 (s, 3H), 1.15 (d, J = 6.1 Hz, 3H);13C NMR (126 MHz, DMSO) δ 165.35, 141.95, 140.71, 140.22, 127.65, 127.58, 123.92, 122.79, 120.98, 115.75, 110.95, 71.03, 65.38, 53.97, 47.65, 18.83, 12.14; HRMS (ESI) m / z calcd for C17H18N6OS [M+H]+355.134106, found 355.13367.

[0183] Example 59: (S)-4-(5-(6-fluoro-3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2- methylmorpholine (62)Off-white solid (51%).1H NMR (500 MHz, DMSO) δ 8.41 (d, J = 7.0 Hz, 1H), 7.37 (d, J = 11.5 Hz, 1H), 7.35 (d, J = 3.8 Hz, 1H), 3.95 – 3.88 (m, 1H), 3.69 – 3.60 (m, 4H), 3.21 (td, J = 12.2, 3.6 Hz, 1H), 2.90 (dd, J = 12.8, 10.9 Hz, 1H), 2.48 (s, 3H), 1.14 (d, J = 6.1 Hz, 3H);13C NMR (126 MHz, DMSO) δ 165.36, 159.46, 157.51, 142.44, 141.01, 140.06, 139.96, 130.26, 130.17, 122.01, 119.60, 119.19, 111.00, 110.86, 96.89, 96.68, 70.99, 65.37, 53.95, 47.67, 18.81, 11.98; HRMS (ESI) m / z calcd for C17H17FN6OS [M+H]+373.124684, found 373.12437.

[0184] Example 60: (R)-2-methyl-4-(5-(3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2- yl)morpholine (63) Off-white solid (56%).1H NMR (500 MHz, DMSO) δ 8.27 (s, 1H), 7.86 (dd, J = 8.7, 1.6 Hz, 1H), 7.52 – 7.48 (m, 2H), 3.97 – 3.86 (m, 1H), 3.72 – 3.62 (m, 4H), 3.22 (td, J = 12.0, 3.7 Hz, 1H), 2.91 (dd, J = 12.3, 10.6 Hz, 1H), 2.50 (s, 3H), 1.16 (d, J = 6.1 Hz, 3H);13C NMR (126 MHz, DMSO) δ 165.37, 141.96, 140.72, 140.22, 127.59, 123.93, 122.79, 120.98, 115.76, 110.96, 71.04, 65.39, 53.98, 47.66, 18.83, 12.14; HRMS (ESI) m / z calcd for C17H18N6OS [M+H]+355.134106, found 355.13379.

[0185] Example 61: (R)-4-(5-(6-fluoro-3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2- methylmorpholine (64)Off-white solid (50%).1H NMR (500 MHz, DMSO) δ 8.41 (d, J = 7.0 Hz, 1H), 7.36 (d, J = 11.3 Hz, 1H), 7.34 (d, J = 3.7 Hz, 1H), 3.95 – 3.88 (m, 1H), 3.70 – 3.61 (m, 4H), 3.21 (td, J = 12.0, 3.6 Hz, 1H), 2.89 (dd, J = 12.8, 10.8 Hz, 1H), 2.48 (s, 3H), 1.14 (d, J = 6.1 Hz, 3H);13C NMR (126 MHz, DMSO) δ 165.35, 159.46, 157.50, 142.43, 141.01, 140.05, 139.95, 130.25, 130.16, 122.01, 119.59, 119.12, 111.00, 110.86, 96.88, 96.67, 70.98, 65.37, 53.95, 47.66, 18.80, 11.98; HRMS (ESI) m / z calcd for C17H17FN6OS [M+H]+373.124684, found 373.12437.

[0186] Example 62: 4-(5-(6-fluoro-3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)morpholine (65) White solid (45%)1H NMR (500 MHz, DMSO) δ 8.40 (d, J = 7.1 Hz, 1H), 7.39 – 7.33 (m, 2H), 3.74 (t, J = 4.9 Hz, 4H), 3.46 (t, J = 4.9 Hz, 4H), 2.48 (s, 3H).13C NMR (126 MHz, DMSO) δ 165.62, 159.45, 157.49, 142.45, 141.04, 140.06, 139.95, 130.29, 130.20, 122.03, 119.60, 119.15, 119.10, 111.00, 110.86, 96.90, 96.69, 65.65, 48.41, 12.05. HRMS (ESI) m / z calcd for C16H15FN6OS [M+H]+359.109034, found 359.10886.

[0187] Example 63: 4-(5-(3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)morpholine (66)Pale yellow solid (56%)1H NMR (500 MHz, DMSO) δ 8.27 (s, 1H), 7.86 (dd, J = 8.7, 1.6 Hz, 1H), 7.54 – 7.47 (m, 2H), 3.76 (t, J = 4.9 Hz, 4H), 3.49 (dd, J = 6.0, 3.9 Hz, 4H), 2.50 (s, 3H);13C NMR (126 MHz, DMSO) δ 165.61, 141.96, 140.74, 140.22, 127.65, 123.92, 122.78, 120.98, 115.73, 110.96, 65.68, 48.43, 12.18; HRMS (ESI) m / z calcd for C16H16N6OS [M+H]+341.118456, found 341.11844.

[0188] Example 64: 4-(5-(3-ethyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)morpholine (67)Pale yellow solid (48%).1H NMR (500 MHz, DMSO) δ 8.33 (d, J = 1.6 Hz, 1H), 7.84 (dd, J = 8.7, 1.6 Hz, 1H), 7.53 – 7.48 (m, 2H), 3.75 (t, J = 4.9 Hz, 4H), 3.48 (t, J = 3.7 Hz, 4H), 2.94 (q, J = 7.6 Hz, 2H), 1.33 (t, J = 7.6 Hz, 3H).13C NMR (126 MHz, DMSO) δ 165.59, 147.29, 140.76,  140.39, 127.65, 127.60, 123.90, 121.91, 120.90, 115.82, 111.04, 65.65, 48.43, 20.37, 13.77. HRMS (ESI) m / z calcd for C17H18N6OS [M+H]+355.134106, found 355.13383.

[0189] Example 65: (2S,6R)-4-(5-(1H-indol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2,6-dimethylmorpholine (68)Off-white solid (49%).1H NMR (500 MHz, DMSO) δ 11.15 (s, 1H), 8.12 (d, J = 1.6 Hz, 1H), 7.61 (dd, J = 8.5, 1.7 Hz, 1H), 7.44 (d, J = 8.5 Hz, 1H), 7.39 (s, 1H), 7.35 (t, J = 2.7 Hz, 1H), 6.47 (ddd, J = 3.0, 1.9, 0.9 Hz, 1H), 3.73 (dq, J = 11.6, 3.4 Hz, 4H), 2.83 (dd, J = 12.8, 11.0 Hz, 2H), 1.17 (d, J = 6.1 Hz, 6H).13C NMR (126 MHz, DMSO) δ 165.02, 140.19, 135.53, 128.65, 128.20, 126.97, 126.53, 120.31, 119.05, 116.67, 112.24, 102.05, 70.97, 53.24, 18.90; HRMS (ESI) m / z calcd for C18H19N5OS [M+H]+354.13887, found 354.13793.

[0190] Example 66: 2,2-dimethyl-4-(5-(3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2- yl)morpholine (71)Off-white solid (55%).1H NMR (800 MHz, DMSO) δ 12.70 (s, 1H), 8.29 (s, 1H), 7.88 (dd, J = 8.7, 1.7 Hz, 1H), 7.55 – 7.50 (m, 2H), 3.81 (t, J = 5.1 Hz, 2H), 3.52 (dd, J = 6.1, 4.1 Hz, 2H), 2.53 (s, 3H), 1.26 (s, 6H).13C NMR (201 MHz, DMSO) δ 165.61, 141.95, 140.62, 140.22, 127.63, 127.55, 123.94, 122.79, 121.00, 115.78, 110.97, 71.11, 59.41, 57.36, 47.81, 24.47, 12.15. HRMS (ESI) m / z calcd for C18H20N6OS [M+H]+369.149756, found 369.15002.

[0191] Example 67: 7-(5-(3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-4-oxa-7- azaspiro[2.5]octane (72) 8 White solid (54%).1H NMR (500 MHz, DMSO) δ 8.26 (s, 1H), 7.85 (d, J = 8.9 Hz, 1H), 7.50 (d, J = 5.0 Hz, 2H), 3.81 (dd, J = 6.5, 3.4 Hz, 2H), 3.62 – 3.57 (m, 2H), 3.50 (s, 2H), 2.49 (s, 3H), 0.78 – 0.68 (m, 4H).13C NMR (126 MHz, DMSO) δ 165.43, 141.97, 140.79, 140.23, 127.65, 123.96, 122.79, 120.96, 115.84, 110.96, 64.98, 58.45, 53.47, 48.01, 12.13, 11.44. HRMS (ESI) m / z calcd for C18H18N6OS [M+H]+367.134106, found 367.13469.

[0192] Example 68: 5-(3-methyl-1H-indazol-5-yl)-2-(3,3,4-trimethylpiperazin-1-yl)imidazo[2,1- b][1,3,4]thiadiazole (73)White solid (46%).1H NMR (500 MHz, DMSO) δ 8.29 – 8.26 (m, 1H), 7.85 (dd, J = 8.7, 1.6 Hz, 1H), 7.53 – 7.49 (m, 1H), 7.48 (s, 1H), 3.57 – 3.52 (m, 3H), 3.22 (s, 2H), 2.60 (dd, J = 6.2, 4.6 Hz, 2H), 2.50 (s, 3H), 2.17 (s, 3H), 1.03 (s, 6H).13C NMR (201 MHz, DMSO) δ 165.22, 141.93, 140.74, 140.21, 127.57, 127.47, 123.93, 122.79, 121.04, 115.73, 110.98, 59.97, 53.55, 48.46, 37.37, 19.45, 12.12.

[0193] Example 69: 1-(5-(3-cyclopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-4- methylpiperidin-4-ol (74)  Pale yellow solid (57%).1H NMR (500 MHz, DMSO) δ 8.40 (s, 1H), 7.80 (dd, J = 8.8, 1.6 Hz, 1H), 7.53 – 7.43 (m, 2H), 4.54 (s, 1H), 3.61 (dt, J = 13.0, 4.1 Hz, 2H), 3.49 (ddd, J = 12.9, 10.5, 4.1 Hz, 2H), 2.26 (p, J = 6.8 Hz, 1H), 1.66 – 1.53 (m, 4H), 1.17 (s, 3H), 1.00 (d, J = 6.3 Hz, 4H).13C NMR (126 MHz, DMSO) δ 164.83, 147.14, 140.99, 140.44, 127.44, 127.36, 123.92, 121.71, 121.06, 115.51, 111.17, 66.39, 45.65, 37.39, 30.12, 8.87, 7.49.

[0194] Example 70: 1-(5-(3-ethyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-4-methylpiperidin-4-ol (75)White solid (55%).1H NMR (500 MHz, DMSO) δ 8.37 (s, 1H), 7.83 (dd, J = 10.0, 1.2 Hz, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.48 (s, 1H), 4.53 (s, 1H), 3.59 (dt, J = 13.0, 4.2 Hz, 2H), 3.48 (ddd, J = 13.4, 10.3, 4.1 Hz, 2H), 2.94 (q, J = 7.6 Hz, 2H), 1.61 (td, J = 12.2, 6.8 Hz, 5H), 1.34 (t, J = 7.6 Hz, 3H), 1.17 (s, 3H).13C NMR (126 MHz, DMSO) δ 164.83, 147.27, 140.97, 140.39, 127.53, 127.38, 123.90, 121.90, 121.02, 115.82, 111.06, 66.37, 45.61, 37.38, 30.11, 20.46, 13.75.

[0195] Example 71: 4-(5-(3-ethyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2,2,6,6- tetramethylmorpholine (76)White solid (45%).1H NMR (500 MHz, DMSO) δ 8.41 (s, 1H), 7.80 (dd, J = 8.8, 1.6 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.49 (s, 1H), 3.42 (s, 4H), 2.95 (q, J = 7.6 Hz, 2H), 1.35 (t, J = 7.6 Hz, 3H), 1.24 (s, 12H).13C NMR (126 MHz, DMSO) δ 165.18, 147.27, 140.41, 127.53, 127.38, 123.90, 121.85, 120.92, 115.89, 111.12, 71.57, 56.65, 28.51, 20.57, 13.84.

[0196] Example 72: 4-(5-(3-cyclopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2,2,6,6- tetramethylmorpholine (77) 8 White solid (42%).1H NMR (500 MHz, DMSO) δ 8.46 – 8.40 (m, 1H), 7.77 (dd, J = 8.7, 1.6 Hz, 1H), 7.53 – 7.45 (m, 2H), 3.43 (s, 4H), 2.27 (tt, J = 8.3, 5.2 Hz, 1H), 1.24 (s, 12H), 1.08 – 0.96 (m, 4H).13C NMR (126 MHz, DMSO) δ 165.20, 147.04, 140.55, 140.48, 127.34, 123.85, 121.29, 120.95, 115.49, 111.24, 71.57, 56.64, 28.50, 9.41, 7.18.

[0197] Example 73: 4-methyl-1-(5-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2- yl)piperidin-4-ol (78)White solid (52%).1H NMR (500 MHz, DMSO) δ 9.04 (d, J = 2.1 Hz, 1H), 8.63 (d, J = 2.1 Hz, 1H), 7.59 (s, 1H), 4.54 (s, 1H), 3.61 (dd, J = 12.9, 4.1 Hz, 2H), 3.50 – 3.45 (m, 2H), 2.52 (s, 3H), 1.68 – 1.56 (m, 4H), 1.17 (s, 3H).13C NMR (126 MHz, DMSO) δ 165.17, 151.74, 146.31, 141.78, 141.47, 128.03, 124.95, 124.67, 118.35, 114.15, 66.32, 45.63, 37.42, 30.09, 12.66.

[0198] Example 74: 1-(5-(6-fluoro-3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-4- methylpiperidin-4-ol (79)Off-white solid (51%).1H NMR (500 MHz, DMSO) δ 8.43 (d, J = 7.1 Hz, 1H), 7.37 (d, J = 11.4 Hz, 1H), 7.33 (d, J = 3.6 Hz, 1H), 4.53 (s, 1H), 3.57 (dt, J = 13.1, 3.8 Hz, 2H), 3.47 (td, J = 10.1, 5.2 Hz, 2H), 1.60 (dt, J = 17.6, 8.7 Hz, 4H), 1.16 (s, 3H).13C NMR (201 MHz, DMSO) δ 164.85, 8  159.11, 142.41, 141.23, 140.03, 130.04, 121.91, 119.61, 119.16, 111.11, 96.86, 96.72, 66.33, 45.63, 37.38, 30.08, 11.99.

[0199] Example 75: 1-(5-(3-ethyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol (80)White solid (48%).1H NMR (500 MHz, DMSO) δ 8.35 (d, J = 1.6 Hz, 1H), 7.83 (dd, J = 8.7, 1.6 Hz, 1H), 7.51 (d, J = 8.7 Hz, 1H), 7.48 (s, 1H), 4.86 (d, J = 4.1 Hz, 1H), 3.86 – 3.60 (m, 4H), 2.94 (q, J = 7.6 Hz, 2H), 1.87 (ddt, J = 14.1, 7.0, 3.8 Hz, 2H), 1.52 (dtd, J = 12.8, 8.6, 3.9 Hz, 2H), 1.34 (t, J = 7.6 Hz, 3H).13C NMR (126 MHz, DMSO) δ 164.86, 147.27, 141.01, 140.39, 127.55, 127.42, 123.90, 121.90, 121.00, 115.82, 111.06, 65.25, 46.40, 33.33, 20.45, 13.75.

[0200] Example 76: 1-(5-(3-cyclopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol (81)White solid (50%).1H NMR (500 MHz, DMSO) δ 8.39 (s, 1H), 7.81 (dd, J = 8.7, 1.6 Hz, 1H), 7.50 – 7.46 (m, 2H), 4.87 (d, J = 4.1 Hz, 1H), 3.88 – 3.63 (m, 4H), 3.38 – 3.36 (m, 1H), 2.30 – 2.23 (m, 1H), 1.88 (dq, J = 9.7, 3.4 Hz, 2H), 1.53 (dtd, J = 12.8, 8.7, 4.0 Hz, 2H), 1.03 – 0.97 (m, 4H).13C NMR (126 MHz, DMSO) δ 164.87, 147.16, 141.04, 140.45, 127.48, 127.41, 123.93, 121.75, 121.04, 115.54, 111.17, 65.25, 46.43, 33.34, 8.82, 7.53.

[0201] Example 77: 1-(5-(6-fluoro-3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol (82) 8 Off-white solid (49%).1H NMR (500 MHz, DMSO) δ 8.42 (d, J = 7.1 Hz, 1H), 7.37 (d, J = 11.4 Hz, 1H), 7.33 (d, J = 3.7 Hz, 1H), 4.86 (d, J = 4.1 Hz, 1H), 3.73 (ddt, J = 34.8, 13.3, 4.4 Hz, 4H), 2.48 (s, 3H), 1.90 – 1.82 (m, 2H), 1.51 (dtd, J = 12.8, 8.7, 4.0 Hz, 2H).13C NMR (126 MHz, DMSO) δ 164.89, 159.48, 157.52, 142.43, 141.28, 140.06, 130.14, 130.05, 121.93, 119.61, 119.19, 111.11, 110.97, 96.90, 96.69, 65.21, 46.41, 33.32, 12.01.

[0202] Example 78: 1-(5-(6-fluoro-3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-3- methylazetidin-3-ol (83)White solid (48%).1H NMR (500 MHz, DMSO) δ 8.40 (d, J = 7.0 Hz, 1H), 7.40 – 7.31 (m, 2H), 5.88 (s, 1H), 4.05 – 3.98 (m, 4H), 1.46 (s, 3H), 1.44 (s, 3H).13C NMR (201 MHz, DMSO) δ 165.09, 159.12, 157.89, 142.40, 141.62, 140.11, 130.23, 122.06, 119.60, 119.36, 110.93, 96.88, 96.75, 69.42, 67.65, 26.61, 12.01.

[0203] Example 79: 1-(5-(3-cyclopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-3- methylazetidin-3-ol (84)White solid (55%).1H NMR (500 MHz, DMSO) δ 8.39 (s, 1H), 7.79 (dd, J = 8.7, 1.6 Hz, 1H), 7.58 – 7.43 (m, 2H), 5.89 (s, 1H), 4.07 – 3.99 (m, 4H), 2.26 (tt, J = 8.1, 5.2 Hz, 1H), 1.47 (s, 3H), 1.04 – 0.96 (m, 4H).13C NMR (126 MHz, DMSO) δ 165.12, 147.19, 141.38, 140.45, 127.60, 123.97, 121.87, 120.96, 115.58, 111.17, 69.45, 67.65, 26.63, 8.69, 7.69. 8

[0204] Example 80: (S)-4-(5-(3-cyclopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2- methylmorpholine (85)White solid (51%).1H NMR (500 MHz, DMSO) δ 8.40 (s, 1H), 7.81 (dd, J = 8.8, 1.6 Hz, 1H), 7.52 – 7.47 (m, 2H), 3.94 (dd, J = 10.9, 3.4 Hz, 1H), 3.74 – 3.63 (m, 4H), 3.25 (td, J = 11.9, 3.6 Hz, 1H), 2.94 (dd, J = 12.3, 10.4 Hz, 1H), 2.27 (p, J = 6.8 Hz, 1H), 1.19 – 1.10 (m, 4H), 1.00 (d, J = 6.7 Hz, 3H).13C NMR (126 MHz, DMSO) δ 165.40, 147.19, 140.80, 140.47, 127.55, 123.94, 121.75, 120.94, 115.57, 111.20, 71.00, 65.42, 53.96, 47.79, 18.86, 8.87, 7.55.

[0205] Example 81: (R)-4-(5-(3-ethyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2- methylmorpholine (86)White solid (54%).1H NMR (500 MHz, DMSO) δ 8.37 (s, 1H), 7.83 (dd, J = 8.8, 1.6 Hz, 1H), 7.53 – 7.49 (m, 2H), 3.97 – 3.92 (m, 1H), 3.74 – 3.63 (m, 4H), 3.24 (td, J = 12.1, 3.7 Hz, 1H), 3.00 – 2.89 (m, 3H), 1.34 (t, J = 7.6 Hz, 3H), 1.16 (d, J = 6.1 Hz, 3H).13C NMR (201 MHz, DMSO) δ 165.35, 147.29, 140.74, 140.40, 127.62, 127.55, 123.89, 121.89, 120.89, 115.86, 111.06, 70.97, 65.39, 53.94, 47.73, 20.44, 18.83, 13.79.

[0206] Example 82: (S)-4-(5-(3-ethyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-methylmorpholine (87) 8 White solid (52%).1H NMR (500 MHz, DMSO) δ 8.37 (s, 1H), 7.83 (dd, J = 8.7, 1.6 Hz, 1H), 7.55 – 7.45 (m, 2H), 3.97 – 3.89 (m, 1H), 3.68 (dddd, J = 24.2, 14.9, 11.9, 2.5 Hz, 4H), 3.24 (td, J = 12.1, 3.6 Hz, 1H), 2.99 – 2.88 (m, 3H), 1.34 (t, J = 7.6 Hz, 3H), 1.16 (d, J = 6.1 Hz, 3H).13C NMR (126 MHz, DMSO) δ 165.37, 147.30, 140.75, 140.41, 127.63, 127.57, 123.91, 121.90, 120.90, 115.87, 111.07, 70.99, 65.40, 53.96, 47.74, 20.45, 18.84, 13.80.

[0207] Example 83: 5-(3-ethyl-1H-indazol-5-yl)-2-(4-(methylsulfonyl)piperazin-1-yl)imidazo[2,1- b][1,3,4]thiadiazole (88)White solid (52%).1H NMR (500 MHz, DMSO) δ 8.33 (s, 1H), 7.83 (dd, J = 8.7, 1.8 Hz, 1H), 7.55 – 7.48 (m, 2H), 3.68 – 3.61 (m, 4H), 3.28 – 3.24 (m, 4H), 2.96 (q, J = 7.6 Hz, 2H), 2.91 (s, 3H), 1.34 (t, J = 7.6 Hz, 3H).

[0208] Example 84: 5-(3-cyclopropyl-1H-indazol-5-yl)-2-(4-(methylsulfonyl)piperazin-1-yl)imidazo[2,1- b][1,3,4]thiadiazole (89)White soliid (54%).1H NMR (500 MHz, DMSO) δ 8.39 (s, 1H), 7.81 (dd, J = 8.8, 1.6 Hz, 1H), 7.53 – 7.47 (m, 2H), 3.67 – 3.62 (m, 4H), 3.28 – 3.25 (m, 4H), 2.93 (s, 3H), 2.28 (p, J = 5.2 Hz, 1H), 1.05 – 0.96 (m, 4H). 8

[0209] Example 85: 7-(5-(3-cyclopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-4-oxa-7- azaspiro[2.5]octane (90)White solid (54%).1H NMR (500 MHz, DMSO) δ 8.38 (d, J = 1.5 Hz, 1H), 7.80 (dd, J = 8.8, 1.6 Hz, 1H), 7.53 – 7.45 (m, 2H), 3.85 – 3.77 (m, 2H), 3.63 – 3.57 (m, 2H), 3.53 (s, 2H), 2.26 (p, J = 6.7 Hz, 1H), 0.99 (d, J = 6.7 Hz, 4H), 0.80 – 0.69 (m, 4H).13C NMR (126 MHz, DMSO) δ 165.40, 147.16, 140.83, 140.46, 127.56, 123.92, 121.68, 120.91, 115.58, 111.18, 65.00, 58.43, 53.42, 48.09, 11.47, 8.89, 7.49.

[0210] Example 86: 7-(5-(3-ethyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-4-oxa-7- azaspiro[2.5]octane (91)White solid (46%).1H NMR (500 MHz, DMSO) δ 8.34 (d, J = 1.5 Hz, 1H), 7.82 (dd, J = 8.7, 1.6 Hz, 1H), 7.50 (t, J = 4.4 Hz, 2H), 3.82 (dd, J = 5.8, 4.0 Hz, 2H), 3.62 – 3.57 (m, 2H), 3.51 (s, 2H), 2.94 (q, J = 7.6 Hz, 2H), 1.33 (t, J = 7.6 Hz, 3H), 0.80 – 0.69 (m, 4H).13C NMR (126 MHz, DMSO) δ 165.40, 147.31, 140.81, 140.41, 127.63, 123.92, 121.89, 120.87, 115.91, 111.07, 64.99, 58.43, 53.44, 48.07, 20.43, 13.79, 11.45.

[0211] Example 87: 4-(5-(3-ethyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2,2-dimethylmorpholine (92) 8 Brown solid (41 %).1H NMR (500 MHz, DMSO) δ 8.36 (d, J = 1.6 Hz, 1H), 7.82 (dd, J = 8.7, 1.7 Hz, 1H), 7.54 – 7.47 (m, 2H), 3.78 (dd, J = 6.2, 4.0 Hz, 2H), 3.52 – 3.46 (m, 2H), 3.32 (s, 2H), 2.95 (q, J = 7.6 Hz, 2H), 1.34 (t, J = 7.6 Hz, 3H), 1.23 (s, 6H).13C NMR (126 MHz, DMSO) δ 165.56, 147.28, 140.64, 140.40, 127.60, 127.50, 123.91, 121.89, 120.91, 115.86, 111.07, 71.09, 59.42, 57.26, 47.89, 24.49, 20.46, 13.79.

[0212] Example 88: (R)-4-(5-(3-cyclopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2- methylmorpholine (93)White solid (52%).1H NMR (500 MHz, DMSO) δ 8.40 (s, 1H), 7.84 – 7.78 (m, 1H), 7.53 – 7.46 (m, 2H), 3.94 (dd, J = 10.8, 3.2 Hz, 1H), 3.75 – 3.63 (m, 4H), 3.25 (td, J = 11.8, 3.5 Hz, 1H), 2.93 (dd, J = 12.3, 10.4 Hz, 1H), 2.31 – 2.24 (m, 1H), 1.16 (d, J = 6.2 Hz, 3H), 1.00 (d, J = 6.7 Hz, 4H).13C NMR (126 MHz, DMSO) δ 165.37, 147.16, 140.77, 140.45, 127.53, 123.91, 121.73, 120.93, 115.54, 111.17, 70.98, 65.40, 53.94, 47.77, 18.85, 8.86, 7.54.

[0213] Example 89: 3-(5-(3-cyclopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-8-oxa-3- azabicyclo[3.2.1]octane (94)  White solid (55%).1H NMR (500 MHz, DMSO) δ 8.37 (s, 1H), 7.82 (dd, J = 8.7, 1.6 Hz, 1H), 7.51 – 7.46 (m, 2H), 4.47 (d, J = 4.1 Hz, 2H), 3.50 (d, J = 11.9 Hz, 2H), 3.37 (dd, J = 12.0, 2.7 Hz, 2H), 2.27 (ddd, J = 8.1, 6.9, 4.1 Hz, 1H), 1.87 (dq, J = 20.2, 5.5 Hz, 4H), 1.01 – 0.95 (m, 4H).13C NMR (126 MHz, DMSO) δ 165.98, 147.21, 140.51, 140.44, 127.55, 123.95, 121.94, 121.00, 115.59, 111.13, 72.97, 53.74, 27.98, 8.60, 7.73.

[0214] Example 90: 3-(5-(3-ethyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-8-oxa-3- azabicyclo[3.2.1]octane (95)White solid (54%).1H NMR (500 MHz, DMSO) δ 8.36 – 8.30 (m, 1H), 7.84 (dd, J = 8.8, 1.6 Hz, 1H), 7.54 – 7.47 (m, 2H), 4.47 (d, J = 4.2 Hz, 2H), 3.49 (d, J = 11.8 Hz, 2H), 3.37 (dd, J = 12.0, 2.6 Hz, 2H), 2.94 (q, J = 7.6 Hz, 2H), 1.93 – 1.81 (m, 4H), 1.34 (t, J = 7.6 Hz, 3H).13C NMR (126 MHz, DMSO) δ 165.98, 147.29, 140.49, 140.39, 127.57, 123.90, 121.93, 120.96, 115.85, 111.03, 72.97, 53.73, 27.98, 20.38, 13.77.

[0215] Example 91: 3-(5-(3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-8-oxa-3- azabicyclo[3.2.1]octane (96)White Solid (58%).1H NMR (500 MHz, DMSO) δ 8.26 (s, 1H), 7.86 (dd, J = 8.7, 1.6 Hz, 1H), 7.55 – 7.46 (m, 2H), 4.47 (d, J = 0.7 Hz, 2H), 3.50 (d, J = 11.9 Hz, 3H), 3.37 (dd, J = 12.0, 2.7 Hz, 3H), 2.50 (s, 3H), 1.88 (ddd, J = 20.0, 9.2, 5.1 Hz, 4H).13C NMR (126 MHz, DMSO) δ 165.97, 141.95, 140.21, 127.57, 123.91, 122.79, 121.04, 115.75, 110.94, 72.97, 53.73, 27.98, 12.20.

[0216] Example 92:  3-methyl-1-(5-(3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)azetidin-3-ol (97)White Solid (51%).1H NMR (500 MHz, DMSO) δ 8.27 (s, 1H), 7.83 (dd, J = 8.7, 1.6 Hz, 1H), 7.54 – 7.47 (m, 2H), 5.88 (s, 1H), 4.07 – 4.01 (m, 4H), 2.50 (s, 3H), 1.47 (s, 3H).13C NMR (126 MHz, DMSO) δ 165.14, 141.93, 141.35, 140.24, 127.71, 127.61, 123.96, 122.79, 121.01, 115.81, 110.98, 69.44, 67.71, 26.63, 12.15.

[0217] Example 93: 3-(5-(6-fluoro-3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-8-oxa-3- azabicyclo[3.2.1]octane (98)White Solid (60%).1H NMR (500 MHz, DMSO) δ 8.41 (d, J = 7.1 Hz, 1H), 7.40 – 7.32 (m, 2H), 4.46 (d, J = 4.5 Hz, 2H), 3.47 (d, J = 11.9 Hz, 2H), 3.36 (dd, J = 12.1, 2.7 Hz, 2H), 2.49 (s, 3H), 1.92 – 1.80 (m, 4H).13C NMR (201 MHz, DMSO) δ 166.00, 159.10, 157.88, 142.44, 140.77, 140.04, 130.24, 130.18, 121.93, 119.60, 119.19, 110.94, 96.85, 96.72, 72.95, 53.71, 27.95, 12.05.

[0218] Example 94: 7-(5-(3-cyclopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-oxa-7- azaspiro[3.5]nonane (99)  Brown Solid (58%).1H NMR (500 MHz, DMSO) δ 8.39 (s, 1H), 7.81 (dd, J = 8.7, 1.6 Hz, 1H), 7.53 – 7.46 (m, 2H), 4.36 (s, 4H), 3.49 – 3.44 (m, 4H), 2.27 (tt, J = 8.1, 5.3 Hz, 1H), 1.96 – 1.91 (m, 4H), 1.01 (dd, J = 10.4, 3.6 Hz, 4H).13C NMR (126 MHz, DMSO) δ 164.95, 147.16, 140.98, 140.44, 127.44, 123.91, 121.80, 121.01, 115.50, 111.17, 80.45, 46.03, 38.62, 33.32, 8.78, 7.58.

[0219] Example 95: 7-(5-(3-ethyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-oxa-7- azaspiro[3.5]nonane (100)Brown Solid (55%).1H NMR (500 MHz, DMSO) δ 8.35 (s, 1H), 7.83 (dd, J = 8.7, 1.5 Hz, 1H), 7.54 – 7.46 (m, 2H), 4.35 (s, 4H), 3.50 – 3.40 (m, 4H), 2.94 (q, J = 1.8 Hz, 2H), 1.98 – 1.88 (m, 4H), 1.35 (t, J = 1.8 Hz, 3H).13C NMR (126 MHz, DMSO) δ 164.95, 147.26, 140.95, 140.39, 127.57, 127.46, 123.88, 121.91, 120.98, 115.79, 111.06, 80.43, 45.98, 38.59, 33.31, 20.44, 13.78.

[0220] Example 96: 7-(5-(3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1-oxa-7- azaspiro[3.5]nonane (101)White solid (60%).1H NMR (500 MHz, DMSO) δ 8.27 (s, 1H), 7.86 (dd, J = 8.7, 1.6 Hz, 1H), 7.53 – 7.46 (m, 2H), 4.43 (t, J = 7.7 Hz, 2H), 3.54 – 3.45 (m, 4H), 2.50 (s, 3H), 2.41 (t, J = 7.7 Hz, 2H), 1.98 – 1.91 (m, 4H).13C NMR (201 MHz, DMSO) δ 164.78, 141.94, 141.02, 140.22, 127.61, 127.50, 123.93, 122.79, 121.06, 115.75, 110.97, 83.20, 64.47, 45.25, 36.56, 31.43, 12.15.

[0221] Example 97: 7-(5-(3-cyclopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1-oxa-7- azaspiro[3.5]nonane (102) Brown solid (58%).1H NMR (500 MHz, DMSO) δ 8.39 (s, 1H), 7.80 (dd, J = 8.8, 2.7 Hz, 1H), 7.52 – 7.45 (m, 2H), 4.43 (t, J = 3.3 Hz, 2H), 3.58 – 3.49 (m, 4H), 2.41 (t, J = 6.2 Hz, 2H), 2.31 – 2.22 (m, 1H), 1.98 – 1.92 (m, 4H), 1.01 (dt, J = 8.2, 2.4 Hz, 4H).13C NMR (126 MHz, DMSO) δ 164.75, 147.17, 141.09, 140.45, 127.44, 123.93, 121.77, 121.01, 115.54, 111.18, 83.21, 64.48, 45.28, 36.53, 31.48, 8.81, 7.55.

[0222] Example 98: 7-(5-(3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-oxa-7- azaspiro[3.5]nonane (103)White solid (60%).1H NMR (500 MHz, DMSO) δ 8.27 (s, 1H), 7.86 (dd, J = 8.7, 1.6 Hz, 1H), 7.52 – 7.46 (m, 2H), 4.36 (s, 4H), 3.48 – 3.42 (m, 4H), 2.50 (s, 3H), 1.96 – 1.92 (m, 4H).13C NMR (201 MHz, DMSO) δ 165.01, 141.94, 140.21, 127.49, 123.92, 122.79, 121.06, 115.71, 110.97, 80.42, 45.97, 38.56, 33.35, 12.16.

[0223] Example 99: 7-(5-(3-ethyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1-oxa-7- azaspiro[3.5]nonane (104)Brown solid (56%).1H NMR (500 MHz, DMSO) δ 8.35 (s, 1H), 7.82 (dd, J = 8.7, 1.6 Hz, 1H), 7.53 – 7.46 (m, 2H), 4.43 (t, J = 7.8 Hz, 2H), 3.54 – 3.47 (m, 4H), 2.95 (q, J = 7.6 Hz, 2H), 2.40 (t, J = 7.8 Hz, 2H), 1.97 – 1.91 (m, 4H), 1.35 (t, J = 7.6 Hz, 3H).13C NMR (201 MHz, DMSO) δ  164.76, 147.28, 141.05, 140.40, 127.46, 123.91, 121.90, 120.96, 115.84, 111.07, 83.20, 64.47, 45.26, 36.52, 31.45, 20.44, 13.77.

[0224] Example 100: 5-(3-ethyl-1H-indazol-5-yl)-2-(4-(isopropylsulfonyl)piperazin-1-yl)imidazo[2,1- b][1,3,4]thiadiazole (105)White Solid (51%).NMR (500 MHz, DMSO) δ 8.33 (s, 1H), 7.83 (dd, J = 8.7, 1.6 Hz, 1H), 7.53 – 7.48 (m, 2H), 3.60 – 3.56 (m, 4H), 3.47 – 3.43 (m, 4H), 3.42 – 3.36 (m, 2H), 2.95 (q, J = 7.5 Hz, 2H), 1.34 (t, J = 7.6 Hz, 3H), 1.23 (d, J = 6.8 Hz, 6H).13C NMR (126 MHz, DMSO) δ 165.16, 147.30, 140.89, 140.39, 127.62, 123.92, 121.90, 120.85, 115.86, 111.05, 52.54, 48.85, 45.11, 20.35, 16.86, 13.78.

[0225] Example 101: 5-(3-cyclopropyl-1H-indazol-5-yl)-2-(4-(isopropylsulfonyl)piperazin-1-yl)imidazo[2,1- b][1,3,4]thiadiazole (106)White Solid (53%).1H NMR (500 MHz, DMSO) δ 8.39 (s, 1H), 7.81 (dd, J = 8.7, 1.6 Hz, 1H), 7.55 – 7.46 (m, 2H), 3.61 – 3.56 (m, 4H), 3.48 – 3.44 (m, 4H), 3.42 – 3.36 (m, 2H), 2.31 – 2.25 (m, 1H), 1.23 (d, J = 6.8 Hz, 6H), 1.03 – 0.95 (m, 4H).13C NMR (126 MHz, DMSO) δ 165.16, 147.24, 140.94, 140.43, 127.60, 123.95, 121.92, 120.89, 115.55, 111.17, 52.54, 48.87, 45.11, 16.86, 8.58, 7.72.

[0226] Example 102: methyl 4-(5-(3-cyclopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2- yl)piperazine-1-carboxylate (107) White Solid (54%).1H NMR (500 MHz, DMSO) δ 8.38 (s, 1H), 7.81 (dd, J = 8.8, 1.6 Hz, 1H), 7.53 – 7.45 (m, 2H), 3.63 (s, 3H), 3.59 – 3.52 (m, 8H), 2.28 (td, J = 8.3, 4.1 Hz, 1H), 1.04 – 0.96 (m, 4H).13C NMR (201 MHz, DMSO) δ 165.22, 155.49, 147.25, 140.89, 140.45, 127.59, 123.97, 121.91, 120.92, 115.56, 111.18, 53.07, 48.15, 8.62, 7.72.

[0227] Example 103: methyl 4-(5-(3-ethyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperazine-1- carboxylate (108)White Solid (51%).1H NMR (500 MHz, DMSO) δ 8.34 (d, J = 6.6 Hz, 1H), 7.92 – 7.75 (m, 1H), 7.59 – 7.35 (m, 2H), 3.64 (d, J = 7.1 Hz, 3H), 3.60 – 3.44 (m, 8H), 2.95 (t, J = 6.3 Hz, 2H), 1.35 (q, J = 7.5 Hz, 3H).13C NMR (201 MHz, DMSO) δ 165.21, 155.49, 147.33, 140.85, 140.41, 127.69, 127.61, 123.94, 121.92, 120.88, 115.88, 111.06, 53.06, 48.12, 20.37, 13.78.

[0228] Example 104: 1-(4-(5-(3-ethyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperazin-1-yl)ethan- 1-one (109)White Solid (55%). H NMR (500 MHz, DMSO) δ 8.34 (d, J = 1.5 Hz, 1H), 7.83 (dd, J = 8.7, 1.6 Hz, 1H), 7.53 – 7.48 (m, 2H), 3.66 – 3.62 (m, 4H), 3.58 – 3.55 (m, 2H), 3.49 – 3.46 (m, 2H), 2.95 (q, J = 7.6 Hz, 2H), 2.04 (d, J = 11.5 Hz, 3H), 1.34 (t, J = 7.6 Hz, 3H).13C NMR (201 MHz,  DMSO) δ 169.04, 165.20, 147.31, 140.86, 140.40, 127.58, 123.93, 121.91, 120.89, 115.83, 111.07, 48.44, 48.27, 45.07, 21.73, 20.37, 13.80.

[0229] Example 105: 1-(4-(5-(3-cyclopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperazin-1- yl)ethan-1-one (110)White Solid (58%).1H NMR (500 MHz, DMSO) δ 8.39 (s, 1H), 7.81 (dd, J = 8.7, 1.5 Hz, 1H), 7.53 – 7.46 (m, 2H), 3.64 (t, J = 5.2 Hz, 4H), 3.58 – 3.56 (m, 2H), 3.49 (t, J = 5.3 Hz, 2H), 2.32 – 2.24 (m, 1H), 2.05 (s, 3H), 1.06 – 0.98 (m, 4H).13C NMR (201 MHz, DMSO) δ 169.04, 165.21, 147.23, 140.89, 140.45, 127.60, 127.53, 123.97, 121.92, 120.92, 115.56, 114.27, 111.18, 48.50, 48.27, 45.09, 21.74, 8.60, 7.73.

[0230] Example 106: 6-(5-(3-ethyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-oxa-6- azaspiro[3.3]heptane (111)White Solid (52%).1H NMR (500 MHz, DMSO) δ 8.34 (s, 1H), 7.85 – 7.78 (m, 1H), 7.54 – 7.46 (m, 2H), 4.74 (s, 4H), 4.35 (s, 4H), 2.94 (q, J = 3.2 Hz, 2H), 1.35 (t, J = 3.1 Hz, 3H).13C NMR (201 MHz, DMSO) δ 164.97, 147.26, 141.30, 140.39, 127.62, 123.89, 121.91, 120.91, 115.80, 111.07, 79.91, 62.66, 20.40, 13.80.

[0231] Example 107: 6-(5-(3-cyclopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-oxa-6- azaspiro[3.3]heptane (112) White Solid (51%).1H NMR (500 MHz, DMSO) δ 8.38 (s, 1H), 7.79 (dd, J = 8.8, 1.6 Hz, 1H), 7.52 – 7.46 (m, 2H), 4.74 (s, 5H), 4.36 (s, 4H), 2.30 – 2.23 (m, 1H), 1.04 – 0.96 (m, 4H).13C NMR (201 MHz, DMSO) δ 164.99, 147.20, 141.33, 140.44, 127.60, 123.95, 121.96, 120.94, 115.55, 111.16, 79.92, 62.68, 8.59, 7.76.

[0232] Example 108: 6-(5-(3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-oxa-6- azaspiro[3.3]heptane (113)White Solid (55%).NMR (500 MHz, DMSO) δ 8.27 (s, 1H), 7.83 (dd, J = 7.3, 7.3 Hz, 1H), 7.53 – 7.45 (m, 2H), 4.74 (s, 4H), J4.36 (s, 4H), 2.51 (s, 3H).13C NMR (201 MHz, DMSO) δ 164.99, 141.91, 141.29, 140.23, 127.64, 123.92, 122.78, 120.99, 115.75, 110.98, 79.91, 62.71, 12.16.

[0233] Example 109: 6-(5-(6-fluoro-3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-oxa-6- azaspiro[3.3]heptane (114)White Solid (58%).1H NMR (500 MHz, DMSO) δ 8.39 (d, J = 7.0 Hz, 1H), 7.38 (d, J = 11.4 Hz, 1H), 7.36 – 7.27 (m, 1H), 4.72 (s, 4H), 4.33 (s, 4H), 2.50 (s, 3H).13C NMR (201 MHz, DMSO) δ 164.92, 159.10, 157.87, 142.38, 141.57, 140.10, 140.03, 130.27, 130.21, 122.06, 119.59, 119.25, 111.01, 110.92, 96.89, 96.75, 79.89, 62.66, 12.03.

[0234] Example 110:  4-(5-(3-ethyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-N,N- dimethylpiperazine-1-carboxamide (115)Off-white solid (44%).1H NMR (800 MHz, DMSO) δ 12.70 (s, 1H), 8.35 (s, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.55 – 7.49 (m, 2H), 3.54 (t, J = 5.1 Hz, 4H), 3.30 (t, J = 5.2 Hz, 4H), 2.97 (q, J = 7.6 Hz, 2H), 2.78 (s, 6H), 1.36 (t, J = 7.6 Hz, 3H).13C NMR (201 MHz, DMSO) δ 165.32, 163.92, 147.29, 140.79, 127.67, 127.46, 123.94, 121.90, 120.88, 115.90, 111.06, 48.17, 48.12, 45.96, 45.92, 38.46, 20.36, 13.79.

[0235] Example 111: cyclopropyl(4-(5-(3-ethyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperazin-1- yl)methanone (116)Off-white solid (45%).1H NMR (800 MHz, DMSO) δ 12.70 (s, 1H), 8.37 (s, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.57 – 7.49 (m, 2H), 3.91 – 3.49 (m, 8H), 2.97 (q, J = 7.6 Hz, 2H), 2.12 – 2.02 (m, 1H), 1.37 (t, J = 7.7 Hz, 3H), 0.80 – 0.72 (m, 4H).13C NMR (201 MHz, DMSO) δ 171.86, 165.19, 147.31, 140.88, 140.40, 127.60, 123.92, 121.92, 120.92, 115.84, 111.06, 48.58, 48.25, 44.34, 41.06, 20.38, 13.79, 10.87, 7.67.

[0236] Example 112: cyclopropyl(4-(5-(3-cyclopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2- yl)piperazin-1-yl)methanone (117) White solid (48%).1H NMR (800 MHz, DMSO) δ 12.64 (s, 1H), 8.42 (s, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.55 – 7.48 (m, 2H), 3.94 – 3.51 (m, 8H), 2.30 (tt, J = 8.8, 5.2 Hz, 1H), 2.05 (tt, J = 8.3, 4.8 Hz, 1H), 1.07 – 0.97 (m, 4H), 0.80 – 0.75 (m, 4H).13C NMR (201 MHz, DMSO) δ 171.86, 165.20, 147.23, 140.91, 140.45, 127.58, 123.97, 121.94, 120.95, 115.56, 111.17, 48.62, 48.25, 44.35, 41.06, 10.87, 8.61, 7.72, 7.67.

[0237] Example 113: 7-(5-(3-ethyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1,4-dioxa-7- azaspiro[4.4]nonane ((118)White solid (52%).1H NMR (800 MHz, DMSO) δ 12.69 (s, 1H), 8.40 (s, 1H), 7.86 (d, J = 1.3 Hz, 1H), 7.52 (d, J = 8.7 Hz, 1H), 7.51 (s, 1H), 3.99 (s, 4H), 3.64 (t, J = 7.2 Hz, 2H), 3.56 (s, 2H), 2.97 (q, J = 8.2 Hz, 2H), 2.24 (t, J = 7.3 Hz, 2H), 1.39 – 1.34 (m, 3H).13C NMR (201 MHz, DMSO) δ 161.69, 147.28, 140.54, 140.38, 127.56, 127.38, 123.90, 121.91, 121.05, 115.84, 113.43, 111.01, 64.96, 56.35, 47.95, 34.30, 20.42, 13.75.

[0238] Example 114: 7-(5-(3-cyclopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1,4-dioxa-7- azaspiro[4.4]nonane (119)  White solid (49%).1H NMR (800 MHz, DMSO) δ 8.44 (s, 1H), 7.84 (d, J = 8.9 Hz, 1H), 7.53 – 7.47 (m, 2H), 3.99 (s, 4H), 3.65 (t, J = 7.3 Hz, 2H), 3.57 (s, 2H), 2.31 – 2.26 (m, 1H), 2.25 (t, J = 7.3 Hz, 2H), 1.05 – 1.01 (m, 4H).13C NMR (201 MHz, DMSO) δ 161.72, 147.18, 140.57, 140.43, 127.49, 127.37, 123.95, 121.80, 121.08, 115.58, 113.42, 111.12, 64.96, 56.38, 47.96, 34.30, 8.77, 7.62.

[0239] Example 115: 7-(5-(3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1,4-dioxa-7- azaspiro[4.4]nonane (120)White solid (56%).1H NMR (800 MHz, DMSO) δ 12.69 (s, 1H), 8.32 (s, 1H), 7.89 (d, J = 8.7 Hz, 1H), 7.56 – 7.45 (m, 2H), 3.99 (s, 4H), 3.65 (t, J = 7.3 Hz, 2H), 3.57 (s, 2H), 2.52 (s, 3H), 2.24 (t, J = 7.3 Hz, 2H).13C NMR (201 MHz, DMSO) δ 161.72, 141.95, 140.53, 140.20, 127.58, 127.43, 123.94, 122.79, 121.13, 115.75, 113.45, 110.92, 64.97, 56.39, 48.01, 34.32, 12.16.

[0240] Example 116: (2S,6R)-2,6-dimethyl-4-(5-(2-methylquinolin-6-yl)imidazo[2,1-b][1,3,4]thiadiazol-2- yl)morpholine (123)White solid (56%).1H NMR (400 MHz, DMSO) δ 8.56 (d, J = 2.0 Hz, 1H), 8.32 (d, J = 8.4 Hz, 1H), 8.24 (dd, J = 8.9, 2.1 Hz, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.74 (s, 1H), 7.44 (d, J = 8.4 Hz, 1H), 3.86 – 3.67 (m, 4H), 2.88 (dd, J = 12.3, 10.5 Hz, 2H), 2.66 (s, 3H), 1.21 (d, J = 6.1 Hz, 6H).13C NMR (101 MHz, DMSO) δ 165.49, 158.97, 146.74, 141.98, 136.80, 129.42, 129.20, 126.83, 126.65, 126.35, 123.09, 122.03, 70.99, 53.18, 25.28, 18.88.

[0241] Example 117:  (2S,6R)-2,6-dimethyl-4-(5-(3-methyl-1H-indol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2- yl)morpholine (129)Off-white solid (59%).1H NMR (400 MHz, DMSO) δ 10.84 (s, 1H), 8.09 (d, J = 1.6 Hz, 1H), 7.63 (dd, J = 8.5, 1.7 Hz, 1H), 7.44 – 7.37 (m, 2H), 7.14 (dd, J = 2.3, 1.2 Hz, 1H), 3.81 – 3.67 (m, 4H), 2.85 (dd, J = 12.5, 10.7 Hz, 2H), 2.29 (s, 3H), 1.17 (d, J = 6.2 Hz, 6H).13C NMR (101 MHz, DMSO) δ 164.90, 140.12, 135.85, 128.74, 128.44, 126.79, 124.03, 119.61, 118.92, 114.98, 112.05, 110.12, 70.91, 53.26, 18.87, 9.91.

[0242] Example 118: (2S,6R)-4-(5-(3-cyclopropyl-1H-indazol-6-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2,6- dimethylmorpholine (132)White solid (52%).1H NMR (400 MHz, DMSO) δ 12.61 (s, 1H), 8.12 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.64 (s, 1H), 7.58 (dd, J = 8.6, 1.4 Hz, 1H), 3.75 (dd, J = 10.8, 2.1 Hz, 4H), 2.88 (dd, J = 12.8, 11.0 Hz, 2H), 2.27 (tt, J = 8.2, 5.2 Hz, 1H), 1.19 (d, J = 6.1 Hz, 6H), 1.08 – 0.90 (m, 4H).13C NMR (101 MHz, DMSO) δ 165.40, 146.94, 141.78, 141.55, 129.02, 127.25, 126.85, 120.73, 120.67, 117.33, 105.28, 70.94, 53.21, 18.90, 8.41, 7.96.

[0243] Example 119: 4-(5-(3-cyclopropyl-1H-indazol-6-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2,2,6,6- tetramethylmorpholine (133) White solid (61%).1H NMR (400 MHz, DMSO) δ 12.63 (s, 1H), 8.12 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.62 (s, 1H), 7.57 (dd, J = 8.5, 1.4 Hz, 1H), 3.43 (s, 4H), 2.27 (tt, J = 8.1, 5.3 Hz, 1H), 1.25 (s, 12H), 1.01 – 0.93 (m, 4H).13C NMR (101 MHz, DMSO) δ 165.52, 146.95, 141.78, 141.38, 128.90, 127.23, 126.89, 120.72, 120.66, 117.34, 105.32, 71.53, 56.65, 28.51, 8.43, 7.94.

[0244] Example 120: (2S,6R)-2,6-dimethyl-4-(5-(quinazolin-6-yl)imidazo[2,1-b][1,3,4]thiadiazol-2- yl)morpholine (142)White solid (54%).1H NMR (400 MHz, DMSO) δ 9.20 (s, 1H), 8.41 (d, J = 2.1 Hz, 1H), 8.20 (dd, J = 8.9, 2.1 Hz, 1H), 7.61 (s, 1H), 7.47 (d, J = 8.8 Hz, 1H), 6.92 (s, 1H), 3.78 (ddd, J = 18.8, 11.4, 4.5 Hz, 4H), 2.86 (dd, J = 12.3, 10.4 Hz, 2H), 1.20 (d, J = 6.1 Hz, 6H).13C NMR (101 MHz, DMSO) δ 165.43, 163.06, 161.34, 151.41, 141.39, 131.32, 128.41, 126.33, 125.63, 122.84, 122.34, 119.87, 71.01, 53.20, 18.88.

[0245] Example 121: (2S,6R)-2,6-dimethyl-4-(5-(3-methyl-1H-indazol-6-yl)imidazo[2,1-b][1,3,4]thiadiazol-2- yl)morpholine (143)White solid (56%).1H NMR (400 MHz, DMSO) δ 12.68 (s, 1H), 8.15 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.64 (s, 1H), 7.59 (dd, J = 8.5, 1.4 Hz, 1H), 3.76 (dt, J = 11.0, 2.5 Hz, 4H), 2.89 (dd, J  = 12.8, 11.0 Hz, 2H), 2.49 (s, 3H), 1.20 (d, J = 6.1 Hz, 6H).13C NMR (101 MHz, DMSO) δ 165.39, 141.61, 141.57, 129.02, 127.28, 126.80, 121.34, 120.89, 117.31, 105.15, 70.94, 53.22, 18.90, 12.18.

[0246] Example 122: 8-(5-(3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-5-oxa-8- azaspiro[3.5]nonane (148)White solid (62%).1H NMR (400 MHz, DMSO) δ 12.72 (s, 1H), 8.31 (s, 1H), 7.87 (dd, J = 8.7, 1.6 Hz, 1H), 7.56 – 7.48 (m, 2H), 3.73 – 3.66 (m, 2H), 3.49 (d, J = 7.7 Hz, 4H), 2.52 (s, 3H), 2.09 – 1.97 (m, 4H), 1.84 – 1.72 (m, 2H).13C NMR (101 MHz, DMSO) δ 165.71, 141.94, 140.65, 140.20, 127.60, 123.92, 122.77, 120.97, 115.70, 111.00, 75.10, 60.17, 54.56, 47.67, 30.99, 12.51, 12.12.

[0247] Example 123: 8-(5-(3-cyclopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-5-oxa-8- azaspiro[3.5]nonane (149)White solid (59%).1H NMR (400 MHz, DMSO) δ 12.66 (s, 1H), 8.44 (s, 1H), 7.81 (dd, J = 8.7, 1.6 Hz, 1H), 7.57 – 7.44 (m, 2H), 3.69 (dd, J = 6.2, 3.7 Hz, 2H), 3.51 (s, 2H), 3.45 (dd, J = 6.0, 3.7 Hz, 2H), 2.29 (tt, J = 8.0, 5.3 Hz, 1H), 2.06 – 1.95 (m, 4H), 1.77 (qdt, J = 11.1, 8.8, 3.5 Hz, 2H), 1.04 (ddd, J = 9.8, 6.3, 2.3 Hz, 4H).13C NMR (101 MHz, DMSO) δ 165.77, 147.11, 140.71, 140.45, 127.52, 127.47, 123.88, 121.59, 120.91, 115.45, 111.20, 75.03, 60.13, 54.43, 47.73, 31.02, 12.49, 9.01, 7.44.

[0248] Example 124:  8-(5-(3-ethyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-5-oxa-8- azaspiro[3.5]nonane (150)White solid (61%).1H NMR (400 MHz, DMSO) δ 12.71 (s, 1H), 8.41 (s, 1H), 7.84 (dd, J = 8.7, 1.6 Hz, 1H), 7.53 (t, J = 4.4 Hz, 2H), 3.70 (dd, J = 6.1, 3.8 Hz, 2H), 3.55 – 3.44 (m, 4H), 2.97 (q, J = 7.6 Hz, 2H), 2.08 – 1.96 (m, 4H), 1.86 – 1.67 (m, 2H), 1.37 (t, J = 7.6 Hz, 3H).13C NMR (101 MHz, DMSO) δ 165.73, 147.27, 140.68, 140.39, 127.56, 123.89, 121.86, 120.88, 115.79, 111.11, 75.05, 60.16, 54.44, 47.72, 31.01, 20.49, 13.84, 12.49.

[0249] Example 125: 11-(5-(3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-5-oxa-11- azadispiro[3.1.36.34]dodecane (151)White solid (59%).1H NMR (400 MHz, DMSO) δ 12.72 (s, 1H), 8.36 (s, 1H), 7.85 (dd, J = 8.6, 1.6 Hz, 1H), 7.61 – 7.46 (m, 2H), 3.60 (s, 4H), 2.52 (s, 3H), 2.11 (dt, J = 12.5, 9.5 Hz, 4H), 2.04 – 1.93 (m, 4H), 1.82 – 1.63 (m, 4H).13C NMR (101 MHz, DMSO) δ 165.41, 141.87, 140.58, 140.18, 127.50, 123.90, 122.74, 121.00, 115.50, 111.05, 74.43, 54.20, 32.97, 13.47, 12.05.

[0250] Example 126: 11-(5-(3-ethyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-5-oxa-11- azadispiro[3.1.36.34]dodecane (152) White solid (60%).1H NMR (400 MHz, DMSO) δ 12.72 (s, 1H), 8.46 (s, 1H), 7.81 (dd, J = 8.8, 1.6 Hz, 1H), 7.57 – 7.43 (m, 2H), 3.58 (s, 4H), 2.97 (q, J = 7.6 Hz, 2H), 2.11 (qd, J = 9.9, 2.7 Hz, 4H), 2.05 – 1.93 (m, 4H), 1.83 – 1.61 (m, 4H), 1.36 (t, J = 7.6 Hz, 3H).13C NMR (101 MHz, DMSO) δ 165.53, 147.23, 140.60, 140.37, 127.51, 127.48, 123.88, 121.81, 120.91, 115.57, 111.18, 74.35, 54.19, 32.96, 20.54, 13.96, 13.43.

[0251] Example 127: 11-(5-(3-cyclopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-5-oxa-11- azadispiro[3.1.36.34]dodecane (153)White solid (59%).1H NMR (400 MHz, DMSO) δ 12.67 (s, 1H), 8.48 (s, 1H), 7.80 (dd, J = 8.8, 1.5 Hz, 1H), 7.60 – 7.42 (m, 2H), 3.59 (s, 4H), 2.28 (tt, J = 8.3, 5.1 Hz, 1H), 2.13 (dt, J = 12.4, 9.5 Hz, 4H), 1.97 (dt, J = 12.9, 5.0 Hz, 4H), 1.72 (qd, J = 9.7, 6.9 Hz, 4H), 1.04 (ddt, J = 15.8, 6.2, 2.6 Hz, 4H).13C NMR (101 MHz, DMSO) δ 165.69, 147.03, 140.65, 140.45, 127.49, 127.43, 123.89, 121.49, 120.94, 115.29, 111.29, 74.32, 54.24, 32.99, 13.41, 9.14, 7.33.

[0252] Example 128: 8-(5-(3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-3-oxa-8- azabicyclo[3.2.1]octane (154)  Off-white solid (64%).1H NMR (400 MHz, DMSO) δ 12.71 (s, 1H), 8.28 (s, 1H), 7.87 (dd, J = 8.7, 1.7 Hz, 1H), 7.64 – 7.40 (m, 2H), 4.25 (s, 2H), 3.84 (d, J = 11.1 Hz, 2H), 3.69 – 3.52 (m, 2H), 2.52 (s, 3H), 2.13 – 1.89 (m, 4H).13C NMR (101 MHz, DMSO) δ 162.39, 141.98, 141.10, 140.23, 127.86, 127.69, 123.99, 122.79, 120.95, 115.87, 110.98, 70.04, 60.22, 26.90, 12.16.

[0253] Example 129: 8-(5-(3-ethyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-3-oxa-8- azabicyclo[3.2.1]octane (155)Off-white solid (61%).1H NMR (400 MHz, DMSO) δ 12.70 (s, 1H), 8.36 (s, 1H), 7.84 (dd, J = 8.6, 1.6 Hz, 1H), 7.52 (t, J = 4.3 Hz, 2H), 4.24 (s, 2H), 3.86 (d, J = 11.2 Hz, 2H), 3.62 (d, J = 11.1 Hz, 2H), 2.96 (q, J = 7.6 Hz, 2H), 2.12 – 1.91 (m, 4H), 1.35 (t, J = 7.6 Hz, 3H).13C NMR (101 MHz, DMSO) δ 162.31, 147.30, 141.14, 140.41, 127.84, 127.66, 123.96, 121.89, 120.86, 115.98, 111.07, 69.95, 60.21, 26.90, 20.40, 13.76.

[0254] Example 130: 8-(5-(3-cyclopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-3-oxa-8- azabicyclo[3.2.1]octane (156)Off-white solid (61%).1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 8.39 (s, 1H), 7.82 (dd, J = 8.7, 1.7 Hz, 1H), 7.60 – 7.37 (m, 2H), 4.25 (s, 2H), 3.87 (d, J = 11.2 Hz, 2H), 3.62 (d, J = 11.1 Hz, 2H), 2.28 (tt, J = 7.6, 5.7 Hz, 1H), 2.10 – 1.95 (m, 4H), 1.08 – 0.89 (m, 4H).13C NMR (101 MHz, DMSO) δ 162.25, 147.20, 141.18, 140.46, 127.76, 127.64, 123.97, 121.75, 120.90, 115.67, 111.17, 69.93, 60.22, 26.93, 8.79, 7.59.

[0255] Example 131: (1S,4S)-5-(5-(3-ethyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-oxa-5- azabicyclo[2.2.1]heptane (157) White solid (57%).1H NMR (400 MHz, DMSO) δ 12.70 (s, 1H), 7.84 (dd, J = 8.7, 1.6 Hz, 1H), 7.64 – 7.41 (m, 2H), 4.81 – 4.70 (m, 1H), 4.65 (t, J = 1.6 Hz, 1H), 3.91 (d, J = 7.8 Hz, 1H), 3.82 (dd, J = 7.8, 1.5 Hz, 1H), 3.64 (dd, J = 9.7, 1.5 Hz, 1H), 3.42 (d, J = 9.7 Hz, 1H), 2.96 (q, J = 7.6 Hz, 2H), 2.07 (dd, J = 10.1, 2.4 Hz, 1H), 2.01 – 1.90 (m, 1H), 1.36 (t, J = 7.6 Hz, 3H).13C NMR (101 MHz, DMSO) δ 162.00, 147.28, 140.70, 140.37, 127.64, 127.46, 123.92, 121.90, 120.98, 115.84, 111.04, 75.99, 72.58, 61.31, 58.90, 36.85, 20.41, 13.78.

[0256] Example 132: (1S,4S)-5-(5-(3-cyclopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-oxa-5- azabicyclo[2.2.1]heptane (158)White solid (56%).1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 8.43 (s, 1H), 7.82 (dd, J = 8.7, 1.6 Hz, 1H), 7.61 – 7.49 (m, 2H), 4.87 – 4.75 (m, 1H), 4.66 (s, 1H), 3.92 (d, J = 7.9 Hz, 1H), 3.87 – 3.76 (m, 1H), 3.65 (dd, J = 9.8, 1.5 Hz, 1H), 3.44 (d, J = 9.8 Hz, 1H), 2.29 (tt, J = 7.9, 5.6 Hz, 1H), 2.08 (dd, J = 10.1, 2.3 Hz, 1H), 2.00 – 1.93 (m, 1H), 1.11 – 0.89 (m, 4H).

[0257] Example 133: (1R,4R)-5-(5-(3-ethyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-oxa-5- azabicyclo[2.2.1]heptane (159)  White solid (55%).1H NMR (400 MHz, DMSO) δ 12.70 (s, 1H), 8.39 (s, 1H), 7.84 (dd, J = 8.7, 1.6 Hz, 1H), 7.59 – 7.44 (m, 2H), 4.77 (d, J = 2.7 Hz, 1H), 4.65 (s, 1H), 3.91 (d, J = 7.9 Hz, 1H), 3.83 (d, J = 7.8 Hz, 1H), 3.64 (d, J = 9.7 Hz, 1H), 3.44 (s, 1H), 2.96 (q, J = 7.6 Hz, 2H), 2.07 (dd, J = 10.0, 2.4 Hz, 1H), 2.01 – 1.90 (m, 1H), 1.36 (t, J = 7.6 Hz, 3H).13C NMR (101 MHz, DMSO) δ 162.01, 147.29, 140.70, 140.37, 127.45, 123.93, 121.89, 120.98, 115.85, 111.05, 75.99, 72.58, 61.31, 58.90, 36.85, 20.40, 13.77.

[0258] Example 134: 3-(5-(3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-6-oxa-3- azabicyclo[3.1.1]heptane (160)White solid (55%).1H NMR (400 MHz, DMSO) δ 12.71 (s, 1H), 8.36 (s, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.65 – 7.44 (m, 2H), 4.75 (d, J = 6.5 Hz, 2H), 3.87 – 3.71 (m, 4H), 3.28 – 3.14 (m, 1H), 2.52 (s, 3H), 2.05 – 1.98 (m, 1H).13C NMR (101 MHz, DMSO) δ 164.36, 141.94, 140.18, 127.50, 123.91, 122.80, 121.18, 115.72, 110.93, 77.42, 51.33, 32.24, 12.16.

[0259] Example 135: 3-(5-(3-ethyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-6-oxa-3- azabicyclo[3.1.1]heptane (161)White solid (52%).1H NMR (400 MHz, DMSO) δ 12.70 (s, 1H), 8.43 (s, 1H), 7.88 (d, J = 8.7 Hz, 1H), 7.59 – 7.42 (m, 2H), 4.75 (d, J = 6.5 Hz, 2H), 3.75 (q, J = 11.5 Hz, 4H), 3.20 (q, J = 7.5 Hz, 1H), 2.96 (q, J = 7.6 Hz, 2H), 2.09 – 1.91 (m, 1H), 1.36 (t, J = 1.7 Hz, 3H).13C NMR (101 MHz, DMSO) δ 164.33, 147.28, 140.35, 127.46, 123.88, 121.92, 121.09, 115.80, 111.00, 77.40, 51.31, 32.24, 20.39, 13.79.

[0260] Example 136:  3-(5-(3-cyclopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-6-oxa-3- azabicyclo[3.1.1]heptane (162)White solid (51%).1H NMR (400 MHz, DMSO) δ 12.64 (s, 1H), 8.47 (s, 1H), 7.86 (dd, J = 8.7, 1.6 Hz, 1H), 7.64 – 7.42 (m, 2H), 4.75 (d, J = 6.5 Hz, 2H), 3.77 (q, J = 11.5 Hz, 4H), 3.21 (dt, J = 9.3, 6.8 Hz, 1H), 2.29 (tt, J = 7.4, 5.9 Hz, 1H), 2.02 (d, J = 9.1 Hz, 1H), 1.13 – 0.87 (m, 4H).

[0261] Example 137: (1S,4S)-5-(5-(3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-oxa-5- azabicyclo[2.2.1]heptane (163)White solid (55%).1H NMR (400 MHz, DMSO) δ 12.71 (s, 1H), 8.32 (s, 1H), 7.87 (dd, J = 8.8, 1.6 Hz, 1H), 7.56 – 7.45 (m, 2H), 4.76 (t, J = 1.8 Hz, 1H), 4.68 (d, J = 2.2 Hz, 1H), 3.90 (d, J = 7.9 Hz, 1H), 3.83 (dd, J = 7.9, 1.5 Hz, 1H), 3.64 (dd, J = 9.7, 1.5 Hz, 1H), 3.44 (d, J = 9.7 Hz, 1H), 2.52 (s, 3H), 2.07 (dd, J = 10.0, 2.4 Hz, 1H), 2.00 – 1.92 (m, 1H).13C NMR (101 MHz, DMSO) δ 162.03, 141.95, 140.68, 140.19, 127.65, 127.49, 123.95, 122.78, 121.06, 115.75, 110.95, 76.00, 72.64, 61.33, 58.91, 36.86, 12.16.

[0262] Example 138: (1R,4R)-5-(5-(3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-oxa-5- azabicyclo[2.2.1]heptane (164)  White solid (56%).1H NMR (400 MHz, DMSO) δ 12.71 (s, 1H), 8.32 (s, 1H), 7.87 (dd, J = 8.7, 1.6 Hz, 1H), 7.55 – 7.48 (m, 2H), 4.80 – 4.72 (m, 1H), 4.69 – 4.64 (m, 1H), 3.90 (d, J = 7.8 Hz, 1H), 3.83 (dd, J = 7.9, 1.5 Hz, 1H), 3.64 (dd, J = 9.7, 1.5 Hz, 1H), 3.44 (d, J = 9.7 Hz, 2H), 2.52 (s, 3H), 2.07 (dd, J = 10.1, 2.4 Hz, 1H), 1.98 – 1.92 (m, 1H).13C NMR (101 MHz, DMSO) δ 162.05, 141.93, 140.26, 127.43, 123.97, 122.77, 121.08, 115.79, 110.99, 76.00, 75.94, 72.64, 61.33, 61.15, 58.92, 36.86, 12.13.

[0263] Example 139: (1R,4R)-5-(5-(3-cyclopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-oxa-5- azabicyclo[2.2.1]heptane (165)White solid (54%).1H NMR (400 MHz, DMSO) δ 12.64 (s, 1H), 8.43 (s, 1H), 7.82 (dd, J = 8.7, 1.6 Hz, 1H), 7.60 – 7.33 (m, 2H), 4.77 (t, J = 1.7 Hz, 1H), 4.66 (d, J = 1.9 Hz, 1H), 3.92 (d, J = 7.9 Hz, 1H), 3.83 (dd, J = 7.9, 1.5 Hz, 1H), 3.65 (dd, J = 9.7, 1.5 Hz, 1H), 3.44 (d, J = 9.7 Hz, 1H), 2.29 (tt, J = 7.7, 5.6 Hz, 1H), 2.08 (dd, J = 10.1, 2.4 Hz, 1H), 2.02 – 1.90 (m, 1H), 1.02 (dt, J = 6.7, 2.1 Hz, 4H).13C NMR (101 MHz, DMSO) δ 162.01, 147.19, 140.72, 140.42, 127.56, 127.44, 123.95, 121.80, 121.01, 115.55, 111.15, 75.99, 72.58, 61.31, 58.93, 36.86, 8.75, 7.66, 7.63.

[0264] Example 140: 5-(3-ethyl-1H-indazol-5-yl)-2-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)imidazo[2,1- b][1,3,4]thiadiazole (166)White solid (48%).1H NMR (400 MHz, DMSO) δ 12.71 (s, 1H), 8.33 (s, 1H), 7.84 (dd, J = 8.8, 1.6 Hz, 1H), 7.61 – 7.42 (m, 2H), 4.19 (t, J = 7.7 Hz, 2H), 4.02 (dd, J = 8.3, 5.1 Hz, 2H), 3.42 (ddd, J = 7.1, 5.1, 1.9 Hz, 1H), 2.96 (q, J = 7.6 Hz, 2H), 2.36 (s, 8H), 2.16 (s, 3H), 1.36 (t, J = 7.6 1  Hz, 3H).13C NMR (101 MHz, DMSO) δ 164.89, 147.26, 141.26, 140.39, 127.71, 127.58, 123.93, 121.91, 120.92, 115.94, 111.01, 57.28, 55.87, 54.79, 49.21, 46.17, 20.38, 13.78.

[0265] Example 141: 5-(3-cyclopropyl-1H-indazol-5-yl)-2-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)imidazo[2,1- b][1,3,4]thiadiazole (167)White solid (51%).1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 8.38 (s, 1H), 7.82 (dd, J = 8.8, 1.6 Hz, 1H), 7.60 – 7.45 (m, 2H), 4.21 (t, J = 7.7 Hz, 2H), 4.06 – 4.00 (m, 2H), 3.43 (tt, J = 7.1, 5.2 Hz, 1H), 2.51 – 2.22 (m, 9H), 2.17 (s, 3H), 1.17 (t, J = 7.1 Hz, 1H), 1.01 (tt, J = 7.6, 2.4 Hz, 4H).

[0266] Example 142: 8-(5-(3-cyclopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1-oxa-8- azaspiro[4.5]decane (168)White solid (57%).1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 8.42 (d, J = 1.5 Hz, 1H), 7.82 (dd, J = 8.7, 1.6 Hz, 1H), 7.54 – 7.45 (m, 2H), 3.77 (t, J = 6.7 Hz, 2H), 3.63 (dt, J = 13.2, 4.6 Hz, 2H), 3.51 (ddd, J = 13.3, 9.4, 4.0 Hz, 2H), 2.28 (tt, J = 7.2, 5.9 Hz, 1H), 1.95 – 1.84 (m, 2H), 1.78 – 1.64 (m, 6H), 1.10 – 0.89 (m, 4H).13C NMR (101 MHz, DMSO) δ 164.80, 147.15, 140.42, 127.41, 123.92, 121.75, 121.05, 115.50, 111.16, 79.55, 66.78, 46.62, 36.43, 35.16, 25.43, 8.81, 7.55.

[0267] Example 143: 8-(5-(3-cyclopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1,4-dioxa-8- azaspiro[4.5]decane (169) 1 Off-white solid (58%).1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 8.41 (s, 1H), 7.82 (dd, J = 8.7, 1.6 Hz, 1H), 7.50 (d, J = 8.8 Hz, 2H), 3.95 (s, 4H), 3.66 – 3.57 (m, 4H), 2.28 (tt, J = 7.2, 5.9 Hz, 1H), 1.85 – 1.77 (m, 4H), 1.09 – 0.96 (m, 4H).13C NMR (101 MHz, DMSO) δ 164.63, 147.17, 140.44, 127.47, 123.94, 121.77, 121.01, 115.57, 111.16, 106.41, 64.43, 47.13, 33.95, 8.79, 7.56.

[0268] Example 144: 8-(5-(6-fluoro-3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1-oxa-8- azaspiro[4.5]decane (170)White solid (56%).1H NMR (400 MHz, DMSO) δ 12.80 (s, 1H), 8.45 (d, J = 7.1 Hz, 1H), 7.49 – 7.28 (m, 2H), 3.76 (t, J = 6.7 Hz, 2H), 3.59 (dt, J = 13.1, 4.7 Hz, 2H), 3.48 (ddd, J = 13.1, 9.3, 4.1 Hz, 2H), 2.50 (s, 3H), 1.96 – 1.81 (m, 2H), 1.80 – 1.59 (m, 6H).13C NMR (101 MHz, DMSO) δ 164.81, 159.69, 157.25, 142.40, 141.25, 140.03, 139.89, 130.14, 130.03, 121.92, 119.59, 119.10, 119.04, 111.12, 110.94, 96.92, 96.65, 79.50, 66.76, 46.60, 36.37, 35.13, 25.42, 11.99.

[0269] Example 145: 5-(3-methyl-1H-indazol-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)imidazo[2,1- b][1,3,4]thiadiazole (171)  White solid (46%).1H NMR (800 MHz, DMSO) δ 12.71 (s, 1H), 8.33 (s, 1H), 7.87 (dd, J = 8.6, 1.6 Hz, 1H), 7.55 – 7.49 (m, 2H), 3.71 (d, J = 12.3 Hz, 2H), 2.96 (t, J = 11.7 Hz, 2H), 2.52 (s, 3H), 2.34 (s, 2H), 2.21 (s, 3H), 1.11 (d, J = 6.2 Hz, 6H).13C NMR (201 MHz, DMSO) δ 164.60, 141.93, 140.95, 140.21, 127.51, 123.94, 122.78, 121.00, 115.73, 111.00, 56.73, 54.51, 37.20, 17.89, 12.06.

[0270] Example 146: 5-(6-fluoro-3-methyl-1H-indazol-5-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-1- yl)imidazo[2,1-b][1,3,4]thiadiazole (172)White solid (48%).1H NMR (800 MHz, DMSO) δ 12.80 (s, 1H), 8.49 (d, J = 6.9 Hz, 1H), 7.40 (d, J = 11.3 Hz, 1H), 7.37 (d, J = 3.5 Hz, 1H), 3.69 (d, J = 12.4 Hz, 2H), 2.96 (t, J = 11.8 Hz, 2H), 2.51 (s, 3H), 2.34 (s, 2H), 2.20 (s, 3H), 1.10 (d, J = 6.1 Hz, 6H).13C NMR (201 MHz, DMSO) δ 164.59, 159.10, 157.88, 142.43, 141.27, 140.03, 130.12, 121.95, 119.61, 119.10, 111.01, 110.92, 96.88, 96.74, 56.68, 54.52, 37.18, 17.86, 11.89.

[0271] Example 147: 5-(6-fluoro-3-methyl-1H-indazol-5-yl)-2-(3,3,4-trimethylpiperazin-1-yl)imidazo[2,1- b][1,3,4]thiadiazole (173)White Solid (45%).1H NMR (800 MHz, DMSO) δ 12.80 (s, 1H), 8.45 (d, J = 6.9 Hz, 1H), 7.40 (d, J = 11.2 Hz, 1H), 7.36 (s, 1H), 3.54 (s, 2H), 3.26 (s, 2H), 2.70 – 2.57 (m, 2H), 2.20 (s, 3H), 1.06 (s, 6H).13C NMR (201 MHz, DMSO) δ 165.17, 159.10, 157.88, 142.43, 141.09, 140.06, 130.11, 121.96, 119.61, 119.20, 111.02, 96.87, 96.74, 48.44, 37.28, 19.48, 11.97.

[0272] Example 148: 1  6-(5-(6-fluoro-3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-oxa-6- azaspiro[3.4]octane (174)White solid (54%).1H NMR (800 MHz, DMSO) δ 12.79 (s, 1H), 8.51 (d, J = 7.0 Hz, 1H), 7.39 (d, J = 11.3 Hz, 1H), 7.35 (d, J = 3.6 Hz, 1H), 4.65 (d, J = 6.4 Hz, 2H), 4.53 (d, J = 6.4 Hz, 2H), 3.74 (s, 2H), 3.52 (t, J = 6.9 Hz, 2H), 2.52 (s, 3H), 2.34 (t, J = 7.0 Hz, 2H).13C NMR (201 MHz, DMSO) δ 161.33, 159.09, 157.87, 142.39, 140.88, 139.97, 139.91, 130.03, 129.97, 121.84, 119.61, 119.01, 111.21, 111.12, 96.83, 96.70, 79.86, 57.56, 48.52, 45.60, 35.04, 12.04.

[0273] Example 149: 1-(4-(5-(3-isopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperazin-1- yl)ethan-1-one (175)Off-white solid (47%).1H NMR (500 MHz, DMSO) δ 8.44 (s, 1H), 7.80 (dd, J = 8.7, 1.6 Hz, 1H), 7.53 – 7.48 (m, 2H), 3.63 (t, J = 5.2 Hz, 4H), 3.56 (ddd, J = 10.7, 6.3, 3.3 Hz, 2H), 3.48 (dd, J = 6.7, 4.3 Hz, 2H), 3.41 – 3.36 (m, 1H), 2.05 (s, 3H), 1.40 (d, J = 6.9 Hz, 6H).13C NMR (126 MHz, DMSO) δ 169.1, 165.2, 151.1, 140.9, 140.6, 127.6, 127.5, 123.8, 121.0, 120.7, 114.2, 111.2, 48.5, 48.2, 45.0, 27.7, 22.6, 21.7, 21.7. HRMS (ESI) m / z calcd for C20H23N7OS [M + H]+410.176305, found 410.17626.

[0274] Example 150: 1-(4-(5-(3-methoxy-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperazin-1- yl)ethan-1-one (176) 1 Off-white solid (54%).1H NMR (500 MHz, DMSO) δ 11.99 (s, 1H), 8.16 (d, J = 1.6 Hz, 1H), 7.85 (dd, J = 8.8, 1.6 Hz, 1H), 7.50 (s, 1H), 7.45 – 7.37 (m, 1H), 4.01 (s, 3H), 3.63 (dd, J = 6.6, 4.0 Hz, 4H), 3.54 (dd, J = 6.5, 3.9 Hz, 2H), 3.45 (dd, J = 6.6, 4.1 Hz, 2H), 2.05 (s, 3H).13C NMR (126 MHz, DMSO) δ 169.0, 165.3, 157.1, 141.3, 140.9, 127.6, 127.5, 125.1, 120.6, 114.8, 111.5, 111.2, 56.3, 48.4, 48.3, 45.0, 31.2, 21.7. HRMS (ESI) m / z calcd for C18H19N7O2S [M + H]+398.139919, found 398.13997.

[0275] Example 151: cyclopropyl(4-(5-(3-isopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2- yl)piperazin-1-yl)methanone (177)Light pink solid (46%).1H NMR (500 MHz, CDCl3) δ 8.39 (s, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.49 (s, 2H), 3.86 (s, 5H), 3.61 (s, 3H), 3.45 (q, J = 7.0 Hz, 1H), 1.78 – 1.70 (m, 1H), 1.51 (d, J = 6.9 Hz, 6H), 1.04 (ddd, J= 7.4, 4.4, 2.8 Hz, 2H), 0.85 – 0.81 (m, 2H).13C NMR (126 MHz, CDCl3) δ 172.4, 164.9, 164.8, 152.7, 140.7, 130.4, 126.8, 124.6, 121.3, 121.1, 117.2, 110.4, 48.3, 44.5, 41.1, 27.9, 22.1, 11.1, 7.9, 7.8. HRMS (ESI) m / z calcd for C22H25N7OS [M + H]+436.191955, found 436.19183.

[0276] Example 152: 1-(4-(5-(3-isopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperazin-1-yl)-2- methylpropan-1-one (178) 1 Off-white solid (48%).1NMR (500 MHz, CDCl3) δ 8.37 (s, 1H), 7.77 (dd, J = 8.7, 1.5 Hz, 1H), 7.50 – 7.35 (m, 2H), 3.80 (d, J = 22.3 Hz, 2H), 3.71 (s, 2H), 3.62 – 3.48 (m, 4H), 3.44 (dt, J = 13.5, 6.7 Hz, 1H), 2.87 – 2.77 (m, 1H), 1.51 (d, J = 7.0 Hz, 6H), 1.17 (d, J = 6.8 Hz, 6H).13C NMR (126 MHz, CDCl3) δ 175.7, 164.8, 152.8, 141.4, 140.6, 127.1, 127.0, 124.7, 121.4, 120.7, 117.1, 110.3, 48.4, 44.4, 40.7, 30.2, 27.9, 22.1, 19.4. HRMS (ESI) m / z calcd for C22H27N7OS [M + H]+438.207605, found 438.20740.

[0277] Example 153: Methyl 4-(5-(3-isopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperazine- 1-carboxylate (179)Off-white solid (51%). HRMS (ESI) m / z calcd for C20H23N7O2S [M + H]+426.171220, found 426.17086.

[0278] Example 154: 4-(5-(3-isopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-N,N- dimethylpiperazine-1-carboxamide (180)HRMS (ESI) m / z calcd for C21H26N8OS [M + H]+439.202854, found 439.20256. 1

[0279] Example 155: Cyclopropyl(4-(5-(3-methoxy-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2- yl)piperazin-1-yl)methanone (181)Off-white solid (53%).1H NMR (500 MHz, MeOD) δ 8.22 (s, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.43 – 7.29 (m, 2H), 4.07 (d, J = 2.0 Hz, 3H), 3.93 (s, 2H), 3.77 (s, 2H), 3.55 (d, J = 48.3 Hz, 4H), 1.99 (dd, J = 8.8, 3.8 Hz, 1H), 0.88 (ddt, J = 28.9, 5.7, 2.7 Hz, 4H).13C NMR (126 MHz, DMSO) δ 171.8, 165.3, 157.1, 141.3, 140.9, 127.7, 127.5, 125.1, 120.6, 114.8, 111.5, 111.2, 56.3, 48.5, 48.3, 44.3, 41.1, 10.8, 7.7. HRMS (ESI) m / z calcd for C20H21N7O2S [M + H]+424.155570, found 424.15552.

[0280] Example 156: 1-(4-(5-(3-methoxy-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperazin-1-yl)-2- methylpropan-1-one (182)Off-white solid (49%).1H NMR (500 MHz, CDCl3) δ 9.24 (s, 1H), 8.21 (s, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.42 – 7.32 (m, 2H), 4.13 (s, 3H), 3.82 (s, 2H), 3.71 (s, 2H), 3.58 (s, 2H), 3.53 – 3.43 (m, 2H), 2.83 (p, J = 6.8 Hz, 1H), 1.17 (d, J = 6.6 Hz, 6H).13C NMR (126 MHz, CDCl3) δ 175.8, 158.2, 141.7, 131.3, 128.4, 127.2, 125.7, 121.0, 115.9, 112.6, 110.2, 56.2, 48.4, 44.4, 40.7, 30.2, 19.4. HRMS (ESI) m / z calcd for C20H23N7O2S [M + H]+426.171220, found 426.17110.

[0281] Example 157: Methyl 4-(5-(3-methoxy-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperazine-1- carboxylate (183) 1 Off-white solid (44%).1H NMR (500 MHz, MeOD) δ 8.23 (s, 1H), 7.82 (dd, J = 8.8, 1.9 Hz, 1H), 7.43 – 7.30 (m, 2H), 4.08 (d, J = 1.7 Hz, 3H), 3.74 (d, J = 1.7 Hz, 3H), 3.66 (t, J = 5.5 Hz, 4H), 3.55 (t, J = 5.2 Hz, 4H).13C NMR (126 MHz, DMSO) δ 165.3, 157.1, 155.4, 141.3, 140.8, 127.6, 127.5, 125.1, 120.5, 114.8, 111.5, 111.2, 56.3, 56.3, 53.0, 48.1, 48.0, 42.9. HRMS (ESI) m / z calcd for C18H19N7O3S [M + H]+414.134834, found 414.13485.

[0282] Example 158: 4-(5-(3-methoxy-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-N,N- dimethylpiperazine-1-carboxamide (184)Off-white solid (59%).1H NMR (500 MHz, MeOD) δ 8.26 – 8.23 (m, 1H), 7.82 (dt, J = 8.8, 1.4 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 4.08 (d, J = 1.0 Hz, 3H), 3.57 (dd, J = 6.7, 3.8 Hz, 4H), 3.40 (t, J = 5.1 Hz, 4H), 2.90 (d, J = 1.0 Hz, 6H).13C NMR (126 MHz, MeOD) δ 165.2, 157.6, 152.8, 141.4, 141.0, 127.9, 125.9, 125.2, 120.3, 115.2, 111.4, 110.1, 55.3, 45.6, 37.3. HRMS (ESI) m / z calcd for C19H22N8O2S [M + H]+427.166469, found 427.16638.

[0283] Example 159: 5-(3-ethyl-1H-indazol-5-yl)-2-(4-(ethylsulfonyl)piperazin-1-yl)imidazo[2,1- b][1,3,4]thiadiazole (185)  White solid (49%).1H NMR (400 MHz, DMSO) δ 12.71 (s, 1H), 8.35 (s, 1H), 7.87 – 7.76 (m, 1H), 7.65 – 7.41 (m, 2H), 3.62 (t, J = 5.1 Hz, 3H), 3.40 (t, J = 5.1 Hz, 4H), 3.13 (q, J = 7.6 Hz, 2H), 2.97 (q, J = 7.6 Hz, 2H), 1.36 (t, J = 7.6 Hz, 3H), 1.22 (t, J = 3.7 Hz, 3H).

[0284] Example 160: 2-(4-(ethylsulfonyl)piperazin-1-yl)-5-(3-methoxy-1H-indazol-5-yl)imidazo[2,1- b][1,3,4]thiadiazole (186)Off-white solid (47%).1H NMR (400 MHz, DMSO) δ 12.03 (s, 1H), 8.16 (s, 1H), 7.88 (dd, J = 8.9, 1.6 Hz, 1H), 7.52 (s, 1H), 7.43 (d, J = 8.8 Hz, 1H), 4.02 (s, 3H), 3.61 (t, J = 5.0 Hz, 4H), 3.40 (d, J = 5.4 Hz, 4H), 3.13 (q, J = 7.4 Hz, 2H), 1.23 (t, J = 7.3 Hz, 3H).

[0285] Example 161: 5-(3-cyclopropyl-1H-indazol-5-yl)-2-(4-(ethylsulfonyl)piperazin-1-yl)imidazo[2,1- b][1,3,4]thiadiazole (187)White solid (45%).1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 8.41 (s, 1H), 7.88 – 7.76 (m, 1H), 7.60 – 7.41 (m, 2H), 3.64 (t, J = 3.5 Hz, 4H), 3.41 (t, J = 5.1 Hz, 4H), 3.13 (q, J = 7.6 Hz, 2H), 2.36 – 2.25 (m, 1H), 1.23 (t, J = 4.6 Hz, 3H), 1.11 – 0.91 (m, 4H).

[0286] Example 162: 2-(4-(cyclopropylsulfonyl)piperazin-1-yl)-5-(3-ethyl-1H-indazol-5-yl)imidazo[2,1- b][1,3,4]thiadiazole (188) 1 White solid (42%).1H NMR (400 MHz, DMSO) δ 12.71 (s, 1H), 8.35 (s, 1H), 7.89 – 7.82 (m, 1H), 7.57 – 7.48 (m, 2H), 3.65 (t, J = 5.0 Hz, 4H), 3.42 (t, J = 5.2 Hz, 4H), 2.97 (q, J = 7.6 Hz, 2H), 2.74 – 2.60 (m, 1H), 1.37 (t, J = 7.6 Hz, 2H), 1.06 – 0.91 (m, 4H).

[0287] Example 163: 5-(3-cyclopropyl-1H-indazol-5-yl)-2-(4-(cyclopropylsulfonyl)piperazin-1-yl)imidazo[2,1- b][1,3,4]thiadiazole (189)White solid (44%).1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 8.40 (s, 1H), 7.83 (dd, J = 8.9, 1.7 Hz, 1H), 7.57 – 7.46 (m, 2H), 3.66 (t, J = 3.9 Hz, 4H), 3.41 (t, J = 4.3 Hz, 4H), 2.72 – 2.64 (m, 1H), 2.34 – 2.25 (m, 1H), 1.05 – 0.95 (m, 8H).

[0288] Example 164: 2-(4-(cyclopropylsulfonyl)piperazin-1-yl)-5-(3-isopropyl-1H-indazol-5-yl)imidazo[2,1- b][1,3,4]thiadiazole (190)White solid (41%).1H NMR (400 MHz, DMSO) δ 12.68 (s, 1H), 8.45 (s, 1H), 7.84 – 7.81 (m, 1H), 7.56 – 7.50 (m, 2H), 3.65 (t, J = 5.0 Hz, 4H), 3.41 (t, J = 5.5 Hz, 4H), 3.37 (q, 1H), 2.68 – 2.64 (m, 1H), 1.42 (d, J = 6.9 Hz, 6H), 1.02 – 0.96 (m, 4H).

[0289] Example 165: 1  5-(3-isopropyl-1H-indazol-5-yl)-2-(4-((trifluoromethyl)sulfonyl)piperazin-1- yl)imidazo[2,1-b][1,3,4]thiadiazole (191)White Solid (38%).1H NMR (400 MHz, DMSO) δ 12.68 (s, 1H), 8.42 (s, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.56 – 7.50 (m, 2H), 3.75 – 3.65 (m, 8H), 3.44 – 3.39 (m, 1H), 1.41 (d, J = 6.9 Hz, 6H).

[0290] Example 166: 4-(5-(3-methoxy-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2,2,6,6- tetramethylmorpholine (192)White Solid (56%).1H NMR (400 MHz, DMSO) δ 12.02 (s, 1H), 8.13 (s, 1H), 7.89 (dd, J = 8.8, 1.6 Hz, 1H), 7.51 – 7.36 (m, 2H), 4.02 (s, 3H), 3.42 (s, 4H), 1.25 (s, 12H).

[0291] Example 167: 4-(5-(3-isopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2,2,6,6- tetramethylmorpholine (193)White Solid (55%).1H NMR (400 MHz, DMSO) δ 12.68 (s, 1H), 8.58 (s, 1H), 7.77 (dd, J = 8.8, 1.6 Hz, 1H), 7.59 – 7.47 (m, 2H), 3.43 (s, 4H), 3.41 – 3.36 (m, 1H), 1.43 (d, J = 6.9 Hz, 6H), 1.25 (s, 12H).13C NMR (101 MHz, DMSO) δ 165.13, 150.95, 140.61, 127.41, 127.29, 123.72, 120.86, 120.73, 116.12, 111.24, 71.55, 56.62, 28.46, 28.01, 22.48.

[0292] Example 168: 8-(5-(3-cyclopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-oxa-8- azaspiro[4.5]decane (194)  White Solid (52%).1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 8.42 (s, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.54 – 7.47 (m, 2H), 3.77 (t, J = 7.0 Hz, 2H), 3.62 – 3.48 (m, 6H), 2.32 – 2.22 (m, 1H), 1.78 (t, J = 7.1 Hz, 2H), 1.72 – 1.62 (m, 4H), 1.11 – 0.95 (m, 4H).13C NMR (101 MHz, DMSO) δ 164.99, 147.16, 140.97, 140.42, 127.41, 123.91, 121.76, 121.02, 115.46, 111.17, 77.11, 66.92, 46.89, 41.92, 36.54, 33.47, 8.78, 7.56.

[0293] Example 169: 8-(5-(6-fluoro-3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1,4-dioxa-8- azaspiro[4.5]decane (195)White Solid (57%).1H NMR (400 MHz, DMSO) δ 12.80 (s, 1H), 8.43 (d, J = 7.1 Hz, 1H), 7.40 (d, J = 11.4 Hz, 1H), 7.36 (d, J = 3.7 Hz, 1H), 3.94 (s, 4H), 3.59 (t, J = 5.8 Hz, 4H), 2.50 (s, 3H), 1.80 (t, J = 5.8 Hz, 4H).

[0294] Example 170: 8-(5-(3-ethyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-oxa-8- azaspiro[4.5]decane (196)  White Solid (52%).(400 MHz, DMSO) δ 12.70 (s, 1H), 8.38 (s, 1H), 7.85 (d, J = 8.7 Hz, 1H), 7.55 – 7.46 (m, 2H), 3.77 (t, J = 7.0 Hz, 2H), 3.61 – 3.47 (m, 6H), 2.96 (q, J = 7.6 Hz, 2H), 1.78 (t, J = 7.1 Hz, 2H), 1.67 (t, J = 5.8 Hz, 4H), 1.43 – 1.26 (m, 3H).13C NMR (101 MHz, DMSO) δ 165.00, 147.26, 140.93, 140.37, 127.54, 127.43, 123.88, 121.88, 120.99, 115.77, 111.06, 77.11, 66.93, 46.87, 46.78, 41.91, 36.52, 33.47, 20.43, 13.76.

[0295] Example 171: 8-(5-(3-ethyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1,4-dioxa-8- azaspiro[4.5]decane (197)White Solid (51%).1H NMR (400 MHz, DMSO) δ 12.70 (s, 1H), 8.37 (s, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.60 – 7.46 (m, 2H), 3.95 (s, 4H), 3.60 (t, J = 5.6 Hz, 4H), 2.96 (q, J = 7.6 Hz, 2H), 1.81 (t, J = 5.7 Hz, 4H), 1.35 (t, J = 7.5 Hz, 3H).

[0296] Example 172: 4-(5-(3-ethyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1-methylpiperazin-2- one (198)White Solid (49%).1H NMR (400 MHz, DMSO) δ 8.38 (s, 1H), 7.88 (dd, J = 8.7, 1.6 Hz, 1H), 7.61 (s, 1H), 7.55 (d, J = 8.7 Hz, 1H), 4.15 (s, 2H), 3.79 (t, J = 4.4 Hz, 2H), 3.54 (t, J = 5.5 Hz, 2H), 3.01 – 2.90 (m, 5H), 1.36 (t, J = 7.6 Hz, 3H).

[0297] Example 173: 2-(5-(6-fluoro-3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-8-oxa-2- azaspiro[4.5]decane (199) 1 White Solid (47%).1H NMR (400 MHz, DMSO) δ 12.80 (s, 1H), 8.52 (d, J = 7.1 Hz, 1H), 7.39 (d, J = 11.5 Hz, 1H), 7.35 (d, J = 3.8 Hz, 1H), 3.68 – 3.51 (m, 6H), 3.39 (s, 2H), 2.51 (s, 3H), 1.98 (t, J = 7.1 Hz, 2H), 1.69 – 1.49 (m, 4H).13C NMR (101 MHz, DMSO) δ 161.53, 159.72, 157.28, 142.39, 140.87, 140.01, 139.88, 130.00, 129.88, 121.80, 119.60, 119.13, 119.08, 111.27, 111.09, 96.90, 96.63, 64.76, 59.27, 47.95, 35.76, 35.00, 11.98.

[0298] Example 174: methyl 4-(5-(3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperazine-1- carboxylate (200)White Solid (51%).1H NMR (400 MHz, DMSO) δ 12.71 (s, 1H), 8.29 (s, 1H), 7.87 (dd, J = 8.8, 1.5 Hz, 1H), 7.57 – 7.40 (m, 2H), 3.65 (s, 3H), 3.63 – 3.49 (m, 8H), 2.53 (s, 3H).13C NMR (101 MHz, DMSO) δ 165.23, 155.48, 141.99, 140.82, 140.22, 127.67, 127.61, 123.95, 122.77, 120.95, 115.78, 110.97, 53.06, 48.11, 42.93, 12.18.

[0299] Example 175: 8-(5-(3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1-oxa-8- azaspiro[4.5]decane (201)  White Solid (54%).1H NMR (400 MHz, DMSO) δ 12.71 (s, 1H), 8.29 (s, 1H), 7.87 (dd, J = 8.8, 1.6 Hz, 1H), 7.59 – 7.28 (m, 2H), 3.77 (t, J = 6.7 Hz, 2H), 3.71 – 3.58 (m, 2H), 3.58 – 3.44 (m, 2H), 2.51 (s, 3H), 1.94 – 1.84 (m, 2H), 1.84 – 1.46 (m, 6H).13C NMR (101 MHz, DMSO) δ 164.83, 141.92, 140.96, 140.19, 127.56, 127.46, 123.92, 122.78, 121.08, 115.70, 110.96, 79.53, 66.75, 46.60, 36.35, 35.16, 25.42, 12.14.

[0300] Example 176: 8-(5-(3-cyclopropyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1-oxa-8- azaspiro[4.5]decane (202)White Solid (51%).1H NMR (400 MHz, DMSO) δ 12.64 (s, 1H), 8.41 (s, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.65 – 7.42 (m, 2H), 3.68 – 3.58 (m, 4H), 3.43 – 3.39 (m, 2H), 2.33 – 2.22 (m, 1H), 1.74 – 1.54 (m, 4H), 1.54 – 1.35 (m, 4H), 1.08 – 0.84 (m, 4H).

[0301] Example 177: 8-(5-(3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1,4-dioxa-8- azaspiro[4.5]decane (203)White Solid (49%).1H NMR (400 MHz, DMSO) δ 12.71 (s, 1H), 8.28 (s, 1H), 7.87 (dd, J = 8.8, 1.6 Hz, 1H), 7.62 – 7.42 (m, 2H), 3.94 (s, 4H), 3.60 (t, J = 4.9 Hz, 4H), 2.52 (s, 3H), 1.81 (t, J = 5.8 Hz, 4H).

[0302] Example 178: 8-(5-(3-ethyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1-oxa-8- azaspiro[4.5]decane (204) 1 White Solid (47%).(400 MHz, DMSO) δ 12.70 (s, 1H), 8.38 (s, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.57 – 7.45 (m, 2H), 3.77 (t, J = 6.7 Hz, 2H), 3.65 – 3.57 (m, 2H), 3.55 – 3.47 (m, 2H), 2.95 (q, J = 7.5 Hz, 2H), 1.94 – 1.84 (m, 2H), 1.78 – 1.63 (m, 6H), 1.35 (t, J = 7.5 Hz, 3H).13C NMR (101 MHz, DMSO) δ 164.80, 147.26, 141.00, 140.37, 127.55, 127.41, 123.89, 121.88, 120.99, 115.80, 111.05, 79.53, 66.76, 46.59, 36.38, 35.14, 25.42, 20.43, 13.75.

[0303] Example 179: 2-(5-(3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-8-oxa-2- azaspiro[4.5]decane (205)White Solid (47%).1H NMR (400 MHz, DMSO) δ 12.70 (s, 1H), 8.34 (s, 1H), 7.89 (d, J = 8.7 Hz, 1H), 7.56 – 7.44 (m, 2H), 3.66 – 3.55 (m, 6H), 3.41 (s, 2H), 2.52 (s, 3H), 2.03 – 1.95 (m, 2H), 1.64 – 1.52 (m, 4H).13C NMR (101 MHz, DMSO) δ 161.53, 141.91, 140.59, 140.16, 127.45, 127.30, 123.91, 122.78, 121.23, 115.68, 110.92, 64.76, 59.34, 47.98, 35.65, 35.00, 12.13.

[0304] Example 180: 8-(5-(3-methyl-1H-indazol-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-oxa-8- azaspiro[4.5]decane (206)  White Solid (50%).1H NMR (400 MHz, DMSO) δ 12.71 (s, 1H), 8.30 (s, 1H), 7.88 (dd, J = 8.8, 1.6 Hz, 1H), 7.57 – 7.47 (m, 2H), 3.78 (t, J = 7.0 Hz, 2H), 3.57 – 3.45 (m, 6H), 2.52 (s, 3H), 1.79 (t, J = 7.1 Hz, 2H), 1.67 (t, J = 5.3 Hz, 4H). Enumerated Embodiments: The following list of enumerated embodiments presents claims with multiply dependent claims depending from multiply dependent claims for presentation in those jurisdictions where such dependencies are allowed as well as additional claims, which may be pursued during the examination of the application or a divisional thereof.

[0305] EE1. A compound of formula (I):wherein: each X is independently N, NRa, or CRb, wherein Rais selected from H, C1-C6alkyl, C3- C8 cycloalkyl, hetero C1-C6 alkyl, C1-C6 alkylcarbonyl, arylcarbonyl, hetero C1-C6 alkylcarbonyl, amide, and sulfonamide; and Rbis selected from H, cyano, halo, alkoxy, C1-C6alkyl, trifluoro C1- C6 alkyl, halo C1-C6 alkyl, dihalo C1-C6 alkyl, hydroxy C1-C6 alkyl, alkoxy C1-C6 alkyl, C3-C8 cycloalkyl, hetero C1-C6alkyl, amino C1-C6alkyl, cyano C1-C6alkyl, C1-C6dialkylaminoalkyl, morpholinyl C1-C6 alkyl, piperazinyl C1-C6 alkyl, C1-C6 dialkylaminocarbonyl, C1-C6 dialkylaminosulfonyl, hydroxyaryl, alkoxyaryl, carboxylic acid, ester, ORd, and NRdRd, wherein each Rdis independently selected from hydrogen, C1-C6alkyl, hetero C1-C6alkyl and heteroaryl; wherein alkyl is optionally substituted with C1-C6 alkyl or hetero C1-C6 alkyl; The bond between X-X or X-C in a 5-membered ring can be a single bond or a double bond; each E is independently N or CRc, wherein Rcis H or halogen; 1  W is H, aryl, heteroaryl, ORd, NRdRd, CRdRdRd, wherein each Rd is independently selected from hydrogen, C1-C6alkyl, hetero C1-C6alkyl, and heteroaryl; and Y is a 4- to 12-membered mono- or bi-cyclic ring, wherein the bi-cyclic ring is a fused bi-cyclic ring, a bridged bi-cyclic ring, or a spiro bi-cyclic ring, substituted with one or more groups selected from R1-R8 based on the ring size and represented by a structure:wherein T is sp3-carbon, sp2-carbon, or N; each R1, R2, R3, R4, R5, R6, R7,and R8is independently selected from H, halo, nitro, CN, C1-C6 alkyl, amino C1-C6 alkyl, hydroxy C1-C6 alkyl, alkoxy C1-C6 alkyl, C3-C8 cycloalkyl, aryl, heteroaryl, and hetero C1-C6 alkyl; or any two R groups from R1-R8, together with the carbon atom to which they are attached, form a 3- to 8-membered cyclic ring; and Q is O, S, S=O, SO2, NRa, or CRbRb, wherein Ra and each Rb is independently as defined above or the two Rb, together with the carbon atom to which they are attached, form a 3- to 6- membered cyclic ring, which optionally contains one or more heteroatoms, wherein each heteroatom is independently N, S or O, or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof. EE2. The compound of EE1, wherein each X is independently N, NRa or CRb, wherein Ra is H or C1-C6alkyl; and Rbis selected from H, cyano, halo, alkoxy, C1-C6alkyl, trifluoro C1-C6alkyl and C3-C8 cycloalkyl; wherein alkyl is optionally substituted with C1-C6 alkyl or hetero C1-C6 alkyl. EE3. The compound of EE1, wherein the Y is: . EE4. The compound of EE1, wherein the Y is: . EE5. The compound of EE1, wherein the Y is:   wherein X is as defined in claim 1. EE6. The compounds of EE 5, wherein each X is independently selected from CH2, O, S, S=O, SO2, NH, N-alkyl, N-heteroalkyl, amide, sulfonamide, urea and carbamate. EE7. The compound of EE1, wherein the Y is: .  EE8. The compound of EE1, wherein the Y is: .EE9. The compound of any one of EE1-EE8, wherein the Y is: . EE10: The compound of EE1, wherein the W is H. EE11. The compound of EE1, wherein each E is independently CH or C-halogen. EE12. The compound of EE 1, wherein each E is independently CH or C-halogen; each X is independently N, NH, C-C1-C4 alkyl, C- C3-C8 cycloalkyl, or C-ORd, wherein Rd is C1- C4alkyl; W is H; and   .  EE13. The compound of EE 12, wherein each X is independently N, NH, or C-C1-C4 alkyl. EE14. The compound of EE12, wherein each X is independently N, NH, or C- C3-C8 cycloalkyl. EE15. The compound of EE12, wherein each X is independently N, NH, or C-ORd, wherein Rd is C1-C4alkyl.   EE16. The compound of claim 1, wherein the compound of formula (I) is: 1                         oor a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof. EE17. A pharmaceutical composition comprising a compound of formula (I) of any one of EE1- EE16, or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof, and a pharmaceutically acceptable excipient. EE18. A method of inhibiting transforming growth factor-β activated kinase (TAK1) in a patient in need thereof, which method comprises administering to the patient an inhibitory effective amount of the compound of any one of EE1-EE16 or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof, or a pharmaceutical composition comprising the same and a pharmaceutically acceptable excipient, whereupon TAK1 in the patient is inhibited. EE19. The method of EE 18, wherein the patient has an inflammatory disease. EE20. A method of treating cancer in a patient in whom the transforming growth factor-β activated kinase (TAK1) is overexpressed, wherein the method comprises administering to the  patient a therapeutically effective amount of a compound of formula (I) of any one of EE1-EE16, or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof, or a pharmaceutical composition comprising the compound and a pharmaceutically acceptable excipient, whereupon the cancer in the patient is treated. EE21. The method of EE 20, wherein the cancer is multiple myeloma.

[0306] As used herein, the following terms and phrases shall have the meanings set forth below. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art.

[0307] The term "about" can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range.

[0308] The term "substantially" can allow for a degree of variability in a value or range, for example, within 90%, within 95%, or within 99% of a stated value or of a stated limit of a range.

[0309] The terms "a," "an," or "the" are used to include one or more than one unless the context clearly dictates otherwise. The term "or" is used to refer to a nonexclusive "or" unless otherwise indicated. In addition, the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting. Further, information that is relevant to a section heading may occur within or outside of that particular section. The terms "including" and "having" are defined as comprising (i.e., open language).

[0310] It will be appreciated by persons skilled in the art that the present disclosure is not limited by what has been particularly shown and described herein above. Rather the scope of the present disclosure includes both combinations and sub-combinations of the various features described hereinabove as well as variations and modifications which would occur to persons skilled in the art upon reading the specification and which are not in the prior art.

[0311] All patents, patent application publications, journal articles, textbooks, and other publications mentioned in the specification are indicative of the level of skill of those in the art to which the disclosure pertains. All such publications are incorporated herein by reference to the same extent as if each individual publication were specifically and individually indicated to be incorporated by reference.

Claims

1. WHAT IS CLAIMED IS:

1. A compound of formula (I): wherein: each X is independently N, NRa, or CRb, wherein Rais selected from H, C1-C6alkyl, C3- C8 cycloalkyl, hetero C1-C6 alkyl, C1-C6 alkylcarbonyl, arylcarbonyl, hetero C1-C6 alkylcarbonyl, amide, and sulfonamide; and Rbis selected from H, cyano, halo, alkoxy, C1-C6alkyl, trifluoro C1- C6 alkyl, halo C1-C6 alkyl, dihalo C1-C6 alkyl, hydroxy C1-C6 alkyl, alkoxy C1-C6 alkyl, C3-C8 cycloalkyl, hetero C1-C6alkyl, amino C1-C6alkyl, cyano C1-C6alkyl, C1-C6dialkylaminoalkyl, morpholinyl C1-C6 alkyl, piperazinyl C1-C6 alkyl, C1-C6 dialkylaminocarbonyl, C1-C6 dialkylaminosulfonyl, hydroxyaryl, alkoxyaryl, carboxylic acid, ester, ORd, and NRdRd, wherein each Rd is independently selected from hydrogen, C1-C6 alkyl, hetero C1-C6 alkyl and heteroaryl; wherein alkyl is optionally substituted with C1-C6alkyl or hetero C1-C6alkyl; The bond between X-X or X-C in a 5-membered ring can be a single bond or a double bond; each E is independently N or CRc, wherein Rcis H or halogen; W is H, aryl, heteroaryl, ORd, NRdRd, CRdRdRd, wherein each Rdis independently selected from hydrogen, C1-C6 alkyl, hetero C1-C6 alkyl, and heteroaryl; and Y is a 4- to 12-membered mono- or bi-cyclic ring, wherein the bi-cyclic ring is a fused bi-cyclic ring, a bridged bi-cyclic ring, or a spiro bi-cyclic ring, substituted with one or more groups selected from R1-R8 based on the ring size and represented by a structure:   wherein T is sp3-carbon, sp2-carbon, or N; each R1, R2, R3, R4, R5, R6, R7,and R8is independently selected from H, halo, nitro, CN, C1-C6 alkyl, amino C1-C6 alkyl, hydroxy C1-C6 alkyl, alkoxy C1-C6 alkyl, C3-C8 cycloalkyl, aryl, heteroaryl, and hetero C1-C6alkyl; or any two R groups from R1-R8, together with the carbon atom to which they are attached, form a 3- to 8-membered cyclic ring; and Q is O, S, S=O, SO2, NRa, or CRbRb, wherein Ra and each Rb is independently as defined above or the two Rb, together with the carbon atom to which they are attached, form a 3- to 6- membered cyclic ring, which optionally contains one or more heteroatoms, wherein each heteroatom is independently N, S or O, or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof.

2. The compound of claim 1, wherein each X is independently N, NRa or CRb, wherein Ra is H or C1-C6alkyl; and Rbis selected from H, cyano, halo, alkoxy, C1-C6alkyl, trifluoro C1-C6alkyl and C3-C8 cycloalkyl; wherein alkyl is optionally substituted with C1-C6 alkyl or hetero C1-C6 alkyl.

3. The compound of claim 1, wherein the Y is:   .

4. The compound of claim 1, wherein the Y is: .

5. The compound of claim 1, wherein the Y is:   wherein X is as defined in claim 1. 1   6. The compounds of claim 5, wherein each X is independently selected from CH2, O, S, S=O, SO2, NH, N-alkyl, N-heteroalkyl, amide, sulfonamide, urea, and carbamate.

7. The compound of claim 1, wherein the Y is:

8. The compound of claim 1, wherein the Y is:       .

9. The compound of any one of claims 1-8, wherein the Y is:   .

10. The compound of claim 1, wherein the W is H.

11. The compound of claim 1, wherein each E is independently CH or C-halogen.

12. The compound of claim 1, wherein each E is independently CH or C-halogen; each X is independently N, NH, C- C1-C4alkyl, C- C3-C8cycloalkyl, or C-ORd, wherein Rdis C1- C4 alkyl; W is H; and    .

13. The compound of claim 12, wherein each X is independently N, NH, or C- C1-C4 alkyl.

14. The compound of claim 12, wherein each X is independently N, NH, or C- C3-C8 cycloalkyl.

15. The compound of claim 12, wherein each X is independently N, NH, or C-ORd, wherein Rd is C1-C4alkyl.

16. The compound of claim 1, wherein the compound of formula (I) is:                   oor a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof.

17. A pharmaceutical composition comprising a compound of formula (I) of any one of claims 1- 16, or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof, and a pharmaceutically acceptable excipient.

18. A method of inhibiting transforming growth factor-β activated kinase (TAK1) in a patient in need thereof, which method comprises administering to the patient an inhibitory effective amount of the compound of any one of claims 1-16 or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof, or a pharmaceutical composition comprising the same and a pharmaceutically acceptable excipient, whereupon TAK1 in the patient is inhibited.

19. The method of claim 18, wherein the patient has an inflammatory disease.

20. A method of treating cancer in a patient in whom the transforming growth factor-β activated kinase (TAK1) is overexpressed, wherein the method comprises administering to the patient a therapeutically effective amount of a compound of formula (I) of any one of claims 1-16, or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof, or a pharmaceutical  composition comprising the compound and a pharmaceutically acceptable carrier, excipient, or diluent, whereupon the cancer in the patient is treated.

21. The method of claim 20, wherein the cancer is multiple myeloma.

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